Substituted isoquinolines and isoquinolinones as Rho kinase inhibitors

1. A compound of the formula (I)

wherein

R 1 is H, OH or NH 2 ;

R 3 is H, halogen, CN, (C 1 -C 6 )alkyl, OH, NH 2 , or NHR′;

R 4 is H, halogen, hydroxy, CN, (C 1 -C 6 )alkyl, R′, or (C 1 -C 6 )alkylene-R′;

R 5 is H, halogen, CN, (C 1 -C 6 )alkyl, or R′;

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

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

R 9 is

R′,

OH,

halogen,

(C 1 -C 6 )alkyl,

O—(C 1 -C 6 )alkyl,

(C 1 -C 6 )alkylene-R′,

(C 2 -C 6 )alkenyl,

(C 2 -C 6 )alkynyl,

(C 1 -C 6 )alkylene-O—R′,

(C 1 -C 6 )alkylene-CH[R′] 2 ,

(C 1 -C 6 )alkylene-C(O)—R′,

(C 1 -C 6 )alkylene-C(O)NH 2 ,

(C 1 -C 6 )alkylene-C(O)NH—R′,

(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)N[R′] 2 ;

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

COOH,

C(O)O—(C 1 -C 6 )alkyl,

C(O)OR′

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

C(O)R′,

C(O)NH 2 ,

C(O)—NH—(C 2 -C 6 )alkenyl,

C(O)—NH—(C 2 -C 6 )alkynyl,

C(O)NH—(C 1 -C 6 )alkyl,

C(O)NHR′,

C(O)—NH(C 1 -C 6 )alkylene-R′,

C(O)N[(C 1 -C 6 )alkyl]R′

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

C(O)—(C 1 -C 6 )alkylene-R′, or

C(O)O(C 1 -C 6 )alkylene-R′;

R 6 is absent;

or is one (C 1 -C 4 )alkylene bound to the cycloalkyl ring, in which the (C 1 -C 4 )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—R 15 , S, SO or SO 2 ;

or, if m; and s are 2, m is 3 and s is 1, or m is 4 and s is 0,

R 6 is CH 2 —CH—(CH 2 ) 2 which is bound with one CH 2 to the cycloalkyl ring and the two other CH 2 are bound to different carbon atoms of the cycloalkyl ring;

and, if m is 3 and s is 3,

R 6 are two methylene groups bound to different carbon atoms of the cycloalkyl ring, wherein the methylene groups or the CH 2 —CH—(CH 2 ) 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 R 9 ;

R 10 is

H,

(C 6 -C 10 )aryl,

O—(C 6 -C 10 )aryl,

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

(C 5 -C 10 )heteroaryl, wherein (C 6 -C 10 )aryl or (C 5 -C 10 )heteroaryl are unsubstituted or substituted;

R 11 is

H,

(C 1 -C 6 )alkyl,

(C 1 -C 6 )alkylene-R′,

(C 3 -C 8 )cycloalkyl,

(C 5 -C 10 )heteroaryl,

(C 3 -C 8 )heterocycloalkyl,

(C 6 -C 10 )aryl;

or R 11 and R 12 together with carbon atom to which they are attached form a (C 3 -C 8 )cycloalkyl or a (C 3 -C 8 )-heterocycloalkyl ring;

R 12 is

(C 1 -C 6 )alkyl,

(C 3 -C 8 )cycloalkyl,

(C 5 -C 10 )heteroaryl,

(C 3 -C 8 )heterocycloalkyl, or

(C 6 -C 10 )aryl;

or R 12 is H, provided that r=2 and the other R 12 is not H;

or R 11 and R 12 together with carbon atom to which they are attached form a (C 3 -C 8 )cycloalkyl or a (C 3 -C 8 )-heterocycloalkyl ring;

