Quinazoline derivatives as angiogenesis inhibitors

Abstract

The invention relates to the use of compounds of formula (I), wherein ring C is an 8, 9, 10, 12 or 13-membered bicyclic or tricyclic moiety which optionally may contain 1-3 heteroatoms selected independently from O, N and S; Z is —O—, —NH—, —S—, —CH 2 — or a direct bond; n is 0-5; m is 0-3; R 2 represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylsulphanyl, —NR 3 R 4 (wherein R 3 and R 4 , which may be the same or different, each represents hydrogen or C 1-3 alkyl), or R 5 X t — (wherein X 1 and R 5 are as defined herein; R 1 represents hydrogen, oxo, halogeno, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, C 1-4 alkoxymethyl, C 1-4 alkanoyl, C 1-4 haloalkyl, cyano, amino, C 2-5 alkenyl, C 2-5 alkynyl, C 1-3 alkanoyloxy, nitro, C 1-4 alkanoylamino, C 1-4 alkoxycarbonyl, C 1-4 alkylsulphanyl, C 1-4 alkylsulphinyl, C 1-4 alkylsulphonyl, carbamoyl, N —C 1-4 alkylcarbamoyl, N,N -di(C 1-4 alkyl)carbamoyl, aminosulphonyl, N —C 1-4 alkylaminosulphonyl, N,N -di(C 1-4 alkyl)aminosulphonyl, N -(C 1-4 alkylsulphonyl)amino, N —(C 1-4 alkylsulphonyl)— N —(C 1-4 alkyl)amino, N,N -di(C 1-4 alkylsulphonyl)amino, a C 3-7 alkylene chain joined to two ring C carbon atoms, C 1-4 alkanoylaminoC 1-4 alkyl, carboxy or a group R 56 X 10 (wherein X 10 and R 56 are as defined herein); and salts thereof, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals, processes for the preparation of such compounds, pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient and compounds of formula (I). The compounds of formula (I) and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.

1 - 30 . (canceled)  
     
