Substituted isoquinoline and isoquinolinone derivatives

1. A method for the treatment in a mammal of a disease associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase comprising administering to the mammal in need thereof at least one compound of the formula (I)

wherein

R 1 is OH;

R 2 is H, halogen or (C 1 -C 6 )alkyl;

R 3 is

H,

halogen,

(C 1 -C 6 )alkyl,

(C 1 -C 6 )alkylene-R′,

OH,

O—R″,

NH 2 ,

NHR″,

NR″R″ or

NH—C(O)—R″,

R 4 is

H,

halogen,

hydroxy,

CN,

(C 1 -C 6 )alkyl,

R′,

(C 1 -C 6 )alkylene-R′;

R 5 is

H,

halogen,

CN,

NO 2 ,

(C 1 -C 6 )alkyl,

(C 2 -C 6 )alkenyl,

R′,

(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl,

(C 2 -C 6 )alkenylene-(C 6 -C 10 )aryl,

(C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl,

CH(OH)—(C 1 -C 6 )alkyl,

NH 2 ,

NH—R′,

NH—SO 2 H,

NH—SO 2 —(C 1 -C 6 )alkyl,

NH—SO 2 —R′,

NH—C(O)—(C 1 -C 6 )alkyl,

NH—C(O)—R′,

C(O)N[(C 1 -C 6 )alkyl] 2 ,

C(O)OH, or

C(O)O—(C 1 -C 6 )alkyl;

R 6 is

(C 1 -C 6 )alkylene-C(O)NH—(C 1 -C 6 )alkyl,

(C 1 -C 6 )alkylene-C(O)N[(C 1 -C 6 )alkyl] 2 ,

(C 1 -C 6 )alkylene-C(O)O—(C 1 -C 6 )alkyl,

C(O)(C 1 -C 6 )alkyl,

C(O)R′,

C(O)—(C 1 -C 6 )alkylene-R′;

R 7 is

H,

Halogen,

CN,

NO 2 ,

(C 1 -C 6 )alkyl,

O—(C 1 -C 6 )alkyl,

(C 2 -C 6 )alkenyl,

R′,

(C 2 -C 6 )alkenylene-(C 6 -C 10 )aryl,

(C 1 -C 6 )alkylene-R′,

CH(OH)—(C 1 -C 6 )alkyl,

NH 2 ,

NH—R′,

NH—SO 2 H,

NH—SO 2 —(C 1 -C 6 )alkyl,

NH—SO 2 —R′,

SO 2 —NH 2 ,

SO 2 —NHR′,

NH—C(O)—(C 1 -C 6 )alkyl,

NH—C(O)—R′,

C(O)N[(C 1 -C 6 )alkyl] 2 ,

C(O)OH, or

C(O)O—(C 1 -C 6 )alkyl;

R 8 is H, halogen or (C 1 -C 6 )alkyl;

n is 1, 2, 3 or 4;

m is 1, 2, 3, 4 or 5; and

L is O or O—(C 1 -C 6 )alkylene;

wherein

R′ is

(C 3 -C 8 )cycloalkyl,

(C 5 -C 10 )heterocyclyl,

(C 6 -C 10 )aryl;

R″ is

(C 3 -C 8 )cycloalkyl,

(C 5 -C 10 )heterocyclyl,

(C 6 -C 10 )aryl,

(C 1 -C 6 )alkyl,

(C 1 -C 6 )alkylene-R′,

(C 1 -C 6 )alkylene-O—(C 1 -C 6 )alkyl,

(C 1 -C 6 )alkylene-O—R′, or

(C 1 -C 6 )alkylene-NR x R y ; and

wherein R x and R y are independently of each other

(C 1 -C 6 )alkyl,

(C 5 -C 10 )heterocyclyl,

(C 6 -C 10 )aryl,

(C 1 -C 4 )alkylene-(C 5 -C 10 )heterocyclyl,

(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl,

(C 1 -C 4 )alkylene-NH(C 1 -C 6 )alkyl,

(C 1 -C 4 )alkylene-N[(C 1 -C 6 )alkyl] 2 ,

(C 1 -C 4 )alkylene-N[(C 6 -C 10 )aryl] 2 , or

(C 1 -C 4 )alkylene-N[(C 5 -C 10 )heterocyclyl] 2 ;

wherein in residues R 4 , R 5 , R 6 , R 7 and R 8 alkyl, alkylene or cycloalkyl can optionally be substituted one or more times by OH, OCH 3 , COOH, COOCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , CONHCH 3 or CON(CH 3 ) 2 ;

wherein in residues R 2 to R 8 alkyl or alkylene can optionally be substituted one or more times by halogen;