R 13 and R 14 are independently of each other

H,

R′,

(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′,

(C 1 -C 6 )alkylene-CH[R′] 2 ,

(C 1 -C 6 )alkylene-C(O)—R′,

(C 1 -C 6 )alkylene-C(O)NH 2 ,

(C 1 -C 6 )alkylene-C(O)NH—R′,

(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)N[R′] 2 ,

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

C(O)O—(C 1 -C 6 )alkyl,

C(O)OR′,

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

C(O)R′,

C(O)NH—(C 1 -C 6 )alkyl,

C(O)NHR′,

C(O)N [(C 1 -C 6 )alkyl]R′

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

C(O)—(C 1 -C 6 )alkylene-R′,

C(O)O(C 1 -C 6 )alkylene-R′, or

R 13 and R 14 , together with the N-atom to which they are attached, form a (C 3 -C 8 ) heterocycloalkyl;

R 15 is H or (C 1 -C 6 )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(CH 2 ) p , S(CH 2 ) p , S(O)(CH 2 ) p , SO 2 (CH 2 ) p , NH(CH 2 ) p , N(C 1 -C 6 )alkyl-(CH 2 ) p , N(C 3 -C 6 )cycloalkyl-(CH 2 ) p ; or N[(C 1 -C 3 )alkylene-R]-(CH 2 ) p ;

p is 0, 1, 2, 3 or 4;

R′ is

(C 3 -C 8 )cycloalkyl,

(C 5 -C 10 )heteroaryl,

(C 3 -C 8 )heterocycloalkyl,

(C 6 -C 10 )aryl;

wherein in residues R 3 to R 15 alkyl or alkylene is unsubstituted or optionally substituted one or more times by OH, OCH 3 , C(O)OH, C(O)OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , C(O)NH 2 , C(O)NHCH 3 or C(O)N(CH 3 ) 2 ;

wherein in residues R 3 to R 15 cycloalkyl or heterocycloalkyl is unsubstituted or optionally substituted one or more times by (C 1 -C 6 )alkyl, halogen, OH, OCH 3 , C(O)OH, C(O)OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , C(O)NH 2 , C(O)NHCH 3 or C(O)N(CH 3 ) 2 ;

wherein in residues R 3 to R 15 alkyl or alkylene is unsubstituted or optionally substituted one or more times by halogen;

wherein in residues R 3 to R 15 (C 6 -C 10 )aryl and (C 5 -C 10 )heteroaryl are unsubstituted or optionally substituted one or more times by a group 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-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 , SF 5 ,

C(NH)(NH 2 ), NH 2 , NH—(C 1 -C 6 )alkyl, [(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 )heteroaryl, NH—SO 2 —(C 3 -C 8 )heterocycloalkyl, 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 )heteroaryl, (C 3 -C 8 )heterocycloalkyl,

(C 1 -C 6 )alkylene-(C 5 -C 10 )heteroaryl, (C 1 -C 6 )alkylene-(C 3 -C 8 )heterocycloalkyl, O—(C 1 -C 6 )alkylene-(C 5 -C 10 )heteroaryl, O—(C 1 -C 6 )alkylene-(C 3 -C 8 )heterocycloalkyl,

wherein said (C 6 -C 10 )aryl, (C 5 -C 10 )heteroaryl, (C 3 -C 8 )heterocycloalkyl or (C 3 -C 8 )cycloalkyl 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-β-(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 substituents of (C 6 -C 10 )aryl, (C 5 -C 10 )hetero aryl, (C 3 -C 8 )heterocycloalkyl or (C 3 -C 8 )cycloalkyl groups may not be further substituted by an aryl, heteroaryl, heterocycloalkyl, or (C 3 -C 8 )cycloalkyl containing group;

their stereoisomeric and/or tautomeric forms or a pharmaceutically acceptable salt.

2. A compound of formula (I) according to claim 1 , wherein R 1 is H and is characterized by the formula (II)

3. A compound of formula (I) according to claim 1 , wherein R 1 is OH and is characterized by the formula (IIIa)

or of the formula (IIIb)

4. A compound according to claim 1 , wherein R 1 is NH 2 .

5. A compound according to one of claims 1 to 4 , wherein R 3 is H, halogen, (C 1 -C 6 )alkyl, or NHR′, wherein (C 1 -C 6 )alkyl and R′ are unsubstituted or substituted.

