Substituted Quinazoline Derivatives as Inhibitors of Aurora Kinases

Abstract

The invention provides quinazoline derivatives of formula (I): in the preparation of a medicament for use in the inhibition of Aurora kinase and also novel quinazoline derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

1 . Use of a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a salt, ester or amide thereof, 
         where: 
         X is O or S, S(O) or S(O) 2 , or NR 6  where R 6  is hydrogen or C 1-6 alkyl; 
         R 5  is a group of formula (a) or (b): 
       
       
         
           
           
               
               
           
         
         where * indicates the point of attachment to the group X in formula (I); 
         R 1 , R 2 , R 3 , R 4  are independently selected from hydrogen, halo, cyano, nitro, trifluoromethyl, C 1-3 alkyl, —NR 7 R 8  or —X 1 R 9 ; 
         R 7  and R 8  are independently hydrogen or C 1-3 alkyl; 
         X 1  is a direct bond, —O—, —CH 2 —, —OCO—, carbonyl, —S—, —SO—, —SO 2 —, —NR 10 CO—, —CONR 11 —, —SO 2 NR 12 —, —NR 13 SO 2 — or —NR 14 —; 
         R 10 , R 11 , R 12 , R 13  and R 14  are independently hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl; 
         R 9  is selected from one of the following groups: 
         1) hydrogen or C 1-5 alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro or amino; 
         2) C 1-5 alkylX 2 COR 15  (wherein X 2  represents —O— or —NR 16 — (in which R 15  represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 16  represents C 1-3 alkyl, —NR 17 R 18  or —OR 19  (wherein R 17 , R 18  and R 19  which may be the same or different each represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl)); 
         3) C 1-5 alkylX 3 R 20  (wherein X 3  represents —O—, —S—, —SO—, —SO 2 —, —OCO—, —NR 21 CO—, —CONR 22 —, —SO 2 NR 23 —, —NR 24 SO 2 — or —NR 25 — (wherein R 21 , R 22 , R 23 , R 24  and R 25  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 20  represents hydrogen, C 1-3 alkyl, cyclopentyl, cyclohexyl or a 5- or 6-membered saturated heterocyclic group with 1 or 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, halo and C 1-4 alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halo, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy); 
         4) C 1-5 alkylX 4 C 1-5 alkylX 5 R 26  (wherein X 4  and X 5  which may be the same or different are each —O—, —S—, —SO—, —SO 2 —, —NR 27 CO—, —CONR 28 —, —SO 2 NR 29 —, —NR 30 SO 2 — or —NR 31 — (wherein R 27 , R 28 , R 29 , R 30  and R 31  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 26  represents hydrogen or C 1-13 alkyl); 
         5) R 32  (wherein R 2  is a 5- or 6-membered saturated heterocyclic group (linked via carbon or nitrogen) with 1 or 2 heteroatoms, selected independently from O, S and N, which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halo, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl and C 1-4 alkylsulphonylC 1-4 alkyl); 