wherein in residues R 3 to R 8 (C 6 -C 10 )aryl and (C 5 -C 10 )heterocyclyl are unsubstituted or substituted one or more times by suitable groups independently selected from halogen, OH, NO 2 , N 3 , CN, C(O)—(C 1 -C 6 )alkyl, C(O)—(C 6 -C 10 )aryl, COOH, COO(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, CON[(C 1 -C 6 )alkyl] 2 , (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylene-OH, (C 1 -C 6 )alkylene-NH 2 , (C 1 -C 6 )alkylene-NH(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylene-N[(C 1 -C 6 )alkyl] 2 , (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, O—(C 1 -C 6 )alkyl, O—C(O)—(C 1 -C 6 )alkyl, PO 3 H 2 , SO 3 H, SO 2 —NH 2 , SO 2 NH(C 1 -C 6 )alkyl, SO 2 N[(C 1 -C 6 )alkyl] 2 , S—(C 1 -C 6 )alkyl; SO—(C 1 -C 6 )alkyl, SO 2 —(C 1 -C 6 )alkyl, SO 2 —N═CH—N[(C 1 -C 6 )alkyl] 2 ,

C(NH)(NH 2 ), NH 2 , NH—(C 1 -C 6 )alkyl, N[(C 1 -C 6 )alkyl] 2 , NH—C(O)—(C 1 -C 6 )alkyl, NH—C(O)O—(C 1 -C 6 )alkyl,

NH—SO 2 —(C 1 -C 6 )alkyl, NH—SO 2 —(C 6 -C 10 )aryl, NH—SO 2 —(C 5 -C 10 )heterocyclyl, N(C 1 -C 6 )alkyl-C(O)—(C 1 -C 6 )alkyl, N(C 1 -C 6 )alkyl-C(O)O—(C 1 -C 6 )alkyl,

N(C 1 -C 6 )alkyl-C(O)—NH—(C 1 -C 6 )alkyl],

(C 6 -C 10 )aryl, (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, O—(C 6 -C 10 )aryl,

O—(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, (C 5 -C 10 )heterocyclyl,

(C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl, or O—(C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl,

wherein the (C 6 -C 10 )aryl or (C 5 -C 10 )heterocyclyl may be substituted one to three times by a group independently selected from halogen, OH, NO 2 , CN, O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, NH 2 , NH(C 1 -C 6 )alkyl, N[(C 1 -C 6 )alkyl] 2 , SO 2 CH 3 , COOH, C(O)O—(C 1 -C 6 )alkyl, CONH 2 , (C 1 -C 6 )alkylene-O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylene-O—(C 6 -C 10 )aryl,

or O—(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl;

or wherein (C 6 -C 10 )aryl is vicinally substituted by a O—(C 1 -C 4 )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 or heterocyclyl substituents of (C 6 -C 10 )aryl and (C 5 -C 10 )heterocyclyl groups may not be further substituted by an aryl or heterocyclyl containing group;

or their stereoisomeric and/or tautomeric forms and/or their pharmaceutically acceptable salts.

2. The method according to claim 1 , wherein the disease is selected from the group consisting of hypertension, pulmonary hypertension, ocular hypertension, retinopathy, glaucoma, peripheral circulatory disorder, peripheral arterial occlusive disease (PAOD), coronary heart disease, angina pectoris, heart hypertrophy, heart failure, ischemic diseases, ischemic organ failure, thrombotic disorders, stroke, cerebral vasospasm, cerebral ischemia, Alzheimer's disease, arteriosclerosis, blood vessel restenosis, or atherosclerosis.

3. The method according to claim 1 wherein the compound of formula (I) is characterized by the formula (III)

4. The method according to claim 1 wherein the compound of formula (I) is characterized by the formula (III′)

5. The method according to claim 1 wherein in formula (I) R 3 is H, halogen, (C 1 -C 4 )alkylene-R′, O—R″ or NHR″.

6. The method according to claim 1 wherein in formula (I) R 8 is H, halogen or (C 1 -C 4 )alkyl.

7. The method according to claim 1 wherein in formula (I) R 4 is H, halogen or (C 1 -C 6 )alkyl.

8. The method according to claim 1 wherein in formula (I) R 5 is H, halogen, CN, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, R′, NH—(C 6 -C 10 )aryl, (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl or (C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl.

9. The method according to claim 1 wherein in formula (I) R 7 is H, halogen, CN, (C 1 -C 6 )alkyl, O—(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, R′ or (C 1 -C 6 )alkylene-(C 3 -C 8 )cycloalkyl.