6. A compound according to one of claims 1 to 4 , wherein R 3 is H.

7. A compound according to one of claims 1 to 4 , wherein R 4 is H, halogen, (C 1 -C 6 )alkyl or (C 1 -C 2 )alkylene-phenyl, wherein (C 1 -C 6 )alkyl or phenyl are unsubstituted or substituted.

8. A compound according to one of claims 1 to 4 , wherein R 4 is H or halogen.

9. A compound according to one of claims 1 to 4 , wherein R 5 is H, halogen, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl or (C 5 -C 10 )hetero aryl, wherein (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl or (C 5 -C 10 )heteroaryl are unsubstituted or substituted.

10. A compound according to one of claims 1 to 4 , wherein R 5 is H.

11. A compound according to one of claims 1 to 4 , wherein R 7 is H, halogen, (C 1 -C 6 )alkyl, O—(C 1 -C 6 )alkyl, or R′, wherein (C 1 -C 6 )alkyl or R′ are unsubstituted or substituted.

12. A compound according to one of claims 1 to 4 , wherein R 7 is H, methyl or chloro.

13. A compound according to one of claims 1 to 4 , wherein R 8 is H.

14. A compound according to one of claims 1 to 4 , wherein R 9 is

R′,

OH,

halogen,

(C 1 -C 6 )alkyl,

(C 1 -C 6 )alkylene-R′,

(C 2 -C 6 )alkenyl,

(C 1 -C 6 )alkylene-C(O)NH—R′,

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

C(O)OH,

C(O)NH 2 ,

C(O)NH—(C 1 -C 6 )alkyl,

C(O)NHR′,

C(O)—NH—(C 1 -C 6 )alkynyl,

C(O)—NH(C 1 -C 6 )alkylene-R′, or

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

wherein (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylene or R′ are unsubstituted or substituted.

15. A compound according to one of claims 1 to 4 , wherein R 9 is OH, halogen, (C 1 -C 6 )alkyl, C(O)OH, C(O)NH 2 , or O—CH 3 , wherein (C 1 -C 6 )alkyl is unsubstituted or substituted.

16. A compound according to one of claims 1 to 4 , wherein R 9 is unsubstituted or substituted (C 1 -C 6 )alkyl.

17. A compound according to any of claims 1 to 4 , wherein R 10 is H, phenyl, O-phenyl, or (C 5 -C 6 )heteroaryl,

wherein phenyl or (C 5 -C 6 )heteroaryl is unsubstituted or substituted.

18. A compound according to any of claims 1 to 4 , wherein R 10 is H or phenyl optionally substituted by (C 1 -C 6 )alkyl, F, Cl, Br, OMe or CF 3 .

19. A compound according to any of claims 1 to 4 , wherein R 10 is H.

20. A compound according to any of claims 1 to 4 , wherein R 11 is H or methyl.

21. A compound according to any of claims 1 to 4 , wherein R 12 is

(C 1 -C 6 )alkyl, wherein optionally one or more hydrogen are substituted by fluoro;

(C 3 -C 8 )cycloalkyl,

(C 5 -C 6 )heteroaryl, or

(C 6 -C 10 )aryl,

wherein (C 3 -C 8 )cycloalkyl, (C 5 -C 6 )heteroaryl or (C 6 -C 10 )aryl are unsubstituted or substituted.

22. A compound according to any of claims 1 to 4 , wherein R 12 is methyl, ethyl, propyl, isopropyl, cyclopropyl, trifluoromethyl, thiazolyl or phenyl unsubstituted or substituted by (C 1 -C 4 )alkyl or halogen.

23. A compound according to any of claims 1 to 4 , wherein R 11 and R 12 form a substituted or unsubstituted (C 3 -C 8 )cycloalkyl ring.

24. A compound according to one of claims 1 to 4 , wherein R 13 and R 14 are independently of each other

H,

R′

(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′,

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

C(O)R′, or

C(O)(C 1 -C 6 )alkyene-R′

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

wherein R′, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylene are unsubstituted or substituted, or

R 13 and R 14 , together with the N-atom to which they are attached, form a unsubstituted or substituted (C 3 -C 8 ) heterocycloalkyl ring.

