Pyrimidine compounds

1. A pyrimidine derivative of the formula (I):

wherein:

Q 1 and Q 2 are independently selected from aryl or carbon linked heteroaryl; and Q 1 is substituted on a ring carbon by a sulphamoyl group, or one of Q 1 and Q 2 or both Q 1 and Q 2 is substituted on a ring carbon by one group selected from N—(C 1-4 alkyl)sulphamoyl (optionally substituted by halo or hydroxy), N,N-di-(C 1-4 alkyl)sulphamoyl (optionally substituted by halo or hydroxy), C 1-4 alkylsulphonyl (optionally substituted by halo or hydroxy) or a substituent of the formula (Ia) or (Ia′):

wherein:

Y is —NHS(O) 2 —, —S(O) 2 NH— or —S(O) 2 —;

Z is R a O—, R b R c N—, R d S—, R e R f NNR g —, C 3-8 cycloalkyl, phenyl or a heteroc wherein said phenyl, C 3-8 cycloalkyl or heterocyclic group are optionally substituted on a rig carbon by one or more groups selected from R h ; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R i ;

R a , R b , R c , R d , R e , R f and R g are independently selected from hydrogen, C 1-4 alkyl, C 2-4 alkenyl, phenyl, heterocyclic group and C 3-8 cycloalkyl; wherein said C 1-4 alkyl, C 2-4 alkenyl and C 3-8 cycloalkyl are optionally substituted by one or more groups selected from R j ;

n is 0 or 1;

m is 1, 2 or 3, in addition m may be 0 when Z is C 3-8 cycloalkyl, phenyl or a heterocyclic group;

Q 3 is a nitrogen linked heterocycle; wherein said heterocycle is optionally substituted on a ring carbon by one or more groups selected from R k ; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R m

G is —O—, —S— or —NR 2 —;

R 2 is selected from hydrogen, C 1-6 alkyl, C 3-6 alkenyl and C 3-6 alkynyl; wherein said C 1-6 alkyl, C 3-6 alkenyl and C 3-6 alkynyl are optionally substituted by one or more groups selected from R n ;

R 1 is selected from hydrogen, halo, hydroxy, amino, N—(C 1-3 alkyl)amino, N,N-di-(C 1-3 alkyl)amino, cyano, trifluoromethyl, trichloromethyl, C 1-3 alkyl [optionally substituted by 1 or 2 substituents independently selected from halo, cyano, amino, N—(C 1-3 alkyl)amino, N,N-di-(C 1-3 alkyl)amino, hydroxy and trifluoromethyl], C 3-5 alkenyl [optionally substituted by up to three halo substituents, or by one trifluoromethyl substituent], C 3-5 alkynyl, C 1-3 alkoxy, mercapto, C 1-3 alkylsulphanyl, carboxy and C 1-3 alkoxycarbonyl;

Q 1 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, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl [wherein said C 1-4 alkyl, C 2-4 alkenyl and C 2-4 alkynyl are optionally substituted by one or more groups selected from R o ], C 1-4 alkanoyl, C 1-4 alkoxycarbonyl, heterocyclic group, C 1-4 alkylS(O) a wherein a is 0 or 1 [optionally substituted by hydroxy], N′—(C 1-4 alkyl)ureido, N′,N′-di-(C 1-4 alkyl)ureido, N′—(C 1-4 alkyl)-N—(C 1-4 alkyl)ureido, N′,N′-di-(C 1-4 alkyl)-N—(C 1-4 alkyl)ureido, N—C 1-4 alkylamino, N,N-di-(C 1-4 alkyl)amino, N—C 1-4 alkylcarbamoyl, N,N-di-(C 1-4 alkyl)carbamoyl and C 1-4 alkanoylamino;

and also independently, or in addition to, the above substituents, Q 1 may be optionally substituted by one to two substituents independently selected from aryl, C 3-8 cycloalkyl and a heterocyclic group; wherein said aryl, C 3-8 cycloalkyl or heterocyclic group may be optionally substituted on a ring carbon by one or more groups selected from R p ; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R q ;

and also independently, or in addition to, the above substituents, Q 1 may be optionally substituted by one C 1-4 alkoxy or by one hydroxy substituent;

