Substituted 2-anilinopyrimidines useful as protein kinase inhibitors

Anilinopyrimidines, processes for their preparation, pharmaceutical compositions containing them, their use in medicine. In a preferred embodiment, the compounds have the general formula (1):

• ##STR12## wherein R.sup.1 is preferably methoxy;
• R.sup.2 and R.sup.3 are preferably methyl;
• R.sup.4 is preferably a hydrogen atom;
• R.sup.5 is a hydrogen atom or an optionally substituted straight or branched chain alkyl, alkenyl or alkynyl group;
• R.sup.6 is a hydrogen or halogen atom or an amino (--NH.sub.2), substituted amino, nitro, carboxyl (--CO.sub.2 H), esterified carboxyl or --X.sup.1 R.sup.6a where X.sup.1 is a direct bond or a linker atom or group and R.sup.6a is an optionally substituted straight or branched chain alkyl, alkenyl or alkynyl group;
• X is a direct bond or a linker atom or group;
• and R.sup.7 is an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group. Compounds of the invention are selective protein kinase inhibitors, particularly the kinases p56.sup.lck, p59.sup.fyn, ZAP-70 and protein kinase C and are of use in the prophylaxis and treatment of immune diseases, hyperproliferative disorders and other diseases in which inappropriate protein kinase action is believed to have a role.

A compound of formula 1(a) ##STR13## wherein:

• R.sup.5 is a hydrogen atom;
• R.sup.6 is a hydrogen or halogen atom or an amino (--NH.sub.2), --NHR.sup.9, --NR.sup.9 R.sup.10, nitro, carboxyl (--CO.sub.2 H), esterified carboxyl or --X.sup.1 R.sup.6a group;
• X.sup.1 is a direct bond or a linker atom or group selected from --O--, --S--, --C(O)--, --C(S)--, --S(O)--, --S(O).sub.2 --, --N(R.sup.11)--, --CON(R.sup.11)--, --OC(O)N(R.sup.11)--, --CSN(R.sup.11)--, --N(R.sup.11)CO--, --N(R.sup.11)C(O)O--, --N(R.sup.11)CS--, --SON(R.sup.11)--, --SO.sub.2 N(R.sup.11)--, --N(R.sup.11)SO.sub.2 --, --N(R.sup.11)CON(R.sup.11)--, --N(R.sup.11)CSN(R.sup.11)--, --N(R.sup.11)SON(R.sup.11)-- and --N(R.sup.11)SO.sub.2 N(R.sup.11)--;
• X is a direct bond, an oxygen or sulphur atom, or a group --N(R.sup.11)--;
• and
• R.sup.7 is an optionally substituted monocyclic or bicyclic C.sub.6-12 aryl group or an optionally substituted monocyclic or bicyclic C.sub.5-13 heteroaryl group containing one to four heteroatoms selected from oxygen, sulfur or nitrogen atoms, wherein said optional substituents on R.sup.7 are from one to about three R.sup.12 groups;
• R.sup.9 and R.sup.10, which may be the same or different is each R.sup.a or --COR.sup.a ;
• R.sup.a and R.sup.6a, which may be the same or different, is each an optionally substituted straight or branched chain C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkanyl group;
• R.sup.11 is a hydrogen atom or a C.sub.1-6 alkyl group;
• R.sup.12 is R.sup.13,-Alk(R.sup.13).sub.m, optionally substituted heteroC.sub.3-6 cycloalkyl or optionally substituted -Alk-heteroC.sub.3-6 cycloalkyl, wherein said optional substituents on R.sup.12 are one or two groups selected from C.sub.1-6 alkyl, hydroxyl (--OH), hydroxyC.sub.1-6 alkyl and C.sub.1-6 alkyoxy groups;
• R.sup.13 is a halogen atom, amino (--NH.sub.2), --NHR.sup.14, --N(R.sup.14).sub.2, nitro, cyano, hydroxyl (--OH), --OR.sup.14, formyl carboxyl (--CO.sub.2 H), --CO.sub.2 Alk.sup.1, thiol (--SH), SR.sup.14, --COR.sup.14, --CSR.sup.14, --SO.sub.3 H, --SO.sub.2 R.sup.14, --SO.sub.2 NH.sub.2, --SO.sub.2 NHR.sup.14, --SO.sub.2 N(R.sup.14).sub.2, --CONH.sub.2, --CSNH.sub.2, --CONHR.sup.14, --CSNHR.sup.14, --CON(R.sup.14).sub.2, --CSN(R.sup.14).sub.2, --NHSO.sub.2 H, --NHSO.sub.2 R.sup.14, --N(SO.sub.2 R.sup.14).sub.2, --NHSO.sub.2 NH.sub.2, --NHSO.sub.2 NHR.sup.14, --NHSO.sub.2 N(R.sup.14).sub.2,--NHCOR.sup.14,--NHCONH.sub.2, --NHCONHR.sup.14, --NHCON(R.sup.14).sub.2, --NHCSR.sup.14, --NHCSNH.sub.2, --NHCSNHR.sup.14, --NHCSN(R.sup.14).sub.2, --NHC(O)OR.sup.14, optionally substituted C.sub.5-7 cycloalkyl optionally substituted monocyclic or bicyclic C.sub.6-12 aryl or optionally substituted monocyclic or bicyclic C.sub.5-13 heteroaryl wherein, said cycloalkyl, aryl and heteroaryl substituents are one or two groups selected from C.sub.1-6 alkyl, hydroxyl (--OH), hydroxyC.sub.1-6 alkyl and C.sub.1-6 alkyoxy groups;
• R.sup.14 is -Alk(R.sup.13).sub.m, optionally substituted heteroC.sub.3-6 cycloalkyl, optionally substituted -Alk-heteroC.sub.3-6 cycloalkyl, optionally substituted monocyclic or bicyclic C.sub.6-12 aryl or optionally substituted monocyclic or bicyclic C.sub.5-13 heteroaryl;
• Alk is a straight or branched chain C.sub.1-6 alkylene, C.sub.2-6 alkenylene or C.sub.2-6 alkynylene group optionally interrupted by one, two or three --O-- or --S-- atoms or --SO--, --S(O).sub.2 - or --N(R.sup.11)-- groups;
• m is zero or an integer 1, 2 or 3;
• wherein said optional substituents on R.sup.5, R.sup.a and R.sup.6a are one to three groups selected from halogen, hydroxyl, C.sub.1-6 alkoxy thiol, C.sub.1-6 alkylthio, amino C.sub.1-6 alkylamino and C.sub.1-6 dialkylamino;
• and the salts, solvates, hydrates and N-oxides thereof with the provisos that when R.sup.12 is a heterocycloalkyl group, then X is other than a direct bond or X is a direct bond and R.sup.7 is other than a pyridyl group, and when X is a direct bond and R.sup.7 is an optionally substituted C.sub.1-10 aliphatic group optionally containing one to four X.sup.2 heteroatoms or heteroatom containing groups or an optionally substituted C.sub.3-10 cycloaliphatic group optionally containing one to four X.sup.2 heteroatoms or heteroatom containing groups, then R.sup.1 is other than a hydrogen atom.

