Rho kinase inhibitors

Abstract

Disclosed are novel substituted 2H-isoquinolin-1-one and 3H-quinazolin-4-one derivatives useful as inhibitors of Rho kinase and for treating a variety of diseases and disorders that are mediated or sustained through the activity of Rho kinase, including cardiovascular diseases, pharmaceutical compositions comprising such compounds, methods for using such compounds and processes for making such compounds.

1 . A method for treating a cardiovascular disease or condition in a warm-blooded animal which comprises administering to the animal a therapeutically effective amount of a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is chosen from 
 C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-6 alkyl, haloC 1-6 alkyl, aminoC 1-6 alkyl, hydroxyC 1-6 alkyl, aryl, heteroaryl, heteroarylC 1-6 alkyl, heterocyclyl, —C 1-3 alkylOaryl, CH 2 OCH 2 aryl, —CH 2 OC(O)C 1-6 alkyl, —(CH 2 ) 1-3 S(O) 0-2 aryl, —(CH 2 ) 1-2 S(O) 0-2 C 1-6 alkyl, —(CH 2 ) 1-3 CO 2 C 1-6 alkyl, —(CH 2 ) 1-3 NHC 1-6 alkyl, —(CH 2 ) 1-3 NHC 1-6 alkylC 3-8 cycloalkyl, —(CH 2 ) 1-2 CN and —CH(R 3 )N(R 4 )(R 5 ) 
 
       wherein:
 R 3  is chosen from H, C 1-6 alkyl, —(CH 2 ) 1-3 aryl and —(CH 2 ) 1-3 heteroaryl; 
 R 4  is chosen from H, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-7 cycloalkylC 1-6 alkyl, aryl, aryl (CH 2 ) 1-3 , heteroaryl(CH 2 ) 1-3 , C 1-3 alkylO(CH 2 ) 1-3 , tetrahydropyran-4-ylmethyl and (C 1-3 alkyl) 2 N(CH 2 ) 2-4 —; 
 
       and R 5  is chosen from H and C 1-6 alkyl; 
       or R 4  and R 5  together with the nitrogen atom they are connected to may form a heterocyclyl group; 
       wherein each aryl, arylalkyl, heteraryl, heteroarylalkyl, cycloalkylalkyl, cycloalkyl and heterocyclyl group is optionally substituted with 1-3 groups selected from halogen, C 1-6 alkoxy, C 3-8 cycloalkyl, C 1-6 alkyl, —CN, —NO 2 , —OH, oxo, —CF 3 , —OCF 3 , —C 0-3 alkylCO 2 H, C 1-6 alkylCO 2 —, C 1-6 alkylsulfonylC 0-3 alkyl—, —SO 2 C 1-6 alkylNR 6 R 7 , —C 0-3 alkylSO 2 NR 6 R 7 , —C 0-3 C(O)NR 6 R 7 , heteroaryl, heteroarylC 1-3 alkyl, heterocyclyl, heterocyclylSO 2 —, arylC 1-3 alkyl, aryloxy, arylthio and C 0-3 NR 6 R 7 ; 
       wherein each aryl and heteroaryl group is optionally substituted with 1-3 groups selected from halogen, C 1-6 alkoxy, C 1-6 alkyl, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , —C(O)NR 8 R 9 , —SO 2 NR 8 R 9 , —SO 2 Me and amino optionally substituted by one or two C 1-6 alkyl groups or a C(O)C 1-6 alkyl group;
 R 2  is chosen from H, halogen, C 1-6 alkoxy, —CN, —CF 3  and C 1-6 alkyl; 
 R 6  and R 7  are independently selected from H, C 1-6 alkyl, —C(O)C 1-6 alkyl and —C 1-6 alkylNH 2 ; or R 6  and 
 R 7 , together with the nitrogen they are connected to may form a piperazine, piperidine or pyrrolidine ring; 
 R 8  and R 9  are independently selected from H and methyl; 
 R 10  is selected from H, Cl and F; 
 X is CH; and 
 Y is chosen from —NHC(O)—; 
 
       or a tautomer or a salt of the compound of formula (I). 
     
