Substituted quinazoline derivatives as inhibitors of aurora kinases

A compound of formula (IA):

• or a salt, ester or amide thereof;
• X is O or S, S(O) or S(O)2, or NR6 where R6 is hydrogen or C1-6alkyl;
• R5a is a group of formula (a) or (b):
• where * indicates the point of attachment to the group X in formula (I);
• R1′, R2′, R3′, R4′ are independently selected from hydrogen, halo, cyano, nitro, trifluoromethyl, C1-3alkyl, —NR7R8 or —X1R9;
• wherein at least one of R1′, R2′, R3′ and R4′ is —X1R9;
• R7 and R8 are independently hydrogen or C1-3alkyl;
• X1 is —O—, —CH2—, —OCO—, carbonyl, —S—, —SO—, —SO2—, —NR10CO—, —CONR11—, —SO2NR12—, —NR13SO2— or —NR14—;
• R10, R11, R12, R13 and R14 are independently hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl;
• R9 is selected from one of the following groups:
• 1) hydrogen or C1-5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro or amino;
• 2) C1-5alkylX2COR15 wherein X2 represents —O— or —NR16— in which R15 represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl and R16 represents C1-3alkyl, —NR17R18 or —OR19 wherein R17, R18 and R19 which may be the same or different each represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl;
• 3) C1-5alkylX3R20 wherein X3 represents —O—, —S—, —SO—, —SO2—, —OCO—, —NR21CO—, —CONR22—, —SO2NR23—, —NR24SO2— or —NR25— wherein R21, R22, R23, R24 and R25 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl and R20 represents hydrogen, C1-3alkyl, cyclopentyl, cyclohexyl or a 5- or 6-membered saturated heterocyclic group with 1 or 2 heteroatoms, selected independently from O, S and N, which C1-3alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halo and C1-4alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halo, C1-4alkyl, C1-4hydroxyalkyl and C1-4alkoxy;
• 4) C1-5alkylX4C1-5alkylX5R26 wherein X4 and X5 which may be the same or different are each —O—, —S—, —SO—, —SO2—, —NR27CO—, —CONR28—, —SO2NR29—, —NR30SO2— or —NR31— wherein R27, R28, R29, R30 and R31 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl and R26 represents hydrogen or C1-3alkyl;
• 5) R32 wherein R32 is a 5- or 6-membered saturated heterocyclic group linked via carbon or nitrogen with 1 or 2 heteroatoms, selected independently from O, S and N, which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halo, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, C1-4alkoxyC1-4alkyl and C1-4alkylsulphonylC1-4alkyl;
• 6) C1-5alkylR32 wherein R32 is as defined hereinbefore;
• 7) C2-5alkenylR32 wherein R32 is as defined hereinbefore;
• 8) C2-5alkynylR32 wherein R32 is as defined hereinbefore;
• 9) R33 wherein R33 represents a pyridone group, a phenyl group or a 5- or 6-membered aromatic heterocyclic group linked via carbon or nitrogen with 1, 2 or 3 heteroatoms selected from O, N and S, which pyridone, phenyl or aromatic heterocyclic group may carry up to 5 substituents on available carbon atoms selected from hydroxy, halo, amino, C1-4alkyl, C1-4alkoxy, C1-4hydroxyalkyl, C1-4aminoalkyl, C1-4alkylamino, C1-4hydroxyalkoxy, carboxy, trifluoromethyl, cyano, —CONR34R35 and —NR36COR37 wherein R34, R35, R36 and R37, which may be the same or different, each represents hydrogen, C1-4alkyl or C1-3alkoxyC2-3alkyl;
• 10) C1-5alkylR33 wherein R33 is as defined hereinbefore;
• 11) C2-5alkenylR33 wherein R33 is as defined hereinbefore;
• 12) C2-5alkynylR33 wherein R33 is as defined hereinbefore;
• 13) C1-5alkylX6R33 wherein X6 represents —O—, —S—, —SO—, —SO2—, —NR38CO—, —CONR39—, —SO2NR40—, —NR41SO2— or —NR42— wherein R38, R39, R40, R41 and R42 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl and R33 is as defined hereinbefore;
