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Title:
QUINOLINE DERIVATIVES
Document Type and Number:
WIPO Patent Application WO/2003/048159
Kind Code:
A1
Abstract:
The invention concerns quinoline derivatives of Formula (I) wherein each of Z, m, R¿1?, n and R¿3? have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease.

Inventors:
HENNEQUIN LAURENT FRANCOIS AND (GB)
GIBSON KEITH HOPKINSON (GB)
FOOTE KEVIN MICHAEL (GB)
Application Number:
PCT/GB2002/005493
Publication Date:
June 12, 2003
Filing Date:
December 05, 2002
Export Citation:
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Assignee:
ASTRAZENECA AB (SE)
ASTRAZENECA UK LTD (GB)
HENNEQUIN LAURENT FRANCOIS AND (GB)
GIBSON KEITH HOPKINSON (GB)
FOOTE KEVIN MICHAEL (GB)
International Classes:
A61P35/00; C07D405/12; (IPC1-7): C07D405/12; A61K31/47; A61P35/00
Domestic Patent References:
WO1998043960A11998-10-08
WO2000068201A12000-11-16
Attorney, Agent or Firm:
Astrazeneca (Mereside Alderley Par, Macclesfield Cheshire SK10 4TG, GB)
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Claims:
CLAIMS
1. A quinoline derivative of the Formula I wherein Z is an O, S, SO, SO2, N (R2) or C (R2) 2 group, wherein each R2 group, which may be the same or different, is hydrogen or (16C) alkyl; m is 0, 1,2, 3 or 4 ; each W group, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, (16C) alkyl, (28C) alkenyl, (28C) alkynyl, (16C) alkoxy, (26C) alkenyloxy, (26C) alkynyloxy, (16C) alkylthio, (16C) alkylsulphinyl, (16C) alkylsulphonyl, (16C) alkylamino, di[(16C) alkyl] amino, (16C) alkoxycarbonyl, N (16C) alkylcarbamoyl, N, Ndi [ (16C) alkyl] carbamoyl, (26C) alkanoyl, (26C) alkanoyloxy, (26C) alkanoylamino, N(16C)alkyl(26C) alkanoylamino, (36C) alkenoylamino, N(16C) alkyl (36C) alkenoylamino, (36C) alkynoylamino, N(16C)alkyl(36C) alkynoylamino, N (16C) alkylsulphamoyl, N, Ndi [ (16C) alkyl] sulphamoyl, (16C) alkanesulphonylamino and N (16C) alkyl (16C) alkanesulphonylamino, or from a group of the formula: Q1X1 wherein Xl is a direct bond or is selected from O, S, SO, SO2, N (R4), CO, CH (oR4), CON (R4), N (R4) CO, S02N (R4), N (R4) S02, OC (R4) 2, SC (R4) 2 and N (R4) C (R4) 2, wherein R4 is hydrogen or (16C) alkyl, and Ql is aryl, aryl (16C) alkyl, (37C) cycloalkyl, (37C) cycloalkyl (16C) alkyl, (37C) cycloalkenyl, (37C) cycloalkenyl (16C) alkyl, heteroaryl, heteroaryl (16C) alkyl, heterocyclyl or heterocyclyl(16C) alkyl, or (Rl) m is (13C) alkylenedioxy, and wherein adjacent carbon atoms in any (26C) alkylene chain within a R'substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N (R5), CO, CH (OR5), CON (R5), N (R5) CO, S02N (R5), N (R5) SO2, CH=CH and C=C wherein R5 is hydrogen or (16C) alkyl or, when the inserted group is N (R5), R5 may also be (26C) alkanoyl, and wherein any CH2=CHor HCCgroup within a Rl substituent optionally bears at the terminal CH2= or HC= position a substituent selected from halogeno, carboxy, carbamoyl, (16C) alkoxycarbonyl, N(16C)alkylcarbamoyl, N, Ndi [ (16C) alkyl] carbamoyl, amino (16C) alkyl, (16C) alkylamino (16C) alkyl and di [ (16C) alkyl] amino(16C) alkyl or from a group of the formula: Q2X2 wherein X2 is a direct bond or is selected from CO and N (R6) CO, wherein R6 is hydrogen or (16C) alkyl, and Q2 is aryl, aryl (16C) alkyl, heteroaryl, heteroaryl (16C) alkyl, heterocyclyl or heterocyclyl (l6C) alkyl, and wherein any CH2 or CH3 group within a Rl substituent optionally bears on each said CH2 or CH3 group one or more halogeno or (16C) alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, (16C) alkoxy, (16C) alkylthio, (16C) alkylsulphinyl, (16C) alkylsulphonyl, (16C) alkylamino, di[(16C)alkyl] amino, (16C) alkoxycarbonyl, N (16C) alkylcarbamoyl, N, Ndi[(16C) alkyl] carbamoyl, (26C) alkanoyl, (26C) alkanoyloxy, (26C) alkanoylamino, N(16C)alkyl (26C) alkanoylamino, N (16C) alkylsulphamoyl, N, Ndi [ (16C) alkyl] sulphamoyl, (16C) alkanesulphonylamino and N(16C)alkyl(16C) alkanesulphonylamino, or from a group of the formula: X3Q3 wherein X3 is a direct bond or is selected from O, S, SO, SO2, N (R), CO, CH (oR7), CON (R7), N (R7) CO, S02N (R7), N (R7) SO2, C (R7) 20, C (R7) 2S and N (R) C (R7) 2, wherein R7 is hydrogen or (16C) alkyl, and Q3 is aryl, aryl (16C) alkyl, (37C) cycloalkyl, (37C) cycloalkyl (16C) alkyl, (37C) cycloalkenyl, (37C) cycloallcenyl (16C) alkyl, heteroaryl, heteroaryl (16C) alkyl, heterocyclyl or heterocyclyl (16C) alkyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1,2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (16C) alkyl, (28C) alkenyl, (28C) alkynyl, (16C) alkoxy, (26C) alkenyloxy, (26C) alkynyloxy, (16C) alkylthio, (16C) alkylsulphinyl, (16C) alkylsulphonyl, (16C) alkylamino, di[(16C)alkyl] amino, (16C) alkoxycarbonyl, N (16C) alkylcarbamoyl, N, Ndi [ (16C) alkyl] carbamoyl, (26C) alkanoyl, (26C) alkanoyloxy, (26C) alkanoylamino, N (16C) alkyl (26C) alkanoylamino, N (16C) alkylsulphamoyl, N, Ndi[(16C)alkyl] sulphamoyl, (16C) alkanesulphonylamino and N (16C) alkyl (16C) alkanesulphonylamino, or from a group of the formula: X4R8 wherein X4 is a direct bond or is selected from O and N (R9), wherein R9 is hydrogen or (16C) alkyl, and Rs is halogeno (16C) alkyl, liydroxy (16C) alkyl, (16C) alkoxy (16C) alkyl, cyano (16C) alkyl, amino (16C) alkyl, (16C) alkylamino (16C) alkyl, di[(16C) alkyl] amino (16C) alkyl, (26C) alkanoylamino (16C) alkyl or (16C) alkoxycarbonylamino (16C) alkyl, or from a group of the formula: X5Q4 wherein Xi vis a direct bond or is selected from O, N (R10) and CO, wherein Rlo is hydrogen or (16C) alkyl, and Q4 is aryl, aryl (16C) alkyl, heteroaryl, heteroaryl (16C) alkyl, heterocyclyl or heterocyclyl(16C) alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (16C) alkyl, (28C) alkenyl, (28C) alkynyl and (16C) alkoxy, and wherein any heterocyclyl group within a substituent on R'optionally bears 1 or 2 oxo or thioxo substituents; n is 0, 1, 2 or 3 ; and R3 is halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (16C) alkyl, (28C) alkenyl, (28C) alkynyl, (16C) alkoxy, (26C) alkenyloxy, (26C) alkynyloxy, (16C) alkylthio, (16C) alkylsulphinyl, (16C) alkylsulphonyl, (16C) alkylamino, di [ (16C) alkyl] amino, (16C) alkoxycarbonyl, N(16C) alkylcarbamoyl, N, Ndi [ (16C) alkyl] carbamoyl, (26C) alkanoyl, (26C) alkanoyloxy, (26C) alkanoylamino, N (16C) alkyl (26C) alkanoylamino, (36C) alkenoylamino, N (16C) alkyl (36C) alkenoylamino, (36C) alkynoylamino, N(16C)alkyl(36C) alkynoylamino, N (16C) alkylsulphamoyl, N, Ndi [ (16C) alkyl] sulphamoyl, (16C) alkanesulphonylamino and N (16C) alkyl (16C) alkanesulphonylamino, or from a group of the formula: _X6_Rll wherein X6 is a direct bond or is selected from O and N (R12), wherein R12 is hydrogen or (16C) alkyl, and R11 is halogeno(16C) alkyl, hydroxy (16C) alkyl, (16C) alkoxy (16C) alkyl, cyano (16C) alkyl, amino (l6C) alkyl, (16C) alkylamino (16C) alkyl or di [ (16C) alkyl] amino (16C) alkyl, or from a group of the formula: X7Q5 wherein X7 is a direct bond or is selected from O, S, SO, SO2, N (R13), CO, CH (OR13), CON (R13), N(R13)CO, SO2N(R13), N (R13) S02, C (R13) 20, C (R) 2S andN (R) ( wherein R13 is hydrogen or (16C) alkyl, and Q5 is aryl, aryl (16C) alkyl, heteroaryl, heteroaryl (16C) alkyl, heterocyclyl or heterocylyl(16C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (16C) alkyl, (28C) alkenyl, (28C) alkynyl and (16C) alkoxy, and any heterocyclyl group within Q5 optionally bears 1 or 2 oxo or thioxo substituents, or a pharmaceuticallyacceptable salt thereof.
2. A quinoline derivative of the Formula I as claimed in claim 1 wherein m is 1 or 2, and each Ri group, which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (16C) alkyl, (16C) alkoxy, (16C) alkylamino, di[(16C) alkyl] amino, N (16C) alkylcarbamoyl, N, Ndi [ (16C) alkyl] carbamoyl, (26C) alkanoylamino and N (16C) alkyl (26C) alkanoylamino, or from a group of the formula: Q1X1 wherein Xl is selected from O, N (R4), CON (R4), N (R4) CO and OC (R4)2 wherein R4 is hydrogen or (16C) alkyl, and Ql is aryl, aryl (16C) alkyl, cycloalkyl (16C) alkyl, heteroaryl, heteroaryl(16C)alkyl, heterocyclyl or heterocyclyl(16C) alkyl, or Xl is a direct bond and Ql is aryl (16C) alkyl, cycloallcyl (16C) alkyl, heteroaryl (16C) alkyl or heterocyclyl (16C) alkyl, and wherein adjacent carbon atoms in any (26C) alkylene chain within a R'substituent are optionally separated by the insertion into the chain of a group selected from O, N (R5), CON (R5), N (R) CO, CH=CH and C=C wherein R5 is hydrogen or (16C) alkyl, or, when the inserted group is N (R5), Rs may also be (26C) alkanoyl, and wherein any CH2 or CH3 group within a R'substituent optionally bears on each said CH2 or CH3 group one or more halogeno groups or a substituent selected from hydroxy, amino, (16C) alkoxy, (16C) alkylsulphonyl, (16C)alkylamino, di[(16C)alkyl] amino, (26C) alkanoyloxy, (26C) alkanoylamino and N (16C) alkyl (26C) alkanoylamino, or from a group of the formula: X3Q3 wherein X3 is a direct bond or is selected from O, N (R6), CON (R7), N (R) CO and C (R7)2O, wherein R7 is hydrogen or (16C) alkyl, and Q3 is heteroaryl, heteroaryl (16C) alkyl, heterocyclyl or heterocyclyl (16C) alkyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1,2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (16C) alkyl, (28C) alkenyl, (28C) alkynyl, (16C) alkoxy, (16C) alkylsulphonyl, N(16C)alkylcarbamoyl, N, Ndi[(16C) alkyl] carbamoyl and (26C) alkanoyl, or optionally bears 1 substituent selected from a group of the formula: X4_R8 wherein X4 is a direct bond or is selected from O and N (R9), wherein R9 is hydrogen or (16C) alkyl, and R is hydroxy (16C) alkyl, (16C) alkoxy (16C) alkyl, cyano(16C)alkyl, amino (16C) alkyl, (16C) allcylamino (16C) alkyl, di [ (16C) alkyl] amino (16C) alkyl, (26C) alkanoylamino (16C) alkyl or (16C) alkoxycarbonylamino (16C) alkyl, and from a group of the formula: X5Q4 wherein Xi vis a direct bond or is selected from O, N (R10) and CO, wherein Rlo is hydrogen or (16C) alkyl, and Q4 is heterocyclyl or heterocyclyl(16C) alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (16C) alkyl and (16C) alkoxy, and wherein any heterocyclyl group within a substituent on R'optionally bears 1 or 2 oxo substituents.
3. A quinoline derivative of the Formula I as claimed in claim 1 wherein R'substituents may only be located at the 5, 6and/or 7positions on the quinoline ring.
4. A quinoline derivative of the Formula I as claimed in claim 1 wherein: Z is O or NH ; m is 1 and the Ru group is located at the 5, 6or 7position or m is 2 and each R group, which may be the same or different, is located at the 5and 7positions or at the 6and 7positions and R1 is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pent4ynyloxy, hex5ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, 2imidazol1ylethoxy, 2 (1, 2, 4triazol1yl) ethoxy, tetrahydrofuran3yloxy, tetrahydropyran4yloxy, 2pyrrolidin1ylethoxy, 3pyrrolidin1ylpropoxy, 4pyrrolidin1ylbutoxy, pyrrolidin3yloxy, pyrrolidin2ylmethoxy, 2pyrrolidin2ylethoxy, 3pyrrolidin2ylpropoxy, 2morpholinoethoxy, 3morpholinopropoxy, 4morpholinobutoxy, 2 (1, 1dioxotetrahydro4H1, 4thiazin4yl) ethoxy, 3 (1, 1dioxotetrahydro 4H1, 4thiazin4yl) propoxy, 2piperidinoethoxy, 3piperidinopropoxy, 4piperidinobutoxy, piperidin3yloxy, piperidin4yloxy, piperidin3ylmethoxy, piperidin4ylmethoxy, 2piperidin3ylethoxy, 3piperidin3ylpropoxy, 2piperidin4ylethoxy, 3piperidin4ylpropoxy, 2homopiperidin1ylethoxy, 3homopiperidin1ylpropoxy, 2piperazin1ylethoxy, 3piperazin1ylpropoxy, 4piperazin1ylbutoxy, 2homopiperazin1ylethoxy and 3homopiperazin1ylpropoxy, and wherein adjacent carbon atoms in any (26C) alkylene chain within a R'substituent are optionally separated by the insertion into the chain of a group selected from O, NH, N (Me), CH=CH and C=C, and wherein any CH2 or CH3 group within a R'substituent optionally bears on each said CH2 or CH3 group one or more chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diethylamino, NethylNmethylamino, NisopropylNmethylamino, NmethylNpropylamino and acetoxy; and wherein any heteroaryl or heterocyclyl group within a substituent on R'optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, methoxy, Nmethylcarbamoyl and N, Ndimethylcarbamoyl and a pyrrolidin2yl, piperidin3yl, piperidin4yl, piperazin1yl or homopiperazin1yl group within a R'substituent is optionally Nsubstituted with allyl, methylsulphonyl, acetyl, 2methoxyethyl, 3methoxypropyl, cyanomethyl, 2aminoethyl, 3aminopropyl, 2methylaminoethyl, 3methylaminopropyl, 2dimethylaminoethyl, 3dimethylaminopropyl, 2pyrrolidin1ylethyl, 3pyrrolidin1ylpropyl, 2morpholinoethyl, 3morpholinopropyl, 2piperidinoethyl, 3piperidinopropyl, 2piperazin1ylethyl or 3piperazin1ylpropyl, the last 8 of which substituents each optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, methyl and methoxy, and wherein any heterocyclyl group within a substituent on R'optionally bears 1 or 2 oxo substituents; and n is 0 or 1 and the R3 group, if present, is located at the 3, 5or 6position of the benzofuran7yl group and is selected from fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, ethynyl, methoxy and ethoxy; or a pharmaceuticallyacceptable acidaddition salt thereof.
5. A quinoline derivative of the Formula I as claimed in claim 1 wherein: Z is O or NH; m is 2 and the first Ru group is a 6methoxy group and the second Ru group is located at the 7position and is selected from 2dimethylaminoethoxy, 3dimethylaminopropoxy, 4dimethylaminobutoxy, 2diethylaminoethoxy, 3diethylaminopropoxy, 4diethylaminobutoxy, 2diisopropylaminoethoxy, 3diisopropylaminopropoxy, 4diisopropylaminobutoxy, 2 (NisopropylNmethylamino) ethoxy, 3 (NisopropylNmethylamino) propoxy, 4 (NisopropylNmethylamino) butoxy, 2 (NisobutylNmethylamino) ethoxy, 3 (NisobutylNmethylamino) propoxy, 4 (NisobutylNmethylamino) butoxy, 2 (NallylNmethylamino) ethoxy, 3 (NallylNmethylamino) propoxy, 2 (Nprop2ynylamino) ethoxy, 3 (Nprop2ynylamino) propoxy, 2 (NmethylNprop2ynylamino) ethoxy, 3NmethylNprop2ynylamino) propoxy, 2pyrrolidin1ylethoxy, 3pyrrolidin1ylpropoxy, 4pyrrolidin1ylbutoxy, pyrrolidin3yloxy, Nmethylpyrrolidin3yloxy, pyrrolidin2ylmethoxy, 2pyrrolidin2ylethoxy, 3pyrrolidin2ylpropoxy, 2morpholinoethoxy, 3morpholinopropoxy, 4morpholinobutoxy, 2 (1, 1dioxotetrahydro4H1, 4thiazin4yl) ethoxy, 3 (1, 1dioxotetrahydro 4H1, 4thiazin4yl) propoxy, 2piperidinoethoxy, 3piperidinopropoxy, 4piperidinobutoxy, piperidin3yloxy, Nmethylpiperidin3yloxy, piperidin4yloxy, Nmethylpiperidin4yloxy, piperidin3ylmethoxy, Nmethylpiperidin3ylmethoxy, Ncyanomethylpiperidin3ylmethoxy, piperidin4yhnethoxy, Nmethylpiperidin4ylmethoxy, Ncyanomethylpiperidin4ylmethoxy, 2piperidin3ylethoxy, 2 (Nmethylpiperidin3yl) ethoxy, 3piperidin3ylpropoxy, 3 (Nmethylpiperidin3yl) propoxy, 2piperidin4ylethoxy, 2 (Nmethylpiperidin4yl) ethoxy, 3piperidin4ylpropoxy, 3 (Nmethylpiperidin4yl) propoxy, 2 (4hydroxypiperidin1yl) ethoxy, 3 (4hydroxypiperidin1yl) propoxy, 4 (4hydroxypiperidin1yl) butoxy, 2homopiperidin1ylethoxy, 3homopiperidin1ylpropoxy, 4homopiperidin1ylbutoxy, 2 (1, 2,3, 6tetrahydropyridin1yl) ethoxy, 3 (1, 2,3, 6tetrahydropyridin1yl) propoxy, 4 (1, 2,3, 6tetrahydropyridin1yl) butoxy, 2piperazin1ylethoxy, 2 (4methylpiperazin1yl) ethoxy, 3piperazin1ylpropoxy, 3 (4methylpiperazin1yl) propoxy, 4piperazin1ylbutoxy, 4 (4methylpiperazin1yl) butoxy, 2 (4allylpiperazin1yl) etlioxy, 3 (4allylpiperazin1yl) propoxy, 4 (4allylpiperazin1yl) butoxy, 2 (4prop2ynylpiperazin1yl) ethoxy, 3 (4prop2ynylpiperazin1yl) propoxy, 4 (4prop2ynylpiperazin1yl) butoxy, 2 (4methylsulphonylpiperazin1yl) ethoxy, 3 (4methylsulphonylpiperazin1yl) propoxy, 4 (4methylsulphonylpiperazin1yl) butoxy, 2 (4acetylpiperazin1yl) ethoxy, 3 (4acetylpiperazin1yl) propoxy, 4 (4acetylpiperazin1yl) butoxy, 2 [4 (2fluoroethyl) piperazin1yl] ethoxy, 3 [4 (2fluoroethyl) piperazin1yl] propoxy, 4 [4 (2fluoroethyl) piperazin1yl] butoxy, 2 (4cyanomethylpiperazin1yl) ethoxy, 3 (4cyanomethylpiperazin1yl) propoxy, 4 (4cyanomethylpiperazin1yl) butoxy, 2 (2piperazin1ylethoxy) ethoxy, 2 [2 (4methylpiperazin1yl) ethoxy] ethoxy, 2chloroethoxy, 3chloropropoxy, 4chlorobutoxy, 2methylsulphonylethoxy, 3methylsulphonylpropoxy, 2tetrahydropyran4ylethoxy, 3tetrahydropyran4ylpropoxy, 2pyrrol1ylethoxy, 3pyrrol1ylpropoxy, 2 (2pyridyloxy) ethoxy, 3 (2pyridyloxy) propoxy, 2 (3pyridyloxy) ethoxy, 3 (3pyridyloxy) propoxy, 2 (4pyridyloxy) ethoxy, 3 (4pyridyloxy) propoxy, 2pyridylmethoxy, 3pyridylmethoxy and 4pyridylmethoxy, and wherein any CH2 group within the second Ru group that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group, and wherein any heteroaryl group within the second Ri group optionally bears 1 or 2 substituents selected from chloro, cyano, hydroxy and methyl, and any heterocyclyl group within the second Ri group optionally bears 1 or 2 substituents selected from fluoro, hydroxy, methyl and oxo; and n is 0 or n is 1 and the R3 group, if present, is located at the 4, 5or 6position of the benzofuran7yl group and is selected from fluoro, chloro, bromo, iodo and cyano; or a pharmaceuticallyacceptable acidaddition salt thereof.
6. A quinoline derivative of the Formula I as claimed in claim 1 wherein : ZisOorNH ; m is 2 and the first Ru group is a 6methoxy group and the second Ru group is located at the 7position and is selected from 2dimethylaminoethoxy, 3dimethylaminopropoxy, 4dimethylaminobutoxy, 2diethylaminoethoxy, 3diethylaminopropoxy, 4diethylaininobutoxy, 2diisopropylaminoethoxy, 3diisopropylaminopropoxy, 4diisopropylaminobutoxy, 2 (NisopropylNmethylamino) ethoxy, 3 (NisopropylNmethylamino) propoxy, 4 (NisopropylNmethylamino) butoxy, 2 (NisobutylNmethylamino) ethoxy, 3 (NisobutylNmethylamino) propoxy, 4 (NisobutylNmethylamino) butoxy, 2 (NallylNmethylamino) ethoxy, 3 (NallylNmethylamino) propoxy, 2 (Nprop2ynylamino) ethoxy, 3 (Nprop2ynylamino) propoxy, 2 (NmethylNprop2ynylamino) ethoxy, 3 (NmethylNprop2ynylamino) propoxy, 2pyrrolidin1ylethoxy, 3pyrrolidin1ylpropoxy, 4pyrrolidin1ylbutoxy, pyrrolidin3yloxy, Nmethylpyrrolidin3yloxy, pyrrolidin2ylmethoxy, 2pyrrolidin2ylethoxy, 3pyrrolidin2ylpropoxy, 2morpholinoethoxy, 3morpholinopropoxy, 4morpholinobutoxy, 2 (1, 1dioxotetrahydro4H1, 4thiazin4yl) ethoxy, 3 (1, 1dioxotetrahydro 4H1, 4thiazin4yl) propoxy, 2piperidinoethoxy, 3piperidinopropoxy, 4piperidinobutoxy, piperidin3yloxy, Nmethylpiperidin3yloxy, piperidin4yloxy, Nmethylpiperidin4yloxy, piperidin3ylmethoxy, Nmethylpiperidin3ylmethoxy, Ncyanomethylpiperidin3ylmethoxy, piperidin4ylmethoxy, Nmethylpiperidin4ylmethoxy, Ncyanomethylpiperidin4ylmethoxy, 2piperidin3ylethoxy, 2 (Nmethylpiperidin3yl) ethoxy, 3piperidin3ylpropoxy, 3 (Nmethylpiperidin3yl) propoxy, 2piperidin4ylethoxy, 2 (Nmethylpiperidin4yl) ethoxy, 3piperidin4ylpropoxy, 3 (Nmethylpiperidin4yl) propoxy, 2homopiperidin1ylethoxy, 3homopiperidin1ylpropoxy, 4homopiperidin1ylbutoxy, 2piperazin1ylethoxy, 2 (4methylpiperazin1yl) ethoxy, 3piperazin1ylpropoxy, 3 (4methylpiperazin1yl) propoxy, 4piperazin1ylbutoxy, 4 (4methylpiperazin1yl) butoxy, 2 (4allylpiperazin1yl) ethoxy, 3 (4allylpiperazin1yl) propoxy, 4 (4allylpiperazin1yl) butoxy, 2 (4methylsulphonylpiperazin1yl) ethoxy, 3 (4methylsulphonylpiperazin1yl) propoxy, 4 (4methylsulphonylpiperazin1yl) butoxy, 2 (4acetylpiperazin1yl) ethoxy, 3 (4acetylpiperazin1yl) propoxy, 4 (4acetylpiperazin1yl) butoxy, 2 (4cyanomethylpiperazin1yl) ethoxy, 3 (4cyanomethylpiperazin1yl) propoxy, 4 (4cyanomethylpiperazin1yl) butoxy, 2 (2piperazin1ylethoxy) ethoxy, 2 [2 (4methylpiperazin1yl) ethoxy] ethoxy, 2chloroethoxy, 3chloropropoxy, 2methylsulphonylethoxy, 3methylsulphonylpropoxy, 2tetrahydropyran4ylethoxy, 3tetrahydropyran4ylpropoxy, 2pyrrol1ylethoxy, 3pyrrol1ylpropoxy, 2 (2pyridyloxy) ethoxy, 3 (2pyridyloxy) propoxy, 2 (3pyridyloxy) ethoxy, 3 (3pyridyloxy) propoxy, 2 (4pyridyloxy) ethoxy, 3 (4pyridyloxy) propoxy, 2pyridylmethoxy, 3pyridylmethoxy and 4pyridylmethoxy, and wherein any CH2 group within the second Ru group that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group, and wherein any heteroaryl group within the second Ru group optionally bears 1 or 2 substituents selected from chloro, cyano, hydroxy and methyl, and any heterocyclyl group within the second Regroup optionally bears 1 or 2 substituents selected from fluoro, hydroxy, methyl and oxo; and n is 0 or n is 1 and the R3 group, if present, is located at the 6position of the benzofuran7yl group and is selected from fluoro, chloro and bromo; or a pharmaceuticallyacceptable acidaddition salt thereof.
7. A quinoline derivative of the Formula I as claimed in claim 1 wherein: ZisNH ; m is 2 and the first Ru group is a 6methoxy group and the second Ru group is located at the 7position and is selected from methoxy, ethoxy, 2pyrrolidin1ylethoxy, 3pyrrolidin1ylpropoxy, 2morpholinoethoxy, 3morpholinopropoxy, 2 (1, 1dioxotetrahydro4H1, 4thiazin4yl) ethoxy, 3 (1, 1dioxotetrahydro4H1, 4thiazin 4yl) propoxy, 2piperidinoethoxy, 3piperidinopropoxy, 2 (1, 2,3, 6tetrahydropyridin 1yl) ethoxy, 3 (1, 2,3, 6tetrahydropyridin1yl) propoxy, 4 (1, 2,3, 6tetrahydropyridin 1yl) butoxy, 2 (4hydroxypiperidin1yl) ethoxy, 3 (4hydroxypiperidin1yl) propoxy, 2piperazin1ylethoxy, 3piperazin1ylpropoxy, 2 (4methylpiperazin1yl) ethoxy, 3 (4methylpiperazin1yl) propoxy, 4 (4methylpiperazin1yl) butoxy, 3 (4allylpiperazin1yl) propoxy, 3 (4prop2ynylpiperazin1yl) propoxy, 3 (4acetylpiperazin1yl) propoxy, 4 (4acetylpiperazin1yl) butoxy, 3 [4 (2fluoroethyl) piperazin1yl] propoxy, 2 (4cyanomethylpiperazin1yl) ethoxy, 3 (4cyanomethylpiperazin1yl) propoxy, 3chloropropoxy, 4chlorobutoxy, 2methylsulphonylethoxy, 3methylsulphonylpropoxy and 2 (2methoxyethoxy) ethoxy; and n is 0 or n is 1 and the R3 group, if present, is located at the 3, 4, 5or 6position of the benzofuranyl group and is selected from fluoro, chloro, bromo, iodo and cyano; or a pharmaceuticallyacceptable acidaddition salt thereof.
8. A quinoline derivative of the Formula I as claimed in claim 1 wherein: Z is O or NH ; m is 1 and the Ri group is located at the 5position and is selected from tetrahydrofuran3yloxy, tetrahydropyran4yloxy, tetrahydrothien3yloxy, 1, 1dioxotetrahydrothien3yloxy, tetrahydrothiopyran4yloxy, 1, 1dioxotetrahydrothiopyran4yloxy, Nmethylazetidin3yloxy, Nethylazetidin3yloxy, Nisopropylazetidin3yloxy, pyrrolidin3yloxy, Nmethylpyrrolidin3yloxy, pyrrolidin2ylmethoxy, 3piperidinyloxy, Nmethylpiperidin3yloxy, 4piperidinyloxy, Nmethylpiperidin4yloxy, Nallylpiperidin4yloxy, Nprop2ynylpiperidin4yloxy, Nacetylpiperidin4yloxy, Nmethylsulphonylpiperidin4yloxy, N (2methoxyethyl) piperidin4yloxy, piperidin3ylmethoxy, Nmethylpiperidin3ylmethoxy, piperidin4ylmethoxy, Nmethylpiperidin4ylmethoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, or m is 2 and the first Ru group is located at the 5position and is selected from the group of substituents listed immediately above and the second Ri group is located at the 7position and is selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, 2fluoroethoxy, 2,2, 2trifluoroethoxy, benzyloxy, 2pyrrolidin1ylethoxy, 3pyrrolidin1ylpropoxy, 2morpholinoethoxy, 3morpholinopropoxy, 2 (1, 1dioxotetrahydro4H1, 4thiazin4yl) ethoxy, 3 (1, 1dioxotetrahydro4H1, 4thiazin 4yl) propoxy, 2piperidinoethoxy, 3piperidinopropoxy, 2piperidin4ylethoxy, 2 (Nmethylpiperidin4yl) ethoxy, 2homopiperidin1ylethoxy, 3homopiperidin1ylpropoxy, 2piperazin1ylethoxy, 3piperazin1ylpropoxy, 2 (4methylpiperazin1yl) ethoxy, 3 (4methylpiperazin1yl) propoxy, 3 (4cyanomethylpiperazin1yl) propoxy, 2[(2S)2carbamoylpyrrolidin1yl] ethoxy, 2[(2S)2(Emethylcarbamoyl) pyrrolidinlyl] ethoxy, 2 [ (2S)2 (N, Ndimethylcarbamoyl) pyrrolidinlyl] ethoxy, 2tetrahydropyran4ylethoxy, 2hydroxyethoxy, 3hydroxypropoxy, 2methoxyethoxy, 3methoxypropoxy, 2methylsulphonylethoxy, 3methylsulphonylpropoxy, 2 (2methoxyethoxy) ethoxy, piperidin4ylmethoxy, Nmethylpiperidin4ylmethoxy, 2 (4pyridyloxy) ethoxy, 2pyridylmethoxy, 3pyridylmethoxy, 4pyridyhnethoxy and 3cyanopyrid4yhnethoxy ; and wherein any CH2 group within a R'substituent that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group, and wherein any heterocyclyl group within a Ri substituent optionally bears 1 or 2 oxo substituents, and wherein any CH2 group within a R'substituent that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group; n is 0 or n is 1 and the R3 group, if present is located at the 3, 4, 5or 6position of the benzofuran7yl group and is selected from fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, ethynyl, methoxy and ethoxy; or a pharmaceuticallyacceptable acidaddition salt thereof.
9. A quinoline derivative of the Formula I as claimed in claim 1 wherein: m is 2 and the first Ru group is located at the 5position and is selected from tetrahydropyran4yloxy, Nmethylpyrrolidin3yloxy, 4piperidinyloxy, Nmethylpiperidin4yloxy, piperidin4ylmethoxy and Nmethylpiperidin4ylmethoxy, and the second Ru ils located at the 7position and is selected from methoxy, benzyloxy, 2pyrrolidin1ylethoxy, 3pyrrolidin1ylpropoxy, 2piperidinoethoxy, 3piperidinopropoxy, 2morpholinoethoxy, 3morpholinopropoxy, 2 (4methylpiperazin 1yl) ethoxy, 3 (4methylpiperazin1yl) propoxy and 3methylsulphonylpropoxy; n is 0 or n is 1 and the R3 group, if present, is located at the 6position of the benzofuran7yl group and is selected from chloro and bromo; or a pharmaceuticallyacceptable acidaddition salt thereof.
10. A quinoline derivative of the Formula I as claimed in claim 1 wherein: Z is NH ; m is 1 and the Ru group is located at the 5position and is selected from tetrahydropyran4yloxy, 4piperidinyloxy and Nmethylpiperidin4yloxy, or m is 2 and the first Ru group is located at the 5position and is selected from tetrahydropyran4yloxy, 4piperidinyloxy and Nmethylpiperidin4yloxy, and the second group is located at the 7position and is selected from methoxy, ethoxy, propoxy, 3pyrrolidin1ylpropoxy, 3piperidinopropoxy, 3morpholinopropoxy, 3piperazin1ylpropoxy and 3 (4methylpiperazin1yl) propoxy; n is 0 or n is 1 and the R3 group, if present, is a chloro group located at the 6position of the benzofuran7yl group; or a pharmaceuticallyacceptable acidaddition salt thereof.
11. A process for the preparation of a quinoline derivative of the Formula I, or a pharmaceuticallyacceptable salt thereof, according to claim 1 which comprises: (a) for the production of those compounds of the Formula I wherein Z is an O, S or N (R2) group, the reaction of a quinoline of the Formula II wherein L is a displaceable group and m and Ru have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with a compound of the Formula m wherein Z is O, S, or N (R2) and n, R3 and R2 have any of the meanings defined in claim 1 except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means; (b) for the production of those compounds of the Formula I wherein at least one Rl group is a group of the formula Q'X' wherein Ql is an aryl (16C) alkyl, (37C) cycloalkyl (16C) alkyl, (37C) cycloalkenyl (16C) alkyl, heteroaryl (16C) alkyl or heterocyclyl (l6C) alkyl group or an optionally substituted alkyl group and Xl is an oxygen atom, the coupling of a quinoline of the Formula V wherein m, Rl, Z, n and R3 have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with an appropriate alcohol wherein any functional group is protected if necessary whereafter any protecting group that is present is removed by conventional means ; (c) for the production of those compounds of the Formula I wherein an Rl group contains a (16C) alkoxy or substituted (16C) alkoxy group or a (16C) alkylamino or substituted (16C) alkylamino group, the reaction of a quinoline derivative of the Formula VI wherein L is a displaceable group and Z, n and R3 have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with an alcohol or amine as appropriate whereafter any protecting group that is present is removed by conventional means; (d) for the production of those compounds of the Formula I wherein Rl is an aminosubstituted (16C) alkoxy group, the reaction of a compound of the Formula I wherein R1 is a halogenosubstituted (16C) alkoxy group with a heterocyclyl compound or an appropriate amine; (e) for the production of those compounds of the Formula I wherein Ru ils a hydroxy group, the cleavage of a quinoline derivative of the Formula I wherein Ru ils a (16C) alkoxy or arylmethoxy group; (f) for the production of those compounds of the Formula I wherein an Ru group contains a primary or secondary amino group, the cleavage of the corresponding compound of the Formula I wherein the Ru group contains a protected primary or secondary amino group; (g) for the production of those compounds of the Formula I wherein an Regroup contains a (16C) alkoxy or substituted (16C) alkoxy group or a (16C) alkylamino or substituted (16C) alkylamino group, the alkylation of a quinoline derivative of the formula I wherein the Ru group contains a hydroxy group or a primary or secondary amino group as appropriate; (h) for the production of those compounds of the Formula I wherein Ru ils an aminohydroxydisubstituted (16C) alkoxy group, the reaction of a compound of the Formula I wherein the Ru group contains an epoxysubstituted (16C) alkoxy group with a heterocyclyl compound or an appropriate amine ; (i) for the production of those compounds of the Formula I wherein an Ru group contains a hydroxy group, the cleavage of the corresponding compound of the Formula I wherein the Rl group contains a protected hydroxy group; (j) for the production of those compounds of the Formula I wherein Z is a SO or SO2 group, the oxidation of a compound of Formula I wherein Z is a S group; or (k) the conversion of a compound of the Formula I wherein an Ri or R3 substituent is a halogeno group into a further compound of the Formula I wherein the R1 or R3 substituent is a cyano, ethynyl or phenyl group; and when a pharmaceuticallyacceptable salt of a quinoline derivative of the Formula I is required, it may be obtained by reaction of said quinoline derivative with a suitable acid using a conventional procedure.
12. A pharmaceutical composition which comprises a quinoline derivative of the Formula I, or a pharmaceuticallyacceptable salt thereof, according to claim 1 in association with a pharmaceuticallyacceptable diluent or carrier.
13. A quinoline derivative of the Formula I, or a pharmaceuticallyacceptable salt thereof, according to claim 1 for use in a method of treatment of the human or animal body by therapy.
14. The use of a quinoline derivative of the Formula I, or a pharmaceuticallyacceptable salt thereof, according to claim 1 in the manufacture of a medicament for use as an antiinvasive agent in the containment and/or treatment of solid tumour disease.
15. A method for producing an antiinvasive effect by the containment and/or treatment of solid tumour disease in a warmblooded animal in need of such treatment which comprises administering to said animal an effective amount of a quinoline derivative of the Formula I, or a phannaceuticallyacceptable salt thereof, according to claim 1.
Description:
QUINOLINE DERIVATIVES The invention concerns certain novel quinoline derivatives, or pharmaceutically-acceptable salts thereof, which possess anti-tumour activity and are accordingly useful in methods of treatment of the human or animal body. The invention also concerns processes for the manufacture of said quinoline derivatives, to pharmaceutical compositions containing them and to their use in therapeutic methods, for example in the manufacture of medicaments for use in the prevention or treatment of solid tumour disease in a warm-blooded animal such as man.

