Claims for Patent: 7,153,964

Summary for Patent: 7,153,964

Title:	Pyrimidine compounds
Abstract:	Pyrimidine derivatives of formula (I) wherein: Qh1 and Q2 are independently selected from aryl or carbon linked heteroaryl optionally substituted as defined within; and one of Q1 and Q2 or both Q1 and Q2 is substituted on a ring carbon by one group selected from sulphamoyl, N—(C1-4alkyl)sulphamoyl (optionally substituted by halo or hydroxy), N,N-di-(C1-4alkyl)sulphamoyl (optionally substituted by halo or hydroxy), C1-4alkylsulphonyl (optionally substituted by halo or hydroxy) or a substituent of the formula (Ia) or (Ia′): wherein Q1, Q2, G, R1, Y, Z, Q3, n and m are as defined within; and pharmaceutically acceptable salts and in vivo hydrolysable esters thereof are described. Processes for their manufacture, pharmaceutical compositions and their use as cyclin-dependent serine/threonine kinase (CDK) inhibitors are also described
Inventor(s):	Elizabeth Janet Pease, Gloria Anne Breault, Jeffrey James Morris
Assignee:	AstraZeneca AB
Application Number:	US10/220,139
Patent Claims:	1. A pyrimidine derivative of the formula (I): wherein: Q1 and Q2 are independently selected from aryl or carbon linked heteroaryl; and Q1 is substituted on a ring carbon by a sulphamoyl group, or one of Q1 and Q2 or both Q1 and Q2 is substituted on a ring carbon by one group selected from N—(C1-4alkyl)sulphamoyl (optionally substituted by halo or hydroxy), N,N-di-(C1-4alkyl)sulphamoyl (optionally substituted by halo or hydroxy), C1-4alkylsulphonyl (optionally substituted by halo or hydroxy) or a substituent of the formula (Ia) or (Ia′): wherein: Y is —NHS(O)2—, —S(O)2NH— or —S(O)2—; Z is RaO—, RbRcN—, RdS—, ReRfNNRg—, C3-8cycloalkyl, phenyl or a heteroc wherein said phenyl, C3-8cycloalkyl or heterocyclic group are optionally substituted on a rig 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; Ra, Rb, Rc, Rd, Re, Rf and Rg are independently selected from hydrogen, C1-4alkyl, C2-4alkenyl, phenyl, heterocyclic group and C3-8cycloalkyl; wherein said C1-4alkyl, C2-4alkenyl and C3-8cycloalkyl are optionally substituted by one or more groups selected from Rj; n is 0 or 1; m is 1, 2 or 3, in addition m may be 0 when Z is C3-8cycloalkyl, phenyl or a heterocyclic group; Q3 is a nitrogen linked heterocycle; wherein said heterocycle is optionally substituted on a ring carbon by one or more groups selected from Rk; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from Rm G is —O—, —S— 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 Rn; R1 is selected from hydrogen, halo, hydroxy, 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, 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 Ro], C1-4alkanoyl, C1-4alkoxycarbonyl, heterocyclic group, C1-4alkylS(O)a wherein a is 0 or 1 [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—C1-4alkylcarbamoyl, 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 Rp; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from Rq; and also independently, or in addition to, the above substituents, Q1 may be optionally substituted by one C1-4alkoxy or by one hydroxy substituent; 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, 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 R1], C1-4alkanoyl, C1-4alkoxycarbonyl, heterocyclic group, C1-4alkylS(O)a wherein a is 0 or 1 [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—C1-4alkylcarbamoyl, N,N-di-(C1-4alkyl)carbamoyl, C1-4alkenyloxy, C2-4alkynyloxy and 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 Rs; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from Rt; Rj, Rn, Ro and Rr 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 Ru; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from Rv; Rh, Rk, Rp Rs and Ru 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 heterocyclic group; and Ri, Rq, Rt and Rv are independently selected from C1-4alkyl, C1-4alkanoyl, C1-4alkylsulphonyl, C1-4alkoxycarbonyl, 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. 2. A pyrimidine compound as claimed in claim 1 wherein Q1 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 Q2 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 Q1 is substituted on a ring carbon by sulphamoyl group or one of Q1 and Q2 or both of Q1 and Q2 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 Q1 is phenyl substituted in the para- or meta-position relative to the —NH— by sulphamoyl, N—(C1-4alkyl)sulphamoyl (optionally substituted by halo or hydroxy), N,N-di-(C1-4alkyl)sulphamoyl (optionally substituted by halo or hydroxy), C1-4alkylsulphonyl (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 R1 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 Q1 is optionally substituted by one C1-4alkoxy 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 Q2 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 —NR2—; reacting a pyrimidine of formula (II): wherein L is a displaceable group as defined below, with a compound of formula (III): where G is —NR2—; 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)2NH—; by reaction of a compound of formula (VI): where L is a displaceable group; with an amine of formula (VII): Z-(CH2)m—NH2 (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-(CH2)m—SO2L (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.