6-Substituted isoquinolines and isoquinolinones

Abstract

The invention relates to 6-substituted isoquinoline and isoquinolinone derivatives of the formula (I) t,21 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.

1 . A method of treating or preventing in a patient a disease selected from 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 and cancer development and progression, comprising administering an effective amount of at least one compound of the formula (I): 
       
         
           
           
               
               
           
         
         to a patient in need thereof; 
         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 atoms 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; 
         or, 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 cycloalkyl 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 
         (C 1 -C 6 )alkyl, 
         (C 1 -C 8 )heteroalkyl, 
         (C 3 -C 8 )cycloalkyl, 
         (C 3 -C 8 )heterocycloalkyl, 
         (C 1 -C 6 )alkylene-(C 3 -C 8 )cycloalkyl, 
         (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, 
         (C 1 -C 6 )alkylene-(C 5 -C 10 )heteroaryl, 
         (C 1 -C 6 )alkylene-(C 3 -C 8 )heterocycloalkyl, 
         C(O)NH—(C 1 -C 6 )alkyl, 
         C(O)N[C 1 -C 6 )alkyl] 2    
         C(O)NH—R′, 
         C(O)N—((C 1 -C 6 )alkyl)-R′, or 
         C(O)NH—(C 1 -C 6 )alkylene-R′; 
         R 11  is 
         H, 
         (C 1 -C 6 )alkyl, 
         (C 1 -C 6 )alkylene-R′ 
         R′, 
         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, C(O)OH, C(O)O(C 1 -C 6 )alkyl, C(O)NH 2 , C(O)NH(C 1 -C 6 )alkyl, C(O)N[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, 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 )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 or (C 5 -C 10 )heteroaryl or (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 , C(O)OH, C(O)O—(C 1 -C 6 )alkyl, C(O)NH 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 substituents of (C 6 -C 10 )aryl, (C 5 -C 10 )heteroaryl, cycloalkyl or (C 3 -C 8 )heterocycloalkyl groups may not be further substituted by an aryl, heteroaryl, cycloalkyl or heterocycloalkyl containing group; 
         their stereoisomeric and/or tautomeric forms and/or their pharmaceutically acceptable salts. 
       
     
     
         2 . The method according to  claim 1  wherein the disease is 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. 
     
     
         3 . The method according to  claim 1  for curative approaches associated with stem cell or induced pluripotent stem cell treatment, improvement of recognition or for the treatment or prevention of fibroid heart, depression, epilepsy, renal papillary necrosis, tubulo-interstitial dysfunction, multiple sclerosis, vessel stenosis or lipid disorders. 
     
     
         4 . The method according to any one of  claims 1  to  3  wherein in formula (I) R 1  is H according to the formula (II): 
       
         
           
           
               
               
           
         
       
     
     
         5 . The method according to any one of  claims 1  to  3  wherein in formula (I) R 1  is OH according to the formula (IIIa): 
       
         
           
           
               
               
           
         
       
       or according to the formula (IIIb): 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method according to any one of  claims 1  to  3  wherein in formula (I) R 1  is NH 2 . 
     
     
         7 . The method according to any one of  claims 1  to  3  wherein in formula (I) R 3  is H, halogen, (C 1 -C 6 )alkyl, or NHR′, wherein (C 1 -C 6 )alkyl and R′ are unsubstituted or substituted. 
     
     
         8 . The method according to any one of  claims 1  to  3  wherein in formula (I) R 4  is H, halogen, (C 1 -C 6 )alkyl or (C 1 -C 2 )alkenyl-phenyl, wherein (C 1 -C 6 )alkyl or phenyl are unsubstituted or substituted. 
     
     
         9 . The method according to any one of  claims 1  to  3  wherein in formula (I) 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 )heteroaryl, wherein (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 6 -C 10 )aryl, or (C 5 -C 10 )heteroaryl are unsubstituted or substituted. 
     
     
         10 . The method according to any one of  claims 1  to  3  wherein in formula (I) 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. 
     
     
         11 . The method according to any one of  claims 1  to  3  wherein in formula (I) R 8  is H. 
     
     
         12 . The method according to any one of  claims 1  to  3  wherein in formula (I) 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, 
 COOH, 
 CONH 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. 
 
     
     
         13 . The method according to any one of  claims 1  to  3  wherein in formula (I) R 10  is
 (C 1 -C 6 )alkyl, 
 (C 1 -C 8 )heteroalkyl, 
 (C 3 -C 8 )cycloalkyl, 
 (C 3 -C 8 )heterocycloalkyl, 
 (C 1 -C 6 )alkylene-(C 3 -C 8 )cycloalkyl, 
 (C 1 -C 6 )alkylene-phenyl, 
 (C 1 -C 6 )alkylene-(C 5 -C 6 )heteroaryl, or 
 (C 1 -C 6 )alkylene-(C 5 -C 6 )heterocycloalkyl, 
 wherein (C 1 -C 6 )alkyl, (C 1 -C 8 )heteroalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )heterocycloalkyl, (C 1 -C 6 )alkylene, phenyl or (C 5 -C 10 )heteroaryl are unsubstituted or substituted. 
 