25. A compound according to one of claims 1 to 4 , wherein R 13 and R 14 are independently of each other

H,

(C 1 -C 6 )alkyl,

(C 3 -C 8 )cycloalkyl,

(C 1 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl,

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

(C 1 -C 4 )alkylene-(C 3 -C 8 )heterocycloalkyl,

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

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

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

R 13 and R 14 , together with the N-atom to which they are attached, form a (C 3 -C 8 ) heterocycloalkyl group,

wherein (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 4 )alkylene, C 5 -C 10 )heteroaryl, (C 3 -C 8 )heterocycloalkyl, or (C 6 -C 10 )aryl are unsubstituted or substituted.

26. A compound according to any of claims 1 to 4 , wherein

R 13 is H or (C 1 -C 6 )alkyl; and

R 14 is

H,

(C 1 -C 6 )alkyl,

(C 3 -C 8 )cycloalkyl,

(C 1 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl,

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

(C 1 -C 4 )alkylene-(C 3 -C 8 )heterocycloalkyl,

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

(C 1 -C 4 )alkylene-O—(C 1 -C 6 )alkyl,

wherein (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 4 )alkylene, (C 5 -C 10 )heteroaryl, (C 3 -C 8 )heterocycloalkyl, or (C 6 -C 10 )aryl are unsubstituted or substituted.

27. A compound according to any of claims 1 to 4 , wherein

R 13 is H, (C 1 -C 6 )alkyl and

R 14 is H, (C 1 -C 6 )alkyl or (C 3 -C 8 )cycloalkyl,

wherein (C 1 -C 6 )alkyl or (C 3 -C 8 )cycloalkyl are unsubstituted or substituted.

28. A compound according to any of claims 1 to 4 , wherein R 13 and R 14 are H.

29. A compound according to one of claims 1 to 4 , wherein R 6 is absent or the bicyclus or adamantane formed with R 6 is selected from

which are unsubstituted or optionally substituted by R 9 .

30. A compound according to one of claims 1 to 4 , wherein R 6 is absent.

31. A compound according to one of claims 1 to 4 , wherein m is 2 and s is 2.

32. A compound according to one of claims 1 to 4 , wherein m is 3 and s is 1.

33. A compound according to one of claims 1 to 4 , wherein n is 0, 1, or 1.

34. A compound according to one of claims 1 to 4 , wherein n is 0.

35. A compound according to one of claims 1 to 4 , wherein r is 1.

36. A compound according to one of claims 1 to 4 , wherein L is S(CH 2 ) p , S(O)(CH 2 )p, or SO 2 (CH 2 )p.

37. A compound according to one of claims 1 to 4 , wherein L is NH(CH 2 )p or N(C 1 -C 6 )alkyl)-(CH 2 )p.

38. A compound according to one of claims 1 to 4 , wherein L is O(CH 2 )p.

39. A compound according to one of claims 1 to 4 , wherein p is 0.

40. A compound according to claim 1 selected from the group consisting of

6-[4-(1-Amino-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

6-[4-(1-Amino-cyclopropyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

6-{[4-(1-aminopropyl)-4-phenylcyclohexyl]oxy}-7-chloroisoquinolin-1(2H)-one,

6-[4-(1-Amino-butyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

6-[4-(1-Amino-butyl)-4-(4-fluoro-phenyl)-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,

6-[4-(1-Amino-propyl)-4-(4-bromo-phenye-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

6-[4-(1-Amino-propyl)-4-(2-bromo-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

6-[4-(1-Amino-propyl)-4-(4-trifluoromethyl-phenyl)-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,

6-[4-(1-Amino-propyl)-4-(2-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2,1-isoquinolin-1-one,

6-[4-(1-Amino-propyl)-4-(2-chloro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,

6-[4-(1-Amino-ethyl)-4-(4-fluoro-phenyl)-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,