         6) C 1-5 alkylR 32  (wherein R 32  is as defined hereinbefore); 
         7) C 2-5 alkenylR 32  (wherein R 32  is as defined hereinbefore); 
         8) C 2-5 alkynylR 32  (wherein R 32  is as defined hereinbefore); 
         9) R 33  (wherein R 33  represents a pyridone group, a phenyl group or a 5- or 6-membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1, 2 or 3 heteroatoms selected from O, N and S, which pyridone, phenyl or aromatic heterocyclic group may carry up to 5 substituents on available carbon atoms selected from hydroxy, halo, 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, —CONR 34 R 35  and —NR 36 COR 37  (wherein R 34 , R 35 , R 36  and R 37 , which may be the same or different, each represents hydrogen, C 1-4 alkyl or C 1-3 alkoxyC 2-3 alkyl)); 
         10) C 1-5 alkylR 33  (wherein R 33  is as defined hereinbefore); 
         11) C 2-5 alkenylR 33  (wherein R 33  is as defined hereinbefore); 
         12) C 2-5 alkynylR 33  (wherein R 33  is as defined hereinbefore); 
         13) C 1-5 alkylX 6 R 33  (wherein X 6  represents —O—, —S—, —SO—, —SO 2 —, —NR 38 CO—, —CONR 39 —, —SO 2 NR 40 —, —NR 41 SO 2 — or —NR 42 — (wherein R 38 , R 39 , R 40 , R 41  and R 42  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 33  is as defined hereinbefore); 
         14) C 2-5 alkenylX 7 R 33  (wherein X 7  represents —O—, —S—, —SO—, —SO 2 —, —NR 43 CO—, —CONR 44 —, —SO 2 NR 45 —, —NR 46 SO 2 — or —NR 47 — (wherein R 43 , R 44 , R 45 , R 46  and R 47  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 33  is as defined hereinbefore); 
         15) C 2-5 alkynylX 8 R 33  (wherein X 8  represents —O—, —S—, —SO—, —SO 2 —, —NR 48 CO—, —CONR 49 —, —SO 2 NR 50 —, —NR 51 SO 2 — or —NR 52  (wherein R 48 , R 49 , R 50 , R 51  and R 52  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 33  is as defined hereinbefore); 
         16) C 1-3 alkylX 9 C 1-3 alkylR 33  (wherein X 9  represents —O—, —S—, —SO—, —SO 2 —, —NR 53 CO—, —CONR 54 —SO 2 NR 55 , —NR 56 SO 2 — or —NR 5 — (wherein R 57 , R 53 , R 54 , R 55  and R 56  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 33  is as defined hereinbefore); 
         17) C 1-3 alkylX 9 C 1-3 alkylR 32  (wherein X 9  and R 28  are as defined hereinbefore); 
         18) C 1-5 alkyl optionally substituted by 1, 2 or 3 halo; 
         19) C 1-5 alkylX 10 C 1-5 alkylX 11 R 90  (wherein X 10  and X 11 , which may be the same or different, are each —O—, —S—, —SO—, —SO 2 —, —NR 91 CO—, —CONR 92 —, —SO 2 NR 93 —, —NR 94 SO 2 — or —NR 95 — (wherein R 91 , R 92 , R 93 , R 94  and R 95  each independently represents C 1-5 alkyl, C 1-3 alkyl (substituted by 1, 2 or 3 halo, C 1-4 alkyl or C 1-4 alkoxy groups (and where there are 2 C 1-4 alkoxy groups the C 1-4 alkyl groups of alkoxy may together form a 5- or 6-membered saturated heterocyclic group having 2 oxygen atoms)), C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl (optionally substituted by halo, hydroxy, C 1-3 alkyl or C 1-4 hydroxyalkyl), C 3-6 cycloalkylC 1-3 alkyl (optionally substituted by halo, hydroxy, C 1-3 alkyl or C 1-4 hydroxyalkyl) or C 1-3 alkoxyC 2-3 alkyl) and R 90  represents hydrogen or C 1-3 alkyl); 