     
     
         14 . The method according to any one of  claims 1  to  3  wherein in formula (I) R 11  is
 H, 
 (C 1 -C 6 )alkyl, 
 (C 3 -C 8 )cycloalkyl, or 
 (C 5 -C 6 )heteroaryl, 
 wherein (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 5 -C 6 )heteroaryl are unsubstituted or substituted. 
 
     
     
         15 . The method according to any one of  claims 1  to  3  wherein in formula (I) 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. 
 
     
     
         16 . The method according to any one of  claims 1  to  3  wherein in formula (I) R 11  and R 12  form a substituted or unsubstituted (C 3 -C 8 )cycloalkyl ring. 
     
     
         17 . The method according to any one of  claims 1  to  3  wherein in formula (I) 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)NH—(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. 
 
     
     
         18 . The method according to any one of  claims 1  to  3  wherein in formula (I) 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 . 
     
     
         19 . The method according to any one of  claims 1  to  3  wherein in formula (I) L is O(CH 2 )p. 
     
     
         20 . The method according to any one of  claims 1  to  3  wherein the compound of formula (I) is selected from the group consisting of
 6-[4-(1-Amino-propyl)-4-(tetrahydro-pyran-4-yl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-ethyl)-4-ethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-propyl)-4-propyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(Amino-cyclopropyl-methyl)-4-propyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-propyl)-4-isopropyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-ethyl)-4-cyclopropylmethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-propyl)-4-cyclopropylmethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-butyl)-4-cyclopropylmethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(Amino-cyclopropyl-methyl)-4-cyclopropylmethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-2-methyl-propyl)-4-cyclopropylmethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-propyl)-4-isopropoxymethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-ethyl)-4-cyclobutyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-propyl)-4-cyclobutyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-propyl)-4-cyclopentyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(Amino-phenyl-methyl)-4-cyclopentyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-propyl)-4-methyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-propyl)-4-isobutyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-propyl)-4-benzyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one 
 6-[4-(1-Amino-propyl)-4-ethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-butyl)-4-isopropyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-butyl)-4-ethyl-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-ethyl)-4-ethyl-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-propyl)-4-butyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-propyl)-4-butyl-cyclohexyloxy]-4-benzyl-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-2,2,2-trifluoro-ethyl)-4-cyclopropylmethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-2,2,2-trifluoro-ethyl)-4-isopropyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-2,2,3,3,3-pentafluoro-propyl)-4-isopropyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(Amino-thiazol-2-yl-methyl)-4-isopropyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, or 
 6-[4-(Amino-thiazol-5-yl-methyl)-4-isopropyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 their stereoisomeric and/or tautomeric forms and/or their pharmaceutically acceptable salts thereof. 
 
     
     
         21 . The method according to any one of  claims 1  to  3  wherein the compound of formula (I) is selected from the group consisting of
 cis-6-[4-(1-amino-propyl)-4-(tetrahydropyran-4-yl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-propyl)-4-ethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-butyl)-4-isopropyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-butyl)-4-ethyl-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-ethyl)-4-ethyl-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-propyl)-4-butyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, and 
 cis-6-[4-(1-Amino-propyl)-4-butyl-cyclohexyloxy]-4-benzyl-7-chloro-2H-isoquinolin-1-one, 
 their stereoisomeric and/or tautomeric forms and/or pharmaceutically acceptable salts thereof. 
 
     
     
         22 . The method according to any one of  claims 1  to  3  wherein the compound of formula (I) is selected from the group consisting of
 cis-6-[4-((S)-1-Amino-propyl)-4-methyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-((R)-1-Amino-propyl)-4-methyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-((S)-1-Amino-propyl)-4-(tetrahydro-pyran-4-yl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-((R)-1-Amino-propyl)-4-(tetrahydro-pyran-4-yl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-((R)-1-Amino-propyl)-4-ethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 Cis-6-[4-((S)-1-Amino-propyl)-4-ethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-((S)-Amino-cyclopropyl-methyl)-4-cyclopropylmethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, and 
 cis-6-[4-((R)-Amino-cyclopropyl-methyl)-4-cyclopropylmethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 their tautomeric forms and/or pharmaceutically acceptable salts thereof. 
 
