Phthalazinones and isoquinolinones as rock inhibitors

Abstract

The present invention provides compounds of Formula (I): or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective ROCK inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating cardiovascular, smooth muscle, oncologic, neuropathologic, autoimmune, fibrotic, and/or inflammatory disorders using the same.

What is claimed is: 
     
         1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
 M is selected from N and CR 10 ; 
 L is —NR 6 C(O)—; 
 R 1  is selected from OC 1-4  alkyl, NR 5 R 5 , C 3-10  carbocycle and 4- to 12-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR 8 , O, and S(O) p ; wherein said alkyl, carbocycle, and heterocycle are substituted with 1-4 R 7 ; 
 R 2 , at each occurrence, is independently selected from halogen, C 1-6  alkyl, C 1-4  alkoxy, C 1-4  alkylthio, C 1-4  haloalkyl, —OH, —CH 2 OH, —OCH 2 F, —OCHF 2 , —OCF 3 , CN, —NH 2 , —NH(C 1-4  alkyl), —N(C 1-4  alkyl) 2 , —CO 2 H, —CH 2 CO 2 H, —CO 2 (C 1-4  alkyl), —CO(C 1-4  alkyl), —CH 2 NH 2 , —CONH 2 , —CONH(C 1-4  alkyl), —CON(C 1-4  alkyl) 2 , —OCH 2 CO 2 H, —NHCO(C 1-4  alkyl), —NHCO 2 (C 1-4  alkyl), —NHSO 2 (C 1-4  alkyl), —SO 2 NH 2 , —C(═NH)NH 2 , carbocycle, and heterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R 9 ; 
 R 3 , at each occurrence, is independently selected from halogen, C 1-6  alkyl, C 1-4  alkoxy, C 1-4  alkylthio, C 1-4  haloalkyl, —CH 2 OH, —OCH 2 F, —OCHF 2 , —OCF 3 , CN, —NH 2 , —NH(C 1-4  alkyl), —N(C 1-4  alkyl) 2 , —CO 2 H, —CH 2 CO 2 H, —CO 2 (C 1-4  alkyl), —CO(C 1-4  alkyl), —CH 2 NH 2 , —CONH 2 , —CONH(C 1-4  alkyl), —CON(C 1-4  alkyl) 2 , —OCH 2 CO 2 H, —NHCO(C 1-4  alkyl), —NHCO 2 (C 1-4  alkyl), —NHSO 2 (C 1-4  alkyl), —SO 2 NH 2 , —C(═NH)NH 2 , carbocycle, and heterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R 9 ; 
 R 4 , at each occurrence, is independently selected from H, halogen, OH, NH 2 , CH 2 NH 2 , C 1-4  haloalkyl, OCH 2 F, OCHF 2 , OCF 3 , —NH(C 1-4  alkyl), —N(C 1-4  alkyl) 2 , C 1-4  alkoxy, CH 2 OH, CH 2 O(C 1-4  alkyl), CH 2 CO 2 H, CH 2 CO 2 (C 1-4  alkyl), C 1-4  alkyl, carbocycle, and heterocycle, wherein said alkyl, alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R 9 ; 
 R 5  and R 5  are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 1-4 R 7 ; 
 R 6 , at each occurrence, is independently selected from H and C 1-4  alkyl; 
 R 7 , at each occurrence, is independently selected from H, ═O, halogen, C 1-4  alkyl, C 1-4  alkoxy, CN, OH, CF 3 , —(CH 2 ) n —CO 2 H, —(CH 2 ) n —CO 2 (C 1-4  alkyl), —(CH 2 ) n —NR 8 R 8 , —NHCO(C 1-4  alkyl), —NHCOCF 3 , —NHCO 2 (C 1-4  alkyl), —NHCO 2 (CH 2 ) 2 O(C 1-4  alkyl), —NHCO 2 (CH 2 ) 3 O(C 1-4  alkyl), —NHCO 2 (CH 2 ) 2 OH, —NHCO 2 (CH 2 ) 2 NH 2 , —NHCO 2 (CH 2 ) 2 N(C 1-4  alkyl) 2 , —NHCO 2 CH 2 CO 2 H, —CH 2 NHCO 2 (C 1-4  alkyl), —NHC(O)NH 2 , —NHC(O)NH(C 1-4  alkyl), —NHC(O)N(C 1-4  alkyl) 2 , —NHSO 2 (C 1-4  alkyl), —SO 2 NH 2 , —SO 2 NH(C 1-4  alkyl), —SO 2 N(C 1-4  alkyl) 2 , —SO 2 NH(CH 2 ) 2 OH, —SO 2 NH(CH 2 ) 2 O(C 1-4  alkyl), —CONH 2 , —CONH(C 1-4  alkyl), —CON(C 1-4  alkyl) 2 , —CH 2 CONH 2 , —(CH 2 ) n -carbocycle, —O(CH 2 ) n -carbocycle, —O(CH 2 ) n -heterocycle, and —(CH 2 ) n -heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR 8 , O, and S(O) p , wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R 9 ; 
 R 8 , at each occurrence, is independently selected from H, C 1-4  alkyl, C(O)C 1-4 alkyl C(O)heterocycle, C(O)NR 5 R 5 , C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO 2 alkyl, SO 2 carbocycle, SO 2 heterocycle, SO 2 NR 5 R 5 , —(CH 2 ) n -carbocycle, and —(CH 2 ) n -heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R 9 ; 
 alternatively, R 8  and R 8  are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 0-4 R 9 ; 
 R 9 , at each occurrence, is independently selected from halogen, OH, NO 2 , CHF 2 , CF 3 , C 1-4  alkyl, C 1-4  alkoxy, CH 2 OH, CO 2 H, CO 2 (C 1-4  alkyl), CONH 2 , —(CH 2 ) n NR a R a , —(CH 2 ) n CONR a R a , —O(CH 2 ) n heterocycle, —O(CH 2 ) (2-4) NR a R a , —(CR 10 R 10 ) n -4-10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R b ; 
 R 10  is selected from H and C 1-4  alkyl; 
 