         20) C 3-6 cycloalkyl; 
         21) R 96  (wherein R 96  is a 5- or 6-membered heterocyclic group which may be saturated or unsaturated (linked via carbon or nitrogen) with 1 or 2 heteroatoms, selected independently from O, S and N which heterocyclic group may bear 1 or 2 substitutents selected from C 1-4 hydroxyalkyl, C 1-4 alkyl, hydroxy and C 1-4 alkoxyC 1-4 alkyl; 
         22) C 1-5 alkylR 96  (wherein R 96  is defined hereinbefore); 
         and where: 
         R 60 , R 61  and R 62  are independently hydrogen, nitro, cyano, halo, oxo, amino, trifluoromethyl, C 1-4 alkoxymethyl, di(C 1-4 alkoxy)methyl or C 1-6 alkanoyl or a group selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heterocyclyl, heterocyclylC 1-10 alkyl, C 1-10 alkoxy, arylC 1-10 alkyl, aryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 cycloalkynyl (which group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, C 1-4 alkyl (optionally substituted by 1, 2 or 3 halo), mercapto, hydroxy, carboxy, C 1-10 alkoxy, nitro, cyano, aryl, heteroaryl, heteroaryloxy, C 2-10 alkenyloxy, C 2-10 alkynyloxy, C 1-4 alkoxyC 1-4 alkoxy, aryloxy (where the aryl group may be substituted by halo, nitro, or hydroxy), amino, cyano, nitro, mono- or di(C 1-6 alkyl)amino, oximino or S(O) y  where y is 0, 1, 2 or 3), or a group selected from ═CR 78 R 79 , C(O) x R 77 , OR 77 , S(O) y R 77 , NR 78 R 79 , C(O)NR 78 R 79 , OC(O)NR 78 R 79 , ═NOR 77 , —NR 77 C(O) x R 78 , —NR 77 CONR 78 R 79 , —N═CR 78 R 79 , S(O) y NR 78 R 79  or —NR 77 S(O) y R 78  or a group selected from phenyl, benzyl or a 5- to 6-membered heterocyclic group with 1, 2 or 3 heteroatoms, selected independently from O, S and N, which heterocyclic group may be aromatic or non-aromatic and may be saturated (linked via a ring carbon or nitrogen atom) or unsaturated (linked via a ring carbon atom), which phenyl, benzyl or heterocyclic group may bear on one or more carbon ring atoms up to 5 substituents selected from hydroxy, halo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino, nitro, C 2-4 alkanoyl, 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, C 1-4 alkylsulphonylamino, and a saturated heterocyclic group selected from morpholino, thiomorpholino, pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl and pyrazolidinyl, which saturated heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino, nitro and C 1-4 alkoxycarbonyl, 
         or a group of sub-formula (k): 
       
