4-hydroxy-3-(heteroaryl)pyridine-2-one apj agonists

Abstract

The present invention provides compounds of Formula (I): wherein all variables are as defined in the specification, and compositions comprising any of such novel compounds. These compounds are APJ agonists which may be used as medicaments.

What is claimed is: 
     
         1 . A method of treating cardiovascular diseases, comprising administering to a patient in need there of a therapeutically effective amount of the pharmaceutical composition of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         a tautomer, or a pharmaceutically acceptable salt thereof, wherein: 
         alk is C 1-6  alkyl substituted with 0-5 R e ; 
         ring A is independently selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         ring B is independently selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
       and 6-membered heteroaryl;
 R 1  is independently selected from the group consisting of: H, halogen, NO 2 , —(CH 2 ) n OR b , (CH 2 ) n S(O) p R c , —(CH 2 ) n C(═O)R b , —(CH 2 ) n NR a R a , —(CH 2 ) n CN, —(CH 2 ) n C(═O)NR a R a , —(CH 2 ) n NR a C(═O)R b , —(CH 2 ) n NR a C(═O)NR a R a , —(CH 2 ) n NR a C(═O)OR b , —(CH 2 ) n OC(═O)NR a R a , —(CH 2 ) n C(═O)OR b , —(CH 2 ) n S(O) p NR a R a , —(CH 2 ) n NR a S(O) p NR a R a , —(CH 2 ) n NR a S(O) p R c , C 1-4  alkyl substituted with 0-3 R e , —(CH 2 ) n —C 3-6  carbocyclyl substituted with 0-3 R e , and —(CH 2 ) n -heterocyclyl substituted with 0-3 R e ; 
 R 2  is independently selected from the group consisting of: C 1-5  alkyl substituted with 0-3 R e ; C 2-5  alkenyl substituted with 0-3 R e , and C 3-6  cycloalkyl substituted with 0-3 R e ; provided when R 2  is C 1-5  alkyl, the carbon atom except the one attached directly to the pyridine ring may be replaced by O, N, and S; 
 R 3  is independently selected from the group consisting of:
 (1) —(CR 4 R 4 ) r C(═O)OC 1-4  alkyl substituted with 0-5 R e , 
 (2) —(CR 4 R 4 ) r NR a R a , 
 (3) —(CR 4 R 4 ) r C(═O)NR a R a , 
 (4) —(CR 4 R 4 ) r NR a C(═O)C 1-4 alkyl substituted with 0-5 R e , 
 (5) —(CR 4 R 4 ) r NR a C(═O)(CR 4 R 4 ) n OC 1-4 alkyl substituted with 0-5 R e , 
 (6) —(CR 4 R 4 ) r —R 5 , 
 (7) —(CR 4 R 4 ) r —OR 5 , 
 (8) —(CR 4 R 4 ) r NR a C(═O)(CR 4 R 4 ) n R 5 , and 
 (9) —(CR 4 R 4 ) r C(═O)NR a (CR 4 R 4 ) n R 5 ; 
 
 R 4  is independently selected from the group consisting of: H, halogen, NR a R a , OC 1-4  alkyl, and C 1-4  alkyl; or R 4  and R 4  together with the carbon atom to which they are both attached form C 3-6  cycloalkyl substituted with 0-5 R e ; 
 R 5  is independently selected from the group consisting of: —(CH 2 ) n —C 3-10  carbocycle and —(CH 2 ) n -heterocycle, each substituted with 0-3 R 6 ; 
 R 6  is independently selected from: H, halogen, ═O, —(CH 2 ) n OR b , (CH 2 ) n S(O) p R c , —(CH 2 ) n C(═O)R b , —(CH 2 ) n NR a R a , —(CH 2 ) n CN, —(CH 2 ) n C(═O)NR a R a , —(CH 2 ) n NR a C(═O)R b , —(CH 2 ) n NR a C(═O)NR a R a , —(CH 2 ) n NR a C(═O)OR b , —(CH 2 ) n OC(═O)NR a R a , —(CH 2 ) n C(═O)OR b , —(CH 2 ) n S(O) p NR a R a , —(CH 2 ) n NR a S(O) p NR a R a , —(CH 2 ) n NR a S(O) p R c , C 1-5  alkyl substituted with 0-3 R e , (CH 2 ) n —C 3-6  carbocyclyl substituted with 0-3 R e ,
 and —(CH 2 ) n -heterocyclyl substituted with 0-3 R e ; 
 
 R a  is independently selected from the group consisting of: H, C 1-6  alkyl substituted with 0-5 R e , C 2-6  alkenyl substituted with 0-5 R e , C 2-6  alkynyl substituted with 0-5 R e , —(CH 2 ) n —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) n -heterocyclyl substituted with 0-5 R e ; or R a  and R a  together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ; 
 R b  is independently selected from the group consisting of: H, C 1-6  alkyl substituted with 0-5 R e , C 2-6  alkenyl substituted with 0-5 R e , C 2-6  alkynyl substituted with 0-5 R e , —(CH 2 ) n —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) n -heterocyclyl substituted with 0-5 R e ; 
 R c  is independently selected from the group consisting of: C 1-6  alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , C 3-6 carbocyclyl, and heterocyclyl; 
 R e  is independently selected from the group consisting of: C 1-6  alkyl substituted with 0-5 R f , C 2-6  alkenyl, C 2-6  alkynyl, —(CH 2 ) n —C 3-6  cycloalkyl, —(CH 2 ) n —C 4-6  heterocyclyl, —(CH 2 ) n -aryl, —(CH 2 ) n -heteroaryl, F, Cl, Br, CN, NO 2 , ═O, CO 2 H, —(CH 2 ) n OR f , S(O) p R f , C(═O)NR f R f , NR f C(═O)R f , S(O) p NR f R f , NR f S(O) P R f , NR f C(═O)OR f , OC(═O)NR f R f , and —(CH 2 ) n NR f R f ; 
 R f  is independently selected from the group consisting of: H, F, Cl, Br, CN, OH, C 1-5 alkyl (optimally substituted with halogen and OH), C 3-6  cycloalkyl, and phenyl, or R f  and R f  together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C 1-4 alkyl; 
 n is independently selected from zero, 1, 2, and 3; 
 r is independently selected from zero, 1, 2, and 3; and 
 p is independently selected from zero, 1, and 2. 
 
     
     
         2 . The method of  claim 1  wherein said cardiovascular diseases are coronary heart disease, stroke, heart failure, systolic heart failure, diastolic heart failure, diabetic heart failure, heart failure with preserved ejection fraction, cardiomyopathy, myocardial infarction, left ventricular dysfunction, left ventricular dysfunction after myocardial infarction, cardiac hypertrophy, myocardial remodeling, myocardial remodeling after infarction or after cardiac surgery and valvular heart diseases.