New 2-anilino-pyrimidine derivatives, are potent cyclin dependent kinase inhibitors, useful e.g. for treating cancer, autoimmune, cardiovascular or neurodegenerative diseases or viral infections

摘要

2-Anilino-pyrimidine derivatives (I) are new. Pyrimidine derivatives of formula (I) and their isomers, diastereomers, enantiomers and salts are new. R1 = H, halo, alkyl, COR5, OCF3, (CH2)nR5, SCF3 or SO2CF3; R2 = (a) 1-10C alkyl, 2-20C alkenyl, 2-10C alkynyl or cycloalkyl (all optionally substituted by one or more of OH, halo, alkoxy, alkylthio, NH2, CN, alkyl, NH(CH2)n-cycloalkyl, cycloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkoxyalkyl, mono or dialkylamino, alkylsulfinyl, alkylsulfonyl, alkanoyl, CONR3R4, COR5, acetoxyalkyl, COOH, aryl, heteroaryl, (CH2)n-aryl, (CH2)n-heteroaryl, phenyl-(CH2)nR5, (CH2)nPO3(R5)2, R6 or NR3R4; where (i) phenyl, cycloalkyl, aryl, heteroaryl, (CH2)n-aryl or (CH2)n-heteroaryl are themselves optionally substituted by one or more of halo, OH, alkyl, alkoxy, heteroaryl, benzoxy, CF3 or OCF3, (ii) 1-10C alkyl or cycloalkyl is optionally interrupted by one or more of N, O and/or S and (iii) the cycloalkyl ring is optionally substituted by one or more =O and optionally contains one or more double bonds; or (b) CHR8CHR9NHR5 or CHR8CR9=NOR10; X = O, NH, N(1-3C alkyl) or O-cycloalkyl (optionally substituted by one or more heteroaromatics); X-R2 = cycloalkyl (optionally containing heteroatom(s) and optionally substituted by one or more of OH, alkyl, alkoxy or halo); A, A' = H, OH, 1-3C alkyl, alkoxy, SR7, SOR7, SO2R7, NHSO2R7, CH(OH)R7, C(R7)2OH, alkyl-P(O)(OR3(OR4), COR7, glycidyloxy or OCH2CH(OH)CH2Q; Q = 4-(Q')-piperazino, 2-(2-thienyl)-ethyl, 2-(N-(2,6-dimethylphenyl)-aminomethyl)-piperidino, N-(tetralin-1-yl)-amino, 4,4-(ethylenedioxy)-piperidino, N-(3-phenylpropyl)-amino, N-benzyl-homopiperazino, morpholino, 4-benzyl-piperidino or azetidino; Q' = pyridin-2-yl, 4,4'-difluorobenzhydryl, 3-trifluoromethylphenyl, Ph, 2-fluorophenyl, 2-ethoxyethyl, 2-phenylethyl, pyrazin-2-yl, Me, 3,4-methylenedioxy-benzyl, tetrahydrofuran-2-ylcarbonyl, 2,4-dimethoxyphenyl or 2-cyanophenyl; A+A' = cycloalkyl ring, optionally interrupted by one or more of N, O, S, C=O and/or SO2, optionally containing one or more double bonds and optionally substituted by one or more of OH, halo, alkoxy, alkylthio, NH2, CN, alkyl, alkenyl, cycloalkyl, alkoxyalkyl, mono or dialkylamino, alkylsulfinyl, SO2R7, alkanoyl, CONR3R4, COR5, acetoxyalkyl, R6 or phenyl (itself optionally substituted by one or more of halo, OH, alkyl, alkoxy, CF3 or OCF3); R3, R4 = H, PH, OCH2Ph, 1-12C alkyl, alkoxy, 2-4C alkenyloxy, 3-6C cycloalkyl, OH, mono or dihydroxyalkyl, heteoaryl, heterocyclo-(3-10C) alkyl or heteroaryl-(1-3C) alkyl; (3-6C) cycloalkyl-(1-3C) alkyl (optionally substituted by CN); or alkyl (optionally substituted by phenyl, pyridyl, phenoxy, 3-6C cycloalkyl, alkyl or alkoxy, where phenyl is itself optionally substituted by halo, alkyl, alkoxy or SO2NR3R4); or (CH2)nNR3R4, CNHNH2 or NR3R4; R3+R4 = cycloalkyl ring, optionally interrupted by one or more of N, O, S and/or C=O and/or optionally containing one or more double bonds; R5 = OH, Ph, alkyl, 3-6C cycloalkyl, benzoxy, alkylthio or alkoxy; R6 = heteroaryl or 3-10C cycloalkyl ring as defined above; R7 = halo, OH, Ph, alkyl, alkenyl, alkynyl, cycloalkyl (as defined above), NR3R4 or Ph'; or 1-10C alkyl, 2-10C alkenyl, 2-10C alkynyl or cycloalkyl, all substituted by one or more of OH, alkoxy, halo, NR3R4 or Ph'; Ph' = phenyl (optionally substituted by one or more of halo, OH, alkyl, alkoxy, haloalkyl or haloalkoxy); R8-R10 = H, OH, aryl or heteroaryl; or as for R2 (a); n = 0-6; alkyl = 1-6C alkyl; alkenyl = 1-6C alkenyl; alkynyl = 1-6 C alkynyl; and cycloalkyl = 3-10 C cycloalkyl. An Independent claim is also included for the use of pyrimidine derivatives of formula (II) as intermediates for (I). D = halo, preferably Cl.