       
         
           
           
               
               
           
         
         or a group of sub-formula (II): 
       
       
         
           
           
               
               
           
         
         or a group of sub-formula (VI): 
       
       
         
           
           
               
               
           
         
         where: 
         p and q are independently 0 or 1; 
         r is 0, 1, 2, 3 or 4; 
         R 1 ′ and R 1 ″ are independently hydrogen, hydroxy, halo, cyano, C 1-10 alkyl, C 3-10 cycloalkyl, C 2-10 alkenyl or C 2-10 alkynyl (wherein C 1-10 alkyl, C 3-10 cycloalkyl, C 2-10 alkenyl and C 2-10 alkynyl are optionally substituted by halo, nitro, cyano, hydroxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-14 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkanoyloxy, C 1-4 alkanoylamino, N,N-di(C 1-4 alkanoyl)amino, N—(C 1-14 alkyl)carbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-14 alkylS, C 1-4 alkylS(O), C 1-4 alkylS(O) 2 , C 1-4 alkoxycarbonyl, N—(C 1-4  alkyl)sulphamoyl, N,N-di(C 1-4 alkyl)sulphamoyl, C 1-14 alkylsulphonylamino or heterocyclyl); 
         or R 1 ′ and R 1 ″ can together form a 3- to 6-membered ring which may be saturated or unsaturated; 
         T is C═O, SO n  (where n is 0, 1 or 2), C(═NOR)CO, C(O)C(O), C═NCN or CV═NO; 
         V is independently R 63  or N(R 63 )R 64 ; 
         R 63  and R 64  are independently selected from hydrogen, —(CH 2 ) q′ R 70  (q′ is 0 or 1), aryl (optionally substituted by 1, 2 or 3 C 1-6 alkyl (optionally substituted by 1, 2 or 3 hydroxy groups)), C 1-10 alkyl (optionally substituted by 1, 2 or 3 groups independently selected from aryl or heterocyclic group where aryl and heterocyclic group are optionally substituted by 1, 2, or 3 groups independently selected from C 1-6 alkyl, nitro, cyano, halo, oxo, ═CR 78 R 79 , C(O) x R 77 , OR 77 , S(O) y R 77 , NR 78 R 79 , C(O)NR 78 R 79 , OC(O)NR 78 R 79 , ═NOR 77 , —NR 77 C(O) x R 78 , —NR 77 CONR 78 R 79 , —N═CR 78 R 79 , S(O) y NR 78 R 79 , —NR 77 S(O) y R 78 ) or a group selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heterocyclyl, C 1-10 alkoxy, C 1-10 alkyl, aryl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 3-10 cycloalkynyl (which group is optionally substituted by 1, 2 or 3 groups independently selected from C 1-6 alkyl, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, nitro, cyano, halo, oxo, ═CR 78 R 79 , C(O) x R 77 , OR 77 , S(O) y R 77 , NR 78 R 79 , C(O)NR 78 R 79 , OC(O)NR 78 R 79 , ═NOR 77 , —NR 77 C(O) x R 78 , —NR 77 CONR 78 R 79 , —N═CR 78 R 79 , S(O) y NR 78 R 79 , —NR 77 S(O) y R 71 ); 
         or R 63  and R 64  together with the nitrogen atom to which they are attached form a heterocyclic ring which ring is aromatic or non-aromatic and which is optionally substituted by hydroxy, C 1-6 alkoxy or C 1-6 alkyl (optionally substituted by hydroxy); 
         R 70  is hydrogen, hydroxy (other than when q is 0), C 1-6 alkyl, C 1-6 alkoxy, amino, N—C 1-6 alkylamino, N,N-di(C 1-6 alkyl)amino, C 2-6 hydroxyalkoxy, C 1-6 alkoxyC 2-6 alkoxy, aminoC 2-6 alkoxy, N—C 1-6 alkylaminoC 2-6 alkoxy, N,N-di(C 1-6 alkyl)aminoC 2-6 alkoxy, C 3-7 cycloalkyl (optionally substituted by 1 or 2 oxo or thioxo substitutents) or of formula (III):
   —K-J  (III) 
 
         K is a bond, oxy, imino, N—(C 1-6 alkyl)imino, oxyC 1-6 alkylene, iminoC 1-6 alkylene, N—(C 1-6 alkyl)iminoC 1-6 alkylene, —NHC(O)—, —SO 2 NH—, —NHSO 2 —, —NHC(O)—C 1-6 alkylene-, —OCO— or C 2-4 alkenylene; 
         J is aryl, heteroaryl or heterocyclyl (where hetrocyclyl is optionally substituents by 1 or 2 oxo or thioxo substituents); 
         and wherein any aryl, heteroaryl or heterocyclyl group in a R 70  group is optionally substituted by 1, 2, 3 or 4 groups selected from hydroxy, halo, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, aminosulphonyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, —O—(C 1-3 alkyl)-O—, C 1-6 alkylS(O) n — (where n is 0, 1 or 2), N—C 1-6 alkylamino, N,N-di(C 1-6 alkyl)amino, C 1-6 alkoxycarbonyl, N—C 1-6 alkylcarbamoyl, N,N-di(C 1-6 alkyl)carbamoyl, C 2-6 alkanoyl, C 1-6 alkanoyloxy, C 1-6 alkanoylamino, N—C 1-6 alkylaminosulphonyl, N,N-di(C 1-6 alkyl)aminosulphonyl, C 1-6 alkylsulphonylamino and C 1-6 alkylsulphonyl-N—(C 1-6 alkyl)amino or by 1, 2, 3 or 4 groups selected from: 
         a group of formula (IV) 
       
       
         
           
           
               
               
           
         