     
         31 . A process for the preparation of a compound of formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 ring C is an 8, 9, 10, 12 or 13-membered bicyclic or tricyclic moiety which moiety may be saturated or unsaturated, which may be aromatic or non-aromatic, and which optionally may contain 1-3 heteroatoms selected independently from O, N and S;  
 Z is —O—, —NH—, —S— or —CH 2 —;  
 n is an integer from 0 to 5;  
 m is an integer from 0 to 3;  
 R 2  represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylsulphanyl, —NR 3 R 4  (wherein R 3  and R 4 , which may be the same or different, each represents hydrogen or C 1-3 alkyl),  
 or R 2  represents a group R 5 X 1 —, wherein X 1  represents a direct bond, —O—, —CH 2 —, —OC(O)—, —C(O)—, —S—, —SO—, —SO 2 —, —NR 6 C(O)—, —C(O)NR 7 —, —SO 2 NR 8 —, —NR 9 SO 2 — or —NR 10 —(wherein R 6 , R 7 , R 8,  R 9  and R 10  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl), and R 5  is selected from one of the following twenty-two groups: 
 1) hydrogen, oxiranylC 1-4 alkyl or C 1-5 alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, chloro, bromo and amino;  
 2) C 1-5 alkylX 2 C(O)R 11  (wherein X 2  represents —O— or —NR 12 — (in which R 12  represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 11  represents C 1-3 alkyl, —NR 13 R 14  or —OR 15  (wherein R 13 , R 14  and R 15  which may be the same or different each represents hydrogen, C 1-5 alkyl or C 1-3 alkoxyC 2-3 alkyl));  
 3) C 1-5 salkylX 3 R 16  (wherein X 3  represents —O—, —S—, —SO—, —SO 2 —, —OC(O)—, —NR 17 C(O)—, —C(O)NR 18 —, —SO 2 NR 19 —, —NR 20 SO 2   13  or —NR 21 — (wherein R 17 , R 18 , R 19 , R 20  and R 21  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 16  represents hydrogen, C 1-3 alkyl, cyclopentyl, cyclohexyl or a 4-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which C 1-3 alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and C 1-4 alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C 1-4 cyanoalkyl, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylsulphonylC 1-4 alkyl, C 1-4 alkoxycarbonyl, C 1-4 aminoalkyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkylaminoC 1-4 alkyl, di(C 1-4 alkyl)aminoC 1-4 alkyl, C 1-4 alkylaminoC 1-4 alkoxy, di(C 1-4 alkyl)aminoC 1-4 alkoxy and a group —(—O—)K(C 1-4 alkyl) g ringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from C 1-4 alkyl));  
 4) C 1-5 alkylX 4 C 1-5 alkylX 5 R 22  (wherein X 4  and X 5  which may be the same or different are each —O—, —S—, —SO—, —SO 2 —, —NR 23 C(O)—, —C(O)NR 24 —, —SO 2 NR 25 —, —NR 26 SO 2 — or —NR 27 —(wherein R 23 , R 24 , R 25 , R 26  and R 27  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 22  represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl);  
 5) R 28  (wherein R 28  is a 4-6-membered saturated heterocyclic group (linked via carbon or nitrogen) with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C 1-4 cyanoalkyl, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylsulphonylC 1-4 alkyl, C 1-4 alkoxycarbonyl, C 1-4 aminoalkyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkylaminoC 1-4 alkyl, di(C 1-4 alkyl)aminoC 1-4 alkyl, C 1-4 alkylaminoC 1-4 alkoxy, di(C 1-4 alkyl)aminoC 1-4 alkoxy and a group —(—O—) f (C 1-4 alkyl) g ringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from C 1-4 alkyl));  
 6) C 1-5 alkylR 28  (wherein R 28  is as defined herein);  
 7) C 2-5 alkenylR 28  (wherein R 28  is as defined herein);  
 8) C 2-5 alkynylR  28  (wherein R 28  is as defined herein);  
