2,4,DI (hetero-) arylamino (-oxy)-5-substituted pyrimidines as antineoplastic agents

A pyrimidine derivative of the formula (I):

• wherein:
• Q1 and Q2 are independently selected from aryl or heteroaryl linked via ring carbon;
• and one of Q1 and Q2 or both of Q1 and Q2 is substituted on a ring carbon by one substituent selected from N-(C1-2alkyl)amino, N,N-di-(C1-2alkyl)amino, phenyl, heterocyclic group, phenoxy, heterocyclic group—O—, substituted C1-2alkyl, substituted C1-2alkoxy, substituted C1-2alkoxycarbonyl, substituted N-(C1-2alkyl)amino, substituted C1-2alkoxyC1-2alkyl, substituted C2-4alkenyl and substituted C2-4alkynyl;
• wherein said substituents for C1-2alkyl, C1-2alkoxy, C1-2alkoxycarbonyl, N-(C1-2alkyl)amino, C1-2alkoxyC1-2alkyl, C2-4alkenyl and C2-4alkynyl are selected from halo, hydroxy, mercapto, nitro, formyl, formamido, carboxy, cyano, amino, ureido, carbamoyl, sulphamoyl, C1-4alkanoyl, C1-4alkoxycarbonyl, phenyl, heterocyclic group, benzoyl, heterocyclic group—C(O)—, C1-4alkylS(O)a wherein a is 0 to 2, N′-(C1-4alkyl)ureido, N′,N′-di-(C1-4alkyl)ureido, N′-(C1-4alkyl)-N-(C1-4alkyl)ureido, N′,N′-di-(C1-4alkyl)-N-(C1-4alkyl)ureido, N-C1-4alkylamino, N,N-di-(C1-4alkyl)amino, N-(C1-4alkyl)sulphamoyl, N,N-di-(C1-4alkyl)sulphamoyl, N-C1-4alkylcarbamoyl, N,N-di-(C1-4alkyl)carbamoyl and C1-4alkanoylamino;
• wherein any phenyl, benzyl, benzoyl or heterocyclic group is optionally substituted on a ring carbon by one or more groups selected from Ra;
• and wherein if any heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from Rb;
• G is —O— or —NR2—;
• R2 is selected from hydrogen, C1-6alkyl, C3-6alkenyl and C3-6alkynyl;
• wherein said C1-6alkyl, C3-6alkenyl and C3-6alkynyl are optionally substituted by one or more groups selected from Rc;
• R1 is selected from hydrogen, halo, hydroxy, nitro, amino, N-(C1-3alkyl)amino, N,N-di-(C1-3alkyl)amino, cyano, trifluoromethyl, trichloromethyl, C1-3alkyl [optionally substituted by 1 or 2 substituents independently selected from halo, cyano, amino, N-(C1-3alkyl)amino, N,N-di-(C1-3alkyl)amino, hydroxy and trifluoromethyl], C3-5alkenyl [optionally substituted by up to three halo substituents, or by one trifluoromethyl substituent], C3-5alkynyl, C1-3alkoxy, mercapto, C1-3alkylsulphanyl, carboxy and C1-3alkoxycarbonyl;
• Q1 is optionally substituted on a ring carbon by one to four substituents independently selected from halo, mercapto, nitro, formyl, formamido, carboxy, cyano, amino, ureido, carbamoyl, sulphamoyl, C1-4alkyl, C2-4alkenyl, C2-4alkynyl [wherein said C1-4alkyl, C2-4alkenyl and C2-4alkynyl are optionally substituted by one or more groups selected from Rd], C1-4alkanoyl, C1-4alkoxycarbonyl, heterocyclic group, C1-4alkylS(O)a [wherein a is 0 to 2 and said C1-4alkyl is optionally substituted by hydroxy], N′-(C1-4alkyl)ureido, N′,N′-di-(C1-4alkyl)ureido, N′-(C1-4alkyl)-N-(C1-4alkyl)ureido, N′,N′-di-(C1-4alkyl)-N-(C1-4alkyl)ureido, N-C1-4alkylamino, N,N-di-(C1-4alkyl)amino, N-(C1-4alkyl)sulphamoyl, N,N-di-(C1-4alkyl)sulphamoyl, N-C1-4alkylcarbamoyl, N,N-di-(C1-4alkyl)carbamoyl and C1-4alkanoylamino;
• and also independently, or in addition to, the above substituents, Q1 may be optionally substituted by one to two substituents independently selected from aryl, C3-8cycloalkyl and a heterocyclic group;