         R a , at each occurrence, is independently selected from H, C 1-4  alkyl, —(CH 2 ) n OH, CO(C 1-4  alkyl), COCF 3 , CO 2 (C 1-4  alkyl), —CONH 2 , —CONH—C 1-4  alkylene-CO 2 (C 1-4  alkyl), C 1-4  alkylene-CO 2 (C 1-4  alkyl), R c , CO 2 R c , and CONHR c ; alternatively, R a  and R a  are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle, wherein said alkyl, alkylene, and heterocycle are substituted with 0-4 R b ;
 R b , at each occurrence, is independently selected from ═O, halo, C 1-4  alkyl, C 1-4  alkoxy, OCF 3 , NH 2 , NO 2 , N(C 1-4  alkyl) 2 , CO(C 1-4  alkyl), CO(C 1-4  haloalkyl), CO 2 (C 1-4  alkyl), CONH 2 , —CONH(C 1-4  alkyl), —CON(C 1-4  alkyl) 2 , —CONH—C 1-4  alkylene-O(C 1-4  alkyl), —CONH—C 1-4  alkylene-N(C 1-4  alkyl) 2 , —CONH—C 1-4  alkylene-N(C 1-4  alkyl) 2 , —C 1-4  alkylene-O—P(O)(OH) 2 , —NHCO 2 (C 1-4  alkyl), —R c , COR c , CO 2 R c , and CONHR c ; 
 R c , at each occurrence, is independently selected from —(CH 2 ) n —C 3-6  cycloalkyl, —(CH 2 ) n -phenyl, and —(CH 2 ) n -5- to 6-membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of: N, NH, N(C 1-4  alkyl), O, and S(O) p ; wherein each ring moiety is substituted with 0-2 R d ; 
 R d , at each occurrence, is independently selected from ═O, halo, —OH, C 1-4  alkyl, NH 2 , NH(C 1-4  alkyl), N(C 1-4  alkyl) 2 , C 1-4  alkoxy, and —NHCO(C 1-4  alkyl), and heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of: N, NH, N(C 1-4  alkyl), O, and S(O) p ; 
 n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4; 
 p, at each occurrence, is independently selected from 0, 1, and 2; 
 provided when L is NHC(O), R 1  is other than 
 
       
       
         
           
           
               
               
           
         
       
       wherein X is N or a substituted or unsubstituted carbon atom. 
     
     
         2 . The compound of  claim 1 , wherein:
 R 4 , at each occurrence, is independently selected from H and C 1-4  alkyl; and
 R 7 , at each occurrence, is independently selected from H, ═O, halogen, C 1-4  alkyl, C 1-4  alkoxy, CN, OH, CF 3 , —(CH 2 ) n —CO 2 H, —(CH 2 ) n —CO 2 (C 1-4  alkyl), —(CH 2 ) n —NR 8 R 8 , —NHCO(C 1-4  alkyl), —NHCOCF 3 , —NHCO 2 (C 1-4  alkyl), —NHCO 2 (CH 2 ) 2 OH, —NHC(O)NH 2 , —NHC(O)NH(C 1-4  alkyl), —NHC(O)N(C 1-4  alkyl) 2 , —NHSO 2 (C 1-4  alkyl), —SO 2 NH 2 , —SO 2 NH(C 1-4  alkyl), —SO 2 N(C 1-4  alkyl) 2 , —CONH 2 , —CONH(C 1-4  alkyl), —CON(C 1-4  alkyl) 2 , —CH 2 CONH 2 , —(CH 2 ) n -carbocycle, —O(CH 2 ) n -carbocycle, —O(CH 2 ) n -heterocycle, and —(CH 2 ) n -heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR 8 , O, and S(O) p  wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R 9 . 
   
