Substituted isoquinoline and isoquinolinone derivatives

摘要

The invention relates to 6-substituted isoquinoline and isoquinoline derivatives of the formula (I);
useful for the treatment and/or prevention of diseases associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase, and compositions containing such compounds.

主权项

1. A compound of the formula (I) wherein R1 is H, OH or NH2 R2 is (C6-C10)aryl, (C7-C8)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylene-C(O)NH2, (C1-C6)alkylene-C(O)NH—(C1-C6)alkyl, (C1-C6)alkylene-C(O)N[(C1-C6)alkyl]2, (C1-C6)alkylene-C(O)O—(C1-C6)alkyl, C(O)O—(C1-C6)alkyl, C(O)(C1-C6)alkyl, C(O)NH—(C1-C6)alkyl, C(O)NHR′, C(O)—NH(C2-C6)alkenyl, C(O)—NH(C2-C6)alkynyl, C(O)—NH(C1-C6)alkylene-R′, C(O)N[(C1-C6)alkyl]2 or R2 is (C1-C6)alkyl, provided that in said alkyl residue at least one hydrogen is substituted by OH, OCH3, COOH, COOCH3, NH2, NHCH3, N(CH3)2, CONH2, CONHCH3 or CON(CH3)2; or R2 is a (C1-C4)alkylene bound to the cyclic amine, in which the (C1-C4) alkylene forms a second bond to a different carbon atom of the cyclic amine ring and forms, together with carbon atoms of cyclic amine, a second, 4-8 membered ring; R3 is H, halogen, (C1-C6)alkyl, (C1-C6)alkylene-R′, OH, O—R″, NH2, NHR″, NR″R″ or NH—C(O)—R″, R4 is H, halogen, hydroxy, CN, (C1-C6)alkyl; R5 is H, halogen, CN, NO2, (C1-C6)alkyl, (C2-C6)alkenyl, CH(OH)—(C1-C6)alkyl, NH2, NH—SO2H, NH—SO2—(C1-C6)alkyl, NH—C(O)—(C1-C6)alkyl, C(O)N[(C1-C6)alkyl]2, C(O)OH, or C(O)O—(C1-C6)alkyl; R6 is H, R′, (C1-C8)alkyl, (C1-C6)alkylene-R′, (C1-C6)alkylene-O—(C1-C6)alkyl, (C1-C6)alkylene-O—R′, (C1-C6)alkylene-CH[R′]2, (C1-C6)alkylene-C(O)—R′, (C1-C6)alkylene-C(O)NH2, (C1-C6)alkylene-C(O)NH—R′, (C1-C6)alkylene-C(O)NH—(C1-C6)alkyl, (C1-C6)alkylene-C(O)N[(C1-C6)alkyl]2, (C1-C6)alkylene-C(O)N[R′]2; (C1-C6)alkylene-C(O)O—(C1-C6)alkyl, C(O)O—(C1-C6)alkyl, C(O)OR′, C(O)(C1-C6)alkyl, C(O)R′, C(O)NH—(C1-C6)alkyl, C(O)NHR′, C(O)N[(C1-C6)alkyl]R′ C(O)N[(C1-C6)alkyl]2, C(O)—(C1-C6)alkylene-R′, or C(O)O(C1-C6)alkylene-R′; R7 is H, halogen, CN, NO2, (C1-C6)alkyl, O—(C1-C6)alkyl, (C2-C6)alkenyl, CH(OH)—(C1-C6)alkyl, NH2, NH—SO2H, NH—SO2—(C1-C6)alkyl, SO2—NH2, NH—C(O)—(C1-C6)alkyl, C(O)N[(C1-C6)alkyl]2, C(O)OH, or C(O)O—(C1-C6)alkyl; R8 is H, halogen or (C1-C6)alkyl; n is 1; m is 3; L is O—(CH2)p, S(CH2)p, S(O)(CH2)p, S(O)(CH2)p, SO2(CH2)p, NH(CH2)p, N(C1-C6)alkyl-(CH2)p, N(C3-C6)cycloalkyl-(CH2)p, N[CO(C1-C6)alkyl]-(CH2)p or N[(C1-C3)alkylene-R′]-(CH2)p; p is 0, 1, 2, 3, or 4; R′ is (C3-C8)cycloalkyl, (C5-C10)heterocyclyl, (C6-C10)aryl; R″ is (C3-C8)cycloalkyl, (C5-C10)heterocyclyl, (C6-C10)aryl, (C1-C6)alkyl, (C1-C6)alkylene-R′, (C1-C6)alkylene-O—(C1-C6)alkyl, (C1-C6)alkylene-O—R′, or (C1-C6)alkylene-NRxRy; and Rx and Ry are independently of each other (C1-C6)alkyl, (C5-C10)heterocyclyl, (C6-C10)aryl, (C1-C4)alkylene-(C5-C10)heterocyclyl, (C1-C4)alkylene-(C6-C10)aryl, (C1-C4)alkylene-NH(C1-C6)alkyl, (C1-C4)alkylene-N[(C1-C6)alkyl]2, (C1-C4)alkylene-N[(C6-C10)aryl]2, or (C1-C4)alkylene-N[(C5-C10)heterocyclyl]2; wherein in residues R2, R4, R5, R6, R7 and R8 as alkyl, alkylene or cycloalkyl can optionally be substituted one or more times by OH, OCH3, COOH, COOCH3, NH2, NHCH3, N(CH3)2, CONH2, CONHCH3 or CON(CH3)2; wherein in residues R2 to R8 as alkyl or alkylene can optionally be substituted one or more times by halogen; wherein in residues R2, R3, R6 as (C6-C10)aryl and (C5-C10)heterocyclyl are unsubstituted or substituted one or more times by suitable groups independently selected from halogen, OH, NO2, N3, CN, C(O)—(C1-C6)alkyl, COOH, COO(C1-C6)alkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2, (C1-C6)alkyl, (C1-C6)alkylene-OH, (C1-C6)alkylene-NH2, (C1-C6)alkylene-NH(C1-C6)alkyl, (C1-C6)alkylene-N[(C1-C6)alkyl]2, (C2-C6)alkenyl, (C2-C6)alkynyl, O—(C1-C6)alkyl, O—C(O)—(C1-C6)alkyl, PO3H2, SO3H, SO2—NH2, SO2NH(C1-C6)alkyl, SO2N[(C1-C6)alkyl]2, S—(C1-C6)alkyl; SO—(C1-C6)alkyl, SO2—(C1-C6)alkyl, SO2—N═CH—N[(C1-C6)alkyl]2, C(NH)(NH2), NH2, NH—(C1-C6)alkyl, N[(C1-C6)alkyl]2, NH—C(O)—(C1-C6)alkyl, NH—C(O)O—(C1-C6)alkyl, NH—SO2—(C1-C6)alkyl, N(C1-C6)alkyl-C(O)—(C1-C6)alkyl, N(C1-C6)alkyl-C(O)O—(C1-C6)alkyl, N(C1-C6)alkyl-C(O)—NH—(C1-C6)alkyl]; or stereoisomeric form thereof and/or tautomeric form thereof and/or pharmaceutically acceptable salt thereof.