     
     
         23 . The method according to any one of  claims 1  to  3  wherein the compound of formula (I) is selected from the group consisting of
 cis-6-[4-(1-Amino-ethyl)-4-ethyl-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-propyl)-4-ethyl-cyclohexyloxy]-7-fluoro-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-propyl)-4-ethyl-cyclohexyloxy]-7-fluoro-5-methyl-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-propyl)-4-ethyl-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-propyl)-4-ethyl-cyclohexyloxy]-5,7-dimethyl-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-propyl)-4-methoxy-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 trans-6-[4-(1-Amino-propyl)-4-methoxy-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-propyl)-4-ethoxy-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(Amino-phenyl-methyl)-4-methyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-butyl)-4-methyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(Amino-phenyl-methyl)-4-cyclopropylmethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-3-methyl-butyl)-4-cyclopropylmethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-2-methyl-propyl)-4-cyclohexyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-propyl)-4-(4,4,4-trifluoro-butyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-propyl)-4-(tetrahydro-pyran-4-ylmethyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(Amino-cyclopropyl-methyl)-4-(tetrahydro-pyran-4-ylmethyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(Amino-cyclopropyl-methyl)-4-methyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(Amino-cyclopropyl-methyl)-4-ethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-propyl)-4-ethoxymethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-ethyl)-4-cyclopropyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(Amino-cyclopropyl-methyl)-4-(4,4,4-trifluoro-butyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-propyl)-4-cyclopropyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(Amino-cyclopropyl-methyl)-4-cyclopropyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-propyl)-4-(tetrahydro-thiopyran-4-yl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-ethyl)-4-propyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-ethyl)-4-ethyl-cyclohexyloxy]-7-fluoro-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-ethyl)-4-ethyl-cyclohexyloxy]-7-fluoro-5-methyl-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-ethyl)-4-ethyl-cyclohexyloxy]-4-benzyl-7-chloro-2H-isoquinolin-1-one, 
 cis-7-Chloro-6-{4-[1-(cyclopropylmethyl-amino)-propyl]-4-ethyl-cyclohexyloxy}-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Benzylamino-propyl)-4-ethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-7-Chloro-6-[4-ethyl-4-(1-isobutylamino-propyl)-cyclohexyloxy]-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Butylamino-propyl)-4-ethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(1-Amino-2-methyl-propyl)-4-isopropyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-propyl)-4-isopropyl-cyclohexyloxy]-7-chloro-4-fluoro-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-propyl)-4-ethyl-cyclohexyloxy]-7-chloro-4-fluoro-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-propyl)-4-ethyl-cyclohexyloxy]-4-bromo-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(1-Amino-propyl)-4-ethyl-cyclohexyloxy]-7-chloro-1-oxo-1,2-dihydro-isoquinoline-4-carbonitrile, 
 cis-6-[4-(1-Amino-propyl)-4-isopropyl-cyclohexyloxy]-4-bromo-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(1-amino-2-fluoro-ethyl)-4-ethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 trans-6-[4-(1-amino-2-fluoro-ethyl)-4-ethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[4-(1-amino-3-methoxy-propyl)-4-ethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 cis-6-[4-(1-amino-propyl)-4-(1,1-dioxo-tetrahydrothiopyran-4-yl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 6-[3-(1-Amino-propyl)-3-propyl-cyclopentoxy]-7-chloro-2H-isoquinolin-1-one, and 
 6-[4-(1-Amino-propyl)-4-trifluoromethyl-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, 
 their stereoisomeric and/or tautomeric forms and/or pharmaceutically acceptable salts thereof. 
 
     
     
         24 . The method according to any one of  claims 1  to  3  wherein the compound of formula (I) is selected from the group consisting of
 cis 1-[4-(5,7-Dimethyl-isoquinolin-6-yloxy)-1-ethyl-cyclohexyl]-propylamine, 
 cis-1-[1-Ethyl-4-(7-fluoro-soquinolin-6-yloxy)-cyclohexyl]-propylamine, 
 cis-1-[1-Ethyl-4-(7-methyl-isoquinolin-6-yloxy)-cyclohexyl]-propylamine, 
 cis-1-[1-Ethyl-4-(7-fluoro-5-methyl-isoquinolin-6-yloxy)-cyclohexyl]-propylamine, 
 cis-1-[1-Ethyl-4-(7-fluoro-5-methyl-isoquinolin-6-yloxy)-cyclohexyl]-ethylamine, 
 cis-1-[4-(7-Bromo-isoquinolin-6-yloxy)-1-ethyl-cyclohexyl]-ethylamine, 
 cis-1-[4-(7-Methyl-isoquinolin-6-yloxy)-1-ethyl-cyclohexyl]-ethylamine, 
 cis-1-[4-(5-Chloro-isoquinolin-6-yloxy)-1-ethyl-cyclohexyl]-ethylamine, 
 cis-6-[4-(1-Amino-ethyl)-4-propyl-cyclohexyloxy]-7-chloro-isoquinolin-1-ylamine, and 
 [4-(1-Amino-propyl)-4-methyl-cyclohexyl]-isoquinolin-6-yl-amine, 
 and their stereoisomeric and/or tautomeric forms and/or pharmaceutically acceptable salts thereof.