         (wherein A 1  is halo, hydroxy, C 1-6 alkoxy, cyano, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, carboxy, C 1-6 alkoxycarbonyl, carbamoyl, N—C 1-6 alkylcarbamoyl or 
         N,N-di(C 1-6 alkyl)carbamoyl; p′ is 1, 2, 3, 4, 5 or 6; and B 1  is a bond, oxy, imino, N—(C 1-6 alkyl)imino or —NHC(O)—; with the proviso that p is 2 or more unless B 1  is a bond or —NHC(O)—); 
         and a group of formula (V) 
       
       
         
           
           
               
               
           
         
         (wherein D 1  is aryl, heteroaryl or heterocyclyl (where heterocyclyl is optionally substituted by 1 or 2 oxo or thioxo substituents) and E 1  is a bond, C 1-6 alkylene, oxyC 1-6 alkylene, oxy, imino, N—(C 1-6 alkyl)imino, iminoC 1-6 alkylene, N—(C 1-6 alkyl)iminoC 1-6 alkylene, C 1-6 alkylene-oxyC 1-6 alkylene, C 1-6 alkylene-iminoC 1-16 alkylene, C 1-16 alkylene-N—(C 1-16 alkyl)-iminoC 1-6 alkylene, —NHC(O)—, —NHSO 2 —, —SO 2 NH— or —NHC(O)—C 1-6 alkylene-, and any aryl, heteroaryl or heterocyclyl group in a substituent on D 1  is optionally substituted with 1, 2, 3 or 4 groups selected from hydroxy, halo, C 1-6 alkyl, C 1-6 alkoxy, carboxy, C 1-6 alkoxycarbonyl, carbamoyl, N—C 1-6 alkylcarbamoyl, N,N-di(C 1-16 alkyl)carbamoyl, C 2-6 alkanoyl, amino, C 1-16 alkylamino and di(C 1-6 alkyl)amino); 
         and any of the R 70  groups defined hereinbefore which comprises a CH 2  group which is attached to 2 carbon atoms or a CH 3  group which is attached to a carbon atom optionally bears on each said CH 2  or CH 3  group a substituent selected from hydroxy, amino, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino and heterocyclyl; 
         R 71  and R 72  are independently selected from hydrogen or C 1-4 alkyl or R 71  and R 72  together form a bond; 
         R 73  is OR 74  or NR 71 R 76 ; 
         R 74 , R 75  and R 76  are independently C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heterocyclyl, C 1-10 alkoxy, arylC 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 3-10 cycloalkynyl, each of which is optionally substituted by 1, 2, 3 or 4 groups selected from nitro, cyano, halo, oxo, ═CR 78 R 79 , C(O) x R 77 , OR 77 , S(O) y R 77 , NR 78 R 79 , C(O)NR 78 R 79 , OC(O)NR 78 R 79 , ═NOR 77 , —NR 77 C(O) x R 78 , —NR 77 CONR 78 R 79 , —N═CR 78 R 79 , S(O) y NR 78 R 79  or —NR 77 S(O) y R 78  where y is 0, 1, 2 or 3; or R 74 , R 75  and R 76  are independently heterocyclyl optionally substituted by C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 3-6 cycloalkyl; 
         or R 75  and R 76  together with the nitrogen to which they are attached form an aromatic or non-aromatic ring which optionally contains 1, 2 or 3 further heteroatoms independently selected from N, O and S; 
         R 77 , R 78  and R 79  are independently selected from hydrogen or a group selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heterocyclyl, C 1-10 alkoxy, arylC 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 3-10 cycloalkynyl where the group is optionally substituted by halo, C 1-4  perhaloalkyl, mercapto, hydroxy, carboxy, C 1-10 alkoxy, aryl, heteroaryl, heteroaryloxy, C 2-10 alkenyloxy, C 2-10 alkynyloxy, C 1-6 alkoxyC 1-6 alkoxy, aryloxy (where the aryl group may be substituted by halo, nitro, or hydroxy), cyano, nitro, amino, mono- or di(C 1-6 alkyl)amino, oximino or S(O) y  where y is 0, 1, 2 or 3; 
         or R 78  and R 79  together form a ring which optionally contains further heteroatoms such as S(O) y  oxygen and nitrogen, x is an integer of 1 or 2, y is 0, 1, 2 or 3 which ring is optionally substituted by 1, 2 or 3 groups independently selected from halo, C 1-4  perhaloalkyl, mercapto, hydroxy, carboxy, C 1-10 alkoxy, aryl, heteroaryl, heteroaryloxy, C 2-10 alkenyloxy, C 2-10 alkynyloxy, C 1-6 alkoxyC 1-6 alkoxy, aryloxy (where the aryl group may be substituted by halo, nitro, or hydroxy), cyano, nitro, amino, mono- or di(C 1-6 alkyl)amino, oximino or S(O) y  where y is 0, 1, 2 or 3; 
         in the preparation of a medicament for use in the inhibition of Aurora kinase. 
       