 9) R 29  (wherein R 29  represents a pyridone group, a phenyl group or a 5-6-membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1-3 heteroatoms selected from O, N and S, which pyridone, phenyl or aromatic heterocyclic group may carry up to 5 substituents selected from hydroxy, halogeno, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 alkylamino, C 1-4 hydroxyalkoxy, carboxy, trifluoromethyl, cyano, —C(O)NR 30 R 31 , —NR 32 C(O)R 33  (wherein R 30 , R 31 , R 32  and R 33 , which may be the same or different, each represents hydrogen, C 1-4 alkyl or C 1-3 alkoxyC 2-3 alkyl) and a group —(—O—) f (C 1-4 alkyl) g ringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from C 14 alkyl));  
 10) C 1-5 alkylR 29  (wherein R 29  is as defined herein);  
 11) C 2-5 alkenylR 29  (wherein R 29  is as defined herein);  
 12) C 2-5 alkynylR 29  (wherein R 29  is as defined herein);  
 13) C 1-5 alkylX 6 R 29  (wherein X 6  represents —O—, —S—, —SO—, —SO 2 —, —NR 34 C(O)—, —C(O)NR 35 —; —SO   2 NR 36 —, —NR SO 2 — or —NR 38 — (wherein R  34 , R 35 , R 36 , R 37  and R 38  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 29  is as defined herein);  
 14) C 2-5 alkenylX 7 R 29  (wherein X 7  represents —O—, —S—, —SO—, —SO 2 —, —NR 39 C(O)—, —C(O)NR 40 —, —SO 2 NR 41 —, —NR 42 SO 2 — or —NR 43 — (wherein R 39 , R 40 , R 41,  R 42  and R 43  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 29  is as defined herein);  
 15) C 2-5 alkynylX 8 R 29  (wherein X 8  represents —O—, —S—, —SO—, —SO 2 —, —NR 44 C(O)—, —C(O)NR 45 —, —SO 2 NR 46 —, —NR 47 SO 2 — or —NR 48 — (wherein R 44 , R 45 , R 46 , R 47  and R 48  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 29  is as defined herein);  
 16) C 1-4 alkylX 9 C 1-4 alkylR 29  (wherein X 9  represents —O—, —S—, —SO—, —SO 2 —, NR 49 C(O)—, —C(O)NR 50 —, —SO 2 NR 51 —, —NR 52 SO 2 — or —NR 53 — (wherein R 49 , R 50 , R 51 , R 52 and R 53  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 29  is as defined herein);  
 17) C 1-4 alkylX 9 C 1-4 alkylR 28  (wherein X 9  and R 28  are as defined herein);  
 18) C 2-5 alkenyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, C 1-4 alkylamino,  N , N -di(C 1-4 alkyl)amino, aminosulphonyl,  N —C 1-4 alkylaminosulphonyl and  N , N -di(C 1-4 alkyl)aminosulphonyl;  
 19) C 2-5 alkynyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, C 1-4 alkylamino,  N , N -di(C 1-4 alkyl)amino, aminosulphonyl,  N —C 1-4 alkylaminosulphonyl and  N , N -di(C 1-4 alkyl)aminosulphonyl;  
 20) C 2-5 alkenylX 9 C 1-4 alkylR 28  (wherein X 9  and R 28  are as defined herein);  
 21) C 2-5 alkynylX 9 C 1-4 alkylR 28  (wherein X 9  and R 28  are as defined herein); and  
 22) C 1-4 alkylR 54 (C 1-4 alkyl) q (X 9 ) r R 55  (wherein X 9  is as defined herein, q is 0 or 1, r is 0 or 1, and R 54  and R 55  are each independently selected from hydrogen, C 1-3 alkyl, cyclopentyl, cyclohexyl and a 4-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which C 1-3 alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and C 1-4 alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C 1-4 cyanoalkyl, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylsulphonylC 1-4 alkyl, C 1-4 alkoxycarbonyl, C 1-4 aminoalkyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkylaminoC 1-4 alkyl, di(C 1-4 alkyl)aminoC 1-4 alkyl, C 1-4 alkylaminoC 1-4 alkoxy, di(C 1-4 alkyl)aminoC 1-4 alkoxy and a group —(—O—) f (C 1-4 alkyl) g ringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from C 1-4 alkyl), with the proviso that R 54  cannot be hydrogen);  
 and additionally wherein any C 1-5 alkyl, C 2-5 alkenyl or C 2-5 alkynyl group in R 5 X 1 —may bear one or more substituents selected from hydroxy, halogeno and amino;  
 