Q 2 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, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy [wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 1-4 alkoxy are optionally substituted by one or more groups selected from R 1 ], C 1-4 alkanoyl, C 1-4 alkoxycarbonyl, heterocyclic group, C 1-4 alkylS(O) a wherein a is 0 or 1 [optionally substituted by hydroxy], N′—(C 1-4 alkyl)ureido, N′,N′-di-(C 1-4 alkyl)ureido, N′—(C 1-4 alkyl)-N—(C 1-4 alkyl)ureido, N′,N′,-di-(C 1-4 alkyl)-N—(C 1-4 alkyl)ureido, N—C 1-4 alkylamino, N,N-di-(C 1-4 alkyl)amino, N—C 1-4 alkylcarbamoyl, N,N-di-(C 1-4 alkyl)carbamoyl, C 1-4 alkenyloxy, C 2-4 alkynyloxy and C 1-4 alkanoylamino;

and also independently, or in addition to, the above substituents, Q 2 may be optionally substituted by one to two substituents independently selected from aryl, C 3-8 cycloalkyl or a heterocyclic group; wherein said aryl, C 3-8 cycloalkyl or heterocyclic group may be optionally substituted on a ring carbon by one or more groups selected from R s ; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R t ;

R j , R n , R o and R r are independently selected from hydroxy, halo, amino, cyano, formyl, formamido, carboxy, nitro, mercapto, carbamoyl, sulphamoyl, N—C 1-4 alkylamino, N,N-di-(C 1-4 alkyl)amino, C 1-4 alkanoyl, C 1-4 alkanoyloxy, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, N—C 1-4 alkylcarbamoyl, N,N-di-(C 1-4 alkyl)carbamoyl, C 1-4 alkanoylamino, C 1-4 alkylS(O) a wherein a is 0 to 2, C 1-4 alkylsulphonylamino, N—(C 1-4 alkyl)sulphamoyl, N—(C 1-4 alkyl) 2 sulphamoyl, N—(C 1-4 alkyl)carbamoyl, N—(C 1-4 alkyl) 2 carbamoyl, phenyl, phenylthio, phenoxy, C 3-8 cycloalkyl and a heterocyclic group; wherein said phenyl, phenylthio, phenoxy, C 3-8 cycloalkyl or heterocyclic group may be optionally substituted on a ring carbon by one or more groups selected from R u ; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R v ;

R h , R k , R p R s and R u are independently selected from hydroxy, halo, amino, cyano, formyl, formamido, carboxy, nitro, mercapto, carbamoyl, sulphamoyl, C 1-4 alkyl [optionally substituted by one or more groups selected from halo, cyano, amino, N—C 1-4 alkylamino, N,N-di-(C 1-4 alkyl)amino or hydroxy], C 2-4 alkenyl [optionally substituted by one or more groups selected from halo], C 2-4 alkynyl, N—C 1-4 alkylamino, N,N-di-(C 1-4 alkyl)amino, C 1-4 alkanoyl, C 1-4 alkanoyloxy, C 1-4 alkoxy [optionally substituted by one or more groups selected from halo], C 1-4 alkoxycarbonyl, N—C 1-4 alkylcarbamoyl, N,N-di-(C 1-4 alkyl)carbamoyl, C 1-4 alkanoylamino, C 1-4 alkylS(O) a wherein a is 0 to 2, C 1-4 alkylsulphonylamino, N—(C 1-4 alkyl)sulphamoyl, N—(C 1-4 alkyl) 2 sulphamoyl, phenyl, C 3-8 cycloalkyl and a heterocyclic group; and

R i , R q , R t and R v are independently selected from C 1-4 alkyl, C 1-4 alkanoyl, C 1-4 alkylsulphonyl, C 1-4 alkoxycarbonyl, carbamoyl, N—(C 1-4 alkyl)carbamoyl, N,N—(C 1-4 alkyl)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.