     
     
         2 . Use according to  claim 1  wherein Aurora kinase is Aurora-A kinase. 
     
     
         3 . Use according to  claim 1  or  2  wherein R 9  is hydrogen, C 3-6 cycloalkyl, —C 1-5 alkyl-O—C 1-3 alkyl or a 5- to 6-membered saturated heterocyclic group (linked via carbon or nitrogen) with 1 or 2 heteroatoms selected independently from O, S or N which heterocyclic group is optionally substituted by C 1-4 alkyl or R 9  is a 5- or 6-membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1, 2 or 3 heteroatoms or R 9  is —C 1-5 alkylR 32 , —C 1-5 alkylR 96 , C 1-5 alkyl (optionally substituted by halo), —C 1-5 alkyl-OR 20 , —C 1-5 alkyl-NHR 20 , —C 1-5 alkyl-N(C 1-3 alkyl)-R 20 , —C 1-5 alkyl-NH—C 1-5 alkyl-OH, —C 1-5 alkyl-N(C 1-3 alkyl)-C 1-5 alkyl-OH and —C 1-5 alkyl-NR 95 —C 1-5 alkyl-OH and wherein R 32 , R 96 , R 20  and R 95  are as defined in  claim 1 . 
     
     
         4 . Use according to any one of the preceding claims wherein X 1  is —O—. 
     
     
         5 . Use according to any one of the preceding claims wherein R 1  is hydrogen, methoxy, N—(C 1-5 alkyl)piperidin-4-yloxy, prop-2-yloxy or methoxyethoxy; R 2  is hydrogen or methoxy; and R 4  is hydrogen. 
     
     
         6 . A method for inhibiting Aurora kinase in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound as defined in  claim 1 , or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 
     
     
         7 . A compound of formula (IA): 
       
         
           
           
               
               
           
         
         or a salt, ester or amide thereof, 
         wherein X is as defined in  claim 1 ; 
         R 1′ , R 2′ , R 3′ , R 4′  are equivalent to R 1 , R 2 , R 3 , R 4  as defined in  claim 1 ; and 
         R 5a  is equivalent to R 5  as defined in  claim 1 ; 
         provided that one of R 60 , R 61  and R 62  of R 5a  is other than hydrogen and that if R 61  is other than hydrogen, it is not a group selected from:
 phenylC 1-3 alkyl, heteroaryl or optionally substituted phenyl; and 
 C 3-5 cycloalkyl, C 3-5 cycloalkylC 1-3 alkyl, C 2-5 alkenyl or optionally substituted C 1-4 alkyl; 
 
         where optional substitutents for phenyl and C 1-4 alkyl are C 1-4 alkyl, halo, methoxy, nitro or trifluoromethyl. 
       
     
     
         8 . A compound according to  claim 7  wherein R 60  and R 62  are both hydrogen and R 61  is a group of sub-formula (k): 
       
         
           
           
               
               
           
         
         wherein R 1 ′ and R 1 ″ are independently hydrogen or C 1-3 alkyl; T is C═O; q is 1; and V is N(R 63 )R 64 . 
       