 R 1  represents hydrogen, oxo, halogeno, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, C 1-4 alkoxymethyl, C 1-4 alkanoyl, C 1-4 haloalkyl, cyano, amino, C 2-5 alkenyl, C 2-5 alkynyl, C 1-3 alkanoyloxy, nitro, C 1-4 alkanoylamino, C 1-4 alkoxycarbonyl, C 1-4 alkylsulphanyl, C 1-4 alkylsulphinyl, C 1-4 alkylsulphonyl, carbamoyl,  N —C 1-4 alkylcarbamoyl,  N , N -di(C 1-4 alkyl)carbamoyl, aminosulphonyl,  N —C 1-4 alkylaminosulphonyl,  N , N -di(C 1-4 alkyl)aminosulphonyl,  N -(C 1-4 alkylsulphonyl)amino,  N -(C 1-4 alkylsulphonyl)- N -(C 1-4 alkyl)amino,  N , N -di(C 1-4 alkylsulphonyl)amino, a C 3-7 alkylene chain joined to two ring C carbon atoms, C 1-4 alkanoylaminoC 1-4 alkyl, carboxy  
 or R 1  represents a group R 56 X 10 , wherein X 10  represents a direct bond, —O—, —CH 2 —, —OC(O)—, —C(O)—, —S—, —SO—, —SO 2 —, —NR 57 C(O)—, —C(O)NR 58 —, —SO 2 NR 59 —, —NR 60 SO 2 — or —NR 61 —(wherein R 57 , R 58 , R 59 , R 60  and R 61  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl), and R 56  is selected from one of the following twenty-two groups: 
 1) hydrogen, oxiranylC 1-4 alkyl or C 1-5 alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, chloro, bromo and amino;  
 2) C 1-5 alkylX 11 C(O)R 62  (wherein X 11  represents —O— or —NR 63 — (in which R 63  represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 62  represents C 1-3 alkyl, —NR 64 R 65  or —OR 66  (wherein R 64 , R 65  and R 66  which may be the same or different each represents hydrogen, C 1-5 alkyl or C 1-3 alkoxyC 2-3 alkyl));  
 3) C 1-5 alkylX 12 R 67  (wherein X 12  represents —O—, —S—, —SO—, —SO 2 —, —OC(O)—, —NR 68 C(O)—, —C(O)NR 69 —, —SO 2 NR 70 —, —NR 71 SO 2 — or —NR 72 — (wherein R 68 , R 69 , R  70 , R 71 and R 72  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 67  represents hydrogen, C 1-3 alkyl, cyclopentyl, cyclohexyl or a 4-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which C 1-3 alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and C 1-4 alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C 1-4 cyanoalkyl, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylsulphonylC 1-4 alkyl, C 1-4 alkoxycarbonyl, C 1-4 aminoalkyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkylaminoC 1-4 alkyl, di(C 1-4 alkyl)aminoC 1-4 alkyl, C 1-4 alkylaminoC 1-4 alkoxy, di(C 1-4 alkyl)aminoC 1-4 alkoxy and a group —(—O—) f (C 1-4 alkyl) g ringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from C 1-4 alkyl));  
 4) C 1-5 alkylX 13 C 1-5 alkylX 14 R 73  (wherein X 14  and X 14  which may be the same or different are each —O—, —S—, —SO—, —SO 2 —, —NR 74 C(O)—, —C(O)NR 75 —, —SO 2 NR 76 —, —NR 77 SO 2 — or —NR 78 — (wherein R 74 , R 75 , R 76 , R 77  and R 78  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 73  represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl);  
 5) R 79  (wherein R 79  is a 4-6-membered saturated heterocyclic group (linked via carbon or nitrogen) with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C 1-4 cyanoalkyl, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylsulphonylC 1-4 alkyl, C 1-4 alkoxycarbonyl, C 1-4 aminoalkyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkylaminoC 1-4 alkyl, di(C 1-4 alkyl)aminoC 1-4 alkyl, C 1-4 alkylaminoC 1-4 alkoxy, di(C 1-4 alkyl)aminoC 1-4 alkoxy and a group —(—O—) f (C 1-4 alkyl) g ringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from C 1-4 alkyl));  
 6) C 1-5 alkylR 79  (wherein R 79  is as defined herein);  
 7) C 2-5 alkenylR 79  (wherein R 79  is as defined herein);  
 8) C 2-5 alkynylR 79  (wherein R 79  is as defined herein);  