     
         2 . The method of  claim 1 , wherein the cardiovascular disease or condition is selected from the group consisting of hypertension, atherosclerosis, restenosis, stroke, heart failure, coronary vasospasm, cerebral vasospasm, ischemia/reperfusion injury, pulmonary hypertension, angina, myocardial infarction, peripheral artery disease, coronary artery disease and combinations thereof. 
     
     
         3 . The method of  claim 1 , wherein:
 R 1  is chosen from C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-6 alkyl, phenyl, thienyl, pyridyl, isoxazolyl, pyrazolyl, thienylmethyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, —CH 2 Ophenyl, —CH 2 OCH 2 phenyl, —CH 2 OC(O)C 1-6 alkyl, —(CH 2 ) 1-3 S(O) 0-2 phenyl, —(CH 2 ) 1-2 S(O) 0-2 C 1-6 alkyl, —(CH 2 ) 1-3 CO 2 C 1-6 alkyl, —(CH 2 ) 1-3 NHC 1-6 alkyl, —(CH 2 ) 1-3 NHC 1-6 alkylC 3-8 cycloalkyl, —(CH 2 ) 1-3 CN and —CH(R 3 )N(R 4 )(R 5 )   wherein:   R 3  is chosen from H, C 1-6 alkyl, benzyl, phenylethyl and pyridylmethyl;   R 4  is chosen from H, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-7 cycloalkylC 1-6 alkyl, phenyl, benzyl, thienylethyl, C 1-3 alkylO(CH 2 ) 1-3 , tetrahydropyran-4-ylmethyl and (C 1-3 ) 2 N(CH 2 ) 2-4 —;   and R 5  is chosen from H and C 1-6 alkyl;   or R 4  and R 5  together with the nitrogen atom they are connected to may form a piperidine, piperazine or thiomorpholine group;   wherein each cycloalkyl, cycloalkylalkyl, phenyl, benzyl, phenylethyl, thienyl, pyridyl, isoxazolyl, pyrazolyl, thienylmethyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and thiomorpholinyl group is optionally substituted with 1-3 groups selected from halogen, C 1-6 alkoxy, C 1-6 alkyl, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , C 1-6 alkylCO 2 —, C 1-6 alkylsulfonyl, pyrimidyl, pyridyl, morpholinyl, benzyl, phenyloxy and phenylthio and amino optionally substituted by one or two C 1-6 alkyl groups or a C(O)C 1-6 alkyl group;   wherein each phenyl, benzyl, pyrimidinyl and pyridyl group is optionally substituted with 1-3 groups selected from halogen, C 1-6 alkoxy, C 1-6 alkyl, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , —C(O)NR 8 R 9 , —SO 2 NR 8 R 9 , —SO 2 Me and amino optionally substituted by one or two C 1-6 alkyl groups or a C(O)C 1-6 -alkyl group;   R 2  is chosen from H, Br, Cl, —CN, —CF 3  and methyl;   R 8  and R 9  are independently selected from H and methyl; and   R 10  is selected from H, Cl and F;   or a tautomer or a salt of the compound of formula (I).   
     
     
         4 . The method of  claim 1 , wherein:
 R 1  is chosen from cyclopentyl, cyclohexyl, phenyl, thienylmethyl, piperidinyl, pyrrolodinyl, —CH 2 Sphenyl and —CH(R 3 )N(R 4 )(R 5 )   wherein:   R 3  is chosen from H, C 1-6 alkyl, benzyl and phenylethyl;   R 4  is chosen from H, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-7 cycloalkylmethyl, benzyl, thienylethyl, and tetrahydropyran-4-ylmethyl;   and R 5  is chosen from H and methyl;   or R 4  and R 5  together with the nitrogen atom they are connected to may form a piperidine group;   wherein each cyclopentyl, cyclohexyl, phenyl, benzyl, phenylethyl, thienylmethyl, piperidinyl and pyrrolidinyl group is optionally substituted with 1-3 groups selected from halogen, C 1-6 alkoxy, C 1-6 alkyl, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , and amino optionally substituted by one or two C 1-6 alkyl groups or a C(O)C 1-6 alkyl group;   R 2  is chosen from H, Br and Cl; and   R 10  is H;   or a tautomer or a salt of the compound of formula (I).   
     