6-[4-(1-Amino-2-methyl-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

6-[4-(1-Amino-3-methyl-butyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

6-[4-(Amino-phenyl-methyl)-4-phenyl-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,

6-[4-(1-Amino-1-methyl-ethyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

6-[4-(1-Amino-cyclopropyl)-4-(2-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

6-[4-(1-Amino-ethyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

6-[4-(1-Amino-1-methyl-ethyl)-4-phenyl-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,

6-(4-[amino(cyclopropyl)methyl]-4-phenyl-cyclohexyl}oxy)-7-chloroisoquinolin-1(2H)-one,

6-[4-(1-Amino-propyl)-4-(4-isopropyl-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

6-[4-(1-Amino-propyl)-4-(3-methoxy)-phenye-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

6-[4-(1-Amino-propyl)-4-(3-bromo-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

6-[4-(1-Amino-2-methyl-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, or

6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-4-bromo-7-chloro-2H-isoquinolin-1-one,

their stereoisomeric and/or tautomeric forms or a pharmaceutically acceptable salt.

41. A compound according to claim 1 selected from the group consisting of

cis-6-[4-(1-Amino-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

trans-6-[4-(1-amino-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-on,

cis-6-[4-(1-Amino-cyclopropyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-{[4-(1-Amino-propyl)-4-phenylcyclohexyl]oxy}-7-chloro-2H-isoquinolin-1-one,

trans-6-[4-(1-Amino-propyl)-4-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-butyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

trans-6-[4-(1-Amino-butyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-butyl)-4-(4-fluoro-phenyl)-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,

trans-6-[4-(1-Amino-butyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(4-bromo-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(2-bromo-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(4-trifluoromethyl-phenyl)-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(2-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(2-chloro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-ethyl)-4-(4-fluoro-phenyl)-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,

trans-6-[4-(1-Amino-ethyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(3-bromo-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

trans-6-[4-(1-Amino-propyl)-4-(3-bromo-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(3-methoxy)-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

trans-6-[4-(1-Amino-propyl)-4-(3-methoxy-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

trans-6-[4-(Amino-phenyl-methyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

trans-6-[4-(1-Amino-2-methyl-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

trans-6-[4-(1-Amino-3-methyl-butyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

trans-6-[4-(Amino-phenyl-methyl)-4-phenyl-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,

trans-6-[4-(1-Amino-1-methyl-ethyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-cyclopropyl)-4-(2-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-ethyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-1-methyl-ethyl)-4-phenyl-cyclo-hexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-(4-[amino(cyclopropyl)methyl]-4-phenyl-cyclo-hexyl}oxy)-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(4-isopropyl-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-2-methyl-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, and

cis-6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-4-bromo-7-chloro-2H-isoquinolin-1-one,

their stereoisomeric and/or tautomeric forms or a pharmaceutically acceptable salt.

42. A compound according to claim 1 selected from the group consisting of

trans-6-[4-((S)-Amino-phenyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

trans-6-[4-((R)-Amino-phenyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-((S)-1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-((R)-1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-((S)-Amino-cyclopropyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-((R)-Amino-cyclopropyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-((R)-Amino-cyclopropyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-((S)-Amino-cyclopropyl-methyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-((S)-1-Amino-ethyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-((R)-1-Amino-ethyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

6-{4-[(S)-Amino-(4-fluoro-phenyl)-methyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,

6-{4-[(R)-Amino-(4-fluoro-phenyl)-methyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-((R)-1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, and

cis-6-[4-((S)-1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

their tautomeric forms or a pharmaceutically acceptable salt.

