# US 8,541,449 B2 · Substituted isoquinolines and isoquinolinones as Rho kinase inhibitors

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- Number: US 8,541,449 B2
- Document ID: US8541449B2
- Status: Granted
- Kind: B2
- Application number: 13/000,754
- Filed: 2009-06-19
- Published: 2011-08-04
- Granted: 2013-09-24
- Earliest claimed: 2008-06-24
- Assignees: Sanofi
- Applicants: Oliver Plettenburg; Katrin Lorenz; John Weston; Matthias Loehn; Heinz-Werner Kleemann; Olivier Duclos; Frederic Jeannot
- Inventors: Oliver Plettenburg; Katrin Lorenz; John Weston; Matthias Loehn; Heinz-Werner Kleemann; Olivier Duclos; Frederic Jeannot
- Web page: https://patentgrep.com/patent/US8541449B2

## CPC

- C07D 217/24: Oxygen atoms
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/00: Drugs for disorders of the endocrine system
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- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to substituted isoquinoline and isoquinolinones 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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

A compound of formula (I) according to claim 1, wherein R1 is H and is characterized by the formula (II)

### Claim 3 (depends on 1)

A compound of formula (I) according to claim 1, wherein R1 is OH and is characterized by the formula (IIIa)
or of the formula (IIIb)

### Claim 4 (depends on 1)

A compound according to claim 1, wherein R1 is NH2.

### Claim 5 (depends on 1, 2, 3, 4)

A compound according to one of claims 1 to 4, wherein R3 is H, halogen, (C1-C6)alkyl, or NHR′, wherein (C1-C6)alkyl and R′ are unsubstituted or substituted.

### Claim 6 (depends on 1, 2, 3, 4)

A compound according to one of claims 1 to 4, wherein R3 is H.

### Claim 7 (depends on 1, 2, 3, 4)

A compound according to one of claims 1 to 4, wherein R4 is H, halogen, (C1-C6)alkyl or (C1-C2)alkylene-phenyl, wherein (C1-C6)alkyl or phenyl are unsubstituted or substituted.

### Claim 8 (depends on 1, 2, 3, 4)

A compound according to one of claims 1 to 4, wherein R4 is H or halogen.

### Claim 9 (depends on 1, 2, 3, 4)

A compound according to one of claims 1 to 4, wherein R5 is H, halogen, (C1-C6)alkyl, (C6-C10)aryl, (C3-C8)cycloalkyl or (C5-C10)hetero aryl, wherein (C1-C6)alkyl, (C6-C10)aryl, (C3-C8)cycloalkyl or (C5-C10)heteroaryl are unsubstituted or substituted.

### Claim 10 (depends on 1, 2, 3, 4)

A compound according to one of claims 1 to 4, wherein R5 is H.

### Claim 11 (depends on 1, 2, 3, 4)

A compound according to one of claims 1 to 4, wherein R7 is H, halogen, (C1-C6)alkyl, O—(C1-C6)alkyl, or R′, wherein (C1-C6)alkyl or R′ are unsubstituted or substituted.

### Claim 12 (depends on 1, 2, 3, 4)

A compound according to one of claims 1 to 4, wherein R7 is H, methyl or chloro.

### Claim 13 (depends on 1, 2, 3, 4)

A compound according to one of claims 1 to 4, wherein R8 is H.

### Claim 14 (depends on 1, 2, 3, 4)

A compound according to one of claims 1 to 4, wherein R9 is
R′,
OH,
halogen,
(C1-C6)alkyl,
(C1-C6)alkylene-R′,
(C2-C6)alkenyl,
(C1-C6)alkylene-C(O)NH—R′,
(C1-C6)alkylene-C(O)NH—(C1-C6)alkyl,
C(O)OH,
C(O)NH2,
C(O)NH—(C1-C6)alkyl,
C(O)NHR′,
C(O)—NH—(C1-C6)alkynyl,
C(O)—NH(C1-C6)alkylene-R′, or
C(O)N[(C1-C6)alkyl]2;
wherein (C1-C6)alkyl, (C1-C6)alkylene or R′ are unsubstituted or substituted.

### Claim 15 (depends on 1, 2, 3, 4)

A compound according to one of claims 1 to 4, wherein R9 is OH, halogen, (C1-C6)alkyl, C(O)OH, C(O)NH2, or O—CH3, wherein (C1-C6)alkyl is unsubstituted or substituted.

### Claim 16 (depends on 1, 2, 3, 4)

A compound according to one of claims 1 to 4, wherein R9 is unsubstituted or substituted (C1-C6)alkyl.

### Claim 17 (depends on 1, 2, 3, 4)

A compound according to any of claims 1 to 4, wherein R10 is H, phenyl, O-phenyl, or (C5-C6)heteroaryl,
wherein phenyl or (C5-C6)heteroaryl is unsubstituted or substituted.

### Claim 18 (depends on 1, 2, 3, 4)

A compound according to any of claims 1 to 4, wherein R10 is H or phenyl optionally substituted by (C1-C6)alkyl, F, Cl, Br, OMe or CF3.

### Claim 19 (depends on 1, 2, 3, 4)

A compound according to any of claims 1 to 4, wherein R10 is H.

### Claim 20 (depends on 1, 2, 3, 4)

A compound according to any of claims 1 to 4, wherein R11 is H or methyl.

