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 Q.sub.1, Q.sub.2, G and R.sup.1 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. ##STR1##
Inventor(s):	Pease; Elizabeth Janet (Macclesfied, GB), Williams; Emma Jane (Macclesfield, GB), Bradbury; Robert Hugh (Macclesfield, GB), Pearson; Stuart Eric (Macclesfied, GB)
Assignee:	AstraZeneca AB (Sodertalje, SE)
Application Number:	10/203,025
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): ##STR27## wherein: Q.sub.1 and Q.sub.2 are independently selected from aryl or heteroaryl linked via ring carbon; and one of Q.sub.1 and Q.sub.2 or both of Q.sub.1 and Q.sub.2 is substituted on a ring carbon by one substituent selected from N--(C.sub.1-2 alkyl)amino, N,N-di-(C.sub.1-2 alkyl)amino, phenyl, heterocyclic group, phenoxy, heterocyclic group-O--, substituted C.sub.1-2 alkyl, substituted C.sub.1-2 alkoxy, substituted C.sub.1-2 alkoxycarbonyl, substituted N--(C.sub.1-2 alkyl)amino, substituted C.sub.1-2 alkcoxyC.sub.1-2 alkyl, substituted C.sub.2-4 alkenyl and substituted C.sub.2-4 alkynyl; wherein said substituents for C.sub.1-2 alkyl, C.sub.1-2 alkoxy, C.sub.1-2 alkoxycarbonyl, N--(C.sub.1-2 alkyl)amino, C.sub.1-2 alkoxyC.sub.1-2 alkyl, C.sub.2-4 alkenyl and C.sub.2-4 alkynyl are selected from halo, hydroxy, mercapto, nitro, formyl, formamido, carboxy, cyano, amino, ureido, carbamoyl, sulphamoyl, C.sub.1-4 alkanoyl, C.sub.1-4 alkoxycarbonyl, phenyl, heterocyclic group, benzoyl, heterocyclic group-C(O)--, C.sub.1-4 alkylS(O).sub.a wherein a is 0 to 2, N'--(C.sub.1-4 alkyl)ureido, N',N'-di-(C.sub.1-4 alkyl)ureido, N'--(C.sub.1-4 alkyl)-N--(C.sub.1-4 alkyl)ureido, N',N'-di-(C.sub.1-4 alkyl)-N--(C.sub.1-4 alkyl)ureido, N--C.sub.1-4 alkylamino, N,N-di-(C.sub.1-4 alkyl)amino, N--(C.sub.1-4 alkyl)sulphamoyl, N,N-di-(C.sub.1-4 alkyl)sulphamoyl, N--C.sub.1-4 alkylcarbamoyl, N,N-di-(C.sub.1-4 alkyl)carbamoyl and C.sub.1-4 alkanoylamino; wherein any phenyl, benzyl, benzoyl or heterocyclic group is optionally substituted on a ring carbon by one or more groups selected from R.sup.a ; and wherein if any heterocyclic group contains an --NH-- moiety that nitrogen may be optionally substituted by a group selected from R.sup.b ; G is --O-- or --NR.sup.2 --; R.sup.2 is selected from hydrogen, C.sub.1-6 alkyl, C.sub.3-6 alkenyl and C.sub.3-6 alkynyl; wherein said C.sub.1-6 alkyl, C.sub.3-6 alkenyl and C.sub.3-6 alkynyl are optionally substituted by one or more groups selected from R.sup.c ; R.sup.1 is hydrogen; Q.sub.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, sulphamoyl, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl [wherein said C.sub.1-4 alkyl, C.sub.2-4 alkenyl and C.sub.2-4 alkynyl are optionally substituted by one or more groups selected from R.sup.d ], C.sub.1-4 alkanoyl, C.sub.1-4 alkoxycarbonyl, heterocyclic group, C.sub.1-4 alkylS(O).sub.a [wherein a is 0 to 2 and said C.sub.1-4 alkyl is optionally substituted by hydroxy], N'--(C.sub.1-4 alkyl)ureido, N',N'-di-(C.sub.1-4 alkyl)ureido, N'--(C.sub.1-4 alkyl)-N--(C.sub.1-4 alkyl)ureido, N',N'-di-(C.sub.1-4 alkyl)-N--(C.sub.1-4 alkyl)ureido, N--C.sub.1-4 alkylamino, N,N-di-(C.sub.1-4 alkyl)amino, N--(C.sub.1-4 alkyl)sulphamoyl, N,N-di-(C.sub.1-4 alkyl)sulphamoyl, N--C.sub.1-4 alkylcarbamoyl, N,N-di-(C.sub.1-4 alkyl)carbamoyl and C.sub.1-4 alkanoylamino; and also independently, or in addition to, the above substituents, Q.sub.1 may be optionally substituted by one to two substituents independently selected from aryl, C.sub.3-8 cycloalkyl and a heterocyclic group; wherein said aryl, C.sub.3-8 cycloalkyl or heterocyclic group may be optionally substituted on a ring carbon by one or more groups selected from R.sup.e ; and wherein if said heterocyclic group contains an --NH-- moiety that nitrogen may be optionally substituted by a group selected from R.sup.f ; Q.sub.