Substituted isoquinoline and isoquinolinone derivatives as inhibitors of RHO-Kinase

A compound of the formula (I)

• wherein
• R1 is H, OH or NH2
• R2 is H, halogen or (C1-C6)alkyl;
• 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,
• R′,
• (C1-C6)alkylene-R′;
• R5 is
• H,
• halogen,
• CN,
• NO2,
• (C1-C6)alkyl,
• (C2-C6)alkenyl, R′,
• (C1-C6)alkylene-(C6-C10)aryl,
• (C2-C6)alkenylene-(C6-C10)aryl,
• (C1-C6)alkylene-(C5-C10)heterocyclyl,
• CH(OH)—(C1-C6)alkyl,
• NH2,
• NH—R′,
• NH—SO2H,
• NH—SO2—(C1-C6)alkyl,
• NH—SO2—R′,
• NH—C(O)—(C1-C6)alkyl,
• NH—C(O)—R′,
• 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′,
• C(O)O(C1-C6)alkylene-R′;
• R7 is
• H,
• halogen,
• CN,
• NO2,
• (C1-C6)alkyl,
• O—(C1-C6)alkyl,
• (C2-C6)alkenyl,
• R′,
• (C2-C6)alkenylene-(C6-C10)aryl,
• (C1-C6)alkylene-R′,
• CH(OH)—(C1-C6)alkyl,
• NH2,
• NH—R′,
• NH—SO2H,
• NH—SO2—(C1-C6)alkyl,
• NH—SO2—R′,
• SO2—NH2,
• SO2—NHR′,
• NH—C(O)—(C1-C6)alkyl,
• NH—C(O)—R′,
• 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, 2, 3 or 4;
• m is 1, 2, 3, 4 or 5;
• L is O or O—(C1-C6)alkylene;
• R′ is
• (C3-C8)cycloalkyl,
• (C5-C10)heterocyclyl,
• (C6-C10)aryl;
• R″ is
• (C3-C9)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 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, 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 R3 to R8 as (C6-C10)aryl and (C5-C10)heterocyclyl are unsubstituted or substituted one or more times by a suitable group independently selected from halogen, OH, NO2, N3, CN, C(O)—(C1-C6)alkyl, C(O)—(C1-C6)aryl, COOH, COO(C1-C6)alkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2, (C3-C9)cycloalkyl, (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, NH—SO2—(C6-C10)aryl, NH—SO2—(C5-C10)heterocyclyl, 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], (C6-C10)aryl, (C1-C6)alkylene-(C6-C10)aryl, O—(C6-C10)aryl, O—(C1-C6)alkylene-(C6-C10)aryl, (C5-C10)heterocyclyl, (C1-C6)alkylene-(C5-C10)heterocyclyl, and O—(C1-C6)alkylene-(C5-C10)heterocyclyl,
• wherein the (C6-C10)aryl or (C5-C10)heterocyclyl in the substituent may be substituted one to three times by a group independently selected from halogen, OH, NO2, CN, O—(C1-C6)alkyl, (C1-C6)alkyl, NH2, NH(C1-C6)alkyl, N[(C1-C6)alkyl]2, SO2CH3, COOH, C(O)O—(C1-C6)alkyl, CONH2, (C1-C6)alkylene-O—(C1-C6)alkyl, (C1-C6)alkylene-O—(C6-C10)aryl, and O—(C1-C6)alkylene-(C6-C10)aryl;
• or
• wherein (C6-C10)aryl is vicinally substituted by a O—(C1-C4)alkylene-O group whereby a 5-8-membered ring is formed together with the carbon atoms the oxygen atoms are attached to;
• and wherein aryl substituent of (C6-C10)aryl and (C5-C10)heterocyclyl substituent groups may not be further substituted by an aryl or heterocyclyl containing group;
• and
• wherein, if m is 3, R6 is not H, (C5-C10)heterocyclyl or (C6-C10)aryl;
• and
• wherein, if m is 3, and R6 is a residue selected from
• (C1-C8)alkyl,
• (C3-C8)cycloalkyl,
• (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′, or
• (C1-C6)alkylene-C(O)N[R′]2;
• alkyl, alkylene or cycloalkyl in said residue is substituted one or more times by OH, OCH3, COOH, COOCH3, NH2, NHCH3, N(CH3)2, CONHCH3 or CON(CH3)2;
• or stereoisomeric form thereof and/or tautomeric form thereof and/or pharmaceutically acceptable salt thereof.