43. A compound according to claim 1 selected from the group consisting of cis-6-[4-(1-Amino-propyl)-4-pyridin-2-yl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(2,4-difluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(4-fluoro-2-methyl-phenyl)cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(3,5-difluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(3,4-difluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-o-tolyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(2-trifluoromethoxy-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(4-fluoro-3-methoxy-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(3-ethoxy-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(3-methoxy-4-methyl-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(3,4-difluoro-phenyl)-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(3,5-difluoro-phenyl)-cyclohexyloxy]-7-fluoro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(3,4-difluoro-phenyl)-cyclohexyloxy]-7-fluoro-5-methyl-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(3,5-difluoro-phenyl)-cyclohexyloxy]-7-methoxy-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(2-methoxy-phenyl)-cyclohexyloxy]-7-chloro-2H isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(4-trifluoro-methoxy-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-1-methyl-ethyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(3,5-difluoro-phenyl)-cyclohexyloxy]-4-benzyl-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(3,5-difluoro-phenyl)-cyclohexyloxy]-5-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(3,5-difluoro-phenyl)-cyclohexyloxy]-5,7-dimethyl-2H-isoquinolin-1-one,

cis-6-[4-(Amino-cyclopropyl-methyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(3-trifluoromethyl-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(3-trifluoromethoxy-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(3-trifluoromethoxy-phenyl)-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-(3-trifluoromethyl-phenyl)-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-fluoro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-fluoro-5-methyl-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-4-benzyl-7-chloro-2H-isoquinolin-1-one,

cis-4-[1-(1-Amino-propyl)-4-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-cyclohexyl]-benzonitrile,

cis-3-[1-(1-Amino-propyl)-4-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-cyclohexyl]benzonitrile,

6-[cis-4-(1-Amino-propyl)-4-(3-methanesulfonyl-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

6-[(1S,4S,5S)-5-(1-Amino-propyl)-5-phenyl-bicyclo[2.2.1]hept-2-yloxy]-7-chloro-2H-isoquinolin-1-one,

6-[(1R,4R,5R)-5-(1-Amino-propyl)-5-phenyl-bicyclo[2.2.1]hept-2-yloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Benzylamino-propyl)-4-phenyl-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,

cis-6-[4-(1-Diethylamino-propyl)-4-phenyl-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,

cis-7-Methyl-6-[4-(1-propylamino-propyl)-4-(3-trifluoromethyl-phenyl)-cyclohexyloxy]-2H-isoquinolin-1-one,

cis-6-[4-(1-Benzylamino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-7-Chloro-6-[4-(1-isobutylamino-propyl)-4-phenyl-cyclohexyloxy]-2H-isoquinolin-1-one,

cis-6-[4-(1-Butylamino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-7-Chloro-6-{4-[1-(cyclopropylmethyl-amino)-propyl]-4-phenyl-cyclohexyloxy}-2H-isoquinolin-1-one,

cis-6-[4-(2-Amino-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(2-Amino-butyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-2-fluoro-ethyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

cis-6-[4-(1-Amino-3-methoxy-propyl)-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

6-[3-(1-Amino-propyl)-3-(4-fluoro-phenyl)-cyclobutyloxy]-7-chloro-2H-isoquinolin-1-one, and

6-[3-(1-Amino-propyl)-3-(4-fluoro-phenyl)-cyclopentyloxy]-7-chloro-2H-isoquinolin-1-one,

and their stereoisomeric and/or tautomeric forms or a pharmaceutically acceptable salt.

44. A compound according to claim 1 is selected from the group consisting of

cis-1-[4-(7-Chloro-isoquinolin-6-yloxy)-1-(3,4-difluoro-phenyl)-cyclohexyl]-propylamine,

cis-1-[4-(7-Bromo-isoquinolin-6-yloxy)-1-(3,4-difluoro-phenyl)-cyclohexyl]-propylamine,

cis-1-[1-(3,5-Difluoro-phenyl)-4-(5,7-dimethyl-isoquinolin-6-yloxy)-cyclohexyl]-propylamine,

cis-1-[1-(3,5-Difluoro-phenyl)-4-(7-fluoro-5-methyl-isoquinolin-6-yloxy)-cyclohexyl]-propylamine,

cis-1-[1-(3,4-Difluoro-phenyl)-4-(7-fluoro-isoquinolin-6-yloxy)-cyclohexyl]-propylamine,

cis-1-[4-(7-Chloro-isoquinolin-6-yloxy)-1-(3,5-difluoro-phenyl)-cyclohexyl]-propylamine,