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, sulphamoyl, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 alkoxy, [wherein said C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl and C.sub.1-4 alkoxy are optionally substituted by one or more groups selected from R.sup.g ], C.sub.1-4 alkanoyl, C.sub.1-4 alkoxycarbonyl, heterocyclic group, C.sub.1-4 alkylS(O).sub.a [wherein a is 0 to 2 and said C.sub.1-4 alkyl is optionally substituted by hydroxy], N'--(C.sub.1-4 alkyl)ureido, N',N'-di-(C.sub.1-4 alkyl)ureido, N'--(C.sub.1-4 alkyl)-N--(C.sub.1-4 alkyl)ureido, N',N'-di-(C.sub.1-4 alkyl)-N--(C.sub.1-4 alkyl)ureido, N--C.sub.1-4 alkylamino, N,N-di-(C.sub.1-4 alkyl)amino, N--(C.sub.1-4 alkyl)sulphamoyl, N,N-di-(C.sub.1-4 alkyl)sulphamoyl, N--C.sub.1-4 alkylcarbamoyl, N,N-di-(C.sub.1-4 alkyl)carbamoyl, C.sub.2-4 alkenyloxy, C.sub.2-4 alkynyloxy, C.sub.1-4 alkanoylamino; and also independently, or in addition to, the above substituents, Q.sub.2 may be optionally substituted by one to two substituents independently selected from aryl, C.sub.3-8 cycloalkyl or a heterocyclic group; wherein said aryl, C.sub.3-8 cycloalkyl or heterocyclic group may be optionally substituted on a ring carbon by one or more groups selected from R.sup.h ; and wherein if said heterocyclic group contains an --NH-- moiety that nitrogen may be optionally substituted by a group selected from R.sup.i ; R.sup.c, R.sup.d and R.sup.g are independently selected from hydroxy, halo, amino, cyano, formyl, formamido, carboxy, nitro, mercapto, carbamoyl, sulphamoyl, N--C.sub.1-4 alkylamino, N,N-di-(C.sub.1-4 alkyl)amino, C.sub.1-4 alkanoyl, C.sub.1-4 alkanoyloxy, C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, N--C.sub.1-4 alkylcarbamoyl, N,N-di-(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoylamino, C.sub.1-4 alkylS(O).sub.a wherein a is 0 to 2, C.sub.1-4 alkylsulphonylamino, N--(C.sub.1-4 alkyl)sulphamoyl, N--(C.sub.1-4 alkyl).sub.2 sulphamoyl, N--(C.sub.1-4 alkyl)carbamoyl, N--(C.sub.1-4 alkyl).sub.2 carbamoyl, phenyl, phenylthio, phenoxy, C.sub.3-8 cycloalkyl and a heterocyclic group; wherein said phenyl, phenylthio, phenoxy, C.sub.3-8 cycloalkyl or heterocyclic group may be optionally substituted on a ring carbon by one or more groups selected from R.sup.j ; and wherein if said heterocyclic group contains an --NH-- moiety that nitrogen may be optionally substituted by a group selected from R.sup.k ; R.sup.a, R.sup.e, R.sup.h and R.sup.j are independently selected from hydroxy, halo, amino, cyano, formyl, formamido, carboxy, nitro, mercapto, carbamoyl, sulphamoyl, C.sub.1-4 alkyl [optionally substituted by one or more groups selected from halo, cyano, amino, N--C.sub.1-4 alkylamino, N,N-di-(C.sub.1-4 alkyl)amino or hydroxy], C.sub.2-4 alkenyl [optionally substituted by one or more groups selected from halo], C.sub.2-4 alkynyl, N--C.sub.1-4 alkylamino, N,N-di-(C.sub.1-4 alkyl)amino, C.sub.1-4 alkanoyl, C.sub.1-4 alkanoyloxy, C.sub.1-4 alkoxy, [optionally substituted by one or more groups selected from halo], C.sub.1-4 alkoxycarbonyl, N--C.sub.1-4 alkylcarbamoyl, N,N-di-(C.sub.1-4 alkyl)carbamoyl, C.sub.1-4 alkanoylamino, C.sub.1-4 alkylS(O).sub.a wherein a is 0 to 2, C.sub.1-4 alkylsulphonylamino, N--(C.sub.1-4 alkyl)sulphamoyl, N--(C.sub.1-4 alkyl).sub.2 sulphamoyl, phenyl, C.sub.3-8 cycloalkyl and a heterocyclic group; and R.sup.b, R.sup.f, R.sup.j and R.sup.k are independently selected from C.sub.1-4 alkyl, C.sub.1-4 alkanoyl, C.sub.1-4 alkylsulphonyl, carbamoyl, N--(C.sub.1-4 alkyl)carbamoyl, N,N--(C.sub.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 derivative as claimed in claim 1 wherein Q.sub.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 derivative as claimed claim 1 wherein Q.sub.2 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 Q.sub.1 and Q.sub.2 or both of Q.sub.1 and Q.sub.2 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 Q.sub.1 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 R.sup.1 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 Q.sub.2 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 --NR.sup.2 --; reacting a pyrimidine of formula (II): ##STR28## wherein L is a displaceable group as defined below, with a compound of formula (III): ##STR29## where G is --NR.sup.2 --; b) reaction of a pyrimidine of formula (IV): ##STR30## wherein L is a displaceable group as defined below, with a compound of formula (V): ##STR31## 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.