Heteroarylhydroxypyrimidinones as agonists of the APJ receptor

Patent metadata

Field	Value
Publication number	US-10669261-B2
Application number	US-201616061365-A
Country	US
Kind code	B2
Filing date	Dec 15, 2016
Priority date	Dec 16, 2015
Publication date	Jun 2, 2020
Grant date	Jun 2, 2020

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, in particular for treating cardiovascular disorders.

First claim

What is claimed is:

1. A compound of Formula (I):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
alk is C 1-6 alkyl substituted with 1-5 R 7 ;
ring A is 5- to 6-membered heteroaryl;
ring B is independently selected from C 3-6 cycloalkyl, C 3-6 cycloalkenyl, aryl, bicyclic carbocyclyl, and 6-membered heteroaryl;
R 1 is independently selected from 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 C 1-5 alkyl substituted with 0-3 R e ; C 2-5 alkenyl substituted with 0-3 R e , aryl substituted with 0-3 R e , heterocyclyl 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 and the groups attached thereto except the one attached to the pyrimidine ring may be replaced by O, N, and S;
R 7 is independently selected from H, 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 , at each occurrence, is independently selected from 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 , at each occurrence, is independently selected from 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 , at each occurrence, is independently selected from 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 , at each occurrence, is independently selected from C 1-6 alkyl (optionally substituted with halogen, OH, and CN), 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 , at each occurrence, is independently selected from H, C 1-5 alkyl (optionally 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 1 and 2; and
p, at each occurrence, is independently selected from zero, 1, and 2.

2. The compound according to claim 1 , or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
ring A is independently selected from

R 3 is independently selected from
(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 8 R 8 ,
(3) —(CR 4 R 4 ) r C(═O)NR 8 R 8 ,
(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 , and
(8) —(CR 4 R 4 ) r NR a C(═O)(CR 4 R 4 ) n R 5 ;

R 4 is independently selected from 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 —(CH 2 ) n —C 3-10 carbocycle and —(CH 2 ) n -heterocycle comprising carbon atoms and 1-3 heteroatoms selected from N, NR 6a , O, and S, each substituted with 0-5 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 6a is independently selected from H, —S(O) p R c , —C(═O)R b , —C(═O)NR a R a , —C(═O)OR b , —S(O) p NR a R a , 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 ; and
R 8 and R 8 together with the nitrogen atom to which they are both attached form a heterocyclic ring comprising carbon atoms and 0-3 additional heteroatoms selected from N, NR 6a , O, and S, and substituted with 0-5 R 6 .

3. The compound according to claim 2 having Formula (II):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
ring B is independently selected from

R 1 is independently selected from H, F, Cl, Br, NO 2 , —(CH 2 ) n OR b , —(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 , C 1-4 alkyl substituted with 0-3 R e and C 3-6 cycloalkyl substituted with 0-3 R e ;
R 2 is independently selected from C 1-5 alkyl substituted with 0-3 R e ; C 2-5 alkenyl, aryl substituted with 0-3 R e , heterocyclyl substituted with 0-3 R e , and C 3-6 cycloalkyl; provided when R 2 is C 1-5 alkyl, the carbon atom and the groups attached thereto except the one attached to the pyrimidine ring may be replaced by O, N, and S;
R 3 is independently selected from
(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 8 R 8 ,
(3) —(CR 4 R 4 ) r C(═O)NR 8 R 8 ,
(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 , and
(8) —(CR 4 R 4 ) r NR a C(═O)(CR 4 R 4 ) n R 5 ;

R 4 is independently selected from H, F, Cl, 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 —(CH 2 ) n -aryl, —(CH 2 ) n —C 3-6 cycloalkyl and —(CH 2 ) n -heterocycle, each substituted with 0-3 R 6 ;
R 6 is independently selected from H, F, Cl, Br, —OR b , ═O, —

Assignees

• Bristol Myers Squibb Co
• Bristl Myers Squibb Company

Inventors

• Myers Michael C
• Lawrence R Michael
• Bilder Donna M
• Meng Wei
• Pi Zulan
• Brigance Robert Paul
• Finlay Heather

Classifications

• C07D403/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title