Many of the current treatment regimes for cell proliferation diseases such as psoriasis and cancer utilise compounds which inhibit DNA synthesis. Such compounds are toxic to cells generally but their toxic effect on rapidly dividing cells such as tumour cells can be beneficial. Alternative approaches to anti-tumour agents which act by mechanisms other than the inhibition of DNA synthesis have the potential to display enhanced selectivity of action.

In recent years it has been discovered that a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene i. e. a gene which, on activation, leads to the formation of malignant tumour cells (Bradshaw, Mutagenesis, 1986, l, 91).

Several such oncogenes give rise to the production of peptides which are receptors for growth factors. Activation of the growth factor receptor complex subsequently leads to an increase in cell proliferation. It is known, for example, that several oncogenes encode tyrosine kinase enzymes and that certain growth factor receptors are also tyrosine kinase enzymes (Yarden et al., Ann. Rev. Biochem., 1988, 57,443 ; Larsen et al., Ann. Reports in Med.

Chem., 1989, Chpt. 13). The first group of tyrosine kinases to be identified arose from such viral oncogenes, for example pp60V-Src tyrosine kinase (otherwise known as v-Src), and the corresponding tyrosine kinases in normal cells, for example pp60C-stc tyrosine kinase (otherwise known as c-Src).

Receptor tyrosine kinases are important in the transmission of biochemical signals which initiate cell replication. They are large enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor (EGF) and an intracellular portion which functions as a kinase to phosphorylate tyrosine amino acids in proteins and hence to influence cell proliferation. Various classes of receptor tyrosine kinases are known (Wilks, Advances in Cancer Research, 1993,60, 43-73) based on families of growth factors which bind to different receptor tyrosine kinases. The classification

includes Class I receptor tyrosine kinases comprising the EGF family of receptor tyrosine kinases such as the EGF, TGFa, Neu and erbB receptors, Class II receptor tyrosine kinases comprising the insulin family of receptor tyrosine kinases such as the insulin and IGFI receptors and insulin-related receptor (IRR) and Class in receptor tyrosine kinases comprising the platelet-derived growth factor (PDGF) family of receptor tyrosine kinases such as the PDGFa, PDGF, and colony-stimulating factor 1 (CSF1) receptors.

It is also known that certain tyrosine kinases belong to the class of non-receptor tyrosine kinases which are located intracellularly and are involved in the transmission of biochemical signals such as those that influence tumour cell motility, dissemination and invasiveness and subsequently metastatic tumour growth (Ullrich et al., Cell, 1990, 61, 203- 212, Bolen et al., FASEB J., 1992,6, 3403-3409, Brickell et al., Critical Reviews in Oncogenesis, 1992,3, 401-406, Bohlen et al., Oncogene, 1993,8, 2025-2031, Courtneidge et al., Semin. Cancer Biol., 1994,5, 239-246, Lauffenburger et al., Cell, 1996, 84, 359-369, Hanks et al., BioEssavs, 1996, 19, 137-145, Parsons et al., Current Opinion in Cell Biology 1997, 9, 187-192, Brown et al., Biochimica et Biophysica Acta, 1996, 1287, 121-149 and Schlaepfer et al., Progress in Biophysics and Molecular Biology, 1999, 71, 435-478). Various classes of non-receptor tyrosine kinases are known including the Src family such as the Src, Lyn and Yes tyrosine kinases, the Abl family such as Abl and Arg and the Jak family such as Jak 1 and Tyk 2.

It is known that the Src family of non-receptor tyrosine kinases are highly regulated in normal cells and in the absence of extracellular stimuli are maintained in an inactive conformation. However, some Src family members, for example c-Src tyrosine kinase, are frequently significantly activated (when compared to normal cell levels) in common human cancers such as gastrointestinal cancer, for example colon, rectal and stomach cancer (Cartwright et al., Proc. Natl. Acad. Sci. USA, 1990,87, 558-562 and Mao et al., Oncogene, 1997,15, 3083-3090), and breast cancer (Muthuswamy et al., Oncogene, 1995, 11, 1801- 1810). The Src family of non-receptor tyrosine kinases has also been located in other common human cancers such as non-small cell lung cancers (NSCLCs) including adenocarcinomas and squamous cell cancer of the lung (Mazurenko et al., European Journal of Cancer, 1992, 28, 372-7), bladder cancer (Fanning et al., Cancer Research, 1992,52, 1457- 62), oesophageal cancer (Jankowski et al., Gut, 1992,33, 1033-8), cancer of the prostate, ovarian cancer (Wiener et al., Clin. Cancer Research, 1999,5, 2164-70) and pancreatic cancer

(Lutz et al., Biochem. and Biophys. Res. Comm., 1998, 243, 503-8). As further human tumour tissues are tested for the Src family of non-receptor tyrosine kinases it is expected that its widespread prevalence will be established.

It is further known that the predominant role of c-Src non-receptor tyrosine kinase is to regulate the assembly of focal adhesion complexes through interaction with a number of cytoplasmic proteins including, for example, focal adhesion kinase and paxillin. In addition c-Src is coupled to signalling pathways that regulate the actin cytoskeleton which facilitates cell motility. Likewise, important roles are played by the c-Src, c-Yes and c-Fyn non-receptor tyrosine kinases in integrin mediated signalling and in disrupting cadherin-dependent cell-cell junctions (Owens et al., Molecular Biology of the Cell, 2000,11, 51-64 and Klinghoffer et al., EMBO Journal, 1999, 18, 2459-2471). Cellular motility is necessarily required for a localised tumour to progress through the stages of dissemination into the blood stream, invasion of other tissues and initiation of metastatic tumour growth. For example, colon tumour progression from localised to disseminated, invasive metastatic disease has been correlated with c-Src non-receptor tyrosine kinase activity (Brunton et al., Oncogene, 1997, 14, 283-293, Fincham et al., EMBO J, 1998,17, 81-92 and Verbeek et al., Exp. Cell Research, 1999, 248, 531-537).

Accordingly it has been recognised that an inhibitor of such non-receptor tyrosine kinases should be of value as a selective inhibitor of the motility of tumour cells and as a selective inhibitor of the dissemination and invasiveness of mammalian cancer cells leading to inhibition of metastatic tumour growth. In particular an inhibitor of such non-receptor tyrosine kinases should be of value as an anti-invasive agent for use in the containment and/or treatment of solid tumour disease.

We have now found that surprisingly certain quinoline derivatives possess potent anti-tumour activity. Without wishing to imply that the compounds disclosed in the present invention possess pharmacological activity only by virtue of an effect on a single biological process, it is believed that the compounds provide an anti-tumour effect by way of inhibition of one or more of the non-receptor tyrosine-specific protein kinases that are involved in the signal transduction steps which lead to the invasiveness and migratory ability of metastasising tumour cells. Ill particular, it is believed that the compounds of the present invention provide an anti-tumour effect by way of inhibition of the Src family of non-receptor tyrosine kinases, for example by inhibition of one or more of c-Src, c-Yes and c-Fyn.

It is also known that c-Src non-receptor tyrosine kinase enzyme is involved in the control of osteoclast-driven bone resorption (Soriano et al., Cell, 1991,64, 693-702; Boyce et al., J. Clin. Invest. , 1992, 90, 1622-1627; Yoneda et al., J. Clin. Invest. , 1993, 91, 2791-2795 and Missbach et al., Bone, 1999,24, 437-49). An inhibitor of c-Src non-receptor tyrosine kinase is therefore of value in the prevention and treatment of bone diseases such as osteoporosis, Paget's disease, metastatic disease in bone and tumour-induced hypercalcaemia.

The compounds of the present invention are also useful in inhibiting the uncontrolled cellular proliferation which arises from various non-malignant diseases such as inflammatory diseases (for example rheumatoid arthritis and inflammatory bowel disease), fibrotic diseases (for example hepatic cirrhosis and lung fibrosis), glomerulonephritis, multiple sclerosis, psoriasis, hypersensitivity reactions of the skin, blood vessel diseases (for example atherosclerosis and restenosis), allergic asthma, insulin-dependent diabetes, diabetic retinopathy and diabetic nephropathy.

Generally the compounds of the present invention possess potent inhibitory activity against the Src family of non-receptor tyrosine kinases, for example by inhibition of c-Src and/or c-Yes, whilst possessing less potent inhibitory activity against other tyrosine kinase enzymes such as the receptor tyrosine kinases, for example EGF receptor tyrosine kinase and/or VEGF receptor tyrosine kinase. Furthermore, certain compounds of the present invention possess substantially better potency against the Src family of non-receptor tyrosine kinases, for example c-Src and/or c-Yes, than against VEGF receptor tyrosine kinase. Such compounds possess sufficient potency against the Src family of non-receptor tyrosine kinases, for example c-Src and/or c-Yes, that they may be used in an amount sufficient to inhibit, for example, c-Src and/or c-Yes whilst demonstrating little activity against VEGF receptor tyrosine kinase.

It is stated in International Patent Application WO 98/43960 that a range of 3-cyanoquinoline derivatives are useful in the treatment of cancer. Certain of the compounds are stated to be inhibitors of EGF receptor tyrosine kinase, others are stated to be inhibitors of the mitogen-activated protein kinase (MAPK) pathway and others are stated to be inhibitors of growth factors such as vascular endothelial growth factor (VEGF). There is no disclosure therein of any 4-benzofuranylamino-3-cyanoquinoline derivatives.

It is stated in International Patent Application WO 00/68201 that a range of 3-cyanoquinoline derivatives are also useful in the treatment of cancer. Certain of the

compounds are stated to be inhibitors of MEK, a MAPK kinase. There is no disclosure therein of any 4-benzofuranylamino-3-cyanoquinoline derivatives.

It is disclosed in Journal Medicinal Chemistry, 2001,44, 822-833 and in Journal Medicinal Chemistry. 2001,44, 3965-3977 that certain 4-anilino-3-cyanoquinoline derivatives are useful for the inhibition of Src-dependent cell proliferation. There is no disclosure therein of any 4-benzofuranylamino-3-cyanoquinoline derivatives.

According to one aspect of the invention there is provided a quinoline derivative of the Formula I wherein Z is an O, S, SO, SO2, N (R2) or Ci) 2 group, wherein each R2 group, which may be the same or different, is hydrogen or (1-6C) alkyl ; m is 0, 1,2, 3 or 4 ; each W group, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, (2-6C) alkenyloxy, (2-6C) alkynyloxy, (1-6C) alkylthio, (1-6C) alkylsulphinyl, (1-6C) alkylsulphonyl, (1-6C) alkylamino, di-[(1-6C) alkyl] amino, (1-6C) alkoxycarbonyl, N-(1-6C) alkylcarbamoyl, N, N-di- [ (1-6C) allcyl] carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, (3-6C) alkenoylamino, N- (1-6C) alkyl- (3-6C) alkenoylamino, (3-6C) alkynoylamino, N- (1-6C) alkyl- (3-6C) alkynoylamino, N- (1-6C) alkylsulphamoyl, N,N-di-[(1-6C) alkyl] sulphamoyl, (1-6C) alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of the formula: Q1-X1- wherein Xl is a direct bond or is selected from O, S, SO, SO2, N (R4), CO, CH (oR4), CON (R4), N (R4) CO, S02N (R4), N (R4) S02, OC (R4) 2, SC (R4) 2 and N (R4) C (R4) 2, wherein R4 is hydrogen or (1-6C) alkyl, and Ql is aryl, aryl- (1-6C) alkyl, (3-7C) cycloalkyl, (3-7C) cycloalkyl-

(1-6C) alkyl, (3-7C) cycloalkenyl, (3-7C) cycloalkenyl- (1-6C) alkyl, heteroaryl, heteroaryl- (1-6C) alkyl, heterocyclyl or heterocyclyl-(1-6C) alkyl, or (Rl) m is (1-3C)alkylenedioxy, and wherein adjacent carbon atoms in any (2-6C) alkylene chain within a Ri substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N (R5), CO, CH (OR5), CON (R5), N (R) CO, S02N (R5), N (R5) SO2, CH=CH and C=-C wherein R5 is hydrogen or (1-6C) alkyl or, when the inserted group is N (R5), R5 may also be (2-6C) alkanoyl, and wherein any CH2=CH-or HC=C-group within a Rl substituent optionally bears at the terminal CH2= or HC=-position a substituent selected from halogeno, carboxy, carbamoyl, (1-6C) alkoxycarbonyl, N- (1-6C) alkylcarbamoyl, N, N-di- [ (1-6C) alkyl] carbamoyl, amino- (1-6C) alkyl, (1-6C) alkylamino- (1-6C) alkyl and di- [ (1-6C) alkyl] amino- (1-6C) alkyl or from a group of the formula : Q2-X2- wherein X2 is a direct bond or is selected from CO and N (R6) CO, wherein R6 is hydrogen or (1-6C) alkyl, and Q2 is aryl, aryl- (1-6C) alkyl, heteroaryl, heteroaryl- (1-6C) alkyl, heterocyclyl or heterocyclyl- (1-6C) alkyl, and wherein any CH2 or CH3 group within a Ri substituent optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C) alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, (1-6C) alkoxy, (1-6C) alkylthio, (1-6C) alkylsulphinyl, (1-6C) alkylsulphonyl, (1-6C) alkylamino, di- [ (l-6C) alkyl] amino, (1-6C) alkoxycarbonyl, N-(1-6C) alkylcarbamoyl, N, N-di-[(1-6C) alkyl] carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino, N- (1-6C) alkyl- (2-6C) alkanoylamino, N- (l-6C) alkylsulphamoyl, N, N-di- [ (l-6C) alkyl] sulphamoyl, (1-6C) alkanesulphonylamino and N- (1-6C) alkyl- (1-6C) alkanesulphonylamino, or from a group of the formula: -X3-Q3 wherein X3 is a direct bond or is selected from O, S, SO, SO2, N (R7), CO, CH (oR7), CON (R7), N (R7) CO, S02N (R7), N (R7) SO2, C (R7) 20, C (R7) 2S and N (R7) C (R7) 2, wherein R7 is hydrogen or (1-6C) alkyl, and Q3 is aryl, aryl- (1-6C) alkyl, (3-7C) cycloalkyl, (3-7C) cycloalkyl- (1-6C) alkyl, (3-7C) cycloalkenyl, (3-7C) cycloalkenyl- (1-6C) alkyl, heteroaryl, heteroaryl- (1-6C) alkyl, heterocyclyl or heterocyclyl- (1-6C) alkyl,

and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on Rl optionally bears 1,2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, (2-6C) alkenyloxy, (2-6C) alkynyloxy, (1-6C) alkylthio, (1-6C) alkylsulphinyl, (1-6C) alkylsulphonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl] amino, (1-6C) alkoxycarbonyl, N- (1-6C) alkylcarbamoyl, N, N-di- [ (1-6C) alkyl] carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino, N- (1-6C) alkyl- (2-6C) alkanoylamino, N- (1-6C) alkylsulphamoyl, N, N-di- [ (1-6C) alkyl] sulphamoyl, (1-6C) alkanesulphonylamino and N- (1-6C) alkyl- (1-6C) alkanesulphonylamino, or from a group of the formula : -X4-R8 wherein X4 is a direct bond or is selected from O and N (R9), wherein R9 is hydrogen or (1-6C) alkyl, and W is halogeno- (1-6C) alkyl, hydroxy- (1-6C) alkyl, (1-6C) alkoxy- (1-6C) alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C) alkyl, di- [ (l-6C) alkyl] amino- (1-6C) alkyl, (2-6C) alkanoylamino- (1-6C) alkyl or (1-6C) alkoxycarbonylamino- (1-6C) alkyl, or from a group of the formula: -X5-Q4 wherein X5 is a direct bond or is selected from O, N(R10) and CO, wherein R10 is hydrogen or (1-6C) alkyl, and Q4 is aryl, aryl- (1-6C) alkyl, heteroaryl, heteroaryl- (1-6C) alkyl, heterocyclyl or heterocyclyl- (l-6C) alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (1-6C) alkoxy, and wherein any heterocyclyl group within a substituent on Rl optionally bears 1 or 2 oxo or thioxo substituents; n is 0, 1, 2or3 ; and R3 is halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, (2-6C) alkenyloxy, (2-6C) alkynyloxy, (1-6C) alkylthio, (1-6C) alkylsulphinyl, (1-6C) alkylsulphonyl, (1-6C) alkylamino, di- [ (l-6C) alkyl] amino, (1-6C) alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N, N-di- [ (1-6C) alkyl] carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino, N- (1-6C) alkyl- (2-6C) alkanoylamino, (3-6C) alkenoylamino, N- (1-6C) alkyl- (3-6C) alkenoylamino, (3-6C) alkynoylamino, N- (1-6C) alkyl- (3-6C) alkynoylamino,

N- (1-6C) alkylsulphamoyl, N, N-di- [ (1-6C) alkyl] sulphamoyl, (1-6C) alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of the formula : -X6-R11 wherein X6 is a direct bond or is selected from O and N (R12), wherein Rl2 is hydrogen or (1-6C) alkyl, and Rll is halogeno- (l-6C) alkyl, hydroxy- (1-6C) alkyl, (1-6C) alkoxy- (1-6C) alkyl, cyano- (1-6C) alkyl, amino- (1-6C) alkyl, (1-6C) alkylamino- (1-6C) alkyl or di-[(1-6C)alkyl]amino-(1-6C) alkyl, or from a group of the formula: -X7-Q5 wherein X7 is a direct bond or is selected from O, S, SO, SO2, N (R13), CO, CH (OR13), CON (R13), N (Rl3) CO, S02N (R13), N (R13) SO2, C (Rl3) C(R13)2S and N(R13) C (Rl3) 2, wherein R13 is hydrogen or (1-6C) alkyl, and Q5 is aryl, aryl- (1-6C) alkyl, heteroaryl, heteroaryl- (1-6C) alkyl, heterocyclyl or heterocylyl-(1-6C) alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (1-6C) alkoxy, and any heterocyclyl group within Q5 optionally bears 1 or 2 oxo or thioxo substituents, or a pharmaceutically-acceptable salt thereof.