cis-1-[4-(5-Chloro-isoquinolin-6-yloxy)-1-(3,5-difluoro-phenyl)-cyclohexyl]-propylamine,

cis-1-[4-(7-Chloro-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-propylamine,

cis-1-[4-(5,7-Dimethyl-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-propylamine,

cis-1-[4-(7-Fluoro-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-propylamine,

cis-1-[4-(5-Chloro-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-propylamine,

cis-1-[4-(7-Fluoro-5-methyl-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-propylamine,

cis-1-[4-(7-Bromo-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-propylamine,

cis-1-[4-(7-Methyl-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-propylamine,

cis-6-[4-(1-Amino-propyl)-4-phenyl-cyclohexyloxy]-7-chloro-isoquinolin-1-ylamine,

[4-(1-Amino-propyl)-4-(4-methoxy-phenyl)-cyclohexyl]-isoquinolin-6-yl-amine, and

1-Amino-[4-(1-amino-propyl)-4-(4-methoxy-phenyl)-cyclohexyl]-isoquinolin-6-yl-amine,

and their stereoisomeric and/or tautomeric forms or a pharmaceutically acceptable salt.

45. A compound according to claim 1 selected from the group consisting of

6-[4-(1-Amino-1-phenyl-ethyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

6-{4-[Amino-(4-methoxy-phenyl)-methyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,

6-{4-[Amino-(4-fluoro-phenyl)-methyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,

6-[4-(Amino-p-tolyl-methyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, or

6-[4-(Amino-phenyl-methyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

and their stereoisomeric and/or tautomeric forms or a pharmaceutically acceptable salt.

46. A compound according to claim 1 is selected from the group consisting of

6-{4-[1-Amino-1-(4-fluoro-phenyl)-ethyl]cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,

6-{4-[1-Amino-1-(4-methoxy-phenyl)-ethyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,

6-{4-[1-Amino-1-cyclopentyl-ethyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,

6-{4-[1-Amino-1-ethyl-propyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,

6-{4-[1-Amino-1-cyclopropyl-ethyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,

6-{4-[1-Amino-1-n-propyl-ethyl]-cyclohexyloxy}-7-chloro-2H-isoquinolin-1-one,

6-[4-(1-Amino-propyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, and

6-[4-(Amino-cyclopropyl-methyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,

and their stereoisomeric and/or tautomeric forms or a pharmaceutically acceptable salt.

47. A method for the treatment and/or prevention 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 (end organ damage), fibroid lung, fibroid liver, liver failure, nephropathy, renal failure, fibroid kidney, renal glomerulosclerosis, organ hypertrophy, asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, thrombotic disorders, stroke, cerebral vasospasm, cerebral ischemia, pain, neuronal degeneration, spinal cord injury, Alzheimer's disease, premature birth, erectile dysfunction, endocrine dysfunctions, arteriosclerosis, prostatic hypertrophy, diabetes and complications of diabetes, metabolic syndrome, blood vessel restenosis, atherosclerosis, inflammation, autoimmune diseases, AIDS, osteopathy, infection of digestive tracts with bacteria, sepsis or cancer development and progression comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 .

48. A method for the treatment and/or prevention of hypertension, pulmonary hypertension, fibroid liver, liver failure, nephropathy, renal failure, chronic obstructive pulmonary disease (COPD), cerebral vasospasm, pain, spinal cord injury, erectile dysfunction, blood vessel restenosis, or cancer development and progression comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 .

49. A method for curative approaches associated with stem cell or induced pluripotent stem cell treatment, improvement of recognition or for treatment or prevention of depression, epilepsy, fibroid heart, renal papillary necrosis, tubulo-interstitial dysfunction, multiple sclerosis, vessel stenosis or lipid disorders comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 .

50. A pharmaceutical composition comprising an effective amount of at least one compound of formula (I) or a pharmacologically acceptable salt according to one of claims 1 to 4 , pharmaceutically tolerated excipients and carriers and, further additives and/or other active ingredients.