     
     
         3 . The compound of  claim 2 , having Formula (IV): 
       
         
           
           
               
               
           
         
         or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
 M is selected from N and CR 10 ; 
 R 1  is selected from NR 5 R 5 , C 3-10  carbocycle, and 5- to 10-membered heterocycle, wherein said carbocycle and heterocycle are substituted with 1-4 R 7 ; 
 R 5  and R 5  are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 1-4 R 7 ; 
 R 6 , at each occurrence, is independently selected from H and C 1-4  alkyl; 
 R 7 , at each occurrence, is independently selected from H, ═O, halogen, C 1-4  alkyl, C 1-4  alkoxy, CN, OH, CF 3 , —(CH 2 ) n —CO 2 H, —(CH 2 ) n —CO 2 (C 1-4  alkyl), —(CH 2 ) n —NR 8 R 8 , —NHCO(C 1-4  alkyl), —NHCOCF 3 , —NHCO 2 (C 1-4  alkyl), —NHC(O)NH 2 , —NHC(O)NH(C 1-4  alkyl), —NHC(O)N(C 1-4  alkyl) 2 , —NHSO 2 (C 1-4  alkyl), —SO 2 NH 2 , —SO 2 NH(C 1-4  alkyl), —SO 2 N(C 1-4  alkyl) 2 , —SO 2 NH(CH 2 ) 2 OH, —SO 2 NH(CH 2 ) 2 O(C 1-4  alkyl), —CONH 2 , —CONH(C 1-4  alkyl), —CON(C 1-4  alkyl) 2 , —CH 2 CONH 2 , —(CH 2 ) n -carbocycle, —O(CH 2 ) n -carbocycle, —O(CH 2 ) n -heterocycle, and —(CH 2 ) n -heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R 9 ; 
 R 8 , at each occurrence, is independently selected from H, C 1-4  alkyl, C(O)C 1-4 alkyl, C(O)carbocycle, C(O)heterocycle, C(O)NR 5 R 5 , C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO 2 alkyl, SO 2 carbocycle, SO 2 heterocycle, SO 2 NR 5 R 5 , —(CH 2 ) n -carbocycle, and —(CH 2 ) n -heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R 9 ; 
 R 9 , at each occurrence, is independently selected from halogen, OH, NO 2 , CHF 2 , CF 3 , C 1-4  alkyl, C 1-4  alkoxy, CH 2 OH, CO 2 H, CO 2 (C 1-4  alkyl), CONH 2 , —(CH 2 ) n NR a R a , —(CH 2 ) n CONR a R a , —O(CH 2 ) n heterocycle, —O(CH 2 ) (2-4) NR a R a , —(CR 10 R 10 ) n -4-10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R b ; 
 n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4; 
 p, at each occurrence, is independently selected from 0, 1, and 2. 
 
       
     
     
         4 . The compound of  claim 3 , wherein:
 R 1  is selected from   
       
         
           
           
               
               
           
         
         R 7 , at each occurrence, is independently selected from H, ═O, halogen, C 1-4  alkyl, C 1-4  alkoxy, CN, OH, CF 3 , —(CH 2 ) n —CO 2 H, —(CH 2 ) n —CO 2 (C 1-4  alkyl), —(CH 2 ) n —NR 8 R 8 , —CH 2 NH 2 , —NHCO(C 1-4  alkyl), —NHCOCF 3 , —NHCO 2 (C 1-4  alkyl), —NHC(O)NH 2 , —NHC(O)NH(C 1-4  alkyl), —NHC(O)N(C 1-4  alkyl) 2 , —NHSO 2 (C 1-4  alkyl), —SO 2 NH 2 , —SO 2 NH(C 1-4  alkyl), —SO 2 N(C 1-4  alkyl) 2 , —SO 2 NH(CH 2 ) 2 OH, —SO 2 NH(CH 2 ) 2 O(C 1-4  alkyl), —CONH 2 , —CONH(C 1-4  alkyl), —CON(C 1-4  alkyl) 2 , and —CH 2 CONH 2 , —(CH 2 ) n -carbocycle, —O(CH 2 ) n -carbocycle, —O(CH 2 ) n -heterocycle, and —(CH 2 ) n -heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR 8 , O, and S(O) p , wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R 9 ; 
         R 8 , at each occurrence, is independently selected from H, C 1-4  alkyl, C(O)C 1-4 alkyl, C(O)carbocycle, C(O)heterocycle, C(O)NR 5 R 5 , C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO 2 alkyl, SO 2 carbocycle, SO 2 heterocycle, SO 2 NR 5 R 5 , —(CH 2 ) n -carbocycle, and —(CH 2 ) n -heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R 9 ; and 
         R 9 , at each occurrence, is independently selected from halogen, OH, NO 2 , CHF 2 , CF 3 , C 1-4  alkyl, C 1-4  alkoxy, CH 2 OH, CO 2 H, CO 2 (C 1-4  alkyl), CONH 2 , —(CH 2 ) n NR a R a , —(CH 2 ) n CONR a R a , —O(CH 2 ) n heterocycle, —O(CH 2 ) (2-4) NR a R a , —(CR 10 R 10 ) n -4-10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R b . 
       
