New 2-anilino-4-heteroaryl-pyrimidine derivatives, are kinase inhibitors, especially IKK inhibitors, useful for treating inflammatory diseases, diabetes and cancers

摘要

2-(4-(Carbamoyl or sulfamoyl)-anilino)-4-(bicyclic N-heteroaryl)-pyrimidine derivatives (I) are new. Pyrimidine derivatives of formula (I) (including racemates, enantiomers and diastereomers) and their acid addition salts are new. Bicycle : partially or completely unsaturated 9-10 membered bicyclic group, containing 1 or 2 N and optionally one=O; R 2 - R 4H, halo, alkyl or alkoxy; R 5H or halo; Z : CO or SO 2; W' : ring(Y'); and D : H, alkyl, cycloalkyl, alkenyl or alkynyl; or N(D)W' : 4-7 membered saturated N-bonded ring, geminally substituted by R 1 and R 6 and optionally containing a 1-3C bridge; ring(Y') : mono- or bicyclic, saturated or partially unsaturated 4-10 membered ring; Y' : O, S, SO, SO 2, NR 10, CO, 1,3-dioxolan-2,2-diyl, CF 2, CHOR 8 or CH=NR 8R 9, the ring optionally containing a 1-3C bridge if Y'= NR 10; R 10H, alkyl, cycloalkyl, CH 2-alkenyl or alkynyl; (i) R 1-X 1-R 7; and R 6H, OH, (CH 2) mOH, CONR a1R b1, CH 2NR a1R b1 or COO-alk; (ii) R 1-X 2-R 7; and R 6H; (iii) R 1-N(R c1)-A; and R 6H; provided that if A= H then Z= CO; (iv) R 1CH 2N(R c1)A; and R 6H; or (v) R 1CON(R c1)OR 'c; and R 6H; X 1(CH 2) m; R 7heterocycloalkyl, aryl or heteroaryl; X 2O, O(CH 2) m, CO, CONR c1, CONR c1O, CH(NR a1R b1), C(=NOH), C(=NNH 2) or (CH 2) nNR c1(CH 2) n; A : H or 1-4C alkyl; n : 0-3; m : 1-3; R c1, R 'cH or 1-4C alkyl; R 8, R 9H, alkyl, cycloalkyl or heterocycloalkyl, or NR 8R 9cyclic amino (optionally containing other O, S, N or NR c1 heteroatoms); R a1, R b1H, 1-4C alkyl or cycloalkyl, or NR a1R b1cyclic amino (optionally containing other O, S, N or NR c heteroatoms), and Q : bicyclic ring. alk is not defined in the claims. Independent claims are included for the preparation of (I). [Image] ACTIVITY : Cytostatic; Antiinflammatory; Antidiabetic; Antiarthritic; Antirheumatic; Antipsoriatic; Osteopathic; Neuroprotective; Antiasthmatic; Immunosuppressive; Dermatological; Antiallergic; Immunomodulator; Antibacterial; Cardiant; Antiarteriosclerotic; Vasotropic; Anti-HIV: Antilipemic; Anorectic; Gynecological; Hypotensive; Ophthalmological; Nephrotropic; Virucide; Cerebroprotective; Antiarrhythmic; Hepatotropic; Antianemic. Unspecified compounds (I) are stated to have IC 50 values of less than 10 mu M for reduction of the proliferation and cellular viability of various tumor cell lines (no detailed results given). MECHANISM OF ACTION : Kinase inhibitor; IKK inhibitor; Nuclear factor kappa-B (NF-KB) activation inhibitor; Cytokine production inhibitor; Apoptosis modulator. Unspecified compounds (I) are stated to have IC 50 values of less than 10 mu M for inhibition of IKK1 and/or IKK2 (no detailed results given).