Pyrimidinone compounds

A process for preparing a compound of formula (I)

• in which:
• R1 is an aryl or heteroaryl group, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C(1-18)alkyl, C(1-18)alkoxy, C(1-18)alkylthio, arylC(1-18)alkoxy, hydroxy, halogen, CN, COR6, carboxy, COOR6, CONR9R10, NR6COR7, SO2NR9R10, NR6SO2R7, NR9R10, mono to perfluoro-C(1-4)alky and mono to perfluoro-C(1-4)alkoxy, oxo, CH2COOH or a salt thereof, CH2COOR8, CH2CONR9R10, CH2CN, (CH2)mNR9R10, (CH2)mOH or (CH2)mOR6 where m is an integer from 1 to 3;
• R2 is an aryl or heteroaryl group, optoinally substituted 1, 2, 3 or 4 substituents which may be the same or different selected from C(1-18)alkyl, C(1-18)alkoxy, C(1-18)alkylthio, arylC(1-18)alkoxy, hydroxy, halogen, CN, COR6, carboxy, COOR6, CONR9R10, NR6COR7, SO2NR9R10, NR6SO2R7, NR9R10, mono to perfluoro-C(1-4)alkyl, mono to perfluoro-C(1-4)alkoxy, and arylC(1-4)alkyl;
• R3 is hydrogen or C(1-4)alkyl which may be unsubstituted or substituted by hydroxy, OR6, COR6, carboxy, COOR6, CONR9R10, NR9R10, mono- or di-(hydroxyC(1-6)alkyl)amino or N-hydroxyC(1-6)alkyl-N-C(1-6)alkyl amino;
• R4 is an aryl or a heteroaryl ring optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C(1-18)alkyl, C(1-18)alkoxy, C(1-18)alkylthio, arylC(1-18)alkoxy, hydroxy, halogen, CN, COR6, carboxy, COOR6, CONR9R10, NR6COR7, SO2NR9R10, NR6SO2R7, NR9R10, mono to perfluoro-C(1-4)alkyl and mono to perfluoro-C(1-4)alkoxy;
• R5 is an aryl ring which is further optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C(1-18)alkyl, C(1-18)alkoxy, C(1-18)alkylthio, arylC(1-18)alkoxy, hydroxy, halogen, CN, COR6, carboxy, COOR6, CONR9R10, NR6COR7, SO2NR9R10, NR6SO2R7, NR9R10, mono to perfluoro-C(1-4)alkyl and mono to perfluoro-C(1-4)alkoxy;
• R6 and R7 are independently hydrogen or C(1-20)alkyl, for instance C(1-4)alkyl (e.g. methyl or ethyl);
• R8 is C(1-4)alkyl or a pharmaceutically acceptable in vivo hydrolysable ester group;
• R9 and R10 which may be the same or different is each selected from hydrogen, C(1-12)alkyl, CH2R11, CHR12CO2H or a salt thereof, or R9 and R10 together with the nitrogen to which they are attached form a 4- to 7-, preferably 5- to 7-, membered ring optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur, and optionally substituted by one or two substituents selected from hydroxy, oxo, C(1-4)alkyl, C(1-4)alkylCO, or aryl;
• R11 is COOH or a salt thereof, COOR8, CONR6R7, CN, CH2OH or CH2OR6;
• R12 is an amino acid side chain;
• n is an integer from 1 to 4, preferably 1 or 3;
• X is O or S;
• and
• Z is CR13R14 where R13 and R14 are each hydrogen or C(1-4)alkyl, or R13 and R14 together with the intervening carbon atom form a C(3-6)cycloalkyl ring;
• which process comprises:
• (a) reacting a compound of formula (II):
• in which X, Y, Z, R1 and R2 are the same as defined herein above for formula (I),
• with a compound of formula (III):
• R5—R4—CH2NHR3 (III)
• in which R3, R4 and R5 are the same as defined herein above for formula (I);
• under amide forming conditions;
• (b) reacting a compound of formula (IV):
• in which X, Z, R1 and R2 are the same as defined herein above for formula (I), with a compound of formula (V):
• R5—R4—CH2NR3—CO—(CH2)n-L1 (V)
• in which n, R3, R4 and R5 are the same as defined herein above for formula (I), and L1 is a leaving group such as halogen;
• in the presence of a base such as a secondary or tertiary amine, in an inert solvent;
• (c) when X is S, reacting a compound of formula (VI):
• in which n, Z, R1, R3, R4 and R5 are the same as defined herein above for formula (I), with a compound of formula (VII):
• R2—CH2-L1 (VII)
• in which R2 and L1 are the same as defined herein above for formula (I),
• in the presence of a base such as a secondary or tertiary amine, in an inert solvent;
• or
• (d) when X is O, reacting a compound of formula (VIII):
• in which n, Z, R1, R3, R4 and R5 are the same as defined herein above for formula (I), and L2 is a leaving group,
• with a compound of formula (IX):
• R2—CH2—OH (IX)
• in which R2 is the same as defined herein above for formula (I), in the presence of a base, in an inert solvent.