• wherein said aryl, C3-8cycloalkyl or heterocyclic group may be optionally substituted on a ring carbon by one or more groups selected from Re;
• and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from Rf;
• Q2 is optionally substituted on a ring carbon by one to four substituents independently selected from halo, hydroxy, mercapto, nitro, formyl, formamido, carboxy, cyano, amino, ureido, carbamoyl, sulphamoyl, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy [wherein said C1-4alkyl, C2-4alkenyl, C2-4alkynyl and C1-4alkoxy are optionally substituted by one or more groups selected from Rg], C1-4alkanoyl, C1-4alkoxycarbonyl, heterocyclic group, C1-4alkylS(O)a [wherein a is 0 to 2 and said C1-4alkyl is optionally substituted by hydroxy], N′-(C1-4alkyl)ureido, N′,N′-di-(C1-4alkyl)ureido, N′-(C1-4alkyl)-N-(C1-4alkyl)ureido, N′,N′-di-(C1-4alkyl)-N-(C1-4alkyl)ureido, N-C1-4alkylamino, N,N-di-(C1-4alkyl)amino, N-(C1-4alkyl)sulphamoyl, N,N-di-(C1-4alkyl)sulphamoyl, N-C1-4alkylcarbamoyl, N,N-di-(C1-4alkyl)carbamoyl, C2-4alkenyloxy, C2-4alkynyloxy, C1-4alkanoylamino;
• and also independently, or in addition to, the above substituents, Q2 may be optionally substituted by one to two substituents independently selected from aryl, C3-8cycloalkyl or a heterocyclic group;
• wherein said aryl, C3-8cycloalkyl or heterocyclic group may be optionally substituted on a ring carbon by one or more groups selected from Rh;
• and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from Ri;
• Rc, Rd and Rg are independently selected from hydroxy, halo, amino, cyano, formyl, formamido, carboxy, nitro, mercapto, carbamoyl, sulphamoyl, N-C1-4alkylamino, N,N-di-(C1-4alkyl)amino, C1-4alkanoyl, C1-4alkanoyloxy, C1-4alkoxy, C1-4alkoxycarbonyl, N-C1-4alkylcarbamoyl, N,N-di-(C1-4alkyl)carbamoyl, C1-4alkanoylamino, C1-4alkylS(O)a wherein a is 0 to 2, C1-4alkylsulphonylamino, N-(C1-4alkyl)sulphamoyl, N-(C1-4alkyl)2sulphamoyl, N-(C1-4alkyl)carbamoyl, N-(C1-4alkyl)2carbamoyl, phenyl, phenylthio, phenoxy, C3-8cycloalkyl and a heterocyclic group;
• wherein said phenyl, phenylthio, phenoxy, C3-8cycloalkyl or heterocyclic group may be optionally substituted on a ring carbon by one or more groups selected from Rj;
• and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from Rk;
• Ra, Re, Rh and Rj are independently selected from hydroxy, halo, amino, cyano, formyl, formamido, carboxy, nitro, mercapto, carbamoyl, sulphamoyl, C1-4alkyl [optionally substituted by one or more groups selected from halo, cyano, amino, N-C1-4alkylamino, N,N-di-(C1-4alkyl)amino or hydroxy], C2-4alkenyl [optionally substituted by one or more groups selected from halo], C2-4alkynyl, N-C1-4alkylamino, N,N-di-(C1-4alkyl)amino, C1-4alkanoyl, C1-4alkanoyloxy, C1-4alkoxy [optionally substituted by one or more groups selected from halo], C1-4alkoxycarbonyl, N-C1-4alkylcarbamoyl, N,N-di-(C1-4alkyl)carbamoyl, C1-4alkanoylamino, C1-4alkylS(O)a wherein a is 0 to 2, C1-4alkylsulphonylamino, N-(C1-4alkyl)sulphamoyl, N-(C1-4alkyl)2sulphamoyl, phenyl, C3-8cycloalkyl and a hetercyclic group;
• and
• Rb, Rf, Ri and Rk are independently selected from C1-4alkyl, C1-4alkanoyl, C1-4alkylsulphonyl, carbamoyl, N-(C1-4alkyl)carbamoyl, N,N-(C1-4alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;
• or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.