     
         5 . A method of treating renal disease, erectile dysfunction, asthma, glaucoma or organ failure resulting from hypertension in a warm-blooded animal which comprises administering to the animal a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is chosen from 
 C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-6 alkyl, haloC 1-6 alkyl, aminoC 1-6 alkyl, hydroxyC 1-6 alkyl, aryl, heteroaryl, heteroarylC 1-6 alkyl, heterocyclyl, —C 1-3 alkylOaryl, CH 2 OCH 2 aryl, —CH 2 OC(O)C 1-6 alkyl, —(CH 2 ) 1-3 S(O) 0-2 aryl, —(CH 2 ) 1-2 S(O) 0-2 C 1-6 alkyl, —(CH 2 ) 1-3 CO 2 C 1-6 alkyl, —(CH 2 ) 1-3 NHC 1-6 alkyl, —(CH 2 ) 1-3 NHC 1-6 alkylC 3-8 cycloalkyl, —(CH 2 ) 1-2 CN and —CH(R 3 )N(R 4 )(R 5 ) 
 
       wherein:
 R 3  is chosen from H, C 1-6 alkyl, (CH) 2 ) 1-3 aryl and (CH 2 ) 1-3 heteroaryl; 
 R 4  is chosen from H, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-7 cycloalkylC 1-6 alkyl, aryl, aryl (CH 2 ) 1-3 , heteroaryl(CH 2 ) 1-3 , C 1-3 alkylO(CH 2 ) 1-3 , tetrahydropyran-4-ylmethyl and (C 1-3 alkyl) 2 N(CH 2 ) 2-4 —; 
 
       and R 5  is chosen from H and C 1-6 alkyl; 
       or R 4  and R 5  together with the nitrogen atom they are connected to may form a heterocyclyl group; 
       wherein each aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkylalkyl, cycloalkyl and heterocyclyl group is optionally substituted with 1-3 groups selected from halogen, C 1-6 alkoxy, C 3-8 cycloalkyl, C 1-6 alkyl, —CN, —NO 2 , —OH, oxo, —CF 3 , —OCF 3 , —C 0-3 alkylCO 2 H, C 1-6 alkylCO 2 —, C 1-6 alkylsulfonylC 0-3 alkyl—, —SO 2 C 1-6 alkylNR 6 R 7 , —C 0-3 alkylSO 2 NR 6 R 7 , —C 0-3 C(O)NR 6 R 7 , heteroaryl, heteroarylC 1-3 alkyl, heterocyclyl, heterocyclylSO 2 —, arylC 1-3 alkyl, aryloxy, arylthio and C 0-3 NR 6 R 7 ;
 wherein each aryl and heteroaryl group is optionally substituted with 1-3 groups selected from halogen, C 1-6 alkoxy, C 1-6 alkyl, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , —C(O)NR 8 R 9 , —SO 2 NR 8 R 9 , —SO 2 Me and amino optionally substituted by one or two C 1-6 alkyl groups or a C(O)C 1-6 alkyl group; 
 R 2  is chosen from H, halogen, C 1-6 alkoxy, —CN, —CF 3  and C 1-6 alkyl; 
 R 6  and R 7  are independently selected from H, C 1-6 alkyl, —C(O)C 1-6 alkyl and —C 1-6 alkylNH 2 ; or R 6  and 
 R 7 , together with the nitrogen they are connected to may form a piperazine, piperidine or pyrrolidine ring; 
 R 8  and R 9  are independently selected from H and methyl; 
 R 10  is selected from H, Cl and F; 
 X is CH; and 
 Y is chosen from —NHC(O)—; 
 or a tautomer or a salt of the compound of formula (I). 
 