2. A pyrimidine compound as claimed in claim 1 wherein Q 1 is phenyl or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

3. A pyrimidine compound as claimed in claims 1 wherein Q 2 is phenyl or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

4. A pyrimidine compound as claimed in claims 1 wherein Q 1 is substituted on a ring carbon by sulphamoyl group or one of Q 1 and Q 2 or both of Q 1 and Q 2 are substituted on a ring carbon by one group selected from mesyl, N-(2-diethylaminoethyl)sulphamoyl, 2-(N-methyl-N-phenylamino)ethylsulphonyl, 2-morpholinoethylsulphonyl, N-(5-methylthiadiazol-2-yl)sulphamoyl, N,N-di-(2-hydroxyethyl)sulphamoyl, N-(thiazol-2-yl)sulphamoyl, N-(3,4-dimethylisoxazol-5-yl)sulphamoyl, N-(pyrid-2-yl)sulphamoyl and N-methylsulphamoyl or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

5. A pyrimidine compound as claimed in claims 1 wherein Q 1 is phenyl substituted in the para- or meta-position relative to the —NH— by sulphamoyl, N—(C 1-4 alkyl)sulphamoyl (optionally substituted by halo or hydroxy), N,N-di-(C 1-4 alkyl)sulphamoyl (optionally substituted by halo or hydroxy), C 1-4 alkylsulphonyl (optionally substituted by halo or hydroxy) or a substituent of the formula (Ia) or (Ia′) or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

6. A pyrimidine compound as claimed in claims 1 wherein G is —O—, —NH—, (4,4,4-trifluorobutyl)N—, -(3-bromo-2-propenyl) N— or -(3-phenyl-2-propenyl)N— or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

7. A pyrimidine compound as claimed in claims 1 wherein R 1 is hydrogen or halo or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

8. A pyrimidine compound as claimed in claims 1 wherein Q 1 is optionally substituted by one C 1-4 alkoxy substituent or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

9. A pyrimidine compound as claimed in claims 1 wherein Q 2 is optionally substituted on a ring carbon by one to two substituents independently selected from halo, cyano, methyl, methoxy and morpholino or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

10. A pyrimidine compound as claimed in claims 1 selected from:

2-(4sulphamoylanilino)-4-(2-cyanoanilino)pyrimidine;

2-(4-N-methylsulphamoylanilino)-4-anilino-5-bromopyrimidine;

2-(4-sulphamoylanilino)-4-anilino-5-bromopyrimidine;

2-(4sulphamoylanilino)-4-(4-methoxyphenoxy)-5-chloropyrimidine;

or pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

11. A process for preparing a pyrimidine compound, or pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof, as claimed in claims 1 which comprises of:

a) for compounds of formula (I) where G is —NR 2 —; reacting a pyrimidine of formula (II):

wherein L is a displaceable group as defined below, with a compound of formula (III):

where G is —NR 2 —;

b) reaction of a pyrimidine of formula (IV):

wherein L is a displaceable group as defined below, with a compound of formula (V):

c) for compounds of formula (I) wherein the sidechain is of formula (Ia) and Y is —S(O) 2 NH—; by reaction of a compound of formula (VI):

where L is a displaceable group; with an amine of formula (VII):

Z-(CH 2 ) m —NH 2   (VII)

d) for compounds of formula (I) wherein the sidechain is of formula (Ia) and Y is —NHS(O) 2 — by reaction of an amine of formula (VIII):

with a compound of formula (IX):

Z-(CH 2 ) m —SO 2 L  (IX)

where L is a displaceable group;

e) for compounds of formula (I) wherein the sidechain is of formula (Ia′); by reaction of a compound of formula (VI) with an amine of formula (X):

and thereafter optionally:

i) converting a compound of the formula (I) into another compound of the formula (I);

ii) removing any protecting groups;

iii) forming a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof.

12. A pharmaceutical composition which comprises a pyrimidine compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof, as claimed in any one of claims 1 to 10 , in association with a pharmaceutically acceptable diluent or carrier.