In this specification the generic term"alkyl"includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl, and also (3-7C) cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. However references to individual alkyl groups such as"propyl"are specific for the straight-chain version only, references to individual branched-chain alkyl groups such as "isopropyl"are specific for the branched-chain version only and references to individual cycloalkyl groups such as"cyclopentyl"are specific for that 5-membered ring only. An analogous convention applies to other generic terms, for example (1-6C) alkoxy includes methoxy, ethoxy, cyclopropyloxy and cyclopentyloxy, (1-6C) alkylamino includes methylamino, ethylamino, cyclobutylamino and cyclohexylamino, and di- [ (l-6Calkyl] amino includes dimethylamino, diethylamino, N-cyclobutyl-N-methlamino and N-cyclohexyl- N-ethylamino.

It is 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.

Suitable values for the generic radicals referred to above include those set out below.

A suitable value for any one of the'Q'groups (Ql to Q5) when it is aryl or for the aryl group within a'Q'group is, for example, phenyl or naphthyl, preferably phenyl.

A suitable value for any one of the'Q'groups (Ql or Q3) when it is (3-7C) cycloalkyl or for the (3-7C) cycloalkyl group within a'Q'group is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo [2.2. 1] heptyl and a suitable value for any one of the'Q'groups (Ql or Q3) when it is (3-7C) cycloalkenyl or for the (3-7C) cycloalkenyl group within a'Q'group is, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl.

A suitable value for any one of the'Q'groups (Ql to Q5) when it is heteroaryl or for the heteroaryl group within a'Q'group is, for example, an aromatic 5-or 6-membered monocyclic ring or a 9-or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur, for example furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3, 5-triazenyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl or naphthyridinyl.

A suitable value for any one of the'Q'groups (Ql to Q5) when it is heterocyclyl or for the heterocyclyl group within a'Q'group is, for example, a non-aromatic saturated or partially saturated 3 to 10 membered monocyclic or bicyclic ring with up to five heteroatoms selected from oxygen, nitrogen and sulphur, for example oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, tetrahydrothienyl, 1, 1-dioxotetrahydrothienyl, tetrahydrothiopyranyl, 1, 1-dioxotetrahydrothiopyranyl, azetidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-l, 4-thiazinyl, 1, 1-dioxotetrahydro-1, 4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetraliydropyridinyl, dihydropyrimidinyl or tetrahydropyrimidinyl, preferably tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, 1, 1-dioxotetrahydro-4H-1, 4-thiazinyl, piperidinyl or piperazinyl. A suitable value for such a group which bears 1 or 2 oxo or thioxo substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.

A suitable value for a'Q'group when it is heteroaryl- (1-6C) alkyl is, for example, heteroarylmethyl, 2-heteroarylethyl and 3-heteroarylpropyl. The invention comprises corresponding suitable values for'Q'groups when, for example, rather than a heteroaryl- (1-6C) alkyl group, an aryl- (1-6C) alkyl, (3-7C) cycloalkyl- (1-6C) alkyl, (3-7C) cycloalkenyl- (1-6C) alkyl or heterocyclyl- (1-6C) alkyl group is present.

In structural Formula I there is a hydrogen atom at the 2-position on the quinoline ring.

It is to be understood thereby that the Rl substituents may only be located at the 5-, 6-, 7-or 8-positions on the quinoline ring i. e. that the 2-position remains unsubstituted. It is further to be understood that the R3 group that may be present on the benzofuranyl group within structural Formula I may be located on either the 5-or 6-membered ring portions thereof, for example at the 2-, 3-, 4-, 5-or 6-positions of the benzofuran-7-yl group. It is further to be understood that, when multiple R3 groups are present, the R3 groups may be the same or different.

Suitable values for any of the'R'groups (Rl to R13) or for various groups within an R or R3 substituent include :- for halogeno fluoro, chloro, bromo and iodo; for (1-6C) alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl; for (2-8C) alkenyl: vinyl, isopropenyl, allyl and butenyl ; for (2-8C) alkynyl : ethynyl, 2-propynyl and but-2-ynyl; for (1-6C) alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for (2-6C) alkenyloxy : vinyloxy and allyloxy; for (2-6C) alkynyloxy: ethynyloxy and 2-propynyloxy; for (1-6C) alkylthio: methylthio, ethylthio and propylthio; for (1-6C) alkylsulphinyl: methylsulphinyl and ethylsulphinyl; for (1-6C) alkylsulphonyl: methylsulphonyl and ethylsulphonyl; for (1-6C) alkylamino: methylamino, ethylamino, propylamino, isopropylamino and butylamino; for di- [ (1-6C) allcyl] amino : dimethylamino, diethylamino, N-ethyl- N-methylamino and diisopropylamino; for (1-6C) alkoxycarbonyl : methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl ; for N- (1-6C) alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl and N-propylcarbamoyl;

for N, N-di- [ (1-6C) alkyl] carbamoyl: N, N-dimethylcarbamoyl, N-ethyl- N-methylcarbamoyl and N, N-diethylcarbamoyl; for (2-6C) alkanoyl: acetyl and propionyl; for (2-6C) alkanoyloxy: acetoxy and propionyloxy; for (2-6C) alkanoylamino : acetamido and propionamido; for N- (1-6C) alkyl- (2-6C) alkanoylamino: N-methylacetamido and N-methylpropionamido; for N- (1-6C) alkylsulphamoyl: N-methylsulphamoyl and N-ethylsulphamoyl ; for N, N-di-[(l-6C) alkyl] sulphamoyl: N, N-dimethylsulphamoyl ; for (1-6C) alkanesulphonylamino: methanesulphonylamino and ethanesulphonylamino; for N- (1-6C) alkyl- (1-6C) alkanesulphonylamino : N-methylmethanesulphonylamino and N-methylethanesulphonylamino; for (3-6C) alkenoylamino : acrylamido, methacrylamido and crotonamido; for N- (1-6C) alkyl- (3-6C) alkenoylamino: N-methylacrylamido and N-methylcrotonamido ; for (3-6C) alkynoylamino : propiolamido; for N- (1-6C) alkyl- (3-6C) alkynoylamino: N-methylpropiolamido; for amino- (1-6C) alkyl : aminomethyl, 2-aminoethyl, 1-aminoethyl and 3-aminopropyl; for (1-6C) alkylamino- (1-6C) alkyl: methylaminomethyl, ethylaminomethyl, 1-methylaminoethyl, 2-methylaminoethyl, 2-ethylaminoethyl and 3-methylaminopropyl; for di- [ (1-6C) alkyl] amino- (1-6C) alkyl: dimethylaminomethyl, diethylaminomethyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl and 3-dimethylaminopropyl ; for halogeno- (1-6C) alkyl: chloromethyl, 2-chloroethyl, 1-chloroethyl and 3-chloropropyl; for hydroxy- (1-6C) alkyl: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl; for (1-6C) alkoxy- (1-6C) alkyl: methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl; for cyano- (1-6C) alkyl : cyanomethyl, 2-cyanoethyl, 1-cyanoethyl and 3-cyanopropyl ;

for (2-6C) alkanoylamino- (1-6C) alkyl: acetamidomethyl, propionamidomethyl and 2-acetamidoethyl; and for (1-6C) alkoxycarbonylamino- (1-6C) alkyl: methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl, tert-butoxycarbonylaminomethyl and 2-methoxycarbonylaminoethyl.

A suitable value for (Rl) m when it is a (1-3C) alkylenedioxy group is, for example, methylenedioxy or ethylenedioxy and the oxygen atoms thereof occupy adjacent ring positions.

When, as defined hereinbefore, an Ri group forms a group of the formula Ql-Xl-and, for example, Xl is a OC (R4) 2 linking group, it is the carbon atom, not the oxygen atom, of the OC (R4) 2 linking group which is attached to the quinoline ring and the oxygen atom is attached to the Ql group. Similarly, when, for example a CH3 group within a Ri substituent bears a group of the fonnula-X3-Q3 and, for example, X3 is a C (R7) 20 linking group, it is the carbon atom, not the oxygen atom, of the C (R7) 20 linking group which is attached to the CH3 group and the oxygen atom is linked to the Q3 group. A similar convention applies to the attachment of the groups of the formulae Q2-X2-and-X7-Q5.

As defined hereinbefore, adjacent carbon atoms in any (2-6C) alkylene chain within a Rl substituent may be optionally separated by the insertion into the chain of a group such as O, CON (rus) or C---C. For example, insertion of a C#C group into the ethylene chain within a 2-morpholinoethoxy group gives rise to a 4-morpholinobut-2-ynyloxy group and, for example, insertion of a CONH group into the ethylene chain within a 3-methoxypropoxy group gives rise to, for example, a 2- (2-methoxyacetamido) ethoxy group.

When, as defined hereinbefore, any CH2=CH-or HC=C-group within a Rl substituent optionally bears at the terminal CH2= or HC= position a substituent such as a group of the formula Q2-X2-wherein X2 is, for example, NHCO and Q2 is a heterocyclyl- (1-6C) alkyl group, suitable Rl substituents so formed include, for example, N- [heterocyclyl- (1-6C) alkyl] carbamoylvinyl groups such as N-(2-pyrrolidin-1-ylethyl) carbamoylvinyl or N- [heterocyclyl- (1-6C) alkyl] carbamoylethynyl groups such as N- (2-pyrrolidin- 1-ylethyl) carbamoylethynyl.

When, as defined hereinbefore, any CH2 or CH3 group within a Rl substituent optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C) alkyl

substituents, there are suitably 1 or 2 halogeno or (1-6C) alkyl substituents present on each said CH2 group and there are suitably 1,2 or 3 such substituents present on each said CH3 group.

When, as defined hereinbefore, any CH2 or CH3 group within a Rl substituent optionally bears on each said CH2 or CH3 group a substituent as defined hereinbefore, suitable Rl substituents so formed include, for example, hydroxy-substituted heterocyclyl- (1-6C) alkoxy groups such as 2-hydroxy-3-piperidinopropoxy and 2-hydroxy- 3-morpholinopropoxy, hydroxy-substituted amino- (2-6C) alkoxy groups such as 3-amino- 2-hydroxypropoxy, hydroxy-substituted (1-6C) alkylamino- (2-6C) alkoxy groups such as 2-hydroxy-3-methylaminopropoxy, hydroxy-substituted di- [ (1-6C) alkyl] amino- (2-6C) alkoxy groups such as 3-dimethylamino-2-hydroxypropoxy, hydroxy-substituted heterocyclyl- (1-6C) alkylamino groups such as 2-hydroxy-3-piperidinopropylamino and 2-hydroxy- 3-morpholinopropylamino, hydroxy-substituted amino- (2-6C) alkylamino groups such as 3-amino-2-hydroxypropylamino, hydroxy-substituted (1-6C) alkylamino- (2-6C) alkylamino groups such as 2-hydroxy-3-methylaminopropylamino, hydroxy-substituted di- [ (1-6C) alkyl] amino- (2-6C) alkylamino groups such as 3-dimethylamino- 2-hydroxypropylamino, hydroxy-substituted (1-6C) alkoxy groups such as 2-hydroxyethoxy, (1-6C) alkoxy-substituted (1-6C) alkoxy groups such as 2-methoxyethoxy and 3-ethoxypropoxy, (1-6C) alkylsulphonyl-substituted (1-6C) alkoxy groups such as 2-methylsulphonylethoxy and heterocyclyl-substituted (1-6C) alkylamino- (1-6C) alkyl groups such as 2-morpholinoethylaminomethyl, 2-piperazin-1-ylethylaminomethyl and 3-morpholinopropylaminomethyl.

A suitable pharmaceutically-acceptable salt of a compound of the Formula I is, for example, an acid-addition salt of a compound of the Formula I, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid ; or, for example, a salt of a compound of the Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine.

Particular novel compounds of the invention include, for example, quinoline derivatives of the Formula I, or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of Z, m, Rl, n and R3 has any of the meanings defined hereinbefore or in paragraphs (a) to (q) hereinafter:-

(a) Z is O, S, SO, SO2, CH2 or NH; (b) ZisO ; (c) Z is NH ; (d) m is 1 or 2, and each Rl group, which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, (2-6C) alkenyloxy, (2-6C) alkynyloxy, (1-6C) alkylamino, di-[(1-6C) alkyl] amino, N- (1-6C) alkylcarbamoyl, N, N-di-[(1-6C)alkyl] carbamoyl, (2-6C) alkanoylamino, N-(1-6C)alkyl-(2-6C) alkanoylamino, (3-6C) alkenoylamino, N-(1-6C)alkyl-(3-6C) alkenoylamino, (3-6C) alkynoylamino and N- (1-6C) alkyl- (3-6C) alkynoylamino, or from a group of the formula: Q1-X1- wherein Xl is a direct bond or is selected from O, N (R4), CON (R4), N (R4) CO and OC(R4) 2 wherein R4 is hydrogen or (1-6C) alkyl, and Ql is aryl, aryl- (1-6C) alkyl, cycloalkyl- (1-6C) alkyl, heteroaryl, heteroaryl- (1-6C) alkyl, heterocyclyl or heterocyclyl-(1-6C) alkyl, and wherein adjacent carbon atoms in any (2-6C) alkylene chain within a Rl substituent are optionally separated by the insertion into the chain of a group selected from O, N (R5), CON (R5), N (rus) CO, CH=CH and C=C wherein R5 is hydrogen or (1-6C) alkyl, or, when the inserted group is N (R5), RS may also be (2-6C) alkanoyl, and wherein any CH2=CH-or HC_C-group within a Ri substituent optionally bears at the terminal CH2= or HC= position a substituent selected from carbamoyl, N-(1-6C) alkylcarbamoyl, N, N-di- [ (1-6C) alkyl] carbamoyl, amino- (1-6C) alkyl, (1-6C) alkylamino- (1-6C) alkyl and di- [ (1-6C) alkyl] amino-(1-6C) alkyl or from a group of the formula : Q2-X2_ wherein X2 is a direct bond or is CO or N (R6) CO, wherein R6 is hydrogen or (1-6C) alkyl, and Q2 is heteroaryl, heteroaryl- (1-6C) alkyl, heterocyclyl or heterocyclyl-(1-6C) alkyl, and wherein any CH2 or CH3 group within a Rl substituent optionally bears on each said CH2 or CH3 group one or more halogeno groups or a substituent selected from hydroxy, amino, (1-6C) alkoxy, (1-6C) alkylsulphonyl, (1-6C) alkylamino, di-[(1-6C)alkyl]amino, (2-6C) alkanoyloxy, (2-6C) alkanoylamino and N-(1-6C)alkyl-(2-6C)alkanoylamino, or from a group of the formula: -X3-Q3

wherein X3 is a direct bond or is selected from O, N (R6), CON (R7), N (R7) CO and C (R7) 20, wherein R7 is hydrogen or (1-6C) alkyl, and Q3 is heteroaryl, heteroaryl- (1-6C) alkyl, heterocyclyl or heterocyclyl- (1-6C) alkyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on Rl optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, (1-6C) alkylsulphonyl, N-(1-6C)alkylcarbamoyl, N, N-di-[(l-6C) alkyl] carbamoyl and (2-6C) alkanoyl, or optionally bears 1 substituent selected from a group of the formula: -X4-R8 wherein X4 is a direct bond or is selected from O and N (R9), wherein R9 is hydrogen or (1-6C) alkyl, and R8 is hydroxy- (1-6C) alkyl, (1-6C) alkoxy- (1-6C) alkyl, cyano- (1-6C) allyl, amino- (1-6C) alkyl, (1-6C) alkylamino- (1-6C) alkyl, di- [ (1-6C) alkyl] amino- (1-6C) alkyl, (2-6C) alkanoylamino- (1-6C) alkyl or (1-6C) alkoxycarbonylamino- (1-6C) alkyl, and from a group of the formula : -X5-Q4 wherein X5 is a direct bond or is selected from O, N(R10) and CO, wherein R10 is hydrogen or (1-6C) alkyl, and Q4 is heterocyclyl or heterocyclyl- (l-6C) alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (1-6C) alkyl and (1-6C) alkoxy, and wherein any heterocyclyl group within a substituent on Rl optionally bears 1 or 2 oxo substituents ; (e) m is 1 or 2, and each Rl group, which may be the same or different, is selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, propyl, butyl, vinyl, allyl, but-3-enyl, pent-4-enyl, hex-5-enyl, ethynyl, 2-propynyl, but-3-ynyl, pent-4-ynyl, hex-5-ynyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, allyloxy, but-3-enyloxy, pent-4-enyloxy, hex-5-enyloxy, ethynyloxy, 2-propynyloxy, but-3-ynyloxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, acetamido, propionamido, acrylamido and propiolamido, or from a group of the formula: Q1-X1- wherein Xl is a direct bond or is selected from O, NH, CONH, NHCO and OCH2 and Ql is phenyl, benzyl, cyclopropylmethyl, 2-thienyl, 1-imidazolyl, 1,2, 3-triazol-1-yl,

1,2, 4-triazol-1-yl, 2-, 3-or 4-pyridyl, 2-imidazol-1-ylethyl, 3-imidazol-1-ylpropyl, 2- (1, 2, 3-triazolyl) ethyl, 3- (1, 2, 3-triazolyl) propyl, 2- (1, 2, 4-triazolyl) ethyl, 3- (1, 2, 4-triazolyl) propyl, 2-, 3-or 4-pyridylmethyl, 2- (2-, 3-or 4-pyridyl) ethyl, 3- (2-, 3-or 4-pyridyl) propyl, tetrahydrofuran-3-yl, 3-or 4-tetrahydropyranyl, 1-, 2-or 3-pyrrolidinyl, morpholino, 1, 1-dioxotetrahydro-4_-1, 4-thiazin-4-yl, piperidino, piperidin-3-yl, piperidin-4-yl, 1-, 3-or 4-homopiperidinyl, piperazin-1-yl, homopiperazin-1-yl, 1-, 2-or 3-pyrrolidinylmethyl, morpholinomethyl, piperidinomethyl, 3-or 4-piperidinylmethyl, 1-, 3-or 4-homopiperidinylmethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-2-ylpropyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-1-ylpropyl, 4-pyrrolidin-1-ylbutyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, 2- (1, 1-dioxotetrahydro-4H-1, 4-thiazin-4-yl) ethyl, 3- (1, 1-dioxotetrahydro-4H-1, 4-thiazin- 4-yl) propyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, 2-piperidin-3-ylethyl, 3-piperidin-3-ylpropyl, 2-piperidin-4-ylethyl, 3-piperidin-4-ylpropyl, 2-homopiperidin-1-ylethyl, 3-homopiperidin-1-ylpropyl, 2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl, 4-piperazin-1-ylbutyl, 2-homopiperazin-1-ylethyl or 3-homopiperazin-1-ylpropyl, and wherein adjacent carbon atoms in any (2-6C) alkylene chain within a Ri substituent are optionally separated by the insertion into the chain of a group selected from O, NH, N (Me), CONH, NHCO, CH=CH and C=C, and wherein any CH2=CH-or HC-C-group within a Ri substituent optionally bears at the terminal CH2= or HC= position a substituent selected from carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N, N-dimethylcarbamoyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl or 4-dimethylaminobutyl, or from a group of the formula : Q2 _ X2- wherein X2 is a direct bond or is CO, NHCO or N (Me) CO and Q2 is pyridyl, pyridyhnethyl, 2-pyridylethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, pyrrolidin-1-yhnethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 4-pyrrolidin-1-ylbutyl, pyrrolidin-2-yhnethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl,

4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, piperidin-3-yhnethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, piperazin-1-ylmethyl, 2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl or 4-piperazin-1-ylbutyl, and wherein any CH2 or CH3 group within a Rl substituent optionally bears on each said CH2 or CH3 group one or more fluoro or chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-N-propylamino, acetoxy, acetamido and N-methylacetamido or from a group of the formula : _X3-Q3 wherein X3 is a direct bond or is selected from O, NH, CONH, NHCO and CH20 and Q3 is pyridyl, pyridylmethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, pyrrolidin- 2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, piperidin-3-ylmethyl, 2-piperidin- 3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, 2-piperazin-1-ylethyl or 3-piperazin- 1-ylpropyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on Ri optionally bears 1,2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, allyl, 2-propynyl, methoxy, methylsulphonyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl and acetyl, or optionally bears 1 substituent selected from a group of the formula: _ Xa _ Rs wherein X4 is a direct bond or is selected from O and NH and R8 is 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-ethylaminoethyl, 3-ethylaminopropyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, acetamidomethyl, methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl or tert-butoxycarbonylaminomethyl, and from a group of the formula: -X5-Q4 wherein X5 is a direct bond or is selected from O, NH and CO and Q4 is pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, morpholinomethyl,

2-morpholinoethyl, 3-morpholinopropyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, piperazin-1-ylmethyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, each of which optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, methyl and methoxy, and wherein any heterocyclyl group within a substituent on Ri optionally bears 1 or 2 oxo substituents; and (f) m is 1 and the Rl group is located at the 5-, 6-or 7-position or m is 2 and each Rl group, which may be the same or different, is located at the 5-and 7-positions or at the 6-and 7-positions and Rl is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, but-3-enyloxy, pent-4-enyloxy, hex-5-enyloxy, but-3-ynyloxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, cyclopropylmethoxy, 2-imidazol-1-ylethoxy, 3-imidazol-1-ylpropoxy, 2- (1, 2, 3-triazol-1-yl) ethoxy, 3- (1, 2, 3-triazol-1-yl) propoxy, 2- (1, 2,4-triazol-1-yl) ethoxy, 3- (1, 2, 4-triazol-1-yl) propoxy, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, pyrid-4-ylmethoxy, 2-pyrid-2-ylethoxy, 2-pyrid-3-ylethoxy, 2-pyrid-4-ylethoxy, 3-pyrid-2-ylpropoxy, 3-pyrid-3-ylpropoxy, 3-pyrid-4-ylpropoxy, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2- (1, 1-dioxotetrahydro- 4H-1, 4-thiazin-4-yl) ethoxy, 3- (1, 1-dioxotetrahydro-4H-1, 4-thiazin-4-yl) propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy, 3-piperidin-4-ylpropoxy, 2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy, 2-homopiperazin-1-ylethoxy, 3-homopiperazin-1-ylpropoxy, 2-pyrrolidin-1-yletliylamino, 3-pyrrolidin-1-ylpropylamino, 4-pyrrolidin-1-ylbutylamino, pyrrolidin-3-ylamino, pyrrolidin-2-ylmethylamino, 2-pyrrolidin-2-ylethylamino, 3-pyrrolidin-2-ylpropylamino, 2-morpholinoethylamino, 3-morpholinopropylamino, 4-morpholinobutylamino, 2- (1, 1-dioxotetrahydro-4H-1,4-thiazin- 4-yl) ethylamino, 3- (1, 1-dioxotetrahydro-4H-1, 4-thiazin-4-yl) propylamino,

2-piperidinoethylamino, 3-piperidinopropylamino, 4-piperidinobutylamino, piperidin-3-ylamino, piperidin-4-ylamino, piperidin-3-ylmethylamino, 2-piperidin-3-ylethylamino, piperidin-4-ylmethylamino, 2-piperidin-4-ylethylamino, 2-homopiperidin-1-ylethylamino, 3-homopiperidin-1-ylpropylamino, 2-piperazin-1-ylethylamino, 3-piperazin-1-ylpropylamino, 4-piperazin-1-ylbutylamino, 2-homopiperazin-1-ylethylamino or 3-homopiperazin-1-ylpropylamino, and wherein adjacent carbon atoms in any (2-6C) alkylene chain within a Rl substituent are optionally separated by the insertion into the chain of a group selected from O, NH, N (Me), CH=CH and C=C, and when Rl is a vinyl or ethynyl group, the Rl substituent optionally bears at the terminal CH2= or HC= position a substituent selected from N- (2-dimethylaminoethyl) carbamoyl, N- (3-dimethylaminopropyl) carbamoyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl and 4-dimethylaminobutyl, or from a group of the formula: Q-X- wherein X2 is a direct bond or is NHCO or N (Me) CO and Q2 is imidazolylmethyl, 2-imidazolylethyl, 3-imidazolylpropyl, pyridyhnethyl, 2-pyridylethyl, 3-pyridylpropyl, <BR> <BR> <BR> pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 4-pyrrolidin-1-ylbutyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, piperazin-1-ylmethyl, 2-piperazin-l-ylethyl, 3-piperazin-1-ylpropyl or 4-piperazin-1-ylbutyl, and wherein any CH2 or CH3 group within a Rl substituent optionally bears on each said CH2 or CH3 group one or more fluoro or chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-N-propylamino, acetoxy, acetamido and N-methylacetamido, and wherein any phenyl, imidazolyl, triazolyl, pyridyl or heterocyclyl group within a substituent on Rl optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl,

N-methylcarbamoyl, N, N-dimethylcarbamoyl and methoxy, and a pyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl group within a Ri substituent is optionally N-substituted with allyl, 2-propynyl, methylsulphonyl, acetyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, the last 8 of which substituents each optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, methyl and methoxy, and wherein any heterocyclyl group within a substituent on Rl optionally bears 1 or 2 oxo substituents.