 9) R 80  (wherein R 80  represents a pyridone group, a phenyl group or a 5-6-membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1-3 heteroatoms selected from O, N and S, which pyridone, phenyl or aromatic heterocyclic group may carry up to 5 substituents selected from hydroxy, halogeno, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 alkylamino, C 1-4 hydroxyalkoxy, carboxy, trifluoromethyl, cyano, —C(O)NR 81 R 82 , —NR 83 C(O)R 84  (wherein R 81 , R 82 , R 83  and R 84 , which may be the same or different, each represents hydrogen, C 1-4 alkyl or C 1-3 alkoxyC 2-3 alkyl) and a group —(—O—) f (C 1-4 alkyl) g ringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from C 1-4 alkyl));  
 10) C 1-5 alkylR 80  (wherein R 80  is as defined herein);  
 11) C 2-5 alkenylR 80  (wherein R 80  is as defined herein);  
 12) C 2-5 alkynylR 80  (wherein R 80  is as defined herein);  
 13) C 1-5 alkylX 15 R 80  (wherein X 15  represents —O—, —S—, —SO—, —SO 2 —, —NR 85 C(O)—, —C(O)NR 86 —, —SO 2 NR 87 —, —NR 88 SO 2 — or —NR 89 — (wherein R 85 , R 86 , R 87 , R 88  and R 89  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 80  is as defined herein);  
 14) C 2-5 alkenylX 16 R 80  (wherein X 16  represents —O—, —S—, —SO—, —SO 2 —, —NR 90 C(O)—, —C(O)NR 91 —, —SO 2 NR 92 —, —NR 93 SO 2 — or —NR 94 — (wherein R 90 , R 91 , R 92 , R 93 and R 94  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 80  is as defined herein);  
 15) C 2-5 alkynylX 17 R 80  (wherein X 17  represents —O—, —S—, —SO—, —SO 2 —, —NR 95 C(O)—, —C(O)NR 96 —, —SO 2 NR 97 —, —NR 98 SO 2 — or —NR 99 — (wherein R 95 , R 96 , R 97 , R 98  and R 99  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 80  is as defined herein);  
 16) C 1-4 alkylX 18 C 1-4 alkylR 80  (wherein X 18  represents —O—, —S—, —SO—, —SO 2 —, —NR 100 C(O)—, —C(O)NR 101 —, —SO 2 NR 102 —, —NR 103 SO 2 — or —NR 104 — (wherein R 100  , R 101 , R 102 , R 103  and R 104  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 80  is as defined herein);  
 17) C 1-4 alkylX 18 C 1-4 alkylR 79  (wherein X 18  and R 79  are as defined herein);  
 18) C 2-5 alkenyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, C 1-4 alkylamino,  N , N -di(C 1-4 alkyl)amino, aminosulphonyl,  N —C 1-4 alkylaminosulphonyl and  N , N -di(C 1-4 alkyl)aminosulphonyl;  
 19) C 2-5 alkynyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro, amino, C 1-4 alkylamino,  N , N -di(C 1-4 alkyl)amino, aminosulphonyl,  N —C 1-4 alkylaminosulphonyl and  N , N -di(C 1-4 alkyl)aminosulphonyl;  
 20) C 2-5 alkenylX 18 C 1-4 alkylR 79  (wherein X 18  and R 79  are as defined herein);  
 21) C 2-5 alkynylX 18 C 1-4 alkylR 79  (wherein X 18  and R 79  are as defined herein); and  
 22) C 1-4 alkylR 105 (C 1-4 alkyl) x (X18) y R 106  (wherein X 18  is as defined herein, x is 0 or 1, y is 0 or 1, and R 105  and R 106  are each independently selected from hydrogen, C 1-3 alkyl, cyclopentyl, cyclohexyl and a 4-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which C 1-3 alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and C 1-4 alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C 1-4 cyanoalkyl, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylsulphonylC 1-4 alkyl, C 1-4 alkoxycarbonyl, C 1-4 aminoalkyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkylaminoC 1-4 alkyl, di(C 1-4 alkyl)aminoC 1-4 alkyl, C 1-4 alkylaminoC 1-4 alkoxy, di(C 1-4 alkyl)aminoC 1-4 alkoxy and a group —(—O—) f (C 1-4 alkyl) g ringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a 4-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which cyclic group may bear one or more substituents selected from C 1-4 alkyl) with the proviso that R 105  cannot be hydrogen);  
 and additionally wherein any C 1-5 alkyl, C 2-5 alkenyl or C 2-5 alkynyl group in R 56 X 10 —may bear one or more substituents selected from hydroxy, halogeno and amino;  
 