### Claim 21 (depends on 1, 2, 3, 4)

A compound according to any of claims 1 to 4, wherein R12 is
(C1-C6)alkyl, wherein optionally one or more hydrogen are substituted by fluoro;
(C3-C8)cycloalkyl,
(C5-C6)heteroaryl, or
(C6-C10)aryl,
wherein (C3-C8)cycloalkyl, (C5-C6)heteroaryl or (C6-C10)aryl are unsubstituted or substituted.

### Claim 22 (depends on 1, 2, 3, 4)

A compound according to any of claims 1 to 4, wherein R12 is methyl, ethyl, propyl, isopropyl, cyclopropyl, trifluoromethyl, thiazolyl or phenyl unsubstituted or substituted by (C1-C4)alkyl or halogen.

### Claim 23 (depends on 1, 2, 3, 4)

A compound according to any of claims 1 to 4, wherein R11 and R12 form a substituted or unsubstituted (C3-C8)cycloalkyl ring.

### Claim 24 (depends on 1, 2, 3, 4)

A compound according to one of claims 1 to 4, wherein 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′,
C(O)(C1-C6)alkyl,
C(O)R′, or
C(O)(C1-C6)alkyene-R′
C(O)N[(C1-C6)alkyl]2,
wherein R′, (C1-C6)alkyl, or (C1-C6)alkylene are unsubstituted or substituted, or
R13 and R14, together with the N-atom to which they are attached, form a unsubstituted or substituted (C3-C8) heterocycloalkyl ring.

### Claim 25 (depends on 1, 2, 3, 4)

A compound according to one of claims 1 to 4, wherein R13 and R14 are independently of each other
H,
(C1-C6)alkyl,
(C3-C8)cycloalkyl,
(C1-C4)alkylene-(C3-C8)cycloalkyl,
(C1-C4)alkylene-(C5-C10)heteroaryl,
(C1-C4)alkylene-(C3-C8)heterocycloalkyl,
C1-C4)alkylene-(C6-C10)aryl,
(C1-C6)alkylene-O—(C1-C6)alkyl,
C(O)(C1-C6)alkyl, or
R13 and R14, together with the N-atom to which they are attached, form a (C3-C8) heterocycloalkyl group,
wherein (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C4)alkylene, C5-C10)heteroaryl, (C3-C8)heterocycloalkyl, or (C6-C10)aryl are unsubstituted or substituted.

### Claim 26 (depends on 1, 2, 3, 4)

A compound according to any of claims 1 to 4, wherein
R13 is H or (C1-C6)alkyl; and
R14 is
H,
(C1-C6)alkyl,
(C3-C8)cycloalkyl,
(C1-C4)alkylene-(C3-C8)cycloalkyl,
(C1-C4)alkylene-(C5-C10)heteroaryl,
(C1-C4)alkylene-(C3-C8)heterocycloalkyl,
(C1-C4)alkylene-(C6-C10)aryl, or
(C1-C4)alkylene-O—(C1-C6)alkyl,
wherein (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C4)alkylene, (C5-C10)heteroaryl, (C3-C8)heterocycloalkyl, or (C6-C10)aryl are unsubstituted or substituted.

### Claim 27 (depends on 1, 2, 3, 4)

A compound according to any of claims 1 to 4, wherein
R13 is H, (C1-C6)alkyl and
R14 is H, (C1-C6)alkyl or (C3-C8)cycloalkyl,
wherein (C1-C6)alkyl or (C3-C8)cycloalkyl are unsubstituted or substituted.

### Claim 28 (depends on 1, 2, 3, 4)

A compound according to any of claims 1 to 4, wherein R13 and R14 are H.

### Claim 29 (depends on 1, 2, 3, 4)

A compound according to one of claims 1 to 4, wherein R6 is absent or the bicyclus or adamantane formed with R6 is selected from
which are unsubstituted or optionally substituted by R9.

### Claim 30 (depends on 1, 2, 3, 4)

A compound according to one of claims 1 to 4, wherein R6 is absent.

### Claim 31 (depends on 1, 2, 3, 4)

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

### Claim 32 (depends on 1, 2, 3, 4)

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

### Claim 33 (depends on 1, 2, 3, 4)

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

### Claim 34 (depends on 1, 2, 3, 4)

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

### Claim 35 (depends on 1, 2, 3, 4)

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

### Claim 36 (depends on 1, 2, 3, 4)

A compound according to one of claims 1 to 4, wherein L is S(CH2)p, S(O)(CH2)p, or SO2(CH2)p.

### Claim 37 (depends on 1, 2, 3, 4)

A compound according to one of claims 1 to 4, wherein L is NH(CH2)p or N(C1-C6)alkyl)-(CH2)p.

### Claim 38 (depends on 1, 2, 3, 4)

A compound according to one of claims 1 to 4, wherein L is O(CH2)p.

### Claim 39 (depends on 1, 2, 3, 4)

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

### Claim 40 (depends on 1)

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.

### Claim 41 (depends on 1)

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.

### Claim 42 (depends on 1)

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.

### Claim 43 (depends on 1)

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.

### Claim 44 (depends on 1)

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.

### Claim 45 (depends on 1)

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.

### Claim 46 (depends on 1)

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.

### Claim 47 (depends on 1, 2, 3, 4)

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.

### Claim 48 (depends on 1, 2, 3, 4)

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.

### Claim 49 (depends on 1, 2, 3, 4)

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.

### Claim 50 (depends on 1, 2, 3, 4)

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.