(g) m is 1 and the R'group is located at the 6-or 7-position and is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, benzyloxy, 2-imidazol-1-ylethoxy, 2- (1, 2, 3-triazol-1-yl) ethoxy, 2- (1, 2, 4-triazol-1-yl) ethoxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-yhnethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2- (1, 1-dioxotetrahydro-4H-1, 4-thiazin-4-yl) ethoxy, 3- (1, 1-dioxotetrahydro-4H-1, 4-thiazin- 4-yl) propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy, 2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy or 3-homopiperazin-1-ylpropoxy, and wherein adjacent carbon atoms in any (2-6C) alkylene chain within a Rl substituent are optionally separated by the insertion into the chain of a group selected from O, NH, CH=CH and C=C, and wherein any CH2 or CH3 group within a Rl substituent optionally bears on each said CH2 or CH3 group one or more chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino and acetoxy,

and wherein any phenyl or heterocyclyl group within a substituent on Rl optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, methyl, ethyl and methoxy, and wherein any heterocyclyl group within a substituent on Rl optionally bears 1 or 2 oxo substituents ; (h) n is 0; (i) n is 1 or 2 and the R3 groups, which may be the same or different, are located at the 3-, 5-and/or 6-positions of the benzofuran-7-yl group and are selected from halogeno, trifluoromethyl, cyano, hydroxy, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (1-6C) alkoxy; (j) n is 1 or 2 and the R3 groups, which may be the same or different, are located at the 3-, 5-and/or 6-positions of the benzofuran-7-yl group and are selected from fluoro, chloro, bromo, iodo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl, methoxy and ethoxy ; (k) n is 1 and the R3 group is located at the 5-or 6-position of the benzofuran-7-yl group, especially the 6-position, and is selected from chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy; (1) m is 1 or 2, and each Rl group, which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (1-6C) alkyl, (1-6C) alkoxy, (1-6C) alkylamino, di- [ (l-6C) alkyl] amino, N-(1-6C) alkylcarbamoyl, N, N-di-[(1-6C) alkyl] carbamoyl, (2-6C) alkanoylamino and N-(1-6C) alkyl- (2-6C) alkanoylamino, or from a group of the formula : Q1-X1- wherein Xl is selected from O, N (R4), CON (R4), N (R4) CO and OC (R4) 2 wherein R4 is hydrogen or (1-6C) alkyl, and Ql is aryl, aryl- (1-6C) alkyl, cycloalkyl- (1-6C) alkyl, heteroaryl, heteroaryl- (1-6C) alkyl, heterocyclyl or heterocyclyl- (l-6C) alkyl, or Xl is a direct bond and Ql is aryl- (1-6C) alkyl, cycloallcyl- (1-6C) alkyl, heteroaryl- (1-6C) alkyl or heterocyclyl- (1-6C) alkyl, and wherein adjacent carbon atoms in any (2-6C) alkylene chain within a Rl substituent are optionally separated by the insertion into the chain of a group selected from O, N (R5), CON (R5), N (R5) CO, CH=CH and C=C wherein Rus is hydrogen or (1-6C) alkyl, or, when the inserted group is N (R5), RS may also be (2-6C) alkanoyl, and wherein any CH2 or CH3 group within a Rl substituent optionally bears on each said CH2 or CH3 group one or more halogeno groups or a substituent selected from hydroxy,

amino, (1-6C) alkoxy, (1-6C) alkylsulphonyl, (1-6C) alkylamino, di- [ (l-6C) alkyl] amino, (2-6C) alkanoyloxy, (2-6C) alkanoylamino and N-(1-6C)alkyl-(2-6C)alkanoylamino, or from a group of the formula: -X3-Q3 wherein X3 is a direct bond or is selected from O, N (R6), CON (R7), N (R7) CO and C (R7) 2O, wherein R7 is hydrogen or (1-6C) alkyl, and Q3 is heteroaryl, heteroaryl- (1-6C) alkyl, heterocyclyl or heterocyclyl- (1-6C) alkyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on Rl optionally bears 1,2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, (1-6C) alkylsulphonyl, N-(1-6C)alkylcarbamoyl, N, N-di-[(1-6C) alkyl] carbamoyl and (2-6C) alkanoyl, or optionally bears 1 substituent selected from a group of the formula: -X4_R8 wherein X4 is a direct bond or is selected from O and N (R9), wherein R9 is hydrogen or (1-6C) alkyl, and k8 is hydroxy- (1-6C) alkyl, (1-6C) alkoxy- (1-6C) alkyl, cyano-(1-6C) alkyl, amino- (1-6C) alkyl, (1-6C) alkylamino- (1-6C) alkyl, di- [ (l-6C) alkyl] amino- (l-6C) alkyl, (2-6C) alkanoylamino- (1-6C) alkyl or (1-6C) alkoxycarbonylamino-(1-6C) alkyl, and from a group of the formula: -X5-Q4 wherein X5 is a direct bond or is selected from O, N (R10) and CO, wherein Rl° is hydrogen or (1-6C) alkyl, and Q4 is heterocyclyl or heterocyclyl- (1-6C) alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (1-6C) alkyl and (1-6C) alkoxy, and wherein any heterocyclyl group within a substituent on Rl optionally bears 1 or 2 oxo substituents; (m) m is 1 or 2, and each Rl group, which may be the same or different, is selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, N-methylcarbamoyl, N, N-dimethylcarbamoyl, acetamido, propionamido, acrylamido and propiolamido, or from a group of the formula : Q1-X1-

wherein Xl is selected from O, NH, CONH, NHCO and OCH2 and Ql is phenyl, benzyl, cyclopropylmethyl, 2-thienyl, 1-imidazolyl, 1,2, 3-triazol-1-yl, 1,2, 4-triazol-1-yl, 2-, 3-or 4-pyridyl, 2-imidazol-1-ylethyl, 3-imidazol-1-ylpropyl, 2- (1, 2,3-triazolyl) ethyl, 3- (1, 2,3-triazolyl) propyl, 2- (1, 2,4-triazolyl) ethyl, 3- (1, 2,4-triazolyl) propyl, 2-, 3-or 4-pyridylmethyl, 2- (2-, 3-or 4-pyridyl) ethyl, 3- (2-, 3-or 4-pyridyl) propyl, tetrahydrofuran-3-yl, 3-or 4-tetrahydropyranyl, 1-, 2-or 3-pyrrolidinyl, morpholino, 1, 1-dioxotetrahydro-4H-1, 4-thiazin-4-yl, piperidino, piperidin-3-yl, piperidin-4-yl, 1-, 3-or 4-homopiperidinyl, piperazin-1-yl, homopiperazin-1-yl, 1-, 2-or 3-pyrrolidinylmethyl, morpholinomethyl, piperidinomethyl, 3-or 4-piperidinylmethyl, 1-, 3-or 4-homopiperidinylmethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-2-ylpropyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-1-ylpropyl, 4-pyrrolidin-1-ylbutyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, 2-(1, 1-dioxotetrahydro-4H-1, 4-thiazin-4-yl) ethyl, 3- (1, 1-dioxotetrahydro-4H-1, 4-thiazin- 4-yl) propyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, 2-piperidin-3-ylethyl, 3-piperidin-3-ylpropyl, 2-piperidin-4-ylethyl, 3-piperidin-4-ylpropyl, 2-homopiperidin-1-ylethyl, 3-homopiperidin-1-ylpropyl, 2- (1, 2,3, 6-tetrahydropyridin-1- yl) ethyl, 3- (1, 2,3, 6-tetrahydropyridin-1-yl) propyl, 4- (1, 2,3, 6-tetrahydropyridin-1-yl) butyl, 2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl, 4-piperazin-1-ylbutyl, 2-homopiperazin-1-ylethyl or 3-homopiperazin-1-ylpropyl, or wherein Xl is a direct bond and Ql is benzyl, cyclopropylmethyl, 2-imidazol-1-ylethyl, 3-imidazol-1-ylpropyl, 2- (1, 2,3-triazolyl) ethyl, 3- (1, 2,3-triazolyl) propyl, 2- (1, 2,4-triazolyl) ethyl, 3- (1, 2,4-triazolyl) propyl, 2-, 3-or 4-pyridylmethyl, 2- (2-, 3-or 4-pyridyl) ethyl, 3- (2-, 3-or 4-pyridyl) propyl, 1-, 2-or 3-pyrrolidinylmethyl, morpholinomethyl, piperidinomethyl, 3-or 4-piperidinylmethyl, 1-, 3-or 4-homopiperidinylmethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-2-ylpropyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-1-ylpropyl, 4-pyrrolidin-1-ylbutyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, 2- (1, 1-dioxotetrahydro-4H-1, 4-thiazin-4-yl) ethyl, 3- (1, 1-dioxotetrahydro-4H-1, 4-thiazin- 4-yl) propyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, 2-piperidin-3-ylethyl, 3-piperidin-3-ylpropyl, 2-piperidin-4-ylethyl, 3-piperidin-4-ylpropyl, 2-homopiperidin-1-ylethyl, 3-homopiperidin-1-ylpropyl, 2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl, 4-piperazin-1-ylbutyl, 2-homopiperazin-1-ylethyl or 3-homopiperazin-1-ylpropyl,

and wherein adjacent carbon atoms in any (2-6C) alkylene chain within a Rl substituent are optionally separated by the insertion into the chain of a group selected from O, NH, N (Me), CONH, NHCO, CH=CH and C_C, and wherein any CH2 or CH3 group within a Ri substituent optionally bears on each said CH2 or CH3 group one or more fluoro or chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-N-propylamino, acetoxy, acetamido and N-methylacetamido or from a group of the formula : -X3-Q3 wherein X3 is a direct bond or is selected from O, NH, CONH, NHCO and CH2O and Q3 is pyridyl, pyridyhnethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, pyrrolidin- 2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, piperidin-3-ylmethyl, 2-piperidin- 3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, 2-piperazin-1-ylethyl or 3-piperazin- 1-ylpropyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on Rl optionally bears 1,2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, allyl, 2-propynyl, methoxy, methylsulphonyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl and acetyl, or optionally bears 1 substituent selected from a group of the formula : - X'-R' wherein X4 is a direct bond or is selected from O and NH and R8 is 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-ethylaminoethyl, 3-ethylaminopropyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, acetamidomethyl, methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl or tert-butoxycarbonylaminomethyl, and from a group of the formula: -X5-Q4 wherein X5 is a direct bond or is selected from O, NH and CO and Q4 is pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, piperidinomethyl, 2-piperidinoethyl,

3-piperidinopropyl, piperazin-1-yhnethyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, each of which optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, methyl and methoxy, and wherein any heterocyclyl group within a substituent on Rl optionally bears 1 or 2 oxo substituents; (n) m is 1 and the Rl group is located at the 5-, 6-or 7-position or m is 2 and each Rl group, which may be the same or different, is located at the 5-and 7-positions or at the 6-and 7-positions and Rl is selected from hydroxy, amino, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, cyclopentyloxy, cyclohexyloxy, phenoxy, benzyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, cyclopropylmethoxy, 2-imidazol-1-ylethoxy, 3-imidazol-1-ylpropoxy, 2- (1, 2, 3-triazol-l-yl) ethoxy, 3- (1, 2, 3-triazol-1-yl) propoxy, 2- (1, 2, 4-triazol-1-yl) ethoxy, 3- (1, 2, 4-triazol-1-yl) propoxy, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, pyrid-4-ylmethoxy, 2-pyrid-2-ylethoxy, 2-pyrid-3-ylethoxy, 2-pyrid-4-ylethoxy, 3-pyrid-2-ylpropoxy, 3-pyrid-3-ylpropoxy, 3-pyrid-4-ylpropoxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2- (1, 1-dioxotetrahydro-4H-1,4-thiazin-4-yl) ethoxy, 3- (1, 1-dioxotetrahydro- 4H-1, 4-thiazin-4-yl) propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy, 3-piperidin-4-ylpropoxy, 2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy, 2- (1, 2,3, 6-tetrahydropyridin-1-yl) ethoxy, 3- (1, 2,3, 6-tetrahydropyridin-1-yl) propoxy, 4- (1, 2,3, 6-tetrahydropyridin-1-yl) butoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy, 2-homopiperazin-1-ylethoxy, 3-homopiperazin-1-ylpropoxy, 2-pyrrolidin-1-ylethylamino, 3-pyrrolidin-1-ylpropylamino, 4-pyrrolidin-1-ylbutylamino, pyrrolidin-3-ylamino, pyrrolidin-2-ylmethylamino, 2-pyrrolidin-2-ylethylamino, 3-pyrrolidin-2-ylpropylamino, 2-morpholinoethylamino, 3-morpholinopropylamino, 4-morpholinobutylamino, 2- (1, 1-dioxotetrahydro-4H-1, 4-thiazin-4-yl) ethylamino, 3- (1, 1-dioxotetrahydro-4H-1, 4-thiazin-4-yl) propylamino, 2-piperidinoethylamino, 3-piperidinopropylamino, 4-piperidinobutylamino, piperidin-3-ylamino, piperidin-4-ylamino, piperidin-3-ylmethylamino, 2-piperidin-3-ylethylamino, piperidin-4-ylmethylamino,

2-piperidin-4-ylethylamino, 2-homopiperidin-1-ylethylamino, 3-homopiperidin-1-ylpropylamino, 2- (1, 2,3, 6-tetrahydropyridin-1-yl) ethylamino, 3- (1, 2,3, 6-tetrahydropyridin-1-yl) propylamino, 4- (1, 2,3, 6-tetrahydropyridin-l-yl) butylamino, 2-piperazin-1-ylethylamino, 3-piperazin-1-ylpropylamino, 4-piperazin-1-ylbutylamino, 2-homopiperazin-1-ylethylamino or 3-homopiperazin-1-ylpropylamino, and wherein adjacent carbon atoms in any (2-6C) alkylene chain within a Rl substituent are optionally separated by the insertion into the chain of a group selected from O, NH, N (Me), CH=CH and C--C, and wherein any CH2 or CH3 group within a Ri substituent optionally bears on each said CH2 or CH3 group one or more fluoro or chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diisopropylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-N-propylamino, acetoxy, acetamido and N-methylacetamido, and wherein any phenyl, imidazolyl, triazolyl, pyridyl or heterocyclyl group within a substituent on R'optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl and methoxy, and a pyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl group within a R substituent is optionally N-substituted with methyl, ethyl, propyl, allyl, 2-propynyl, methylsulphonyl, acetyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-fluoroethyl, 3-fluoropropyl, 2-chloroethyl, 3-chloropropyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, the last 8 of which substituents each optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, methyl and methoxy, and wherein any heterocyclyl group within a substituent on Ri optionally bears 1 or 2 oxo substituents ; (o) n is 1 or 2 and the R3 groups, which may be the same or different, are selected from halogeno, trifluoromethyl, cyano, hydroxy, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (1-6C) alkoxy; (p) n is 1 or 2 and the R3 groups, which may be the same or different, are located at the 3-, 4-, 5-and/or 6-positions of the benzofuran-7-yl group and are selected from fluoro, chloro,

bromo, iodo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl, methoxy and ethoxy; and (q) n is 1 and the R3 group is located at the 4-, 5-or 6-position of the benzofuran-7-yl group, especially the 6-position, and is selected from chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, methoxy and ethoxy.

Further particular novel compounds of the invention include, for example, quinoline derivatives of the Formula I, or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of Z, m, Rl, n and R3 has any of the meanings defined hereinbefore provided that:- (A) Rl substituents may only be located at the 5-, 6-and/or 7-positions on the quinoline ring i. e. the 2-and 8-positions remain unsubstituted; or (B) Rl substituents may only be located at the 6-and/or 7-positions on the quinoline ring i. e. the 2-, 5-and 8-positions remain unsubstituted.

A particular compound of the invention is a quinoline derivative of the Formula I wherein: Z is O or NH ; m is 1 and the Rl group is located at the 5-, 6-or 7-position or m is 2 and each Rl group, which may be the same or different, is located at the 5-and 7-positions or at the 6-and 7-positions and Rl is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, 2-imidazol-1-ylethoxy, 2- (1, 2, 4-triazol-1-yl) ethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2- (1, 1-dioxotetrahydro-4H-1, 4-thiazin-4-yl) ethoxy, 3- (1, 1-dioxotetrahydro- 4H-1, 4-thiazin-4-yl) propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy, 3-piperidin-4-ylpropoxy, 2-homopiperidin-1-yletlioxy, 3-homopiperidin-1-ylpropoxy, 2- (1, 2,3, 6-tetrahydropyridin-1-yl) ethoxy, 3- (1, 2,3, 6-tetrahydropyridin-1-yl) propoxy, 4- (1, 2,3, 6-tetrahydropyridin-1-yl) butoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy, 2-homopiperazin-1-ylethoxy and 3-homopiperazin-1-ylpropoxy,

and wherein adjacent carbon atoms in any (2-6C) alkylene chain within a Ri substituent are optionally separated by the insertion into the chain of a group selected from O, NH, N (Me), CH=CH and C=C, and wherein any CH2 or CH3 group within a Rl substituent optionally bears on each said CH2 or CH3 group one or more chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diethylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-N-propylamino and acetoxy; and wherein any heteroaryl or heterocyclyl group within a substituent on Rl optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, methoxy, N-methylcarbamoyl and N, N-dimethylcarbamoyl and a pyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl group within a Rl substituent is optionally N-substituted with methyl, ethyl, propyl, allyl, prop-2-ynyl, methylsulphonyl, acetyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-fluoroethyl, 3-fluoropropyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, the last 8 of which substituents each optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, methyl and methoxy, and wherein any heterocyclyl group within a substituent on Rl optionally bears 1 or 2 oxo substituents; and n is 0 or 1 and the R3 group, if present, is located at the 3-, 4-, 5-or 6-position of the benzofuran-7-yl group and is selected from fluoro, chloro, bromo, iodo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, ethynyl, methoxy and ethoxy ; or a pharmaceutically-acceptable acid-addition salt thereof.

A particular compound of the invention is a quinoline derivative of the Formula I wherein: Z is O or NH ; m is 1 and the Ri group is located at the 5-, 6-or 7-position or m is 2 and each Rl group, which may be the same or different, is located at the 5-and 7-positions or at the 6-and 7-positions and Rl is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pent-4-ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, 2-imidazol-1-ylethoxy,

2- (1, 2, 4-triazol-1-yl) ethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2- (1, 1-dioxotetrahydro-4H-1, 4-thiazin-4-yl) ethoxy, 3- (l, l-dioxotetrahydro- 4H-1, 4-thiazin-4-yl) propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy, 3-piperidin-4-ylpropoxy, 2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy, 2-piperazin-l-ylethoxy, 3-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy, 2-homopiperazin-1-ylethoxy and 3-homopiperazin-1-ylpropoxy, and wherein adjacent carbon atoms in any (2-6C) alkylene chain within a Rl substituent are optionally separated by the insertion into the chain of a group selected from O, NH, N (Me), CH=CH and C=C, and wherein any CH2 or CH3 group within a Rl substituent optionally bears on each said CH2 or CH3 group one or more chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diethylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-N-propylamino and acetoxy ; and wherein any heteroaryl or heterocyclyl group within a substituent on Rl optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, methoxy, N-methylcarbamoyl and N, N-dimethylcarbamoyl and a pyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl group within a Rl substituent is optionally N-substituted with allyl, methylsulphonyl, acetyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, the last 8 of which substituents each optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, methyl and methoxy, and wherein any heterocyclyl group within a substituent on Rl optionally bears 1 or 2 oxo substituents; and

n is 0 or 1 and the R3 group, if present, is located at the 3-, 5-or 6-position of the benzofuran-7-yl group and is selected from fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, ethynyl, methoxy and ethoxy; or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivative of the Formula I wherein: Z is O or NH; m is 2 and the first Rl group is located at the 6-position and is selected from hydroxy, methoxy, ethoxy and propoxy, and the second Ri group is located at the 7-position and is selected from 2-hydroxyethoxy, 3-hydroxypropoxy, 4-hydroxybutoxy, 2-methoxyethoxy, 3-methoxypropoxy, 4-methoxybutoxy, 2- (2-hydroxyethoxy) ethoxy, 2- (2-methoxyethoxy) ethoxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 4-dimethylaminobutoxy, 2-diethylaminoethoxy, 3-diethylaminopropoxy, 4-diethylaminobutoxy, 2-diisopropylaminoethoxy, 3-diisopropylaminopropoxy, 4-diisopropylaminobutoxy, 2- (N-isopropyl-N-methylamino) ethoxy, 3- (N-isopropyl-N-methylamino) propoxy, 4- (N-isopropyl-N-methylamino) butoxy, 2- (N-allylamino) ethoxy, 3- (N-allylamino) propoxy, 2- (N-allyl-N-methylamino) ethoxy, 3- (N-allyl-N-methylamino) propoxy, 2- (N-prop-2-ynylamino) ethoxy, 3- (N-prop-2-ynylamino) propoxy, 2- (N-methyl-N-prop-2-ynylamino) ethoxy, 3- (N-methyl-N-prop-2-ynylamino) propoxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy, N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2- (1, 1-dioxotetrahydro-4H-1, 4-thiazin-4-yl) ethoxy, 3- (1, 1-dioxotetrahydro-4H-1, 4-thiazin- 4-yl) propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, N-methylpiperidin-3-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-yhnethoxy, piperidin-4-yhnethoxy, N-methylpiperidin-4-yhnethoxy, 2-piperidin-3-ylethoxy, 2- (N-methylpiperidin-3-yl) ethoxy, 3-piperidin-3-ylpropoxy, 3- (N-methylpiperidin-3-yl) propoxy, 2-piperidin-4-ylethoxy, 2- (N-methylpiperidin-4-yl) ethoxy, 3-piperidin-4-ylpropoxy, 3- (N-methylpiperidin-4-yl) propoxy, 2- (4-methylpiperazin-1-yl) ethoxy, 3- (4-methylpiperazin-1-yl) propoxy, 4- (4-methylpiperazin-1-yl) butoxy, 2- (4-allylpiperazin-1-yl) ethoxy, 3- (4-allylpiperazin-1-yl) propoxy,

4- (4-allylpiperazin-1-yl) butoxy, 2- (4-methylsulphonylpiperazin-1-yl) ethoxy, 3- (4-methylsulphonylpiperazin-1-yl) propoxy, 4- (4-methylsulphonylpiperazin-1-yl) butoxy, 2- (4-acetylpiperazin-1-yl) ethoxy, 3- (4-acetylpiperazin-1-yl) propoxy, 4- (4-acetylpiperazin-1-yl) butoxy, 2- (4-cyanomethylpiperazin-1-yl) ethoxy, 3- (4-cyanomethylpiperazin-1-yl) propoxy, 4- (4-cyanomethylpiperazin-1-yl) butoxy, 2- [2- (4-methylpiperazin-1-yl) ethoxy] ethoxy, 2-chloroethoxy, 3-chloropropoxy, 2-methylsulphonylethoxy and 3-methylsulphonylpropoxy, and wherein any CH2 group within the second Rl group that is attached to two carbon atoms optionally bears a hydroxy group or acetoxy group on said CH2 group, and wherein any heterocyclyl group within the second Ri group optionally bears 1 or 2 substituents selected from fluoro, hydroxy, methyl and oxo; and n is 0 or n is 1 and the R3 group, if present, is located at the 5-or 6-position of the benzofuran-7-yl group and is selected from fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, ethynyl, methoxy and ethoxy; or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivative of the Formula I wherein: ZisOorNH ; m is 2 and the first Ri group is a 6-methoxy group and the second Rl group is located at the 7-position and is selected from 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 4-dimethylaminobutoxy, 2-diethylaminoethoxy, 3-diethylaminopropoxy, 4-diethylaminobutoxy, 2-diisopropylaminoethoxy, 3-diisopropylaminopropoxy, 4-diisopropylaminobutoxy, 2- (N-isopropyl-N-methylamino) ethoxy, 3- (N-isopropyl-N-methylamino) propoxy, 4- (N-isopropyl-N-methylamino) butoxy, 2- (N-isobutyl-N-methylamino) ethoxy, 3- (N-isobutyl-N-methylamino) propoxy, 4- (N-isobutyl-N-methylamino) butoxy, 2- (N-allyl-N-methylamino) ethoxy, 3- (N-allyl-N-methylamino) propoxy, 2- (N-prop-2-ynylamino) ethoxy, 3- (N-prop-2-ynylamino) propoxy, 2- (N-methyl-N-prop-2-ynylamino) ethoxy, 3- (N-methyl-N-prop-2-ynylamino) propoxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy, N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2- (1, 1-dioxotetrahydro-4H-1,4-thiazin-4-yl) ethoxy, 3- (1, 1-dioxotetrahydro-

4H-1, 4-thiazin-4-yl) propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, N-methylpiperidin-3-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy, piperidin-3-yhnethoxy, N-methylpiperidin-3-ylmethoxy, N-cyanomethylpiperidin-3-yhnethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, N-cyanomethylpiperidin-4-yhnethoxy, 2-piperidin-3-ylethoxy, 2- (N-methylpiperidin-3-yl) ethoxy, 3-piperidin-3-ylpropoxy, 3- (N-methylpiperidin-3-yl) propoxy, 2-piperidin-4-ylethoxy, 2- (N-methylpiperidin-4-yl) ethoxy, 3-piperidin-4-ylpropoxy, 3- (N-methylpiperidin-4-yl) propoxy, 2- (4-hydroxypiperidin-1-yl) ethoxy, 3- (4-hydroxypiperidin-1-yl) propoxy, 4- (4-hydroxypiperidin-1-yl) butoxy, 2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy, 4-homopiperidin-1-ylbutoxy, 2- (1, 2,3, 6-tetrahydropyridin-1-yl) ethoxy, 3- (1, 2,3, 6-tetrahydropyridin-1-yl) propoxy, 4- (1, 2,3, 6-tetrahydropyridin-1-yl) butoxy, 2-piperazin-1-ylethoxy, 2- (4-methylpiperazin-1-yl) ethoxy, 3-piperazin-1-ylpropoxy, 3- (4-methylpiperazin-1-yl) propoxy, 4-piperazin-1-ylbutoxy, 4- (4-methylpiperazin-1-yl) butoxy, 2- (4-allylpiperazin-1-yl) ethoxy, 3- (4-allylpiperazin-1-yl) propoxy, 4- (4-allylpiperazin-1-yl) butoxy, 2- (4-prop-2-ynylpiperazin-1-yl) ethoxy, 3- (4-prop-2-ynylpiperazin-1-yl) propoxy, 4- (4-prop-2-ynylpiperazin-1-yl) butoxy, 2- (4-methylsulphonylpiperazin-1-yl) ethoxy, 3- (4-methylsulphonylpiperazin-1-yl) propoxy, 4- (4-methylsulphonylpiperazin-1-yl) butoxy, 2- (4-acetylpiperazin-1-yl) ethoxy, 3- (4-acetylpiperazin-1-yl) propoxy, 4- (4-acetylpiperazin-1-yl) butoxy, 2- [4- (2-fluoroethyl) piperazin-1-yl] ethoxy, 3- [4- (2-fluoroethyl) piperazin-1-yl] propoxy, 4- [4- (2-fluoroethyl) piperazin-1-yl] butoxy, 2- (4-cyanomethylpiperazin-1-yl) ethoxy, 3- (4-cyanomethylpiperazin-1-yl) propoxy, 4- (4-cyanomethylpiperazin-1-yl) butoxy, 2- (2-piperazin-1-ylethoxy) ethoxy, 2- [2- (4-methylpiperazin-1-yl) ethoxy] ethoxy, 2-chloroethoxy, 3-chloropropoxy, 4-chlorobutoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-tetrahydropyran-4-ylethoxy, 3-tetrahydropyran-4-ylpropoxy, 2-pyrrol-1-ylethoxy, 3-pyrrol-1-ylpropoxy, 2- (2-pyridyloxy) ethoxy, 3- (2-pyridyloxy) propoxy, 2- (3-pyridyloxy) ethoxy, 3- (3-pyridyloxy) propoxy, 2- (4-pyridyloxy) ethoxy, 3- (4-pyridyloxy) propoxy, 2-pyridylmethoxy, 3-pyridylmethoxy and 4-pyridylmethoxy, and wherein any CH2 group within the second Ri group that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group,

and wherein any heteroaryl group within the second Rl group optionally bears 1 or 2 substituents selected from chloro, cyano, hydroxy and methyl, and any heterocyclyl group within the second Ri group optionally bears 1 or 2 substituents selected from fluoro, hydroxy, methyl and oxo; and n is 0 or n is 1 and the R3 group, if present, is located at the 4-, 5-or 6-position of the benzofuran-7-yl group and is selected from fluoro, chloro, bromo, iodo and cyano; or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivative of the Formula I wherein: Z is O or NH; m is 2 and the first Rl group is a 6-methoxy group and the second Ri group is located at the 7-position and is selected from 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 4-dimethylaminobutoxy, 2-diethylaminoethoxy, 3-diethylaminopropoxy, 4-diethylaminobutoxy, 2-diisopropylaminoethoxy, 3-diisopropylaminopropoxy, 4-diisopropylaminobutoxy, 2- (N-isopropyl-N-methylamino) etlioxy, 3- (N-isopropyl-N-methylamino) propoxy, 4- (N-isopropyl-N-methylamino) butoxy, 2- (N-isobutyl-N-methylamino) ethoxy, 3- (N-isobutyl-N-methylamino) propoxy, 4- (N-isobutyl-N-methylamino) butoxy, 2- (N-allyl-N-methylamino) ethoxy, 3- (N-allyl-N-methylamino) propoxy, 2- (N-prop-2-ynylamino) ethoxy, 3- (N-prop-2-ynylamino) propoxy, 2- (N-methyl-N-prop-2-ynylamino) ethoxy, 3- (N-methyl-N-prop-2-ynylamino) propoxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy, N-methylpyrrolidin-3-yloxy, pyrrolidin-2-yltnethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2- (1, 1-dioxotetrahydro-4H-1, 4-thiazin-4-yl) ethoxy, 3- (1, 1-dioxotetrahydro- 4H-1, 4-thiazin-4-yl) propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, N-methylpiperidin-3-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, N-cyanomethylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, N-cyanomethylpiperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 2- (N-methylpiperidin-3-yl) ethoxy, 3-piperidin-3-ylpropoxy, 3- (N-methylpiperidin-3-yl) propoxy, 2-piperidin-4-ylethoxy, 2- (N-methylpiperidin-4-yl) ethoxy, 3-piperidin-4-ylpropoxy,