     
     
         9 . A compound according to  claim 8  wherein R 64  is hydrogen or C 1-3 alkyl and R 63  is aryl optionally substituted by 1 or 2 substituents independently selected from halo, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, hydroxy, nitro, difluoromethyl, difluoromethoxy and cyano. 
     
     
         10 . A compound according to  claim 9  wherein R 61  is —CH 2 —COR 64 -J and wherein J is phenyl optionally substituted by 1 or 2 halo. 
     
     
         11 . A compound according to any one of  claims 8  to  10  wherein R 9  is hydrogen, C 3-6 cycloalkyl, —C 1-5 alkyl-O—C 1-3 alkyl or a 5- to 6-membered saturated heterocyclic group (linked via carbon or nitrogen) with 1 or 2 heteroatoms selected independently from O, S or N which heterocyclic group is optionally substituted by C 1-14 alkyl or R 9  is a 5- or 6-membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1, 2 or 3 heteroatoms or R 9  is —C 1-5 alkylR 32 , —C 1-5 alkylR 96 , C 1-5 alkyl (optionally substituted by halo), —C 1-15 alkyl-OR 20 , —C 1-5 alkyl-NHR 20 , —C 1-5 alkyl-N(C 1-3 alkyl)-R 20 , —C 1-5 alkyl-NH—C 1-5 alkyl-OH, —C 1-5 alkyl-N(C 1-3 alkyl)-C 1-5 alkyl-OH and —C 1-5 alkyl-NR 95 —C 1-5 alkyl-OH and wherein R 32 , R 96 , R 20  and R 95  are as defined in  claim 1 . 
     
     
         12 . A compound according to any one of  claims 8  to  11  wherein R 1  is hydrogen, methoxy, N—(C 1-15 alkyl)piperidin-4-yloxy, prop-2-yloxy or methoxyethoxy; R 2  is hydrogen or methoxy; and R 4  is hydrogen. 
     
     
         13 . Use of a compound as defined in any one of  claims 7  to  12  as a medicament. 
     
     
         14 . Use of a compound as defined in any one of  claims 8  to  12  in the preparation of a medicament for use in the inhibition of Aurora kinase. 
     
     
         15 . Use according to  claim 14  wherein Aurora kinase is Aurora-A kinase. 
     
     
         16 . A pharmaceutical composition comprising a compound according to any one of  claims 7  to  12 , or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier. 
     
     
         17 . A process for the preparation of a compound according to  claim 7  comprising the step of:
 a) when X is NH, reacting a compound of formula (VII)   
       
         
           
           
               
               
           
         
       
       where R 1 , R 2 , R 3 , and R 4  are R 1′ , R 2′ , R 3′ , and R 4′  as defined in  claim 7  and R 85  is a group NR 86 R 87  where R 86  and R 87  are independently selected from C 1-4 alkyl, with a compound of formula (VIII)
   H 2 N—R 5′   (VIII) 
 where R 5′  is a group R 5a  as defined in  claim 7  or a precursor group thereof, and thereafter if desired or necessary, converting a precursor group R 5′  to a group R 5  or R 5a  and/or modifying substituents on the group R 5  or R 5a ; or 
 b) when X is as defined in  claim 6 , reacting a compound of formula (X) 
 
       
         
           
           
               
               
           
         
         where R 1′ , R 2″ , R 3″ , and R 4′  are equivalent to a group R 1′ , R 2′ , R 3′  and R 4′  as defined in  claim 6  or a precursor thereof, and R 85  is a leaving group, with a compound of formula (XI)
   H—X—R 5   (XI) 
 
         and R 5  is R 5a  as defined in  claim 6 : and thereafter if desired or necessary converting a group R 1′ , R 2″ , R 3″  or R 4′  to a group R 1′ , R 2′ , R 3′  and R 4′  respectively or to a different such group.