     
     
         5 . The compound of  claim 3 , wherein:
 R 1  is NR 5 R 5 ;   R 5  and R 5  are taken together with the nitrogen atom to which they are attached to form 4- to 10-membered heterocycle substituted with 1-4 R 7 ;   R 6 , at each occurrence, is independently selected from H and C 1-4  alkyl;   R 7 , at each occurrence, is independently selected from H, ═O, halogen, C 1-4  alkyl, C 1-4  alkoxy, CN, OH, CF 3 , —(CH 2 ) n —CO 2 H, —(CH 2 ) n —CO 2 (C 1-4  alkyl), —(CH 2 ) n —NR 8 R 8 , —NHCO(C 1-4  alkyl), —NHCOCF 3 , —NHCO 2 (C 1-4  alkyl), —NHC(O)NH 2 , —NHC(O)NH(C 1-4  alkyl), —NHC(O)N(C 1-4  alkyl) 2 , —NHSO 2 (C 1-4  alkyl), —SO 2 NH 2 , —SO 2 NH(C 1-4  alkyl), —SO 2 N(C 1-4  alkyl) 2 , —SO 2 NH(CH 2 ) 2 OH, —SO 2 NH(CH 2 ) 2 O(C 1-4  alkyl), —CONH 2 , —CONH(C 1-4  alkyl), —CON(C 1-4  alkyl) 2 , —CH 2 CONH 2 , —(CH 2 ) n -carbocycle, —O(CH 2 ) n -carbocycle, —O(CH 2 ) n -heterocycle, and —(CH 2 ) n -heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR 8 , O, and S(O) p , wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R 9 ;   R 8 , at each occurrence, is independently selected from H, C 1-4  alkyl, C(O)C 1-4 alkyl, C(O)carbocycle, C(O)heterocycle, C(O)NR 5 R 5 , C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO 2 alkyl, SO 2 carbocycle, SO 2 heterocycle, SO 2 NR 5 R 5 , —(CH 2 ) n -carbocycle, and —(CH 2 ) n -heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R 9 ; and   R 9 , at each occurrence, is independently selected from halogen, OH, NO 2 , CHF 2 , CF 3 , C 1-4  alkyl, C 1-4  alkoxy, CH 2 OH, CO 2 H, CO 2 (C 1-4  alkyl), CONH 2 , —(CH 2 ) n NR a R a , —(CH 2 ) n CONR a R a , —O(CH 2 ) n heterocycle, —O(CH 2 ) (2-4) NR a R a , —(CR 10 R 10 ) n -4-10 membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R b .   
     
     
         6 . The compound of  claim 5 , wherein:
 R 5  and R 5  are taken together with the nitrogen atom to which they are attached to form a heterocycle selected from   
       
         
           
           
               
               
           
         
       
     
     
         7 . A compound of  claim 1  selected from 
       
         
           
           
               
               
           
         
       
       wherein R is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof. 
       
     
     
         8 . A pharmaceutical composition comprising one or more compounds according to  claim 1  and a pharmaceutically acceptable carrier or diluent. 
     
     
         9 . A method for prophylaxis and/or treatment of disorders associated with aberrant Rho kinase activity, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of  claim 1 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The method of  claim 9 , wherein said disorder is selected from the group consisting of a cardiovascular disorder, a smooth muscle related disorder, a fibrotic disease, an inflammatory disease, neuropathic disorders, oncologic disorders, and an autoimmune disorder. 
     
     
         11 . The method of  claim 10 , wherein said cardiovascular disorder is selected from the group consisting of angina, atherosclerosis, stroke, cerebrovascular disease, heart failure, coronary artery disease, myocardial infarction, peripheral vascular disease, stenosis, vasospasm, hypertension and pulmonary hypertension. 
     
     
         12 . The method of  claim 10 , wherein said smooth muscle related disorder is selected from the group consisting of glaucoma, erectile dysfunction, and bronchial asthma. 
     
     
         13 . The method of  claim 10 , wherein said autoimmune disorder is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, irritable bowel syndrome, and systemic sclerosis. 
     
     
         14 . A method for inhibiting Rho kinase activity, comprising (a) providing target cells and a composition comprising a compound described in  claim 1 ; and (b) exposing said target cells to said composition under conditions such that said composition binds to said target cells so as to inhibit Rho kinase activity within said target cells.