3- (N-methylpiperidin-4-yl) propoxy, 2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy, 4-homopiperidin-1-ylbutoxy, 2-piperazin-1-ylethoxy, 2- (4-methylpiperazin-1-yl) ethoxy, 3-piperazin-1-ylpropoxy, 3- (4-methylpiperazin-1-yl) propoxy, 4-piperazin-1-ylbutoxy, 4- (4-methylpiperazin-1-yl) butoxy, 2- (4-allylpiperazin-1-yl) ethoxy, 3- (4-allylpiperazin-1-yl) propoxy, 4- (4-allylpiperazin-1-yl) butoxy, 2- (4-methylsulplionylpiperazin-1-yl) ethoxy, 3- (4-methylsulphonylpiperazin-1-yl) propoxy, 4- (4-methylsulphonylpiperazin-1-yl) butoxy, 2- (4-acetylpiperazin-1-yl) ethoxy, 3- (4-acetylpiperazin-1-yl) propoxy, 4- (4-acetylpiperazin-1-yl) butoxy, 2- (4-cyanomethylpiperazin-1-yl) ethoxy, 3- (4-cyanomethylpiperazin-1-yl) propoxy, 4- (4-cyanomethylpiperazin-1-yl) butoxy, 2- (2-piperazin-1-ylethoxy) ethoxy, 2- [2- (4-methylpiperazin-1-yl) ethoxy] ethoxy, 2-chloroethoxy, 3-chloropropoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-tetrahydropyran-4-ylethoxy, 3-tetrahydropyran-4-ylpropoxy, 2-pyrrol-1-ylethoxy, 3-pyrrol-1-ylpropoxy, 2- (2-pyridyloxy) ethoxy, 3- (2-pyridyloxy) propoxy, 2- (3-pyridyloxy) ethoxy, 3- (3-pyridyloxy) propoxy, 2- (4-pyiidyloxy) ethoxy, 3- (4-pyridyloxy) propoxy, 2-pyridyhnethoxy, 3-pyridylmethoxy and 4-pyridylmethoxy, and wherein any CH2 group within the second Rl group that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group, and wherein any heteroaryl group within the second Rl group optionally bears 1 or 2 substituents selected from chloro, cyano, hydroxy and methyl, and any heterocyclyl group within the second Ri group optionally bears 1 or 2 substituents selected from fluoro, hydroxy, methyl and oxo; and n is 0 or n is 1 and the R3 group, if present, is located at the 6-position of the benzofuran-7-yl group and is selected from fluoro, chloro and bromo; or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivative of the Formula I wherein: Z is NH ; m is 2 and the first Rl group is a 6-methoxy group and the second Ri group is located at the 7-position and is selected from 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2- (1, 1-dioxotetrahydro-4H-1,4-thiazin- 4-yl) ethoxy, 3- (1, 1-dioxotetrahydro-4H-1, 4-thiazin-4-yl) propoxy, 2-piperidinoethoxy,

3-piperidinopropoxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-yllnethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 2- (N-methylpiperidin-3-yl) ethoxy, 3-piperidin-3-ylpropoxy, 3- (N-methylpiperidin- 3-yl) propoxy, 2-piperidin-4-ylethoxy, 2- (N-methylpiperidin-4-yl) etlioxy, 3-piperidin-4-ylpropoxy, 3- (N-methylpiperidin-4-yl) propoxy, 2- (1, 2,3, 6-tetrahydropyridin- 1-yl) ethoxy, 3- (1, 2,3, 6-tetrahydropyridin-1-yl) propoxy, 4- (1, 2,3, 6-tetrahydropyridin- 1-yl) butoxy, 2- (4-hydroxypiperidin-1-yl) ethoxy, 3- (4-hydroxypiperidin-1-yl) propoxy, 4- (4-hydroxypiperidin-1-yl) butoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy, 2- (4-methylpiperazin-1-yl) etlioxy, 3- (4-methylpiperazin- 1-yl) propoxy, 4- (4-methylpiperazin-1-yl) butoxy, 3- (4-allylpiperazin-1-yl) propoxy, 3- (4-prop-2-ynylpiperazin-1-yl) propoxy, 3- (4-methylsulphonylpiperazin-1-yl) propoxy, 3- (4-acetylpiperazin-1-yl) propoxy, 4- (4-acetylpiperazin-1-yl) butoxy, 3- [4- (2-fluoroethyl) piperazin-1-yl] propoxy, 2- (4-cyanomethylpiperazin-1-yl) ethoxy, 3- (4-cyanomethylpiperazin-1-yl) propoxy, 2- [2- (4-methylpiperazin-1-yl) ethoxy] ethoxy, 3-chloropropoxy, 4-chlorobutoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-(2-methoxyethoxy) ethoxy, 2- (4-pyridyloxy) ethoxy, 3-pyridylmethoxy and 2-cyanopyrid-4-ylmethoxy ; and n is 0 or n is 1 and the R3 group, if present, is located at the 4-, 5-or 6-position of the benzofuranyl group and is selected from fluoro, chloro, bromo and iodo; or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivative of the Formula I wherein: Z is NH ; m is 2 and the first Rl group is a 6-methoxy group and the second Ri group is located at the 7-position and is selected from 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2- (1, 1-dioxotetrahydro-4H-1,4-thiazin- 4-yl) ethoxy, 3- (1, 1-dioxotetrahydro-4H-1,4-thiazin-4-yl) propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 2- (N-methylpiperidin-3-yl) ethoxy, 3-piperidin-3-ylpropoxy, 3- (N-methylpiperidin- 3-yl) propoxy, 2-piperidin-4-ylethoxy, 2- (N-methylpiperidin-4-yl) ethoxy, 3-piperidin-4-ylpropoxy, 3- (N-methylpiperidin-4-yl) propoxy, 2- (4-methylpiperazin-1-yl) ethoxy, 3- (4-methylpiperazin-1-yl) propoxy,

3- (4-allylpiperazin-1-yl) propoxy, 3- (4-methylsulphonylpiperazin-1-yl) propoxy, 3- (4-acetylpiperazin-1-yl) propoxy, 2-(4-cyanomethylpiperazin-1-yl) ethoxy, 3-(4-cyanomethylpiperazin-1-yl) propoxy, 2- [2- (4-methylpiperazin-1-yl) ethoxy] ethoxy, 3-chloropropoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2- (4-pyridyloxy) ethoxy, 3-pyridylmethoxy and 2-cyanopyrid-4-yhnethoxy ; and n is 0 or n is 1 and the R3 group, if present, is located at the 6-position of the benzofuranyl group and is selected from chloro and bromo; or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivative of the Formula I wherein: Z is NH ; m is 2 and the first Ri group is a 6-methoxy group and the second Rl group is located at the 7-position and is selected from methoxy, ethoxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(1, 1-dioxotetrahydro-4_-1, 4-tlliazin-4-yl) ethoxy, 3- (1, 1-dioxotetrahydro-4H-1, 4-thiazin- 4-yl) propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2- (1, 2,3, 6-tetrahydropyridin- 1-yl) ethoxy, 3- (1, 2,3, 6-tetrahydropyridin-1-yl) propoxy, 4- (1, 2,3, 6-tetrahydropyridin- 1-yl) butoxy, 2- (4-hydroxypiperidin-1-yl) ethoxy, 3- (4-hydroxypiperidin-1-yl) propoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2- (4-methylpiperazin-1-yl) ethoxy, 3- (4-methylpiperazin-1-yl) propoxy, 4- (4-methylpiperazin-1-yl) butoxy, 3- (4-allylpiperazin-1-yl) propoxy, 3- (4-prop-2-ynylpiperazin-1-yl) propoxy, 3- (4-acetylpiperazin-1-yl) propoxy, 4- (4-acetylpiperazin-1-yl) butoxy, 3- [4- (2-fluoroethyl) piperazin-1-yl] propoxy, 2- (4-cyanomethylpiperazin-1-yl) ethoxy, 3-(4-cyanomethylpiperazin-1-yl) propoxy, 3-chloropropoxy, 4-chlorobutoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy and 2- (2-methoxyethoxy) ethoxy ; and n is 0 or n is 1 and the R3 group, if present, is located at the 3-, 4-, 5-or 6-position of the benzofuranyl group and is selected from fluoro, chloro, bromo, iodo and cyano; or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivative of the Formula I wherein: Z is NH ; m is 2 and the first R1 group is a 6-methoxy group and the second Ri group is located at the 7-position and is selected from methoxy, 3-morpholinopropoxy,

3- (1, 1-dioxotetrahydro-4H-1, 4-thiazin-4-yl) propoxy, 3- (1, 2,3, 6-tetrahydropyridin- 1-yl) propoxy, 4- (1, 2,3, 6-tetrahydropyridin-1-yl) butoxy, 3- (4-hydroxypiperidin-1-yl) propoxy, 3-piperazin-1-ylpropoxy, 3- (4-methylpiperazin-1-yl) propoxy, 4- (4-methylpiperazin-1-yl) butoxy, 3- (4-prop-2-ynylpiperazin-1-yl) propoxy, 3- (4-acetylpiperazin-1-yl) propoxy, 4- (4-acetylpiperazin-1-yl) butoxy, 3- [4- (2-fluoroethyl) piperazin-1-yl] propoxy, 3-chloropropoxy, 4-chlorobutoxy and 2- (2-methoxyethoxy) ethoxy; and n is 0 or n is 1 and the R3 group, if present, is located at the 3-, 4-, 5-or 6-position of the benzofuranyl group and is selected from fluoro, chloro, bromo, iodo and cyano; or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivative of the Formula I wherein : Z is NH ; m is 2 and the first Ri group is a 6-methoxy group and the second Rl group is located at the 7-position and is selected from 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2- (1, 1-dioxotetrahydro-4H-1, 4-thiazin- 4-yl) ethoxy, 3- (1, 1-dioxotetrahydro-4H-1, 4-thiazin-4-yl) propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 2- (N-methylpiperidin-3-yl) ethoxy, 3-piperidin-3-ylpropoxy, 3- (N-methylpiperidin- 3-yl) propoxy, 2-piperidin-4-ylethoxy, 2- (N-methylpiperidin-4-yl) ethoxy, 3-piperidin-4-ylpropoxy, 3- (N-metliylpiperidin-4-yl) propoxy, 2- (4-methylpiperazin-1-yl) ethoxy, 3- (4-methylpiperazin-1-yl) propoxy, 2- (4-cyanomethylpiperazin-1-yl) ethoxy, 3- (4-cyanomethylpiperazin-1-yl) propoxy, 2- [2- (4-methylpiperazin-1-yl) ethoxy] ethoxy, 3-chloropropoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2- (4-pyridyloxy) ethoxy, 3-pyridyhnethoxy and 2-cyanopyrid-4-ylmethoxy; and n is 0 or n is 1 and the R3 group, if present, is located at the 6-position of the benzofuran-7-yl group and is selected from chloro and bromo; or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivative of the Formula I wherein : ZisNH ;

m is 2 and the first Rl group is a 6-methoxy group and the second Rl group is located at the 7-position and is selected from 3- (4-methylpiperazin-1-yl) propoxy, n is 1 and the R3 group is a chloro or bromo group located at the 6-position of the benzofuran-7-yl group ; or a pharmaceutically-acceptable acid-addition salt thereof.

A particular compound of the invention is, for example, a quinoline derivative of the Formula I selected from:- 4- (6-chlorobenzofuran-7-ylamino)-3-cyano-6-methoxy-7- [3- (4-methylpiperazin- 1-yl) propoxy] quinoline and 4-benzofuran-7-ylamino-3-cyano-6-methoxy-7- [3- (4-methylpiperazin-1-yl) propoxy] quinoline, or a pharmaceutically-acceptable acid-addition salt thereof.

A particular compound of the invention is, for example, a quinoline derivative of the Formula I selected from:- 4- (6-chlorobenzofuran-7-ylamino)-3-cyano-6-methoxy-7- [3- (4-methylpiperazin- 1-yl) propoxy] quinoline and 4-benzofuran-7-ylamino-3-cyano-6-methoxy-7- [3- (4-methylpiperazin-1-yl) propoxy] quinoline, or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is, for example, the quinoline derivative of the Formula I being:- 4-benzofuran-7-ylamino-3-cyano-6-methoxy-7- [4- (4-methylpiperazin-1-yl) butoxy] quinoline, or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivative of the Formula I wherein: Z is O or NH ; m is 1 and the Ri group is located at the 5-position and is selected from tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrothien-3-yloxy, 1,1-dioxotetrahydrothien-3-yloxy, tetrahydrothiopyran-4-yloxy, 1,1-dioxotetrahydrothiopyran-4-yloxy, N-methylazetidin-3-yloxy, N-ethylazetidin-3-yloxy, N-isopropylazetidin-3-yloxy, pyrrolidin-3-yloxy, N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 3-piperidinyloxy, N-methylpiperidin-3-yloxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy, N-allylpiperidin-4-yloxy, N-prop-2-ynylpiperidin-4-yloxy, N-acetylpiperidin-4-yloxy, N-methylsulphonylpiperidin-4-yloxy, N- (2-methoxyethyl) piperidin-4-yloxy, piperidin-3-yhnethoxy,

N-methylpiperidin-3-yhnethoxy, piperidin-4-yhnethoxy, N-methylpiperidin-4-ylmethoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, or m is 2 and the first Ri group is located at the 5-position and is selected from the group of substituents listed immediately above and the second Rl group is located at the 7-position and is selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, 2-fluoroethoxy, 2,2, 2-trifluoroethoxy, benzyloxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2- (1, 1-dioxotetrahydro-4H-1, 4-thiazin-4-yl) ethoxy, 3- (1, 1-dioxotetrahydro-4H-1, 4-thiazin- 4-yl) propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-piperidin-4-ylethoxy, 2- (N-methylpiperidin-4-yl) ethoxy, 2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2- (4-methylpiperazin-1-yl) ethoxy, 3- (4-methylpiperazin-1-yl) propoxy, 3- (4-cyanomethylpiperazin-1-yl) propoxy, 2- [ (2S)-2-carbamoylpyrrolidin-1-yl] ethoxy, 2-[(2S)-2-(N-methylcarbamoyl) pyrrolidin-l-yl] ethoxy, 2- [ (2S)-2- (N, N-dimethylcarbamoyl) pyrrolidin-1-yl] ethoxy, 2-tetrahydropyran-4-ylethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 3-methoxypropoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2- (2-methoxyethoxy) ethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2- (4-pyridyloxy) ethoxy, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy and 3-cyanopyrid-4-ylmethoxy ; and wherein any CH2 group within a Ri substituent that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group, and wherein any heterocyclyl group within a Rl substituent optionally bears 1 or 2 oxo substituents, and wherein any CH2 group within a Rl substituent that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group; n is 0 or n is 1 and the R3 group, if present is located at the 3-, 4-, 5-or 6-position of the benzofuran-7-yl group and is selected from fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, ethynyl, methoxy and ethoxy; or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivative of the Formula I wherein: m is 2 and the first Rl group is located at the 5-position and is selected from tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrothien-3-yloxy, 1,1-dioxotetrahydrothien-3-yloxy, tetrahydrothiopyran-4-yloxy,

1, 1-dioxotetrahydrothiopyran-4-yloxy, N-methylazetidin-3-yloxy, N-ethylazetidin-3-yloxy, N-isopropylazetidin-3-yloxy, pyrrolidin-3-yloxy, N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 3-piperidinyloxy, N-methylpiperidin-3-yloxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy, N-allylpiperidin-4-yloxy, N-prop-2-ynylpiperidin-4-yloxy, N-acetylpiperidin-4-yloxy, N-methylsulphonylpiperidin-4-yloxy, N- (2-methoxyethyl) piperidin-4-yloxy, piperidin-3-yhnethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-yhnethoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, and the second Rl is located at the 7-position and is selected from hydroxy, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, 2-fluoroethoxy, 2,2, 2-trifluoroethoxy, benzyloxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2- (1, 1-dioxotetrahydro-4H-1, 4-thiazin-4-yl) ethoxy, 3- (1, 1-dioxotetrahydro-4H-1, 4-thiazin-4-yl) propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-piperidin-4-ylethoxy, 2- (N-methylpiperidin-4-yl) ethoxy, 2-homopiperidin-1-ylethoxy, 3-liomopiperidin-1-ylpropoxy, 2-piperazin-1-yletlioxy, 3-piperazin-1-ylpropoxy, 2- (4-methylpiperazin-1-yl) ethoxy, 3- (4-methylpiperazin-1-yl) propoxy, 3- (4-cyanomethylpiperazin-1-yl) propoxy, 2-[(2S)-2-carbamoylpyrrolidin-1-yl] ethoxy, 2- [ (2S)-2- (N-methylcarbamoyl) pyrrolidin-1- yl] ethoxy, 2-[(2S)-2-(, _-dimethylcarbamoyl) pyrrolidin-l-yl] ethoxy, 2-tetrahydropyran-4-ylethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 3-methoxypropoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2- (2-methoxyethoxy) ethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-yhnethoxy, 2- (4-pyridyloxy) ethoxy, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy and 3-cyanopyrid-4-ylmethoxy ; and wherein any CH2 group within a Rl substituent that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group, and wherein any heterocyclyl group within a Rl substituent optionally bears 1 or 2 oxo substituents, and wherein any CH2 group within a Rl substituent that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group; n is 0 or n is 1 and the R3 group, if present is located at the 3-, 5-or 6-position of the benzofuran-7-yl group and is selected from fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, ethynyl, methoxy and ethoxy; or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivative of the Formula I wherein: m is 2 and the first Rl group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, N-methylpyrrolidin-3-yloxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy, piperidin-4-ylmethoxy and N-methylpiperidin-4-ylmethoxy, and the second Rl is located at the 7-position and is selected from methoxy, benzyloxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2- (4-methylpiperazin- 1-yl) ethoxy, 3- (4-methylpiperazin-1-yl) propoxy and 3-methylsulphonylpropoxy; n is 0 or n is 1 and the R3 group, if present, is located at the 6-position of the benzofuran-7-yl group and is selected from chloro and bromo; or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivative of the Formula I wherein: m is 2 and the first Rl group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, 4-piperidinyloxy, N-methylpiperidin-4-yloxy, piperidin-4-ylmethoxy and N-methylpiperidin-4-ylmethoxy, and the second Ri is located at the 7-position and is selected from methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, 2-fluoroethoxy, 2,2, 2-trifluoroethoxy, benzyloxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 3- (4-hydroxypiperidin-1-yl) propoxy, 2-piperidin-4-ylethoxy, 2- (N-methylpiperidin-4-yl) ethoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2- (4-methylpiperazin-1-yl) ethoxy, 3- (4-methylpiperazin-1-yl) propoxy, 3- (4-cyanomethylpiperazin-1-yl) propoxy, 3-methylsulphonylpropoxy, piperidin-4-ylmethoxy and N-methylpiperidin-4-ylmethoxy; n is 0 or n is 1 and the R3 group, if present, is located at the 6-position of the benzofuran-7-yl group and is selected from chloro and bromo; or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivative of the Formula I wherein: Z is NH ; m is 1 and the Rl group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, 4-piperidinyloxy and N-methylpiperidin-4-yloxy,

or m is 2 and the first Rl group is located at the 5-position and is selected from tetrahydropyran-4-yloxy, 4-piperidinyloxy and N-methylpiperidin-4-yloxy, and the second Ri group is located at the 7-position and is selected from methoxy, ethoxy, propoxy, 3-pyrrolidin-1-ylpropoxy, 3-piperidinopropoxy, 3-morpholinopropoxy, 3-piperazin-1-ylpropoxy and 3- (4-methylpiperazin-1-yl) propoxy; n is 0 or n is 1 and the R3 group, if present, is a chloro group located at the 6-position of the benzofuran-7-yl group; or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is a quinoline derivative of the Formula I wherein: Z is NH ; m is 1 and the Rl group is located at the 5-position and is selected from tetrahydropyran-4-yloxy and N-methylpiperidin-4-yloxy, or m is 2 and the first Rl group is located at the 5-position and is selected from tetrahydropyran-4-yloxy and N-methylpiperidin-4-yloxy, and the second Ri group is located at the 7-position and is selected from methoxy and 3-morpholinopropoxy; and n is 0; or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is, for example, a quinoline derivative of the Formula I selected from:- 4- (6-chlorobenzofuran-7-ylamino)-3-cyano-7-methoxy-5- (N-methylpiperidin- 4-yloxy) quinoline, 4-(6-chlorobenzofuran-7-ylamino)-3-cyano-7-(2-pyrrolidin-1-y lethoxy)- 5-tetrahydropyran-4-yloxyquinoline, 4- (6-chlorobenzofuran-7-ylamino)-3-cyano-7- (3-pyrrolidin-1-ylpropoxy)- 5-tetrahydropyran-4-yloxyquinoline, 4- (6-chlorobenzofuran-7-ylamino)-3-cyano-7- [3- (4-methylpiperazin-1-yl) propoxy] - 5-tetrahydropyran-4-yloxyquinoline, 4- (6-chlorobenzofuran-7-ylamino)-3-cyano-7- [2- (4-methylpiperazin-1-yl) ethoxy] - <BR> <BR> <BR> <BR> <BR> 5-tetrahydropyran-4-yloxyquinoline,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 4- (6-chlorobenzofuran-7-ylamino)-3-cyano-7- (2-piperidinoethoxy)-5-tetrahydropyran- 4-yloxyquinoline and

4- (6-chlorobenzofuran-7-ylamino)-3-cyano-7- (-N-methylpiperidin-4-ylmethoxy)- 5-tetrahydropyran-4-yloxyquinoline; or a pharmaceutically-acceptable acid-addition salt thereof.

A further particular compound of the invention is, for example, a quinoline derivative of the Formula I selected from:- 4-benzofuran-7-ylamino-3-cyano-5- (N-methylpiperidin-4-yloxy) quinoline, <BR> <BR> <BR> 4-benzofuran-7-ylamino-3-cyano-7-methoxy-5-(N-methylpiperidi n-4-yloxy) quinoline and<BR> <BR> <BR> <BR> <BR> 4-benzofuran-7-ylamino-3-cyano-7- (3-morpholinopropoxy)-5-tetrahydropyran- 4-yloxyquinoline; or a pharmaceutically-acceptable acid-addition salt thereof.

A quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of chemically- related compounds. Such processes, when used to prepare a quinoline derivative of the Formula I are provided as a further feature of the invention and are illustrated by the following representative process variants in which, unless otherwise stated, m, Rl, Z, n and R3 have any of the meanings defined hereinbefore. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.

(a) For the production of those compounds of the Formula I wherein Z is an O, S or N (R2) group, the reaction of a quinoline of the Formula II wherein L is a displaceable group and m and Rl have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a compound of the Formula III

wherein Z is O, S, or N (R2) and n, R3 and W have any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means.

The reaction may conveniently be carried out in the presence of a suitable acid or in the presence of a suitable base. A suitable acid is, for example, an inorganic acid such as, for example, hydrogen chloride or hydrogen bromide. A suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo [5.4. 0] undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal amide, for example sodium hexamethyldisilazane, or, for example, an alkali metal hydride, for example sodium hydride.

A suitable displaceable group L is, for example, a halogeno, alkoxy, aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, pentafluorophenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group. The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide. The reaction is conveniently carried out at a temperature in the range, for example, 0 to 250°C, preferably in the range 0 to 120°C.

Typically, the quinoline of the Formula II may be reacted with a compound of the Formula III in the presence of an aprotic solvent such as N, N-dimethylformamide, conveniently in the presence of a base, for example potassium carbonate or sodium hexamethyldisilazane, and at a temperature in the range, for example, 0 to 150°C, preferably in the range, for example, 0 to 70°C.

The quinoline derivative of the Formula I may be obtained from this process in the form of the free base or alternatively it may be obtained in the form of a salt with the acid of

the formula H-L wherein L has the meaning defined hereinbefore. When it is desired to obtain the free base from the salt, the salt may be treated with a suitable base, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo [5.4. 0] undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.

Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question and may be introduced by conventional methods. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.

Specific examples of protecting groups are given below for the sake of convenience, in which"lower", as in, for example, lower alkyl, signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive.

Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned are, of course, within the scope of the invention.

A carboxy protecting group may be the residue of an ester-forming aliphatic or arylaliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms). Examples of carboxy protecting groups include straight or branched chain (1-12C) alkyl groups (for example isopropyl, and tert-butyl); lower alkoxy-lower alkyl groups (for example methoxymethyl, ethoxymethyl and isobutoxymethyl); lower acyloxy-lower alkyl groups, (for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl and pivaloyloxymethyl); lower alkoxycarbonyloxy-lower alkyl groups (for example 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl) ; aryl-lower alkyl groups (for example benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, benzhydryl and phthalidyl); tri (lower alkyl) silyl groups (for example trimethylsilyl and tert-butyldimethylsilyl) ; tri (lower alkyl) silyl-lower alkyl groups (for example trimethylsilylethyl); and (2-6C) alkenyl groups (for example allyl). Methods

particularly appropriate for the removal of carboxyl protecting groups include for example acid-, base-, metal-or enzymically-catalysed cleavage.

Examples of hydroxy protecting groups include lower alkyl groups (for example tert-butyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (for example allyloxycarbonyl) ; aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl) ; tri (lower alkyl) silyl (for example trimethylsilyl and tert-butyldimethylsilyl) and aryl-lower alkyl (for example benzyl) groups.

Examples of amino protecting groups include formyl, aryl-lower alkyl groups (for example benzyl and substituted benzyl, 4-methoxybenzyl, 2-nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-4-anisylmethyl and furylmethyl groups ; lower alkoxycarbonyl (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl) ; aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl) ; trialkylsilyl (for example trimethylsilyl and tert-butyldimethylsilyl); alkylidene (for example methylidene) and benzylidene and substituted benzylidene groups.

Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal-or enzymically-catalysed hydrolysis for groups such as 2-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl and photolytically for groups such as 2-nitrobenzyloxycarbonyl.

The reader is referred to Advanced Organic Chemistry, 4th Edition, by J. March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents and to Protective Groups in Organic Synthesis, 2nd Edition, by T. Green et al., also published by John Wiley & Son, for general guidance on protecting groups.

Quinoline starting materials of the Formula II may be obtained by conventional procedures such as those disclosed in International Patent Applications WO 98/43960 and WO 00/68201. For example, a 1, 4-dihydroquinolin-4-one of Formula IV

wherein m and Rl have any of the meanings defined hereinbefore except that any functional group is protected if necessary, may be reacted with a halogenating agent such as thionyl chloride, phosphoryl chloride or a mixture of carbon tetrachloride and triphenylphosphine whereafter any protecting group that is present is removed by conventional means.

The 4-chloroquinoline so obtained may be converted, if required, into a 4-pentafluorophenoxyquinoline by reaction with pentafluorophenol in the presence of a suitable base such as potassium carbonate and in the presence of a suitable solvent such as N, N-dimethylformamide.

7-Aminobenzofuran starting materials (Formula m, for example when Z is NH) may be obtained by conventional procedures as illustrated in the Examples. Corresponding 7-hydroxybenzofuran and 7-mercaptobenzofuran starting materials (Formula m, when Z is O or S respectively) may be obtained by conventional procedures.

(b) For the production of those compounds of the Formula I wherein at least one Rl group is a group of the formula Q'-XL wherein Ql is an aryl- (1-6C) alkyl, (3-7C) cycloalkyl- (1-6C) alkyl, (3-7C) cycloalkenyl- (1-6C) alkyl, heteroaryl- (1-6C) alkyl or heterocyclyl- (1-6C) alkyl group or an optionally substituted alkyl group and Xl is an oxygen atom, the coupling, conveniently in the presence of a suitable dehydrating agent, of a quinoline of the Formula V wherein m, Rl, Z, n and R3 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an appropriate alcohol wherein any functional group is protected if necessary whereafter any protecting group that is present is removed by conventional means.

A suitable dehydrating agent is, for example, a carbodiimide reagent such as dicyclohexylcarbodiimide or 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide or a mixture of

an azo compound such as diethyl or di-tert-butyl azodicarboxylate and a phosphine such as triphenylphosphine. The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride and at a temperature in the range, for example, 10 to 150°C, preferably at or near ambient temperature.

The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride and at a temperature in the range, for example, 10 to 150°C, preferably at or near ambient temperature.

