Substituted isoquinolines and isoquinolinones as Rho kinase inhibitors

A compound of the formula (I)

• wherein
• R1 is H, OH or NH2;
• R3 is H, halogen, CN, (C1-C6)alkyl, OH, NH2, or NHR′;
• R4 is H, halogen, hydroxy, CN, (C1-C6)alkyl, R′, or (C1-C6)alkylene-R′;
• R5 is H, halogen, CN, (C1-C6)alkyl, or R′;
• R7 is H, halogen, CN, (C1-C6)alkyl, O—(C1-C6)alkyl, R′, or SO2—NH2;
• R8 is H, halogen or (C1-C6)alkyl;
• R9 is
• R′,
• OH,
• halogen,
• (C1-C6)alkyl,
• O—(C1-C6)alkyl,
• (C1-C6)alkylene-R′,
• (C2-C6)alkenyl,
• (C2-C6)alkynyl,
• (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,
• COOH,
• C(O)O—(C1-C6)alkyl,
• C(O)OR′
• C(O)(C1-C6)alkyl,
• C(O)R′,
• C(O)NH2,
• C(O)—NH—(C2-C6)alkenyl,
• C(O)—NH—(C2-C6)alkynyl,
• C(O)NH—(C1-C6)alkyl,
• C(O)NHR′,
• C(O)—NH(C1-C6)alkylene-R′,
• 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′;
• R6 is absent;
• or is one (C1-C4)alkylene bound to the cycloalkyl ring, in which the (C1-C4)alkylene forms a second bond to a different carbon atom of the cycloalkyl ring to form a bicyclic ring system, wherein in the bicyclic ring system optionally one or two carbon atomes are replaced by a group independently selected from O, N—R15, S, SO or SO2;
• or, if m;
• and s are 2, m is 3 and s is 1, or m is 4 and s is 0,
• R6 is CH2—CH—(CH2)2 which is bound with one CH2 to the cycloalkyl ring and the two other CH2 are bound to different carbon atoms of the cycloalkyl ring;
• and, if m is 3 and s is 3,
• R6 are two methylene groups bound to different carbon atoms of the cycloalkyl ring, wherein the methylene groups or the CH2—CH—(CH2)2 group are bound to carbon atoms of the cycloaalkyl ring such that they form an adamantane system of the formula
• wherein L can be bound to any secondary or tertiary carbon atom and
• wherein the bicyclic ring system or adamantane system is unsubstituted or optionally substituted by R9;
• R10 is
• H,
• (C6-C10)aryl,
• O—(C6-C10)aryl,
• O—(C1-C6)alkylene-(C6-C10)aryl, or
• (C5-C10)heteroaryl, wherein (C6-C10)aryl or (C5-C10)heteroaryl are unsubstituted or substituted;
• R11 is
• H,
• (C1-C6)alkyl,
• (C1-C6)alkylene-R′,
• (C3-C8)cycloalkyl,
• (C5-C10)heteroaryl,
• (C3-C8)heterocycloalkyl,
• (C6-C10)aryl;
• or R11 and R12 together with carbon atom to which they are attached form a (C3-C8)cycloalkyl or a (C3-C8)-heterocycloalkyl ring;
• R12 is
• (C1-C6)alkyl,
• (C3-C8)cycloalkyl,
• (C5-C10)heteroaryl,
• (C3-C8)heterocycloalkyl, or
• (C6-C10)aryl;
• or R12 is H, provided that r=2 and the other R12 is not H;
• or R11 and R12 together with carbon atom to which they are attached form a (C3-C8)cycloalkyl or a (C3-C8)-heterocycloalkyl ring;
• R13 and R14 are independently of each other
• H,
• R′,
• (C1-C6)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′, or
• R13 and R14, together with the N-atom to which they are attached, form a (C3-C8) heterocycloalkyl;
• R15 is H or (C1-C6)alkyl;
• n is 0, 1, 2, 3 or 4;
• m is 1, 2, 3 or 4;
• s is 0, 1, 2, or 3;
• r is 1 or 2;
• L is O(CH2)p, S(CH2)p, S(O)(CH2)p, SO2(CH2)p, NH(CH2)p, N(C1-C6)alkyl-(CH2)p, N(C3-C6)cycloalkyl-(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)heteroaryl,
• (C3-C8)heterocycloalkyl,
• (C6-C10)aryl;
• wherein in residues R3 to R15 alkyl or alkylene is unsubstituted or optionally substituted one or more times by OH, OCH3, C(O)OH, C(O)OCH3, NH2, NHCH3, N(CH3)2, C(O)NH2, C(O)NHCH3 or C(O)N(CH3)2;
• wherein in residues R3 to R15 cycloalkyl or heterocycloalkyl is unsubstituted or optionally substituted one or more times by (C1-C6)alkyl, halogen, OH, OCH3, C(O)OH, C(O)OCH3, NH2, NHCH3, N(CH3)2, C(O)NH2, C(O)NHCH3 or C(O)N(CH3)2;
• wherein in residues R3 to R15 alkyl or alkylene is unsubstituted or optionally substituted one or more times by halogen;
• wherein in residues R3 to R15 (C6-C10)aryl and (C5-C10)heteroaryl are unsubstituted or optionally substituted one or more times by a group independently selected from halogen, OH, NO2, N3, CN, C(O)—(C1-C6)alkyl, C(O)—(C6-C10)aryl, COOH, COO(C1-C6)alkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2, (C3-C8)cycloalkyl, (C1-C6)alkyl, (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, SF5,
• C(NH)(NH2), NH2, NH—(C1-C6)alkyl, [(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)heteroaryl, NH—SO2—(C3-C8)heterocycloalkyl, 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)heteroaryl, (C3-C8)heterocycloalkyl,
• (C1-C6)alkylene-(C5-C10)heteroaryl, (C1-C6)alkylene-(C3-C8)heterocycloalkyl, O—(C1-C6)alkylene-(C5-C10)heteroaryl, O—(C1-C6)alkylene-(C3-C8)heterocycloalkyl,
• wherein said (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C8)heterocycloalkyl or (C3-C8)cycloalkyl 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-β-(C6-C10)aryl, or 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 substituents of (C6-C10)aryl, (C5-C10)hetero aryl, (C3-C8)heterocycloalkyl or (C3-C8)cycloalkyl groups may not be further substituted by an aryl, heteroaryl, heterocycloalkyl, or (C3-C8)cycloalkyl containing group;
• their stereoisomeric and/or tautomeric forms or a pharmaceutically acceptable salt.