Dihydropteridine derivatives, methods for their preparation and their use as drugs

摘要

Dihydropteridinone derivatives (I) are new. Dihydropteridinone derivatives of formula (I) and their tautomers, isomers, acid addition salts, solvates and hydrates are new. L = a bond, A, OA or N(R 7>)A; A = 1-6C alkylene, 2-6C alkenylene, 2-6C alkynylene, 3-7C cycloalkylene, (1-4C)alkylene(6-10C)arylene(1-4C)alkylene or (1-4C)alkylene(6-10C)arylene, all optionally substituted with R 9>; R 1>, R 2>= H or 1-6C alkyl, 2-6C alkenyl or 2-6C alkynyl, all optionally substituted with R 9>, or R 1>+R 2>= 2-6C alkylene with 0-2 CH 2groups replaced by O or NR 7>, optionally substituted with R 9>; R 3>= H or 1-8C alkyl, 2-8C alkenyl, 2-8C alkynyl, 3-8C cycloalkyl or 6-14C aryl, all optionally substituted with R 9>; or R 3>+R 2>or R 3>+R 1>= 2-6C alkylene optionally substituted with R 9>; R 4>= H, halo, CN, OH, NR 7>R 8>, A' or OA'; A' = 1-6C alkyl, 2-6C alkenyl or 2-6C alkynyl, all optionally substituted with R 10>; R 5>= phenyl optionally substituted with R 11>; phenyl monosubstituted with R 6>; or 1-4C alkyl optionally substituted with R 9>; R 6>= NR 7>R 8>or 5- to 10-membered heterocycloalkyl with 1-3 heteroatoms (N, O, S), optionally substituted with R 12>; R 7>, R 8>= H or 1-6C alkyl; R 9>= halo, 1-4C alkyl, 1-4C alkoxy, CN, OH or CF 3; R 10>= halo, OH, oxo, 1-6C alkoxy, COOR 7>, NR 7>R 8>, CONR 7>R 8>, SO 2R 7>, CHF 2or CF 3; R 11>= halo, OH, CN, 1-4C alkyl, 1-4C alkoxy, COOR 7>, NR 7>R 8>, CONR 7>R 8>, SO 2R 7>, CHF 2, CF 3, 6-10C aryl or (6-10C)aryl(1-6C)alkyl; and R 12>= halo, CF 3, 1-6C alkyl, (6-10C)aryl(1-6C)alkyl 3-8C cycloalkyl or (3-8C)cycloalkyl(1-6C)alkyl. Independent claims are also included for intermediates of formula (A8), (A7a), (A7b) and (A5). PG = protecting group. [Image] [Image] [Image] ACTIVITY : Virucide; Anti-HIV; Antiinflammatory; Immunosuppressive; Antibacterial; Fungicide; Antiparasitic; Cytostatic; Dermatological; Antipsoriatic; Osteopathic; Vasotropic; Cardiant. Compounds (I) have good to very good activity in a HeLa S3 cytotoxicity assay, e.g. with an EC50 of less than 5 mu M, generally less than 1 mu M. MECHANISM OF ACTION : Polo-like kinase inhibitor.