(c) For the production of those compounds of the Formula I wherein an Rl group contains a (1-6C) alkoxy or substituted (1-6C) alkoxy group or a (1-6C) alkylamino or substituted (1-6C) alkylamino group, the reaction, conveniently in the presence of a suitable base as defined hereinbefore, of a quinoline derivative of the Formula VI wherein L is a displaceable group as defined hereinbefore and Z, n and R3 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an alcohol or amine as appropriate whereafter any protecting group that is present is removed by conventional means.

The reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near 50°C.

(d) For the production of those compounds of the Formula I wherein Rl is an amino-substituted (1-6C) alkoxy group (such as 2-homopiperidin-1-ylethoxy or 3-dimethylaminopropoxy), the reaction of a compound of the Formula I wherein Rl is a halogeno-substituted (1-6C) alkoxy group with a heterocyclyl compound or an appropriate amine.

The reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near ambient temperature.

(e) For the production of those compounds of the Formula I wherein Rl is a hydroxy group, the cleavage of a quinoline derivative of the Formula I wherein Rl is a (1-6C) alkoxy or arylmethoxy group.

The cleavage reaction may conveniently be carried out by any of the many procedures known for such a transformation. The cleavage reaction of a compound of the Formula I wherein Rl is a (1-6C) alkoxy group may be carried out, for example, by treatment of the quinoline derivative with an alkali metal (1-6C) alkylsulphide such as sodium ethanethiolate or, for example, by treatment with an alkali metal diarylphosphide such as lithium diphenylphosphide. Alternatively the cleavage reaction may conveniently be carried out, for example, by treatment of the quinoline derivative with a boron or aluminium trihalide such as boron tribromide. The cleavage reaction of a compound of the Formula I wherein Rl is a arylmethoxy group may be carried out, for example, by hydrogenation of the quinoline derivative in the presence of a suitable metallic catalyst such as palladium or by reaction with an organic or inorganic acid, for example trifluoroacetic acid. Such reactions are preferably carried out in the presence of a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 150°C, preferably at or near ambient temperature.

(f) For the production of those compounds of the Formula I wherein an Ri group contains a primary or secondary amino group, the cleavage of the corresponding compound of the Formula I wherein the Rl group contains a protected primary or secondary amino group.

Suitable protecting groups for an amino group are, for example, any of the protecting groups disclosed hereinbefore for an amino group. Suitable methods for the cleavage of such amino protecting groups are also disclosed hereinbefore. In particular, a suitable protecting group is a lower alkoxycarbonyl group such as a tert-butoxycarbonyl group which may be cleaved under conventional reaction conditions such as under acid-catalysed hydrolysis, for example in the presence of trifluoroacetic acid.

(g) For the production of those compounds of the Formula I wherein an Rl group contains a (1-6C) alkoxy or substituted (1-6C) alkoxy group or a (1-6C) alkylamino or substituted (1-6C) alkylamino group, the alkylation, conveniently in the presence of a suitable base as defined hereinbefore, of a quinoline derivative of the formula I wherein the Rl group contains

a hydroxy group or a primary or secondary amino group as appropriate.

A suitable alkylating agent is, for example, any agent known in the art for the alkylation of hydroxy to alkoxy or substituted alkoxy, or for the alkylation of amino to alkylamino or substituted alkylamino, for example an alkyl or substituted alkyl halide, for example a (1-6C) alkyl chloride, bromide or iodide or a substituted (1-6C) alkyl chloride, bromide or iodide, conveniently in the presence of a suitable base as defined hereinbefore, in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 140°C, conveniently at or near ambient temperature.

Conveniently for the production of those compounds of the Formula I wherein Ri contains a (1-6C) alkylamino or substituted (1-6C) alkylamino group, a reductive amination reaction may be employed. For example, for the production of those compounds of the Formula I wherein Rl contains a N-methyl group, the corresponding compound containing a N-H group may be reacted with formaldehyde in the presence of a suitable reducing agent. A suitable reducing agent is, for example, a hydride reducing agent, for example an alkali metal aluminium hydride such as lithium aluminium hydride or, preferably, an alkali metal borohydride such as sodium borohydride, sodium cyanoborohydride, sodium triethylborohydride, sodium trimethoxyborohydride and sodium triacetoxyborohydride. The reaction is conveniently performed in a suitable inert solvent or diluent, for example tetrahydrofuran and diethyl ether for the more powerful reducing agents such as lithium aluminium hydride, and, for example, methylene chloride or a protic solvent such as methanol and ethanol for the less powerful reducing agents such as sodium triacetoxyborohydride and sodium cyanoborohydride. The reaction is performed at a temperature in the range, for example, 10 to 80°C, conveniently at or near ambient temperature.

(h) For the production of those compounds of the Formula I wherein Rl is an amino-hydroxy-disubstituted (1-6C) alkoxy group (such as 2-hydroxy-3-pyrrolidin- 1-ylpropoxy or 3- [N-allyl-N-methylamino]-2-hydroxypropoxy), the reaction of a compound of the Formula I wherein the Ri group contains an epoxy-substituted (1-6C) alkoxy group with a heterocyclyl compound or an appropriate amine.

The reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near ambient temperature.

(i) For the production of those compounds of the Formula I wherein an Rl group contains a hydroxy group, the cleavage of the corresponding compound of the Formula I wherein the Ri group contains a protected hydroxy group.

Suitable protecting groups for a hydroxy group are, for example, any of the protecting groups disclosed hereinbefore. Suitable methods for the cleavage of such hydroxy protecting groups are also disclosed hereinbefore. In particular, a suitable protecting group is a lower alkanoyl group such as an acetyl group which may be cleaved under conventional reaction conditions such as under base-catalysed conditions, for example in the presence of ammonia.

(j) For the production of those compounds of the Formula I wherein Z is a SO or S02 group, the oxidation of a compound of Formula I wherein Z is a S group.

Conventional oxidation reagents and reaction conditions for such partial or complete oxidation of a sulphur atom are well known to the organic chemist.

(k) The conversion of a compound of the Formula I wherein an Rl or R3 substituent is a halogeno group into a further compound of the Formula I wherein the Rl or R3 substituent is, for example, a cyano, ethynyl or phenyl group.

For example, a compound of the Formula I wherein an Rl or R3 substituent is a halogeno group may be reacted with a metal cyanide to form a compound of the Formula I wherein an Ri or R3 substituent is a cyano group. Conveniently, the reaction may be carried out in the presence of a suitable catalyst. A suitable metal cyanide is, for example, a heavy metal cyanide such as zinc cyanide. A suitable catalyst is, for example, an organometallic reagent, for example an organoiron compound such as diphenylphosphinoferrocene. The conversion reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near 100°C.

For example, a compound of the Formula I wherein an Rl or R3 substituent is a halogeno group may be reacted with a (2-6C) alkyne to form a compound of the Formula I wherein an Ri or R3 substituent is a (2-6C) alkynyl group such as an ethynyl group. The reaction may conveniently be carried out in the presence of a suitable base as defined hereinbefore and in the presence of a suitable catalyst. For this conversion, a suitable catalyst is, for example, an organometallic reagent, for example an organopalladium compound such as tetrakis (triphenylphosphine) palladium (0). The conversion reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near 60°C.

For example, a compound of the Formula I wherein an Rl or R3 substituent is a halogeno group may be reacted with an arylboron reagent to form a compound of the Formula I wherein an Ri or R3 substituent is an aryl group such as a phenyl group. A suitable arylboron reagent is, for example, an arylboronic acid. The reaction may conveniently be carried out in the presence of a suitable catalyst, for example, an organopalladium compound such as tetrakis (triphenylphosphine) palladium (0). The conversion reaction is conveniently carried out in the presence of a suitable inert diluent or carrier as defined hereinbefore and at a temperature in the range 10 to 150°C, preferably at or near 80°C.

When a pharmaceutically-acceptable salt of a quinoline derivative of the Formula I is required, for example an acid-addition salt, it may be obtained by, for example, reaction of said quinoline derivative with a suitable acid using a conventional procedure.

Biological Assays The following assays can be used to measure the effects of the compounds of the present invention as c-Src tyrosine kinase inhibitors, as inhibitors in vitro of the proliferation of c-Src transfected fibroblast cells, as inhibitors in vitro of the migration of A549 human lung tumour cells and as inhibitors in vivo of the growth in nude mice of xenografts of A549 tissue.

(a) In Vitro Enzyme Assay The ability of test compounds to inhibit the phosphorylation of a tyrosine containing polypeptide substrate by the enzyme c-Src kinase was assessed using a conventional Elisa assay.

A substrate solution [lOOjJ. ofa20u, g/ml solution of the polyamino acid Poly (Glu, Tyr) 4: 1 (Sigma Catalogue No. P0275) in phosphate buffered saline (PBS) containing 0.2mg/ml of sodium azide] was added to each well of a number of Nunc 96-well immunoplates (Catalogue No. 439454) and the plates were sealed and stored at 4°C for 16 hours. The excess of substrate solution was discarded, and aliquots of Bovine Serum Albumin (BSA; 150p1 of a 5% solution in PBS) were transferred into each substrate-coated assay well and incubated for 1 hour at ambient temperature to block non specific binding. The assay plate wells were washed in turn with PBS containing 0.05% v/v Tween 20 (PBST) and with Hepes pH7.4 buffer (50mM, 3001/well) before being blotted dry.

Each test compound was dissolved in dimethyl sulphoxide and diluted with distilled water to give a series of dilutions (from 100pM to 0. OOljjM). Portions (25p1) of each dilution of test compound were transferred to wells in the washed assay plates. "Total"control wells

contained diluted DMSO instead of compound. Aliquots (25u. l) of an aqueous magnesium chloride solution (80mM) containing adenosine-5'-triphosphate (ATP; 40uM) was added to all test wells except the"blank"control wells which contained magnesium chloride without ATP.

Active human c-Src kinase (recombinant enzyme expressed in Sf9 insect cells; obtained from Upstate Biotechnology Inc. product 14-117) was diluted immediately prior to use by a factor of 1: 10,000 with an enzyme diluent which comprised 100mM Hepes pH7.4 buffer, 0.2mM sodium orthovanadate, 2mM dithiothreitol and 0.02% BSA. To start the reactions, aliquots (501l1) of freshly diluted enzyme were added to each well and the plates were incubated at ambient temperature for 20 minutes. The supernatant liquid in each well was discarded and the wells were washed twice with PBST. Mouse IgG anti-phosphotyrosine antibody (Upstate Biotechnology Inc. product 05-321 ; 100p1) was diluted by a factor of 1: 6000 with PBST containing 0.5% w/v BSA and added to each well. The plates were incubated for 1 hour at ambient temperature. The supernatant liquid was discarded and each well was washed with PBST (x4). Horse radish peroxidase (HRP)-linked sheep anti-mouse Ig antibody (Amersham Catalogue No. NXA 931 ; 1001) was diluted by a factor of 1: 500 with PBST containing 0.5% w/v BSA and added to each well. The plates were incubated for 1 hour at ambient temperature. The supernatant liquid was discarded and the wells were washed with PBST (x4).

A PCSB capsule (Sigma Catalogue No. P4922) was dissolved in distilled water (100ml) to provide phosphate-citrate pH5 buffer (50mM) containing 0.03% sodium perborate.

An aliquot (50ml) of this buffer was mixed with a 50mg tablet of 2,2'-azinobis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS; Boehringer Catalogue No. 1204 521). Aliquots (1001l1) of the resultant solution were added to each well. The plates were incubated for 20 to 60 minutes at ambient temperature until the optical density value of the"total"control wells, measured at 405nm using a plate reading spectrophotometer, was approximately 1. 0."Blank" (no ATP) and"total" (no compound) control values were used to determine the dilution range of test compound which gave 50% inhibition of enzyme activity.

(b) In Vitro c-Src transfected NIH 3T3 (c-src 3T3) Fibroblast Proliferation Assay This assay determined the ability of a test compound to inhibit the proliferation of National Institute of Health (NAH) mouse 3T3 fibroblast cells that had been stably-transfected with an activating mutant (Y530F) of human c-Src.

Using a similar procedure to that described by Shalloway et al., Cell, 1987,49, 65-73, NIH 3T3 cells were transfected with an activating mutant (Y530F) of human c-Src. The resultant c-Src 3T3 cells were typically seeded at 1.5 x 104 cells per well into 96-well tissue- culture-treated clear assay plates (Costar) each containing an assay medium comprising Dulbecco's modified Eagle's medium (DMEM; Sigma) plus 0.5% foetal calf serum (FCS), 2mM glutamin, 100 units/ml penicillin and 0. lmg/ml streptomycin in 0.9% aqueous sodium chloride solution. The plates were incubated overnight at 37°C in a humidified (7.5% C02 : 95% air) incubator.

Test compounds were solubilised in DMSO to form a lOmM stock solution. Aliquots of the stock solution were diluted with the DMEM medium described above and added to appropriate wells. Serial dilutions were made to give a range of test concentrations. Control wells to which test compound was not added were included on each plate. The plates were incubated overnight at 37°C in a humidified (7.5% C02 : 95% air) incubator.

BrdU labelling reagent (Boehringer Mannheim Catalogue No. 647 229) was diluted by a factor of 1 : 100 in DMEM medium containing 0.5% FCS and aliquots (20111) were added to each well to give a final concentration of 101lu). The plates were incubated at 37°C for 2 hours. The medium was decanted. A denaturating solution (FixDenat solution, Boehringer Mannheim Catalogue No. 647 229; 50A1) was added to each well and the plates were placed on a plate shaker at ambient temperature for 45 minutes. The supernatant was decanted and the wells were washed with PBS (200u. l per well). Anti-BrdU-Peroxidase solution (Boehringer Mannheim Catalogue No. 647 229) was diluted by a factor of 1: 100 in PBS containing 1% BSA and 0.025% dried skimmed milk (Marvel (registered trade mark), Premier Beverages, Stafford, GB) and an aliquot (100111) of the resultant solution was added to each well. The plates were placed on a plate shaker at ambient temperature for 90 minutes. The wells were washed with PBS (x5) to ensure removal of non-bound antibody conjugate. The plates were blotted dry and tetramethylbenzidine substrate solution (Boehringer Mannheim Catalogue No. 647 229; 100u. l) was added to each well. The plates were gently agitated on a plate shaker while the colour developed during a 10 to 20 minute period. The absorbance of the wells was measured at 690nm. The extent of inhibition of cellular proliferation at a range of concentrations of each test compound was determined and an anti-proliferative ICso value was derived.

(c) In Vitro Microdroplet Migration Assay This assay determines the ability of a test compound to inhibit the migration of adherent mammalian cell lines, for example the human tumour cell line A549.

RPMI medium (Sigma) containing 10% FCS, 1% L-glutamine and 0.3% agarose (Difco Catalogue No. 0142-01) was warmed to 37°C in a water bath. A stock 2% aqueous agar solution was autoclaved and stored at 42°C. An aliquot (1.5 ml) of the agar solution was added to RPMI medium (10 ml) immediately prior to its use. A549 cells (Accession No.

ATCC CCL185) were suspended at a concentration of 2 x 107 cells/ml in the medium and maintained at a temperature of 37°C.

A droplet (2p1) of the cell/agarose mixture was transferred by pipette into the centre of each well of a number of 96-well, flat bottomed non-tissue-culture-treated microtitre plate (Bibby Sterilin Catalogue No. 642000). The plates were placed briefly on ice to speed the gelling of the agarose-containing droplets. Aliquots (90111) of medium which had been cooled to 4°C were transferred into each well, taking care not to disturb the microdroplets. Test compounds were diluted from a lOmM stock solution in DMSO using RPMI medium as described above. Aliquots (10111) of the diluted test compounds were transferred to the wells, again taking care not to disturb the microdroplets. The plates were incubated at 37°C in a humidified (7.5% C°2 : 95% air) incubator for about 48 hours.

Migration was assessed visually and the distance of migration was measured back to the edge of the agar droplet. A migratory inhibitory ICso was derived by plotting the mean migration measurement against test compound concentration.

(d) In Vivo A549 Xenograft Growth Ass This test measures the ability of compounds to inhibit the growth of the A549 human carcinoma grown as a tumour in athymic nude mice (Alderley Park nu/nu strain). A total of about 5 x 106 A549 cells in matrigel (Beckton Dickinson Catalogue No. 40234) were injected subcutaneously into the left flank of each test mouse and the resultant tumours were allowed to grow for about 14 days. Tumour size was measured twice weekly using callipers and a theoretical volume was calculated. Animals were selected to provide control and treatment groups of approximately equal average tumour volume. Test compounds were prepared as a ball-milled suspension in 1% polysorbate vehicle and dosed orally once daily for a period of about 28 days. The effect on tumour growth was assessed.

Although the pharmacological properties of the compounds of the Formula I vary with structural change as expected, in general activity possessed by compounds of the Formula I, may be demonstrated at the following concentrations or doses in one or more of the above tests (a), (b), (c) and (d):- Test (a) :-IC50 in the range, for example, 0.001-10 (iM ; Test (b) :- ICso in the range, for example, 0.01-20 RM ; Test (c) :- activity in the range, for example, 0.1-25 aM ; Test (d) :- activity in the range, for example, 1-200 mg/kg/day;.

No physiologically-unacceptable toxicity was observed in Test (d) at the effective dose for compounds tested of the present invention. Accordingly no untoward toxicological effects are expected when a compound of Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore is administered at the dosage ranges defined hereinafter.

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a quinoline derivative of the Formula I, or a pharmaceutically- acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically- acceptable diluent or carrier.

The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.

The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an

appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.

The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.

In using a compound of the Formula I for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg/kg to 25 mg/kg body weight will be used. Oral administration is however preferred, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.

According to a further aspect of the invention there is provided a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in a method of treatment of the human or animal body by therapy.

As stated above, it is known that the predominant role of c-Src non-receptor tyrosine kinase is to regulate cell motility which is necessarily required for a localised tumour to progress through the stages of dissemination into the blood stream, invasion of other tissues and initiation of metastatic tumour growth. We have found that the quinoline derivatives of the present invention possess potent anti-tumour activity which it is believed is obtained by way of inhibition of one or more of the non-receptor tyrosine-specific protein kinases such as c-Src kinase that are involved in the signal transduction steps which lead to the invasiveness and migratory ability of metastasising tumour cells.

Accordingly the quinoline derivatives of the present invention are of value as anti- tumour agents, in particular as selective inhibitors of the motility, dissemination and invasiveness of mammalian cancer cells leading to inhibition of metastatic tumour growth.

Particularly, the quinoline derivatives of the present invention are of value as anti-invasive agents in the containment and/or treatment of solid tumour disease. Particularly, the compounds of the present invention are expected to be useful in the prevention or treatment of those tumours which are sensitive to inhibition of one or more of the multiple non-receptor

tyrosine kinases such as c-Src kinase that are involved in the signal transduction steps which lead to the invasiveness and migratory ability of metastasising tumour cells. Further, the compounds of the present invention are expected to be useful in the prevention or treatment of those tumours which are mediated alone or in part by inhibition of the enzyme c-Src, i. e. the compounds may be used to produce a c-Src enzyme inhibitory effect in a warm-blooded animal in need of such treatment. Specifically, the compounds of the present invention are expected to be useful in the prevention or treatment of solid tumour disease.

Thus according to this aspect of the invention there is provided a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease.

According to a further feature of this aspect of the invention there is provided the use of a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease.

According to a further feature of this aspect of the invention there is provided a method for producing an anti-invasive effect by the containment and/or treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.

According to a further aspect of the invention there is provided the use of a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the prevention or treatment of solid tumour disease in a warm-blooded animal such as man.

According to a further feature of this aspect of the invention there is provided a method for the prevention or treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.

According to a further aspect of the invention there is provided the use of a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the prevention or treatment of those tumours which are sensitive to inhibition of non-receptor tyrosine kinases such as c-Src

kinase that are involved in the signal transduction steps which lead to the invasiveness and migratory ability of metastasising tumour cells.

According to a further feature of this aspect of the invention there is provided a method for the prevention or treatment of those tumours which are sensitive to inhibition of non-receptor tyrosine kinases such as c-Src kinase that are involved in the signal transduction steps which lead to the invasiveness and migratory ability of metastasising tumour cells which comprises administering to said animal an effective amount of a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.

According to a further aspect of the invention there is provided the use of a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in providing a c-Src kinase inhibitory effect.

According to a further feature of this aspect of the invention there is provided a method for providing a c-Src kinase inhibitory effect which comprises administering to said animal an effective amount of a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.

The anti-invasive treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the quinoline derivative of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents:- (i) other anti-invasion agents (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function) ; (ii) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas) ; antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred antimetabolites disclosed in European Patent Application No. 562734 such as (2S)-2- {o-fluoro-p- [N- {2, 7-dimethyl-4-oxo-3, 4-dihydroquinazolin-6-yhnethyl)- N- (prop-2-ynyl) amino] benzamido}-4- (tetrazol-5-yl) butyric acid) ; antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol

and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin); (iii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrazole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride; (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example the EGFR tyrosine kinase inhibitors N- (3-chloro-4-fluorophenyl)-7-methoxy- 6- (3-morpholinopropoxy) quinazolin-4-amine (ZD1839), N- (3-ethynylphenyl)- 6,7-bis (2-methoxyethoxy) quinazolin-4-amine (CP 358774) and 6-acrylamido-N- (3-chloro- 4-fluorophenyl)-7- (3-morpholinopropoxy) quinazolin-4-amine (CI 1033) ), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family; and (v) antiangiogenic agents such as those which inhibit vascular endothelial growth factor such as the compounds disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and those that work by other mechanisms (for example linomide, inhibitors of integrin ocvß3 function and angiostatin).

Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.

According to this aspect of the invention there is provided a pharmaceutical product comprising a quinoline derivative of the formula I as defined hereinbefore and an additional anti-tumour agent as defined hereinbefore for the conjoint treatment of cancer.

Although the compounds of the Formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the effects of c-Src. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.

The invention will now be illustrated in the following Examples in which, generally: (i) operations were carried out at ambient temperature, i. e. in the range 17 to 25°C and under an atmosphere of an inert gas such as argon unless otherwise stated; (ii) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids by filtration ; (iii) column chromatography (by the flash procedure) and medium pressure liquid chromatography (MPLC) were performed on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck, Darmstadt, Germany or high pressure liquid chromatography (HPLC) was performed on CIS reverse phase silica, for example on a Dynamax C-18 60A preparative reversed-phase column; (iv) yields, where present, are not necessarily the maximum attainable; (v) in general, the end-products of the Formula I have satisfactory microanalyses and their structures were confirmed by nuclear magnetic resonance (NMR) and/or mass spectral techniques; fast-atom bombardment (FAB) mass spectral data were obtained using a Platform spectrometer and, where appropriate, either positive ion data or negative ion data were collected; NMR chemical shift values were measured on the delta scale [proton magnetic resonance spectra were determined using a Jeol JNM EX 400 spectrometer operating at a field strength of 400MHz, Varian Gemini 2000 spectrometer operating at a field strength of 300MHz or a Bruker AM300 spectrometer operating at a field strength of 300MHz] ; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; (vi) intermediates were not generally fully characterised and purity was assessed by thin layer chromatographic, HPLC, infra-red (IR) and/or NMR analysis; (vii) melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products of the Formula I were determined after crystallisation from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in admixture; (viii) where certain compounds were obtained as an acid-addition salt, for example a mono hydrochloride salt or a dihydrochloride salt, the stoichiometry of the salt was based on the number and nature of the basic groups in the compound, the exact stoichiometry of the salt was generally not determined, for example by means of elemental analysis data; (ix) the following abbreviations have been used:-

DMF N, N-dimethylformamide DMSO dimethylsulphoxide THF tetrahydrofuran DMA N, N-dimethylacetamide

Example 1 4-benzofuran-7-ylamino-3-eyano-6-methoxy-7- [3- (4-methylpiperazin- 1-yl) propoxy] quinoline dihydrochloride salt Sodium hexamethyldisilazane (1M solution in THF; 1.2 ml) was added to a solution of 7-aminobenzofuran (0.16 g) in DMF (10 ml) that had been cooled to 0°C and the mixture was stirred for 5 minutes. A solution of 4-chloro-3-cyano-6-methoxy-7- [3- (4-methylpiperazin- 1-yl) propoxy] quinoline (0.225 g) in DMF (2 ml) was added and the resultant mixture was stirred at ambient temperature for 24 hours. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution as eluent. The material so obtained was dissolved in diethyl ether and a solution of hydrogen chloride in diethyl ether (1M, 2 ml) was added. The resultant solid was washed with diethyl ether and dried. There was thus obtained the title compound (0.27 g); NMR Spectrum : (DMSOd6 and CD3CO2D) 2.33 (m, 2H), 2.85 (s, 3H), 3.24-3. 89 (m, 10H), 4.0 (s, 3H), 4.33 (m, 2H), 6.84 (s, 1H), 7.34 (d, 1H), 7.42 (t, 1H), 7.51 (s, 1H), 7.69 (d, 1H), 8.01 (s, 1H), 8. 24 (s, 1H), 8.91 (s, 1H); Mass Spectrum: M+H+ 472.

The 7-aminobenzofuran used as a starting material was prepared as follows :- Hydrazine hydrate (0.45 ml) was added dropwise to a stirred mixture of 7-nitrobenzofuran (J. Med. Chem., 1988, 31,1934 ; 0.5 g), Raney nickel (0.02 g) and methanol (9 ml) that had been warmed to 55°C. The resultant mixture was heated to reflux for 30 minutes. The catalyst was removed by filtration and the filtrate was evaporated. The residue was partitioned between methylene chloride and water. The organic phase was dried over magnesium sulphate and evaporated to give 7-aminobenzofuran (0.4 g) as an oil; NMR Spectrum : (DMSOd6) 5.25 (br s, 2H), 6.55 (d, 1H), 6.8 (m, 2H), 6.9 (t, 1H), 7.85 (d, 1H).

The4-chloro-3-cyano-6-methoxy-7- [3- (4-methylpiperazin-l-yl) propoxy] quinoline used as a starting material was prepared as follows:- A mixture of 3-bromopropanol (20 ml), N-methylpiperazine (29 ml), potassium carbonate (83 g) and ethanol (200 ml) was stirred and heated to reflux for 20 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated and the residue was triturated under diethyl ether. The resultant mixture was filtered and the filtrate was evaporated. The residue was purified by distillation at about 60-70°C under about

0.2 mm Hg to give 1- (3-hydroxypropyl)-4-methylpiperazine (17 g); NMR Spectrum : (CDC13) 1.72 (m, 2H), 2.3 (s, 3H), 2.2-2. 8 (m, 8H), 2.6 (t, 2H), 3.8 (t, 2H), 5.3 (br s, 1H).

Diethyl azodicarboxylate (0.25 g) was added dropwise to a suspension of 4-chloro- 3-cyano-7-hydroxy-6-methoxyquinoline (0.2 g; prepared as described in International Patent Application WO 00/68201, disclosed as compound (7) within Preparation 1 therein), 1- (3-hydroxypropyl)-4-methylpiperazine (0.202 g), triphenylphosphine (0.447 g) and methylene chloride (5 ml) and the mixture was stirred at ambient temperature for 2 hours.

The resultant mixture was evaporated and the residue was purified by column chromatography on silica using initially increasingly polar mixtures of methylene chloride and ethyl acetate followed by increasingly polar mixtures of methylene chloride, ethyl acetate and a saturated methanolic ammonia solution as eluent. The material so obtained was triturated under diethyl ether. The resultant solid was isolated and dried under vacuum to give the required starting material (0.15 g); NMR Spectrum : (DMSOd6 and CF3CO2D) 1.95-2. 05 (m, 2H), 2.2 (s, 3H), 2.25-2. 5 (m, 10H), 4.05 (s, 3H), 4.3 (m, 2H), 7.45 (s, 1H), 7. 58 (s, 1H), 9.0 (s, 1H); Mass Spectrum : M+H+ 375 and 377.

Example 2 Using an analogous procedure to that described in Example 1, the appropriate 4-chloro-3-cyanoquinoline was reacted with the appropriate 7-aminobenzofuran to give the compounds described in Table I. Unless otherwise stated, each product was obtained as a dihydrochloride salt.

