Claims for Patent: 6,838,464

Summary for Patent: 6,838,464

Title:	2,4-Di(hetero-)arylamino(-oxy)-5-substituted pyrimidines as antineaoplastic agents
Abstract:	Pyrimidine derivatives of formula (I) wherein Q1, Q2, G and R1 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) and focal adhesion kinase (FAK) inhibitors are also described.
Inventor(s):	Elizabeth Janet Pease, Emma Jane Williams, Robert Hugh Bradbury, Stuart Eric Pearson
Assignee:	AstraZeneca AB
Application Number:	US10/203,025
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,838,464
Patent Claims:	1. 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 C1-2alkcoxyC1-2alkyl, 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 hydrogen; 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 heterocyclic group; and Rb, Rf, Rj 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. 2. A pyrimidine derivative 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 derivative as claimed claim 1 wherein Q2 is phenyl or pyridyl or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof. 4. A pyrimidine derivative as claimed in claim 1 wherein one of Q1 and Q2 or both of Q1 and Q2 is substituted on a ring carbon by one substituent selected from dimethylamino, 4-methylpiperazino, aminomethyl, 2-hydroxyethoxymethyl, succinimid-1-ylmethyl, 2-pyrrolidin-1-ylethyl, 2-aminoethyl, piperid-4-yloxy, 1-methylpiperid-4-yloxy, 1-methylpiperid-3-yloxy, carboxymethoxy, 1-methylpiperid-2-ylmethoxy, 1-methylpiperid-3-ylmethoxy, piperid-4-ylmethoxy, 4-isopropylpiperazinocarbonylmethoxy, 2-pthalimid-1-ylethoxy, 2-morpholinoethoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-(4-methylpiperazino)ethoxy, 2-imidazol-1-ylethoxy, 2-pyrrolidin-1-ylethoxy, 2-aminoethynyl, 2-dimethylaminoethynyl, 2-methylaminoethynyl, 2-(3-hydroxyquinuclidin-3-yl)ethynyl, 2-morpholinoethoxymethyl, 2-diethylaminoethoxymethyl, 2-pyrrolidin-1-ylethoxymethyl, 2-(4-methylpiperazino)ethoxymethyl, 2-diethylaminoethoxycarbonyl, 2-piperidinoethylamino or 2-isopropylaminoethylamino or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof. 5. A pyrimidine derivative as claimed in claim 1 wherein Q1 is substituted in the para- or meta-position relative to the —NH— or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof. 6. A pyrimidine derivative as claimed in claim 1 wherein G is —NH— or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof. 7. A pyrimidine derivative as claimed in claim 1 wherein R1 is hydrogen, chloro or bromo or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof. 8. A pyrimidine derivative as claimed in claim 1 wherein Q2 is unsubstituted or substituted by one group selected from fluoro, bromo, methyl, methoxy and cyano or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof. 9. A process for preparing a pyrimidine derivative as claimed in any one of claims 1 to 8 selected from: 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): and thereafter if necessary: 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. 10. A pharmaceutical composition which comprises a pyrimidine derivative of the 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 8, in association with a pharmaceutically acceptable diluent or carrier. 11. A method for producing a cell cycle inhibitory effect in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a pyrimidine derivative as claimed in any one of claims 1 to 8, 9, or a pharmaceutically acceptable salt or in vivo hydrolysable ester formed from an available carboxy or hydroxy group thereof. 12. A method for producing a FAK enzyme inhibitory effect in a warm-blooded animal in need of such treatment, which comprises administering to said animal an effective amount of a 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 8. 13. A method for producing a selective CDK2, CDK4 or CDK6 enzyme inhibitory effect in a warm-blooded animal in need of such treatment, which comprises administering to said animal an effective amount of a 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 8. 14. A method for producing an anti-cell proliferation effect in a warm-blooded animal in need of such treatment, which comprises administering to said animal an effective amount of a 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 8.