10. The method according to claim 1 wherein in formula (I) m is 2, 3, or 4.

11. The method according to claim 1 wherein in formula (I) m is 3.

12. The method according to claim 1 wherein in formula (I) R 2 is H, halogen, or (C 1 -C 4 )alkyl.

13. The method according to claim 1 wherein in formula (I) n is 1, 2 or 3.

14. The method according to claim 1 wherein in formula (I) R 6 is

(C 1 -C 6 )alkylene-C(O)N[(C 1 -C 6 )alkyl] 2 ,

(C 1 -C 6 )alkylene-C(O)NH—(C 1 -C 6 )alkyl,

(C 1 -C 6 )alkylene-C(O)O—(C 1 -C 6 )alkyl,

C(O)(C 1 -C 6 )alkyl,

C(O)(C 5 -C 10 )heterocyclyl,

C(O)(C 3 -C 8 )cycloalkyl

C(O)(C 1 -C 6 )alkylene-(C 3 -C 8 )cycloalkyl,

C(O)(C 1 -C 6 )alkylene-C 5 -C 10 )heterocyclyl, or

C(O)(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl.

15. The method according to claim 1 wherein in formula (I) R 6 is

C(O)(C 1 -C 6 )alkyl,

C(O)(C 3 -C 8 )cycloalkyl,

C(O)—(C 5 -C 10 )heterocyclyl,

C(O)(C 1 -C 4 )alkylene-(C 5 -C 10 )heterocyclyl, or

C(O)(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl.

16. The method according to claim 1 wherein in formula (I) R 6 is

C(O)(C 1 -C 6 )alkyl;

C(O)(C 3 -C 6 )cycloalkyl;

C(O)—(C 5 -C 6 )heterocyclyl wherein the heterocyclyl is unsubstituted;

C(O)(C 1 -C 4 )alkylene-(C 5 -C 10 )heterocyclyl wherein the heterocyclyl is unsubstituted; or

C(O)(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl wherein the aryl is unsubstituted or substituted one or more times by halogen;

and wherein

a (C 1 -C 4 )alkyl or (C 1 -C 6 )alkyl residue is unsubstituted or substituted one to three times by a group independently selected from halogen, OH, NH 2 , NH(CH 3 ) or N(CH 3 ) 2 ,

a (C 1 -C 4 )alkylene residue is unsubstituted or substituted once by amino or N(CH 3 ) 2 and a (C 3 -C 8 )cycloalkyl residue is unsubstituted or substituted once by NH 2 .

17. The method according to claim 1 wherein in formula (I) m is 3 and L is attached to the 3-position or to the 4-position of the piperidine ring.

18. The method according to claim 1 wherein in formula (I) L is O-methylene, O-ethylene, or O.

19. The method according to claim 1 wherein in formula (I)

R 1 is OH;

R 2 is hydrogen, halogen, or (C 1 -C 6 )alkyl;

R 3 is H, halogen, (C 1 -C 4 )alkylene-R′, O—R″ or NHR″;

R 4 is H, halogen or (C 1 -C 6 )alkyl;

R 5 is H, (C 1 -C 6 )alkyl, halogen, CN, (C 2 -C 6 )alkenyl, (C 6 -C 10 )aryl, NH—(C 6 -C 10 )aryl,

(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, (C 5 -C 10 )heterocyclyl or

(C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl;

R 6 is, (C 1 -C 6 )alkylene-C(O)N[(C 1 -C 4 )alkyl] 2 , C(O)(C 1 -C 6 )alkyl, C(O)(C 3 -C 8 )cycloalkyl, C(O)—(C 1 -C 6 )alkylene-C 3 -C 8 )cycloalkyl, C(O)(C 1 -C 6 )alkylene-C 5 -C 10 )heterocyclyl, or C(O)—(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl;

R 7 is H, halogen, CN, (C 1 -C 6 )alkyl, O—(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl or R′;

R 8 is H, halogen or (C 1 -C 6 )alkyl;

m is 2, 3 or 4

n is 1, 2 or 3, and

L is O,O-methylene or O-ethylene.

20. The method according to claim 1 wherein in formula (I) R 1 is OH;

R 2 is H or (C 1 -C 4 )alkyl;

R 3 is H, halogen or NHR″, wherein R″ is defined as above;

R 4 is H, halogen or (C 1 -C 4 )alkyl;

R 5 is H, (C 1 -C 6 )alkyl, halogen, (C 2 -C 4 )alkenyl, (C 6 -C 10 )aryl, (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl or (C 5 -C 10 )heterocyclyl;

R 6 is C(O)(C 1 -C 6 )alkyl, C(O)(C 3 -C 8 )cycloalkyl, C(O)—(C 5 -C 10 )heterocyclyl, C(O)(C 1 -C 6 )alkylene-(C 3 -C 8 )cycloalkyl, C(O)(C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl, or C(O)(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl;

R 7 is H, halogen, CN, (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl or R′;

R 8 is H, halogen or (C 1 -C 6 )alkyl;

m is 2, 3 or 4

n is 1, 2 or 3; and

L is O.