Table I Compound RU RUZ No. & Note [1] 3- (4-methylpiperazin-1-yl) propoxy 6-chloro [2] 3- (4-methylpiperazin-1-yl) propoxy 3-chloro [3] 3-morpholinopropoxy hydrogen [4] methoxy 5-fluoro [5] 3-chloropropoxy 4-methoxy [6] methoxy 4-methoxy [7] 3-morpholinopropoxy 4-methoxy [8] 3- (4-methylpiperazin-1-yl) propoxy 4-methoxy [9] methoxy 4-iodo

Notes [1] The product gave the following characterising data; NMR Spectrum : (DMSOd6 and CF3CO2D) 2.35 (m, 2H), 2. 86 (s, 3H), 3.31-3. 9 (m, 10H), 4.01 (s, 3H), 4.36 (m, 2H), 7.10 (d, 1H), 7.51 (d, 1H), 7.53 (s, 1H), 7.79 (d, 1H), 8.03 (d, 1H), 8.27 (s, 1H), 8.95 (s, 1H); Mass Spectrum : M+H+ 506 and 508.

The 7-amino-6-chlorobenzofuran used as a starting material was prepared as follows :- Sodium hydride (60% dispersion in mineral oil; 4.6 g) was added to a stirred solution of 6-chloroanthranilic acid (18 g) in DMF (100 ml) and the mixture was stirred at ambient temperature for 30 minutes. Ethyl iodide (10 ml) was added and the reaction mixture was stirred at ambient temperature for 2 days. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed in turn with water and brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 4: 1 mixture of petroleum ether (b. p. 60-80°C) and ethyl acetate as eluent. There was thus obtained ethyl 6-chloroanthranilate (15. 8 g) as an oil; NMR Spectrum : (DMSOd6) 1.3 (t, 3H), 4.3 (q, 2H), 5.7 (br s, 2H), 6.6 (d, 1H), 6.7 (d, 1H), 7.1 (t, 1H).

A solution of sodium nitrite (4.5 g) in water (100 ml) was added dropwise during 5 minutes to a stirred suspension of ethyl 6-chloroanthranilate (12.7 g) in a mixture of concentrated sulphuric acid (27.9 ml), water (38 ml) and ice (76 g). The reaction mixture was stirred at 0°C for an additional 20 minutes and then heated to 120°C for 1 hour. The resultant

mixture was poured into a mixture of ice and water and the product was extracted with diethyl ether. The organic phase was washed in turn with water and brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 4: 1 mixture of petroleum ether (b. p. 60-80°C) and methylene chloride as eluent. There was thus obtained ethyl 6-chloro-2-hydroxybenzoate (9.8 g) ; NMR Spectrum: (DMSOd6) 1.3 (t, 3H), 4.3 (q, 2H), 6.9 (d, 1H), 6.95 (d, 1H), 7.25 (d, 1H), 10.45 (br s, 1H).

Allyl bromide (5.5 ml) was added to a stirred mixture of ethyl 6-chloro- 2-hydroxybenzoate (9.8 g), 1, 5,7-triazabicyclo [4,4, 0] dec-5-ene (10.4 g) and acetonitrile (250 ml) and the reaction mixture was stirred at ambient temperature for 20 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using a 17: 3 mixture of petroleum ether (b. p. 60-80°C) and diethyl ether as eluent. There was thus obtained ethyl 2-allyloxy-6-chlorobenzoate (10.3 g); NMR Spectrum: (DMSOd6) 1.3 (t, 3H), 4.35 (q, 2H), 4.65 (d, 2H), 5.25 (d, 1H), 5.4 (d, 1H), 6.0 (m, 1H), 7.15 (m, 2H), 7.45 (t, 1H).

The material so obtained was heated to 230°C for 1 hour. The reaction product was cooled to ambient temperature and purified by column chromatography on silica using a 4: 1 mixture of petroleum ether (b. p. 60-80°C) and methylene chloride as eluent. There was thus obtained ethyl 3-allyl-6-chloro-2-hydroxybenzoate (7.3 g); NMR Spectrum : (DMSOd6) 1.3 (t, 3H), 3.3 (m, 2H), 4.35 (q, 2H), 5.05 (m, 2H), 5.95 (m, 1H), 6.95 (d, 1H), 7.15 (d, 1H), 9.7 (br s, 1H).

The material so obtained was dissolved in methanol (62 ml) and cooled to-70°C.

Ozone was bubbled through the solution for 30 minutes. Dimethyl sulfide (13 ml) was added and the reaction mixture was allowed to warm to ambient temperature. The mixture was evaporated and the residue was partitioned between diethyl ether and water. The organic phase was washed in turn with water and brine, dried over magnesium sulphate and evaporated. There was thus obtained 2- (4-chloro-3-ethoxycarbonyl- 2-hydroxyphenyl) acetaldehyde which was immediately suspended in 85% phosphoric acid (18 ml) and the mixture was heated to 100°C for 1 hour. The mixture was cooled to ambient temperature and partitioned between diethyl ether and water. The organic phase was washed in turn with water and brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 7: 3 mixture of petroleum ether (b. p. 60-80°C) and methylene chloride as eluent. There was thus obtained ethyl

6-chlorobenzofuran-7-carboxylate (5.9 g); NMR Spectrum: (DMSOd6) 1.35 (t, 3H), 4.45 (q, 2H), 7.10 (d, 1H), 7.45 (d, 1H), 7.85 (d, 1H), 8. 15 (d, 1H).

A mixture of the material so obtained, 35% aqueous potassium hydroxide solution (12.7 ml) and methanol (20 ml) was stirred and heated to reflux for 1 hour. The methanol was evaporated and the residue was diluted with water and acidified to pHl by the addition of 6N aqueous hydrochloric acid. The resultant precipitate was isolated, washed with water and dried under vacuum over phosphorus pentoxide to give 6-chlorobenzofuran-7-carboxylic acid (4.6 g); NMR Spectrum : (DMSOd6) 7.05 (d, 1H), 7.4 (d, 1H), 7.75 (d, 1H), 8.1 (d, 1H).

A mixture of a portion (1 g) of the material so obtained, diphenylphosphoryl azide (2.2 ml), triethylamine (1.4 ml) and tert-butanol (2.7 ml) was stirred and heated to reflux for 18 hours. The mixture was allowed to cool to ambient temperature, poured into water and extracted with ethyl acetate. The organic phase was washed in turn with water and brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on alumina using increasingly polar solvent mixtures starting with mixtures of petroleum ether and methylene chloride and ending with a 4: 1 mixture of methylene chloride and ethyl acetate. There was thus obtained a mixture of 7-amino-6-chlorobenzofuran and tert-butyl 6-chlorobenzofuran-7-carbamate. A solution of the mixture so obtained in methylene chloride (15 ml) was cooled to 0°C and trifluoroacetic acid (1.2 ml) was added.

The resultant mixture was stirred for 1 hour. The mixture was evaporated and the residue was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 3: 1 mixture of petroleum ether (b. p. 60-80°C) and methylene chloride as eluent. There was thus obtained 7-amino-6-chlorobenzofuran (0.376 g); NMR Spectrum : (DMSOd6) 5.5 (br s, 2H), 6.85 (m, 2H), 7.1 (d, 1H), 7.95 (d, 1H) ; Mass Spectrum: M+H+ 167.

[2] The product gave the following characterising data; NMR Spectrum : (DMSOd6 and CF3C02D) 2.27 (m, 2H), 2.82 (s, 3H), 3.11-3. 79 (m, 10H), 3.99 (s, 3H), 4.3 (m, 2H), 7.41-7. 54 (m, 3H), 7.62 (d, 1H), 8. 09 (s, 1H), 8.28 (s, 1H), 8.74 (s, 1H) ; Mass Spectrum M+H+ 506 and 508.

The 7-amino-3-chlorobenzofuran used as a starting material was prepared as follows :- 7-Nitrobenzofuran (1.2 g) was dissolved in glacial acetic acid (12 ml) and chlorine gas was bubbled through the solution for 30 minutes whilst the temperature of the reaction mixture was maintained at about 18°C. The reaction mixture was evaporated and the residue

was purified by column chromatography using a 1: 1 mixture of petroleum ether (b. p. 60-80°C) and ethyl acetate as eluent. There was thus obtained a mixture of the cis-and trans-isomers of 2, 3-dichloro-7-nitro-2, 3-dihydrobenzofuran (0.77 g); Mass Spectrum: M+H+ 233.

After repetition of the preceding reaction, cis-and trans-2, 3-dichloro- 7-nitro-2,3-dihydrobenzofuran (0. 85 g) was dissolved in ethanol (35 ml) and a 0.8N aqueous potassium hydroxide solution (45.5 ml) was added. The reaction mixture was stirred at ambient temperature for 1.25 hours. The mixture was concentrated by evaporation, water was added and the mixture was acidified to pH2 by the addition of 6N aqueous hydrochloric acid.

The mixture was extracted with diethyl ether. The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. There was thus obtained 3-chloro-7-nitrobenzofuran (0.7 g) as a colorless solid; NMR Spectrum : (DMSOd6) 7.65 (t, 1H), 8. 15 (d, 1H), 8. 3 (d, 1H), 8.65 (s, 1H).

The material so obtained was dissolved in methanol (25 ml) was the solution was added dropwise during 5 minutes to a stirred mixture of hydrazine hydrate (0.81 ml), Raney nickel (0.16 g) and methanol (30 ml) which had been heated to 60°C. The resultant reaction mixture was then heated to reflux for 5 minutes. The reaction mixture was cooled to ambient temperature and the catalyst was removed by filtration. The filtrate was evaporated and the residue was partitioned between methylene chloride and water. The organic phase was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 1: 1 mixture of petroleum ether (b. p. 60-80°C) and ethyl acetate as eluent. There was thus obtained 7-amino-3-chlorobenzofuran (0.41 g); NMR Spectrum : (DMSOd6) 5.5 (br s, 2H), 6.65 (d, 1H), 6.75 (d, 1H), 7.05 (t, 1H), 8.2 (s, 1H).

[3] 4-Chloro-3-cyano-6-methoxy-7- (3-morpholinopropoxy) quinoline (International Patent Application WO 00/68201, page 52) was used as a starting material. The reaction mixture was evaporated and the residue was partitioned between methylene chloride and water. The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the required product as a free base. The product gave the following characterising data; NMR Spectrum : (DMSOd6) 1.96 (m, 2H), 2.33-2. 39 (m, 4H), 2.41-2. 5 (m, 2H), 3.55-3. 6 (m, 4H), 3.92 (s, 3H), 4.21 (t, 2H), 7.01 (d, 1H), 7.24-7. 29 (m, 2H), 7.33 (s, 1H), 7.57 (m, 1H), 7.85 (s, 1H), 7.92 (d, 1H), 8.37 (s, 1H), 9.71 (s, 1H); Mass Spectrum : M+H+ 459.

[4] 4-Chloro-3-cyano-6, 7-dimethoxyquinoline (International Patent Application WO 98/43960) was used as a starting material. The reaction mixture was evaporated and the residue was triturated under methylene chloride. The solid so obtained was washed with methylene chloride and diethyl ether and dried. There was thus obtained the required product as a free base. The product gave the following characterising data; NMR Spectrum : (DMSOd6) 3.74 (s, 3H), 3.81 (s, 3H), 6.39 (m, 1H), 6.64 (m, 1H), 6.74 (d, 1H), 6. 89 (s, 1H), 7.7-7. 75 (m, 3H); Mass Spectrum: M-H-362.

The 7-amino-5-fluorobenzofuran used as a starting material was prepared as follows :- Allyl bromide (6 ml) was added to a stirred mixture of 4-fluoro-2-nitrophenol (10 g), 1, 5,7-triazabicyclo [4,4, 0] dec-5-ene (11.5 g) and DMF (120 ml) and the reaction mixture was stirred at ambient temperature for 20 hours. The reaction mixture was then heated to 50°C for 1.5 hours. The mixture was evaporated and the residue was partitioned between diethyl ether and water. The organic phase was washed in turn with a 1N aqueous hydrochloric acid solution, water and brine, dried over magnesium sulphate and evaporated. There was thus obtained 4-allyloxy-3-nitro-1-fluorobenzene (9.6 g); NMR Spectrum : (DMSOd6) 4.85 (d, 2H), 5.3 (d, 1H), 5.45 (d, 1H), 6.05 (m, 1H), 7.4 (m, 1H), 7.6 (m, 1H), 7.9 (m, 1H).

A mixture of 4-allyloxy-3-nitro-1-fluorobenzene (8 g) and 1,2-dichlorobenzene (14 ml) was heated to 230°C for 32 minutes in a microwave oven (651W for 3 minutes to raise the temperature to 230°C and then 300W for 29 min). The solvent was evaporated and the residue was mixed with methylene chloride (30 ml) and filtered. The filtrate was evaporated and the residue was purified by column chromatography on silica using a 4: 1 mixture of petroleum ether (b. p. 60-80°C) and methylene chloride as eluent. There was thus obtained 2-allyl-4-fluoro-6-nitrophenol (3.5 g) as an oil; NMR Spectrum : (DMSOd6) 3.45 (d, 2H), 5.1 (d, 2H), 6.0 (m, 1H), 7.5 (m, 1H), 7.75 (m, 1H), 10.4 (br s, 1H).

The material so obtained was dissolved in methanol and cooled to-78°C. Ozone was bubbled through the solution for 30 minutes. Dimethyl sulfide (5.4 ml) was added and the reaction mixture was allowed to warm to ambient temperature. The mixture was evaporated and the residue was partitioned between diethyl ether and water. The organic phase was washed in turn with water and brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 1: 1 mixture of petroleum ether (b. p. 60-80°C) and methylene chloride and then a 9: 1 mixture of methylene chloride and diethyl ether as eluent. There was thus obtained 2- (5-fluoro-2-hydroxy-

3-nitrophenyl) acetaldehyde which was immediately suspended in 85% phosphoric acid (18 ml) and the mixture was heated to 100°C for 1 hour. The mixture was cooled to ambient temperature and partitioned between diethyl ether and water. The organic phase was washed in turn with water and brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 1: 1 mixture of petroleum ether (b. p. 60- 80°C) and methylene chloride as eluent. There was thus obtained 5-fluoro-7-nitrobenzofuran (1.3 g); NMR Spectrum : (DMSOd6) 7.2 (d, 1H), 8.05 (m, 2H), 8.35 (d, 1H).

Hydrazine hydrate (0.522 ml) was added dropwise to a stirred mixture of 5-fluoro- 7-nitrobenzofuran (0.65 g), Raney nickel (0.03 g) and methanol (12 ml) that had been warmed to 55-60°C. The reaction mixture was then heated to reflux for 45 minutes. The catalyst was removed by filtration and the filtrate was evaporated. The residue was partitioned between methylene chloride and water. The organic phase was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of petroleum ether (b. p. 60-80°C) and methylene chloride as eluent. There was thus obtained 7-amino-5-fluorobenzofuran (0.206 g); NMR Spectrum : (DMSOd6) 5.65 (br s, 2H), 6.3 (m, 1H), 6. 55 (m, 1H), 6. 8 (d, 1H), 7.9 (d, 1H).

[5] 7-Amino-4-methoxybenzofuran (J. Med. Chem., 1995,38, 1942-1954) was used as the appropriate 7-aminobenzofuran. The reaction product was purified by column chromatography on silica using increasingly polar mixtures of isohexane and ethyl acetate as eluent. There was thus obtained the required product as a free base which contained some of the corresponding 7- (3-bromopropoxy) quinoline. The material so obtained gave the following characterising data; Mass Spectrum : M+H+ 438 and 440.

The 4-chloro-7- (3-chloropropoxy)-3-cyano-6-methoxyquinoline used as a starting material was prepared as follows :- A mixture of 4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline (0.2 g, prepared as described in International Patent Application WO 00/68201, disclosed as compound (7) within Preparation 1 therein), potassium tert-butoxide (0.1 g) and DMF (8 ml) was stirred at ambient temperature for 15 minutes. 1-Bromo-3-choropropane (0.134 g) was added and the reaction mixture was stirred at ambient temperature for 16 hours. The resultant mixture was evaporated and the residue was partitioned between methylene chloride and an aqueous sodium bicarbonate solution. The organic layer was dried using magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of ethyl acetate and hexane. There was thus obtained 4-chloro-

7- (3-chloropropoxy)-3-cyano-6-methoxyquinoline (0.131 g containing some 4-chloro- 7- (3-bromopropoxy)-3-cyano-6-methoxyquinoline) ; NMR Spectrum : (DMSOd6) 2.3 (m, 2H), 3. 8 (m, 2H), 4.0 (s, 3H), 4.35 (m, 2H), 7.42 (s, 1H), 7.68 (s, 1H), 8.95 (s, 1H); Mass Spectrum: M+H+ 311.

[6] The reaction mixture was stirred at 0°C for 90 minutes and then poured into a dilute aqueous ammonium chloride solution. The precipitate was isolated and dried. There was thus obtained the required product as a free base which gave the following characterising data; NMR Spectrum : (DMSOd6) 3.93 (s, 3H), 3.95 (s, 6H), 6.84 (d, 1H), 6.99 (d, 1H), 7.27 (d, 1H), 7.31 (s, 1H), 7. 87 (d, 1H), 7.89 (s, 1H), 8.3 (s, 1H), 9.58 (s, 1H); Mass Spectrum : M+H+ 376.

[7] The reaction mixture was stirred at 0°C for 90 minutes and then poured into a dilute aqueous ammonium chloride solution. The precipitate was isolated and purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the required product as a free base which gave the following characterising data; NMR Spectrum : (CDC13) 2.09 (m, 2H), 2.45 (m, 4H), 2.54 (t, 2H), 3.54 (s, 3H), 3.71 (m, 4H), 3.95 (s, 3H), 4.24 (t, 2H), 6.64 (d, 1H), 6.89 (s, 1H), 6.91 (d, 1H), 6.94 (s, 1H), 7.1 (d, 1H), 7.35 (s, 1H), 7. 48 (d, 1H), 8.56 (s, 1H); Mass Spectrum : M+H+ 489.

[8] The reaction mixture was stirred at 0°C for 90 minutes and then poured into a dilute aqueous ammonium chloride solution. The precipitate was isolated and dried. There was thus obtained the required product as a free base which gave the following characterising data; NMR Spectrum : (DMSOd6) 1.94 (m, 2H), 2.16 (s, 3H), 2.25-2. 5 (m, 8H), 2.45 (t, 2H), 3.92 (s, 3H), 3.93 (s, 3H), 4.18 (t, 2H), 6.83 (d, 1H), 6.98 (d, 1H), 7.26 (d, 1H), 7.29 (s, 1H), 7.85 (m, 2H), 8.3 (s, 1H), 9.58 (s, 1H) ; Mass Spectrum: M+H+ 502.

[9] The reaction mixture was stirred at ambient temperature for 1 hour and then poured into a saturated aqueous ammonium chloride solution. The mixture was extracted with methylene chloride and the organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. The residue was triturated under diethyl ether and the resultant solid was isolated and dried. There was thus obtained the required compound as a free base containing 1 equivalent of DMF. The material so obtained gave the following characterising data; NMR Spectrum : (CDC13) 3.62 (s, 3H), 4.04 (s, 3H), 6.72 (d, 1H), 6.75 (d, 1H), 6.92 (s, 1H), 7.02 (s, 1H), 7.4 (s, 1H), 7.53 (d, 1H), 7.65 (d, 1H), 8.68 (s, 1H); Mass Spectrum : M+H+ 472.

Example 3 4-benzofuran-7-ylamino-3-cyano-6, 7-dimethoxyquinoline hydrochloride salt A mixture of 4-chloro-3-cyano-6, 7-dimethoxyquinoline (0.2 g), 7-aminobenzofuran (0.113 g) and n-propanol (15 ml) was stirred and heated to 110°C for 3 hours. The yellow precipitate was isolated, washed in turn with n-propanol and diethyl ether and dried under vacuum. There was thus obtained the title compound (0.175 g); NMR Spectrum: (DMSOd6) 4.0 (s, 6H), 7.18 (s, 1H), 7.36 (t, 1H), 7.44 (d, 1H), 7.51 (s, 1H), 7.73 (d, 1H), 8.0 (s, 1H), 8.24 (s, 1H), 8.92 (s, 1H); Mass Spectrum : M+H+ 346.

Example 4 Using an analogous procedure to that described in Example 3, the appropriate 4-chloro-3-cyanoquinoline was reacted with the appropriate 7-aminobenzofuran to give the compounds described in Table II. Unless otherwise stated, each product was obtained as a hydrochloride salt.

Table II Compound Rl 2 No. & Note [1] hydroxy hydrogen [2] 3-chloropropoxy hydrogen [3] 4-chlorobutoxy hydrogen [1] The reactants were 4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline and 7-aminobenzofuran. The product gave the following characterising data; NMR Spectrum : (DMSOd6) 4.01 (s, 3H), 7.09 (d, 1H), 7.37 (t, 1H), 7.44 (d, 1H), 7.51 (s, 1H), 7.73 (d, 1H), 8.01 (s, 1H), 8.26 (s, 1H), 8.9 (s, 1H); Mass Spectrum : M+H+ 332.

[2] The reactants were 4-chloro-7- (3-chloropropoxy)-3-cyano-6-methoxyquinoline (containing some 4-chloro-7- (3-bromopropoxy)-3-cyano-6-methoxyquinoline) and 7-aminobenzofuran and the reaction mixture was heated to 110°C for 3 hours. The product gave the following characterising data; NMR Spectrum: (DMSOd6) 2.28-2. 42 (m, 2H), 3.67- 3. 87 (m, 2H), 4.01 (s, 3H), 4. 28-4. 35 (m, 2H), 7.08 (d, 1H), 7.37 (t, 1H), 7.44 (d, 1H), 7.54 (s, 1H), 7.73 (d, 1H), 7.99 (d, 1H), 8.23 (s, 1H), 8.94 (s, 1H); Mass Spectrum : M+H+ 407 and 409,452 and 454.

[3] The reactants were 4-chloro-7- (4-chlorobutoxy)-3-cyano-6-methoxyquinoline (J. Medicinal Chemistrv, 2001, 44, 3965-3977) and 7-aminobenzofuran and the reaction mixture was heated to 100°C for 5 hours. The product gave the following characterising data NMR Spectrum: (DMSOd6) 1.95 (m, 4H), 3.75 (m, 2H), 4.0 (s, 3H), 4.23 (m, 2H), 7. 08 (d, 1H), 7.36 (t, 1H), 7.45 (d, 1H), 7.56 (s, 1H), 7.73 (d, 1H), 7.99 (d, 1H), 8.30 (s, 1H), 8.93 (s, 1H), 11.46 (br s, 1H); Mass Spectrum: M+H+ 422 and 424.

Example 5 7- [3- (4-acetylpiperazin-1-yl) propoxy]-4-benzofuran-7-ylamino-3-cyano- 6-methoxyquinoline A mixture of4-benzofuran-7-ylamino-7- (3-chloropropoxy)-3-cyano- 6-methoxyquinoline (0.3 g), 1-acetylpiperazine (0.27 g) and DMF (5 ml) was stirred and heated to 90°C for 4 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and water. The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. The resultant residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution as eluent. There was thus obtained the title compound (0.205 g); NMR Spectrum: (DMSOd6) 1.92-2. 01 (m, 5H), 2.33 (t, 2H), 2.39 (t, 2H), 2.45-2. 52 (m, 2H), 3.42 (m, 4H), 3.92 (s, 3H), 4.21 (t, 2H), 7.01 (d, 1H), 7.27 (m, 2H), 7.32 (s, 1H), 7.58 (m, 1H), 7.86 (s, 1H), 7.94 (s, 1H), 8.38 (s, 1H), 9.72 (s, 1H); Mass Spectrum : M+H+ 500.

Example 6 Using an analogous procedure to that described in Example 5, the appropriate 7- (co-haloalkoxy)-3-cyanoquinoline was reacted with the appropriate amine or heterocycle to give the compounds described in Table III. Unless otherwise stated, each compound described in Table III was obtained as a free base.

Table III

Compound R2 No. & Note [1] 3- [4- (2-fluoroethyl) piperazin-1-yl] propoxy hydrogen [2] 3- (l, l-dioxotetrahydro-4H-thiazin-4-yl) propoxy hydrogen [3] 4- (4-acetylpiperazin-1-yl) butoxy hydrogen [4] 4- (4-methylpiperazin-1-yl) butoxy hydrogen [5] 3- (1, 2,3, 6-tetrahydropyridin-1-yl) propoxy hydrogen [6] 4- (1, 2,3, 6-tetrahydropyridin-1-yl) butoxy hydrogen [7] 3-piperazin-1-ylpropoxy 4-methoxy [8] 3- (4-hydroxypiperidin-1-yl) propoxy 4-methoxy

Notes [1] 1- (2-Fluoroethyl) piperazine trifluoroacetate salt was used as the heterocycle reactant.

Diisopropylethylamine was added to the reaction mixture as an additional reactant to neutralise the trifluoroacetate salt. The product gave the following characterising data; NMR Spectrum: (DMSOd6) 1.96 (m, 2H), 2.3-2. 7 (m, 12H), 3.93 (s, 3H), 4.2 (t, 2H), 4.42 (t, 1H), 4.59 (t, 1H), 7.0 (d, 1H), 7.25-7. 34 (m, 3H), 7.56 (m, 1H), 7.84 (m, 1H), 7.92 (s, 1H), 8.37 (s, 1H), 9.71 (s, 1H); Mass Spectrum: Mass 504.

The 1- (2-fluoroethyl) piperazine trifluoroacetate salt used as a starting material was prepared as follows :- A mixture of 1-(tert-butoxycarbonyl) piperazine (5 g), 1-bromo-2-fluoroethane (5. 11 g), potassium carbonate (9.26 g) and acetonitrile (60 ml) was stirred and heated to 60°C

for 4 hours. The reaction mixture was cooled to ambient temperature and filtered and the filtrate was evaporated. The residue was purified by column chomatography on silica using increasingly polar mixtures of isohexane and ethyl acetate as eluent. There was thus obtained 4-(tert-butoxycarbonyl)-1-(2-fluoroethyl) piperazine as a solid (3.7 g); NMR Spectrum : (DMSOd6 and CD3CO2D) 1.37 (s, 9H), 2. 34-2. 4 (m, 4H), 2.56 (t, 1H), 2.67 (t, 1H), 3.25-3. 34 (m, 4H), 4.42 (t, 1H), 4. 58 (t, 1H).

Trifluoroacetic acid (20 ml) was added to a mixture of 4-(t-butoxycarbonyl)- 1- (2-fluoroethyl) piperazine (3.7 g), triethylsilane (8 ml) and methylene chloride (100 ml) and the resultant mixture was stirred at ambient temperature for 1.5 hours. The mixture was evaporated and the residue was triturated under diethyl ether. The solid so obtained was isolated, washed with diethyl ether and dried. There was thus obtained 1- (2-fluoroethyl) piperazine trifluoroacetic acid salt as a solid (6.0 g); NMR Spectrum (DMSOd6 and CD3CO2D) 3.0-3. 31 (m, 10H), 4.59 (m, 1H), 4.75 (m, 1H).

[2] 1, 1-Dioxotetrahydro-4H-thiazine was used as the heterocycle reactant. The material obtained after chromatographic purification was dissolved in methylene chloride and a solution of hydrogen chloride in diethyl ether (1M) was added. The resultant solid was washed with diethyl ether and dried. The product so obtained was the dihydrochloride salt which gave the following characterising data; NMR Spectrum : (DMSOd6 and CF3CO2D) 2.33 (m, 2H), 3.4 (m, 2H), 3. 6-3. 81 (m, 8H), 4.0 (s, 3H), 4.32 (t, 2H), 7. 08 (d, 1H), 7.35 (t, 1H), 7.44 (d, 1H), 7.49 (s, 1H), 7.72 (d, 1H), 7.96 (d, 1H), 8. 19 (s, 1H), 8. 94 (s, 1H) ; Mass Spectrum : M+H+ 507.