 or a salt or prodrug thereof.  
 which process comprises: 
 (a) the reaction of a compound of the formula III:  
                     
 (wherein R 2  and m are as defined above and L 1  is a displaceable moiety), with a compound of the formula IV:  
                     
 (wherein ring C, R 1 , Z and n are as defined above);  
 (b) a compound of formula I or a salt thereof wherein at least one R 2  is R 5 X 1  wherein R 5  is as defined above and X 1  is —O—, —S—, —OC(O)— or —NR 10 — (wherein R 10  independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) may be prepared by the reaction of a compound of the formula V:  
                     
 (wherein ring C, Z, R 1 , R 2  and n are as defined above and X 1  is as herein defined in this section and s is an integer from 0 to 2) with a compound of formula VI:  
   R 5 -L 1    (VI)  
 (wherein R 5 is as defined above and L 1  is as herein defined);  
 (c) a compound of the formula I or a salt thereof wherein at least one R 2  is R 5 X 1  wherein R 5 is as defined above and X 1  is —O—, —S—, —OC(O)— or —NR 10 — (wherein R 10  represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) may be prepared by the reaction of a compound of the formula VII:  
                     
 with a compound of the formula VIII:  
   R 5 —X 1 —H   (VIII)  
 (wherein R 1 , R 2 , R 5 , ring C, Z and n are as defined above and L 1 , s and X 1  are as herein defined);  
 (d) a compound of the formula I or a salt thereof wherein at least one R 2  is R 5 X 1  wherein X 1  is as defined above and R 5  is C 1-5 alkylR 113 , wherein R 113  is selected from one of the following nine groups: 
 1) X 19 C 1-3 alkyl (wherein X 19  represents —O—, —S—, —SO 2 —, —NR 114 C(O)— or —NR 115 SO 2 —(wherein R 114  and R 115  which may be the same or different are each hydrogen, C 1-3  alkyl or C 1-3 alkoxyC 2-3 alkyl);  
 2) NR 116 R 117  (wherein R 116  and R 117  which may be the same or different are each hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl);  
 3) X 20 C 1-5 alkylX 5 R 22  (wherein X 20  represents —O—, —S—, —SO 2 —, —NR 118 C(O)—, —NR 119 SO 2 — or —NR 120 — (wherein R 118 , R 119 , and R 120  which may be the same or different are each hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and X 5  and R 22  are as defined above);  
 4) R 28  (wherein R 28  is as defined above);  
 5) X 21 R 29  (wherein X 21  represents —O—, —S—, —SO 2 —, —NR 121 C(O)—, —NR 122 SO 2 —, or —NR 123 — (wherein R 121 , R 122 , and R 123  which may be the same or different are each hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 29  is as defined above); and  
 6) X 22 C 1-3 alkylR 29  (wherein X 22  represents —O—, —S—, —SO 2 —, —NR 124 C(O)—, —NR 125 SO 2 — or —NR 126  (wherein R 124 , R 125  and R 126  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 29  is as defined above);  
 7) R 29  (wherein R 29  is as defined above);  
 8) X 22 C 1-4 alkylR 28  (wherein X 22  and R 28  are as defined above); and  
 9) R 54 (C 1-4 alkyl) q (X 9 ) r R 55  (wherein q, r, X 9 , R 54  and R 55  are as defined above); may be prepared by reacting a compound of the formula IX:  
                     
 (wherein X 1 , R 1 , R 2 , ring C, Z and n are as defined above and L 1  and s are as herein defined) with a compound of the formula X:  
   R 113 —H   (X)  
 (wherein R 113  is as defined herein);  
 
 (e) a compound of the formula I or a salt thereof wherein one or more of the substituents (R 2 ) m  is represented by —NR 127 R 128 , where one (and the other is hydrogen) or both of R 127  and R 128  are C 1-3 alkyl, may be effected by the reaction of compounds of formula I wherein the substituent (R 2 ) m  is an amino group and an alkylating agent; or  
 (f) a compound of the formula I or a salt thereof wherein X 1  is —SO— or —SO 2 — may be prepared by oxidation from the corresponding compound in which X 1  is —S— or —SO—;  
 and optionally reacting the compound of formula I with an acid or base whereby to obtain a compound of formula I in salt form.  
 
 
     
     
         32 . The compound 4-fluoro-5-hydroxy-2-methylindole or a salt thereof.  
     
     
         33 . The compound 4-fluoro-5-hydroxyindole or a salt thereof.  
     
     
         34 . The compound 6-fluoro-5-hydroxy-2-methylindole or a salt thereof.  
     
     
         35 . The compound 6-fluoro-5-hydroxyindole or a salt thereof.  
     