• 14) C2-5alkenylX7R33 wherein X7 represents —O—, —S—, —SO—, —SO2—, —NR43CO—, —CONR44—, —SO2NR45—, —NR46SO2— or —NR47— wherein R43, R44, R45, R46 and R47 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl and R33 is as defined hereinbefore;
• 15) C2-5alkynylX8R33 wherein X8 represents —O—, —S—, —SO—, —SO2—, —NR48CO—, —CONR49—, —SO2NR50—, —NR51SO2— or —NR52— wherein R48, R49, R50, R51 and R52 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl and R33 is as defined hereinbefore;
• 16) C1-3alkylX9C1-3alkylR33 wherein X9 represents —O—, —S—, —SO—, —SO2—, —NR53CO—, —CONR54—, —SO2NR55—, —NR56SO2— or —NR57— wherein R53, R54, R55, R56 and R57 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl and R33 is as defined hereinbefore;
• 17) C1-3alkylX9C1-3alkylR32 wherein X9 and R32 are as defined hereinbefore;
• 18) C1-5alkyl optionally substituted by 1, 2 or 3 halo;
• 19) C1-5alkylX10C1-5alkylX11R90 wherein X10 and X11, which may be the same or different, are each —O—, —S—, —SO—, —SO2—, —NR91CO—, —CONR92—, —SO2NR93—, —NR94SO2— or —NR95— where R91, R92, R93, R94 and R95 each independently represents C1-5alkyl, C1-3alkyl substituted by 1, 2 or 3 halo, C1-4alkyl or C1-4alkoxy groups and where there are 2 C1-4alkoxy groups the C1-4alkyl groups of alkoxy may together form a 5- or 6-membered saturated heterocyclic group having 2 oxygen atoms, C2-5alkenyl, C2-5alkynyl, C3-6cycloalkyl optionally substituted by halo, hydroxy, C1-3alkyl or C1-4hydroxyalkyl, C3-6cycloalkylC1-3alkyl optionally substituted by halo, hydroxy, C1-3alkyl or C1-4hydroxyalkyl or C1-3alkoxyC2-3alkyl and R90 represents hydrogen or C1-3alkyl;
• 20) C3-6cycloalkyl;
• 21) R96 wherein R96 is a 5- or 6-membered heterocyclic group which may be saturated or unsaturated linked via carbon or nitrogen with 1 or 2 heteroatoms, selected independently from O, S and N which heterocyclic group may bear 1 or 2 substituents selected from C1-4hydroxyalkyl, C1-4alkyl, hydroxy and C1-4alkoxyC1-4alkyl;
• 22) C1-5alkylR96 wherein R96 is defined hereinbefore;
• and where:
• R60 is hydrogen, nitro, halo, cyano, or C1-3alkyl;
• R61 is a group of sub-formula (k):
• where:
• p is 0 or 1;
• q is 1;
• R1′ and R1″ are independently hydrogen, hydroxy, halo, cyano, C1-10alkyl, C3-10cycloalkyl, C2-10alkenyl or C2-10alkynyl;
• wherein C1-10alkyl, C3-10cycloalkyl, C2-10alkenyl and C2-10alkynyl are optionally substituted by halo, nitro, cyano, hydroxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C3-6cycloalkyl, C3-6cycloalkenyl, C1-4alkoxy, C1-4alkanoyl, C1-4alkanoyloxy, C1-4alkanoylamino, N,N-di(C1-4alkanoyl)amino, N-(C1-4alkyl)carbamoyl, N,N-di(C1-4alkyl)carbamoyl, C1-4alkylS, C1-4alkylS(O), C1-4alkylS(O)2, C1-4alkoxycarbonyl, N-(C1-4 alkyl)sulphamoyl, N,N-di(C1-4alkyl)sulphamoyl, C1-4alkylsulphonylamino or heterocyclyl;
• or R1′ and R1″ can together form a 3- to 6-membered ring which may be saturated or unsaturated;
• T is C═O or SOn wherein n is 0, 1 or 2;
• V is independently selected from R63 or N(R63)R64;
• R63 is —(CH2)q′R70 or aryl or heteroaryl where the latter two groups are optionally substituted by 1 or 2 substituents independently selected from halo, C1-4alkyl, C1-4alkoxy, trifluoromethyl, trifluoromethoxy, hydroxy, nitro, difluoromethyl, difluoromethoxy and cyano;
• R64 is hydrogen or C1-3alkyl;
• q′ is 0 or 1
• R70 is of formula (III):
• —K—J (III)
• K is a bond;
• J is aryl or heteroaryl which are both optionally substituted by 1, 2 or 3 substituents selected from halo, C1-3alkyl, C3-4cycloalkyl, C3-4cycloalkylC1-3alkyl, cyano and C1-3alkoxy;
• and
• R62 is hydrogen, halo or C1-3alkyl.