[3] The reactants were 4-benzofuran-7-ylamino-7- (4-chlorobutoxy)-3-cyano- 6-methoxyquinoline hydrochloride and 1-acetylpiperazine and the reaction solvent was n-propanol. The reaction mixture was heated to 90°C for 18 hours. The resultant mixture was partitioned between ethyl acetate and 1N aqueous sodium hydroxide solution. The organic layer was washed with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution as eluent. The product so obtained gave the following characterising data; NMR Spectrum : (CDC13) 1.9 (m, 4H), 2.0 (s, 3H), 2.8-3. 2 (m, 5H), 3.45 (m, 2H), 3.55 (m, 1H), 3.9-4. 0 (m, 1H), 4.0 (s, 3H), 4.2 (m, 2H), 4.35 (m, 1H), 7.05 (s, 1H), 7.3 (t, 1H), 7.45 (d, 1H), 7.6 (s, 1H), 7.7 (d, 1H), 8.0 (d, 1H), 8.4 (s, 1H), 8.9 (s, 1H), 11.2 (br s, 1H), 11.7 (br s, 1H); Mass Spectrum : M+H+ 514.

[4] The reactants were 4-benzofuran-7-ylamino-7- (4-chlorobutoxy)-3-cyano- 6-methoxyquinoline hydrochloride and 1-methylpiperazine and the reaction solvent was n-propanol. The reaction mixture was heated to 90°C for 18 hours. The resultant mixture was partitioned between ethyl acetate and 1N aqueous sodium hydroxide solution. The organic layer was washed with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution as eluent. The product so obtained gave the following characterising data; NMR Spectrum: (CDC13) 1.9 (m, 4H), 2.8 (s, 3H), 3.15-3. 8 (m, 10H), 4.0 (s, 3H), 4.2 (m, 2H), 7.05 (s, 1H), 7.35 (t, 1H), 7.45 (d, 1H), 7.6 (s, 1H), 7.7 (d, 1H), 8.0 (s, 1H), 8.35 (s, 1H), 8.9 (s, 1H), 11.5 (br s, 1H), 12.0 (br s, 2H); Mass Spectrum: M+H+ 486.

[5] 1,2, 3,6-Tetrahydropyridine was used as the heterocycle reactant and the reaction solvent was 2-methoxyethanol. The reaction mixture was heated to 105°C for 2 hours. The product gave the following characterising data; NMR Spectrum : (CDC13) 2.15 (m, 2H), 2.19 (m, 2H), 2.64 (m, 4H), 3.0 (t, 2H), 3.52 (s, 3H), 4.25 (t, 2H), 5.67 (m, 1H), 5.76 (m, 1H), 6. 84 (d, 1H), 6.89 (s, 1H), 7.01 (t, 1H), 7.2 (t, 1H), 7.38 (s, 1H), 7.45 (d, 1H), 7.6 (d, 1H), 8.65 (s, 1H); Mass Spectrum: M+H+ 455.

[6] 1,2, 3,6-Tetrahydropyridine was used as the heterocycle reactant and the reaction solvent was 2-methoxyethanol. The reaction mixture was heated to 105°C for 4 hours. The product gave the following characterising data; NMR Spectrum : (CDC13) 1.73 (m, 2H), 1.94 (m, 2H), 2.17 (m, 2H), 2.47 (m, 2H), 2.56 (t, 2H), 2.96 (m, 2H), 3.52 (s, 3H), 4.17 (t, 2H), 5.65 (m, 1H), 5.74 (m, 1H), 6.82 (d, 1H), 6.95 (s, 1H), 7.0 (d, 1H), 7.19 (t, 1H), 7.26 (s, 1H), 7.34 (s, 1H), 7.45 (m, 1H), 7.57 (d, 1H), 8.62 (s, 1H); Mass Spectrum : M+H+ 469.

[7] Piperazine was used as the amine reactant and the reaction solvent was 2-methoxyethanol. The reaction mixture was heated to 100°C for 3 hours. The product gave the following characterising data; NMR Spectrum: (DMSOd6) 1.96 (m, 2H), 2.32 (m, 4H), 2.44 (t, 2H), 2.7 (m, 4H), 3.95 (s, 3H), 3.96 (s, 3H), 4.21 (t, 2H), 6.85 (d, 1H), 7.0 (d, 1H), 7.27 (d, 1H), 7.31 (s, 1H), 7.88 (m, 2H), 8.31 (s, 1H), 9.6 (br s, 1H); Mass Spectrum : M+H+ 488.

[8] 4-Hydroxypiperidine was used as the amine reactant and the reaction solvent was 2-methoxyethanol. The reaction mixture was heated to 100°C for 6 hours. The product gave the following characterising data; NMR Spectrum : (DMSOd6) 1.35-1. 5 (m, 2H), 1.7-1. 80 (m, 2H), 1.97 (m, 2H), 2.09 (m, 2H), 2.49 (m, 2H), 2.76 (m, 2H), 3.47 (m, 1H), 3.95 (s, 3H), 3.96

(s, 3H), 4.2 (t, 2H), 4.52 (s, 1H), 6. 85 (d, 1H), 7.0 (s, 1H), 7.28 (d, 1H), 7. 31 (s, 1H), 7. 88 (m, 2H), 8. 32 (s, 1H), 9.6 (s, 1H); Mass Spectrum: M+H+ 503.

Example 7 4-benzofuran-7-ylamino-3-cyano-6-methoxy-7- [3- (4-prop-2-ynylpiperazin-l- yl) propoxy] quinoline A mixture of 4-benzofuran-7-ylamino-7- (3-chloropropoxy)-3-cyano- 6-methoxyquinoline (0.3 g), 1- (2-propynyl) piperazine trifluoroacetate salt (International Patent Application WO 98/01164; 0. 382 g), diisopropylethylamine (0.541 g) and 2-methoxyethanol (12 ml) was stirred and heated to 100°C for 4 hours. The mixture was evaporated and the resultant residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution as eluent. There was thus obtained the title compound (0.125 g); NMR Spectrum : (DMSOd6 and CF3CO2D) 1. 98-2. 09 (m, 2H), 2.52-2. 59 (m, 4H), 2. 64-2. 76 (m, 6H), 3.11 (m, 1H), 3.29 (d, 2H), 3.92 (s, 3H), 4.2 (t, 2H), 7.0 (d, 1H), 7.24-7. 3 (m, 2H), 7.34 (s, 1H), 7.56 (m, 1H), 7.86 (s, 1H), 7.9 (s, 1H), 8.37 (s, 1H); Mass Spectrum: M+H+ 496.

Example 8 4-benzofuran-7-ylamino-3-cyano-6-methoxy-7- [2- (2-methoxyethoxy) ethoxy] quinoline hydrochloride salt Diisopropyl azodicarboxylate (0.414 g) was added dropwise to a stirred suspension of 4-benzofuran-7-ylamino-3-cyano-7-hydroxy-6-methoxyquinoline (0.565 g), 2- (2-methoxyethoxy) ethanol (0.307 g), triphenylphosphine (0.627 g) and methylene chloride (30 ml). The mixture was stirred at ambient temperature for 3 hours. The mixture was evaporated and the residue was purified by column chromatography on silica eluting with increasingly polar mixtures of ethyl acetate and methanol as eluent. The material so obtained was dissolved in methylene chloride and a solution of hydrogen chloride in diethyl ether (1M, 2 ml) was added. The resultant solid was washed with diethyl ether and dried. There was thus obtained the title compound as a solid (0.19 g); NMR Spectrum: (DMSOd6) 3.26 (s, 3H), 3.48 (m, 2H), 3.61 (m, 2H), 3.83 (m, 2H), 3.94 (s, 3H), 4.28 (t, 2H), 7.01 (d, 1H), 7.25-7. 31 (m, 2H), 7.36 (s, 1H), 7.58 (m, 1H), 7.86 (s, 1H), 7.92 (s, 1H), 8.13 (s, 1H), 8.39 (s, 1H), 9.74 (s, 1H); Mass Spectrum : M+H+ 434.

Example 9 3-cyano-4- (4-cyanob enzofuran-7-ylamino)-6, 7-dimethoxyquinoline Tris (dibenzylideneacetone) dipalladium (0.037 g) was added to a mixture of 3-cyano-4- (4-iodobenzofuran-7-ylamino)-6, 7-dimethoxyquinoline (0.25 g), zinc cyanide (0.064 g), diphenylphosphinoferrocene (0.038 g), zinc powder (0.014 g) and DMA (20 ml) and the resultant mixture was stirred and heated to 110°C for 2 hours. The mixture was cooled to ambient temperature and partitioned between methylene chloride and water. The organic layer was washed with water, dried over magnesium sulphate and evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of isohexane and ethyl acetate as eluent. There was thus obtained the title compound as a solid (0.123 g); NMR Spectrum: (DMSOd6) 3.93 (s, 3H), 3.99 (s, 3H), 7.2 (d, 1H), 7.29 (d, 1H), 7.43 (s, 1H), 7.76 (s, 1H), 7.79 (d, 1H), 8. 19 (d, 1H), 8.62 (s, 1H), 10.11 (br s, 1H); Mass Spectrum : M+H+ 371.

Example 10 4- (benzofuran-7-ylamino)-3-cyano-5- (N-methylpiperidin-4-yloxy) quinoline dihydrochloride salt A mixture of 4-chloro-3-cyano-5- (N-methylpiperidin-4-yloxy) quinoline (0.15 g), 7-aminobenzofuran (0.073 g) and DMF (5 ml) was stirred in an ice-bath. Sodium hexamethyldisilazane (1M solution in THF; 1 ml) was added and the mixture was allowed to warm to ambient temperature over 1 hour. The solvent was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixture of methylene chloride and methanol as eluent. The material so obtained was dissolved in ethanol (8 ml) and 2 equivalents of 1M hydrogen chloride in diethyl ether was added. The mixture was evaporated to give the title compound as a solid (0.131 g); NMR Spectrum : (DMSOd6, warmed to 120°C) 2.27 (m, 2H), 2.43 (m, 2H), 2.65 (s, 3H), 3.21 (m, 4H), 5.07 (m, 1H), 7.01 (d, 1H), 7.31 (t, 1H), 7.4 (m, 2H), 7.65 (m, 2H), 7.81 (t, 1H), 7.94 (d, 1H), 8.57 (s, 1H), 10.27 (br s, 1H); Mass Spectrum : M+H+ 399.

The 4-chloro-3-cyano-5- (N-methylpiperidin-4-yloxy) quinoline used as a starting material was prepared as follows:- Dimethyl sulphate (2. 38 ml) was added dropwise to a stirred mixture of 6-fluoroanthranilic acid (3. 9 g), potassium carbonate (7.64 g) and DMF (100 ml) which had

been cooled to 0°C. The reaction was allowed to warm to ambient temperature and was stirred for 2 hours. The mixture was evaporated and the resulting oil was partitioned between methylene chloride and evaporated. There was thus obtained methyl 6-fluoroanthranilate (4. 78 g); NMR Spectrum: (DMSOd6) 3.8 (s, 3H), 6.3 (m, 1H), 6.6 (m, 3H), 7.2 (m, 1H) ; Mass Spectrum : M+H+ 170.

A mixture of the material so obtained and dimethylformamide dimethyl acetal (20 ml) was stirred and heated to 115°C for 12 hours. The reaction mixture was allowed to cool to ambient temperature and the excess of dimethylformamide dimethyl acetal was evaporated.

Methylene chloride (100 ml) was added to the residual oil and the mixture was filtered. The filtrate was evaporated to provide an orange oil (4.11 g, 71%) which was used without further purification; NMR Spectrum : (DMSOd6) 2. 8 (s, 3H), 3.0 (s, 3H), 3.7 (s, 3H), 6.8 (m, 2H), 7.3 (m, 1H), 7.8 (s, 1H); Mass Spectrum : M+H+ 225.

Whilst maintaining a reaction mixture temperature of less than-70°C, a solution in THF (6.5 ml) of a portion (0.8 g) of the material so obtained was added dropwise to the mixture obtained when a solution of acetonitrile (0.37 g) in THF (5 ml) was added dropwise to a solution of n-butyllithium (2. 5M in hexane; 2.98 ml) in THF (3.5 ml) that had been cooled to-78°C. The resultant reaction mixture was stirred at-78°C for 2 hours and at ambient temperature for a further 2 hours. The mixture was cooled to-78°C and acetic acid (3 ml) was added. The reaction mixture was stirred vigorously and allowed to warm to ambient temperature over 12 hours. Water (10 ml) was added and the resultant white solid was isolated and dried. There was thus obtained 3-cyano-5-fluoro-4-hydroxyquilloline (0.43 g); NMR Spectrum : (DMSOd6) 7.1 (m, 1H), 7.4 (d, 1H), 7.7 (m, 1H), 8.6 (s, 1H); Mass Spectrum : M+H+ 189.

4-Hydroxy-N-methylpiperidine (6.08 g) was added to a stirred slurry of sodium hydride (60% dispersion in oil; 4.23 g) in DMA (150 ml) and the mixture was stirred at ambient temperature for 10 minutes. 3-Cyano-5-fluoro-4-hydroxyquinoline (6 g) was added in portions and the resultant mixture was stirred and heated to 80°C for 6 hours. The solvent was evaporated and the residue was partitioned between water and diethyl ether. The aqueous layer was neutralised by the addition of acetic acid and the resultant mixture was evaporated.

Ethanol and toluene were added to the residue and the solution was re-evaporated. This process was repeated using toluene alone. There was thus obtained 3-cyano-4-hydroxy- 5- (N-methylpiperidin-4-yloxy) quinoline as a white solid (8 g).

A mixture of the material so obtained, phosphoryl chloride (50 ml) and acetonitrile (200 ml) was stirred and heated to 95°C for 3 hours. The mixture was allowed to cool to ambient temperature. The solvent was evaporated and the gum so obtained was treated with a mixture of a concentrated aqueous ammonium hydroxide solution and ice. The mixture was allowed to warm to ambient temperature and the solid so obtained was collected, washed with water and dried. There was thus obtained 4-chloro-3-cyano-5- (N-methylpiperidin- 4-yloxy) quinoline (8.07 g); NMR Spectrum : (DMSOd6) 1.9 (m, 2H), 2.06 (m, 2H), 2.27 (s, 3H), 2.36 (m, 2H), 2.71 (m, 2H), 4.72 (m, 1H), 7.35 (d, 1H), 7.69 (d, 1H), 7.88 (t, 1H), 8. 99 (s, 1H) ; Mass Spectrum: M+H+ 302.

Example 11 <BR> <BR> <BR> <BR> <BR> 4- (benzofuran-7-ylamino)-3-cyano-7-methoxy-5- (N-methylpiperidin-4-yloxy) quinoline dihydrochloride salt A solution of hydrogen chloride in diethyl ether (1M, 0.36 ml) was added to a mixture of 4-chloro-3-cyano-7-methoxy-5- (N-methylpiperidin-4-yloxy) quinoline (0.12 g), 7-aminobenzofuran (0.053 g) and n-propanol (8 ml) and the resultant mixture was stirred and heated to reflux for 6 hours. The mixture was cooled to ambient temperature and the precipitate was isolated and washed with n-propanol. There was thus obtained the title compound as a white solid (0.136 g); NMR Spectrum: (DMSOd6 and CD3CO2D ; warmed to 120°C) 2.21 (m, 2H), 2.38 (m, 2H), 2.7 (s, 3H), 3.23 (m, 4H), 3.99 (s, 3H), 5.11 (m, 1H), 7.05 (d, 2H), 7.17 (s, 1H), 7.34 (t, 1H), 7.43 (d, 1H), 7.68 (d, 1H), 7.96 (s, 1H), 8. 7 (s, 1H) ; Mass Spectrum: M+H+ 429.

The 4-chloro-3-cyano-7-methoxy-5- (N-methylpiperidin-4-yloxy) quinoline used as a starting material was prepared as follows:- A mixture of 3, 5-difluoroaniline (32.25 g), ethyl 2-cyano-3-ethoxyacrylate (42.25 g) and ethanol (200 ml) was heated to reflux for 2 hours. The mixture was allowed to cool to ambient temperature and the precipitate was isolated and washed with a small amount of ethanol. There was thus obtained ethyl 2-cyano-3- (3, 5-difluoroanilino) acrylate as white needles (58 g); NMR Spectrum : (DMSOd6) 1.28 (m, 3H), 4.23 (m, 2H), 6.98-7. 42 (m, 3H), 8.44 (m, 1H), 10.8 (m, 1H); Mass Spectrum: M+H+ 253.

Ethyl 2-cyano-3- (3, 5-difluoroanilino) acrylate (12.5 g) was added portionwise over 10 minutes to di (ethylene glycol) dibutyl ether (100 ml) that had been heated to reflux. The

resultant mixture was heated to reflux for a further 30 minutes. The mixture was allowed to cool to ambient temperature and the precipitate was collected and washed with ethyl acetate.

There was thus obtained 3-cyano-5,7-difluoro-4-hydroxyquinoline as a solid (4.24 g); NMR Spectrum : (DMSOd6) 7.21 (m, 1H), 7.3 (m, 1H), 8.72 (s, 1H), 12. 86 (br, 1H); Mass Spectrum : M+H+ 207.

A mixture of 3-cyano-5, 7-difluoro-4-hydroxyquinoline (4.12 g), N-methylpiperidin-4- ol (2.6 g), potassium tert-butoxide (6.72 g) and THF (250 ml) was stirred and heated at 60°C for 2 hours. The mixture was acidified to pH6 by the addition of glacial acetic acid and the resultant mixture was evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution as eluent. There was thus obtained 3-cyano-7-fluoro-4-hydroxy- 5- (N-methylpiperidin-4-yloxy) quinoline as a foam (3.55 g); NMR Spectrum: (DMSOd6) 1.77 (m, 2H), 1.92 (m, 2H), 2.3 (s, 3H), 2.43 (m, 2H), 2.81 (m, 2H), 4.55 (m, 1H), 6. 81 (m, 2H), 8.4 (s, 1H); Mass Spectrum : M+H+ 302.

A mixture of a portion (0.6 g) of the material so obtained, methanol (0.4 ml), potassium tert-butoxide (1M solution in THF; 10 ml) and DMSO (20 ml) was stirred and heated at 70°C for 16 hours. The solution was cooled to ambient temperature and diluted with water (100 ml). The mixture was acidified to pH6 by the addition of dilute aqueous hydrochloric acid and filtered. The filtrate was passed through a cation exchange cartridge (Waters Oasis MCX 6 g) using water (200 ml), a 1: 1 mixture (200 ml) of methanol and water and then methanol (200 ml) as eluent. The product was eluted off the column with methanol containing triethylamine (1%). There was thus obtained 3-cyano-4-hydroxy-7-methoxy-5- (N- methylpiperidin-4-yloxy) quinoline as a white solid (0.46 g); NMR Spectrum: (DMSOd6) 1.67 (m, 2H), 1. 83 (m, 2H), 2.12 (m, 2H), 2.15 (s, 3H), 2.64 (m, 2H), 4.31 (m, 1H), 6.31 (d, 1H), 6.56 (d, 1H), 8.16 (s, 1H); Mass Spectrum : M+H+ 314.

A mixture of a portion (0.313 g) of the material so obtained, phosphoryl chloride (1.8 ml) and acetonitrile (10 ml) was stirred and heated to reflux for 20 hours. The mixture was cooled to ambient temperature and evaporated. The gum so obtained was treated with a mixture of a concentrated aqueous ammonium hydroxide solution (25 ml) and ice. The mixture was allowed to warm to ambient temperature and the solid so obtained was collected and dried overnight. There was thus obtained 4-chloro-3-cyano-7-methoxy- 5- (N-methylpiperidin-4-yloxy) quinoline as a white solid (0.225 g); NMR Spectrum :

(DMSOd6) 1.8 (m, 2H), 1. 98 (m, 2H), 2.18 (s, 3H), 2.27 (m, 2H), 2.58 (m, 2H), 3.94 (s, 3H), 4.72 (m, 1H), 6.92 (d, 1H), 7.09 (d, 1H), 8.93 (s, 1H) ; Mass Spectrum : M+H+ 332.

Example 12 4- (benzofuran-7-ylamino)-3-cyano-7- (3-morpholinopropoxy)-5-tetrahydropyran-4- yloxyquinoline dihydrochloride salt A solution of hydrogen chloride in diethyl ether (1M, 0.37 ml) was added to a mixture of 4-chloro-3-cyano-7- (3-morpholinopropoxy)-5-tetrahydropyran-4-yloxyquinoline (0.16 g), 7-aminobenzofuran (0.073 g) and n-propanol (8 ml) and the resultant mixture was stirred and heated to reflux for 2 hours. The mixture was cooled to ambient temperature and the precipitate was isolated and washed with n-propanol. There was thus obtained the title compound as a white solid (0.159 g); NMR Spectrum : (DMSOd6; warmed to 120°C) 1. 86 (m, 2H), 2.11 (m, 2H), 2.32 (m, 2H), 3.1 (m, 2H), 3.33 (m, 2H), 3.49 (m, 4H), 3.80 (m, 2H), 3.88 (m, 2H), 3.96 (m, 2H), 4. 33 (t, 2H), 5.13 (m, 1H), 7.09 (d, 2H), 7.15 (d, 1H), 7. 35 (t, 1H), 7.46 (d, 1H), 7.72 (d, 1H), 8.04 (d, 1H), 8. 84 (s, 1H), 10.84 (s, 1H), 11.45 (s, 1H) ; Mass Spectrum M+H+ 529.

The 4-chloro-3-cyano-7- (3-morpholinopropoxy)-5-tetrahydropyran-4-yloxyquinoline used as a starting material was prepared as follows:- A mixture of 3-cyano-5, 7-difluoro-4-hydroxyquinoline (2.06 g), 4-liydroxytetraliydropyran (1.02 g), potassium tert-butoxide (1M solution in THF ; 30 ml) and THF (100 ml) was stirred and heated to 60°C for 1.5 hours. The mixture was acidified to pH6 by the addition of glacial acetic acid and the resultant mixture was evaporated. Aqueous sodium hydroxide solution (2M, 20 ml) was added to the residue and the mixture was filtered.

The filtrate was acidified to pH5 by the addition of glacial acetic acid and the resultant oily precipitate was allowed to stand for 3 days when it had solidified fully. The solid was collected, washed with water and dried. There was thus obtained 3-cyano-7-fluoro- 4-hydroxy-5-tetrahydropyran-4-yloxyquinoline (1.8 g); NMR Spectrum : (DMSOd6) 1.67 (m, 2H), 1.92 (m, 2H), 3.5 (m, 2H), 3.91 (m, 2H), 4.76 (m, 1H), 6. 81 (m, 1H), 6.94 (m, 1H), 8. 52 (s, 1H) ; Mass Spectrum : M+H+ 289.

A mixture of a portion (0.864 g) of the material so obtained, 4- (3-hydroxypropyl) morpholine (Bull. Soc. Chim. Fr., 1962,1117 ; 0.876 g), potassium tert-butoxide (1M solution in THF; 9 ml) in DMSO (30 ml) was stirred and heated to 60°C for

8 hours. The resultant mixture was cooled to ambient temperature and diluted with water (120 ml). The mixture was acidified to pH5 by the addition of glacial acetic acid and passed through a cation exchange cartridge (Waters Oasis MCX 6 g) using water (200 ml), a 1: 1 mixture (200 ml) of methanol and water and then methanol (200 ml) as eluent. The product was eluted off the column with methanol containing triethylamine (1%). The material so obtained was purified further using column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained 3-cyano- 4-hydroxy-7- (3-morpholinopropoxy)-5-tetrahydropyran-4-yloxyquinoline as a white solid (0.54 g); NMR Spectrum : (DMSOd6 ; warmed to 120°C) 1.73 (m, 2H), 1.91 (m, 4H), 2.39 (m, 4H), 2.45 (t, 2H), 3.49 (m, 2H), 3.58 (m, 4H), 3.95 (m, 2H), 4.1 (t, 2H), 4.64 (m, 1H), 6.46 (d, 1H), 6.6 (d, 1H), 8. 24 (s, 1H); Mass Spectrum: M+H+ 414.

A mixture of a portion (0.5 g) of the material so obtained, phosphoryl chloride (2.5 ml) and acetonitrile (15 ml) was stirred and heated to reflux for 4 hours. The mixture was cooled to ambient temperature and evaporated. The gum so obtained was treated with a mixture of a concentrated aqueous ammonium hydroxide solution (25 ml) and ice. The mixture was allowed to warm to ambient temperature and the solid so obtained was collected and dried overnight. There was thus obtained 4-chloro-3-cyano-7- (3-morpholinopropoxy)- 5-tetrahydropyran-4-yloxyquinoline as a white solid (0. 48 g); Mass Spectrum : M+H+ 432.

Example 13 Pharmaceutical compositions The following illustrate representative pharmaceutical dosage forms of the invention as defined herein (the active ingredient being termed"Compound X"), for therapeutic or prophylactic use in humans: (a) Tablet I mg/tablet Compound X......................................................... 100 Lactose Ph. Eur...................................................... 182.75 Croscarmellose sodium......................................... 12.0 Maize starch paste (5% w/v paste)....................... 2.25 Magnesium stearate.............................................. 3.0

(b) Tablet II mg/tablet Compound X........................................................ 50 Lactose Ph. Eur..................................................... 223.75 Croscannellose sodium........................................ 6.0 Maize starch 15.0 Polyvinylpyrrolidone (5% w/v paste).................. 2.25 Magnesium stearate............................................. 3.0 (c) Tablet in mg/tablet Compound X........................................................ 1.0 Lactose Ph. Eur..................................................... 93.25 Crosearmellose sodium........................................ 4.0 Maize starch paste (5% w/v paste)...................... 0.75 Magnesium stearate............................................. 1.0 (d) Capsule mg/capsule Compound X....................................................... 10 Lactose Ph. Eur.................................................... 488.5 Magnesium................................................... ...... 1.5 (e) Injection I (50 mg/ml) Compound X...................................................... 5.0% w/v 1M Sodium hydroxide solution......................... 15.0% v/v 0.1M Hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400........................................ 4.5% w/v Water for injection to 100% (f) Injection II (10 mg/ml) Compound X........................................................... . 1.0% w/v Sodium phosphate BP............................................. 3.6% w/v 0. 1M Sodium hydroxide solution...................... 15.0% v/v Water for injection to 100%

(g) Injection III (1mg/ml, buffered to pH6) Compound X....................................................... 0.1% w/v Sodium phosphate BP............................................. 2.26% w/v Citric acid........................................................ .... 0.38% w/v Polyethylene glycol 400........................................ 3.5% w/v Water for injection to 100% (h) Aerosol I mg/ml Compound X..................................................... 10.0 Sorbitan trioleate 13.5 Trichlorofluoromethane.................................... 910.0 Dichlorodifluoromethane.................................. 490.0 (i) Aerosol n mg/ml Compound X..................................................... 0.2 Sorbitan trioleate 0.27 Trichlorofluoromethane.................................... 70.0 Dichlorodifluoromethane.................................. 280.0 Dichlorotetrafluoroethane................................. 1094.0 (j) Aerosol m mg/ml Compound X.................................................... 2.5 Sorbitan trioleate 3.38 Trichlorofluoromethane................................... 67.5 Dichlorodifluoromethane................................. 1086.0 Dichlorotetrafluoroethane................................ 191.6 (k) Aerosol IV mg/ml Compound X.................................................... 2.5 Soya lecithin.................................................... . 2.7 Trichlorofluoromethane................................... 67.5 Dichlorodifluoromethane................................. 1086.0 Dichlorotetrafluoroethane................................ 191.6

(1) Ointment ml Compound X................................................... 40 mg Ethanol..................................................... ....... 300 p. l Water....................................................... ........ 300 1-Dodecylazacycloheptan-2-one..................... 50 p1 Propylene glycol to 1 ml Note The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)- (c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate. The aerosol formulations (h)- (k) may be used in conjunction with standard, metered dose aerosol dispensers, and the suspending agents sorbitan trioleate and soya lecithin may be replaced by an alternative suspending agent such as sorbitan monooleate, sorbitan sesquioleate, polysorbate 80, polyglycerol oleate or oleic acid.