     
         36 . A process for the preparation the compound of  claim 32  comprising the steps of: 
 (i) reacting 2-fluoro-4-nitroanisole with 4-chlorophenoxyacetonitrile to give a mixture of 4-fluoro-5-methoxyindole and 6-fluoro-5-methoxyindole; 
 (ii) reacting 4-fluoro-5-methoxyindole and 6-fluoro-5-methoxyindole with di-tert-butyl dicarbonate to give a mixture of 4-fluoro-5-methoxy-1-tert-butoxycarbonylindole and 6-fluoro-5-methoxy-1-tert-butoxycarbonylindole;  
   (iii) reacting 4-fluoro-5-methoxy-1-tert-butoxycarbonylindole and 6-fluoro-5-methoxy-1-tert-butoxycarbonylindole with tert-butyllithium followed by deprotection to give 6-fluoro-5-methoxy-2-methylindole and 4-fluoro-5-methoxy-2-methylindole; and    (iv) de-alkylating 4-fluoro-5-methoxy-2-methylindole to give 4-fluoro-5-hydroxy-2-methylindole.    
     
     
         37 . A process for the preparation of the compound of  claim 32  comprising the steps: 
 (i) reacting alkyl or aryl acetoacetate and 1,2,3-trifluoro-4-nitrobenzene to give 3-acetylmethyl-1,2-difluoro-4-nitrobenzene;    (ii) reacting 3-acetymethyl-1,2-difluoro-4-nitrobenzene with an orthoformate to give 1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene;    (iii) reacting benzyl alcohol or substituted benzyl alcohol or ethanol or propanol with sodium hydride and 1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene to give 3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene; and    (iv) hydrogenating 3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene to give 4-fluoro-5-hydroxy-2-methylindole.    
     
     
         38 . A process for the preparation of the compound of  claim 32  comprising the steps: 
 (i) reacting alkyl or aryl acetoacetate and 1,2,3-trifluoro-4-nitrobenzene to give 3-acetymethyl-1,2-difluoro-4-nitrobenzene;    (ii) reacting 3-acetymethyl-1,2-difluoro-4-nitrobenzene with an orthoformate to give 1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene;    (iii) reacting sodium methoxide with 1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene to give 3-acetylmethyl-2-fluoro-methoxy-4-nitrobenzene;    (iv) reacting 3-acetylmethyl-2-fluoro-1-methoxy-4-nitrobenzene with titanium trichloride to give 4-fluoro-5-methoxy-2-methylindole; and    (v) dealkylating 4-fluoro-5-methoxy-2-methylindole to give 4-fluoro-5-hydroxy-2-methylindole.    
     
     
         39 . A process for the preparation of a compound of  claim 33  or  claim 35 , comprising the steps: 
 (i) reacting 2-fluoro-4-nitrophenol and benzyl bromide to give 2-fluoro-4-nitrobenzyloxybenzene;    (ii) reacting 2-fluoro-4-nitro-benzyloxybenzene with 4-chlorophenoxyacetonitrile to give a mixture of 3-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene and 5-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene; and    (iii) hydrogenating a mixture of 3-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene and 5-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene to give 4-fluoro-5-hydroxyindole and 6-fluoro-5-hydroxyindole.    
     
     
         40 . A process for the preparation of a compound of  claim 34  comprising the steps: 
 (i) reacting 2-fluoro-4-nitroanisole with 4-chlorophenoxyacetonitrile to give a mixture of 4-fluoro-5-methoxyindole and 6-fluoro-5-methoxyindole;    (ii) reacting 4-fluoro-5-methoxyindole and 6-fluoro-5-methoxyindole with di-tert-butyl dicarbonate to give a mixture of 4-fluoro-5-methoxy-1-tert-butoxycarbonylindole and 6-fluoro-5-methoxy-1-tert-butoxycarbonylindole;    (iii) reacting 4-fluoro-5-methoxy-1-tert-butoxycarbonylindole and 6-fluoro-5-methoxy-1-tert-butoxycarbonylindole with tert-butyllithium followed by deprotection to give 6-fluoro-5-methoxy-2-methylindole and 4-fluoro-5-methoxy-2-methylindole; and    (iv) de-alkylating 6-fluoro-5-methoxy-2-methylindole to give 6-fluoro-5-hydroxy-2-methylindole.