A compound which is selected from the group consisting of

• N,N'-Bis(3,4,5-Trimethoxyphenyl)-2,4-pyrimidinediamine;
• 4-(2-(2-Dimethylaminoethylamino)pyridin-5-yl)-N-(3,4,5-trimethoxyphenyl)-2- pyrimidineamine;
• 4-(2-(4-Hydroxybutylamino)pyridin-5-yl)-N-(3,4,5-trimethoxyphenyl)-2-pyrimi dineamine;
• 4-(3-(3-Aminopropoxy)phenyl)-N-(3,4,5-trimethoxyphenyl)-2-pyrimidineamine;
• N4-(3,4-Dimethoxyphenyl)-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine;
• 4-(4-(2-Hydroxyethoxy)phenyl)-N-(3,4,5-trimethoxyphenyl)-2-pyrimidineamine;
• 4-(2-(3-(Morpholino)propylamino)pyridin-5-yl)-N-(3,4,5-trimethoxyphenyl)-2- pyrimidineamine;
• 4-(2-(2-(1-Methylpyrrolidin-2-yl)ethylamino)pyridin-5-yl)-N-(3,4,5-trimetho xyphenyl)-2-pyrimidineamine;
• N4-(4-(Ethoxycarbonylmethyl)phenyl)-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimid inediamine;
• N4-(4-Hydroxyphenyl)-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine and
• N4-(4-(3-Aminopropoxy)phenyl)-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinedia mine;
• and the salts, solvates, hydrates and N-oxides thereof.