     
     
         6 . The method of  claim 5 , wherein:
 R 1  is chosen from C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-6 alkyl, phenyl, thienyl, pyridyl, isoxazolyl, pyrazolyl, thienylmethyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, —CH 2 Ophenyl, —CH 2 OCH 2 phenyl, —CH 2 OC(O)C 1-6 alkyl, —(CH 2 ) 1-3 S(O) 0-2 phenyl, —(CH 2 ) 1-2 S(O) 0-2 C 1-6 alkyl, —(CH 2 ) 1-3 CO 2 C 1-6 alkyl, —(CH 2 ) 1-3 NHC 1-6 alkyl, —(CH 2 ) 1-3 NHC 1-6 alkylC 3-8 cycloalkyl, —(CH 2 ) 1-3 CN and —CH(R 3 )N(R 4 )(R 5 )   wherein:   R 3  is chosen from H, C 1-6 alkyl, benzyl, phenylethyl and pyridylmethyl;   R 4  is chosen from H, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-7 cycloalkylC 1-6 alkyl, phenyl, benzyl, thienylethyl, C 1-3 alkylO(CH 2 ) 1-3 , tetrahydropyran-4-ylmethyl and (C 1-3 ) 2 N(CH 2 ) 2-4 —;   and R 5  is chosen from H and C 1-6 alkyl;   or R 4  and R 5  together with the nitrogen atom they are connected to may form a piperidine, piperazine or thiomorpholine group;   wherein each cycloalkyl, cycloalkylalkyl, phenyl, benzyl, phenylethyl, thienyl, pyridyl, isoxazolyl, pyrazolyl, thienylmethyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and thiomorpholinyl group is optionally substituted with 1-3 groups selected from halogen, C 1-6 alkoxy, C 1-6 alkyl, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , C 1-6 alkylCO 2 —, C 1-6 alkylsulfonyl, pyrimidyl, pyridyl, morpholinyl, benzyl, phenyloxy and phenylthio and amino optionally substituted by one or two C 1-6 alkyl groups or a C(O)C 1-6 alkyl group;   wherein each phenyl, benzyl, pyrimidinyl and pyridyl group is optionally substituted with 1-3 groups selected from halogen, C 1-6 alkoxy, C 1-6 alkyl, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , —C(O)NR 8 R 9 , —SO 2 NR 8 R 9 , —SO 2 Me and amino optionally substituted by one or two C 1-6 alkyl groups or a C(O)C 1-6 alkyl group;   R 2  is chosen from H, Br, Cl, —CN, —CF 3  and methyl;   R 8  and R 9  are independently selected from H and methyl; and   R 10  is selected from H, Cl and F;   or a tautomer or a salt of the compound of formula (I).   
     
     
         7 . The method of  claim 5 , wherein:
 R 1  is chosen from cyclopentyl, cyclohexyl, phenyl, thienylmethyl, piperidinyl, pyrrolodinyl, —CH 2 Sphenyl and —CH(R 3 )N(R 4 )(R 5 )   wherein:   R 3  is chosen from H, C 1-6 alkyl, benzyl and phenylethyl;   R 4  is chosen from H, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-7 cycloalkylmethyl, benzyl, thienylethyl, and tetrahydropyran-4-ylmethyl;   and R 5  is chosen from H and methyl;   or R 4  and R 5  together with the nitrogen atom they are connected to may form a piperidine group;   wherein each cyclopentyl, cyclohexyl, phenyl, benzyl, phenylethyl, thienylmethyl, piperidinyl and pyrrolidinyl group is optionally substituted with 1-3 groups selected from halogen, C 1-6 alkoxy, C 1-6 alkyl, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , and amino optionally substituted by one or two C 1-6 alkyl groups or a C(O)C 1-6 alkyl group;   R 2  is chosen from H, Br and Cl; and   R 10  is H;   
       or a tautomer or a salt of the compound of formula (I).