6-hydroxy-4-oxo-1,4-dihydropyrimidine-5-carboxamides as APJ agonists

Patent metadata

Field	Value
Publication number	US-10590113-B2
Application number	US-201816122975-A
Country	US
Kind code	B2
Filing date	Sep 6, 2018
Priority date	Mar 24, 2016
Publication date	Mar 17, 2020
Grant date	Mar 17, 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.

First claim

What is claimed is:

1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound 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 , at each occurrence, is independently selected from H, F, Cl, OH, CN, C 1-4 alkyl, OC 1-4 alkyl, and C 3-6 cycloalkyl;
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 , heteroaryl substituted with 0-3 R e , C 3-6 cycloalkyl, —(CH 2 ) 1-4 OC 1-5 alkyl, and —(CH 2 ) 1-3 OC 3-6 cycloalkyl;
R 3 and R 4 together with the nitrogen atom to which they are both attached form a heterocyclic ring selected from

R 5 , at each occurrence, is independently selected from OH, —(CR 7 R 7 ) n —R 6 , —OR 6 , —S(O) p R 6 , —C(═O)R 6 , —NR a R 6 , —C(═O)NR a R 6 , —NR a C(═O)R 6 —NR a C(═O)OR 6 , —OC(═O)NR a R 6 , —C(═O)OR 6 , —S(O) p NR a R 6 , —NR a S(O) p NR a R 6 , and —NR a S(O) p R 6 ;
R 5a is independently selected from —C(═O)OR 6 , —C(═O)NR a R 6 , —(CR 7 R 7 ) n —R 6 , —C(═O)—R 6 , and —S(O) p R 6 ;
R 6 , at each occurrence, is independently selected from —(CR 7 R 7 ) n -aryl, —(CR 7 R 7 ) n —C 3-6 cycloalkyl, and —(CR 7 R 7 ) n -heteroaryl, each substituted with 0-3 R 8 ;
R 7 , at each occurrence, is independently selected from H, C 1-4 alkyl, and (CH 2 ) n —C 3-12 carbocyclyl substituted with 0-3 R e ;
R 8 , at each occurrence, is independently selected from H, F, Cl, Br, —OR b , —(CH 2 ) n C(═O)R b , —(CH 2 ) n C(═O)OR b , —(CH 2 ) n NR a R a , CN, —(CH 2 ) n C(═O)NR a R a , 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 a , at each occurrence, is independently selected from H, C 1-6 alkyl 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 e , at each occurrence, is independently selected from F, Cl, Br, CN, NO 2 , ═O, CO 2 H, C 1-6 alkyl (optionally substituted with F and Cl), OH, OCH 3 , OCF 3 , —(CH 2 ) n —C 3-6 cycloalkyl, —(CH 2 ) n —C 4-6 heterocyclyl, —(CH 2 ) n -aryl, —(CH 2 ) n -heteroaryl, and —(CH 2 ) n OC 1-4 alkyl; and
n, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.

2. The pharmaceutical composition according to claim 1 comprising a pharmaceutically acceptable carrier and a compound of Formula (II), or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
R 1 , at each occurrence, is independently selected from H, F, Cl, OH, CN, C 1-4 alkyl, and OC 1-4 alkyl;
R 2 is independently selected from C 1-5 alkyl substituted with 0-3 R e ; C 2-5 alkenyl, phenyl substituted with 0-3 R e , 5- to 6-membered heteroaryl substituted with 0-3 R e , C 3-6 cycloalkyl, and CH 2 O(CH 2 ) 1-3 CH 3 ;
R 3 and R 4 together with the nitrogen atom to which they are both attached form a heterocyclic ring selected from

R 5 is independently at each occurrence, selected from OH,

R 8 , at each occurrence, is independently selected from H, F, Cl, Br, —OCH 3 , —OCF 3 , ═O, CN, CH 3 , CF 3 —(CH 2 ) n -aryl, —(CH 2 ) n —C 3-6 cycloalkyl substituted with 0-3 R e , and —(CH 2 ) n -heterocyclyl substituted with 0-3 R e ;
R 8a , at each occurrence, is independently selected from H, CH 3 , aryl substituted with 0-3 R e , and 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 , —(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 e , at each occurrence, is independently selected from F, Cl, Br, CN, NO 2 , ═O, CO 2 H, C 1-6 alkyl (optionally substituted with F and Cl), OH, OCH 3 , OCF 3 , —(CH 2 ) n —C 3-6 cycloalkyl, —(CH 2 ) n —C 4-6 heterocyclyl, —(CH 2 ) n -aryl, —(CH 2 ) n -heteroaryl, and —(CH 2 ) n OC 1-4 alkyl; and
n, at each occurrence, is independently selected from zero, 1, 2, and 3.

3. The pharmaceutical composition according to claim 2 comprising a pharmaceutically acceptable carrier and a compound having Formula (III):

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

R 1 , at each occurrence, is independently selected from H, F, Cl, OH, CN, C 1-4 alkyl, and OC 1-4 alkyl;
R 2 is independently selected from C 1-5 alkyl substituted with 0-3 R e ; C 2-5 alkenyl, phenyl substituted with 0-3 R e , 5- to 6-membered heteroaryl substituted with 0-3 R e , C 3-6 cycloalkyl, and CH 2 O(CH 2 ) 1-3 CH 3 ;
R 5 is independently at each occurrence, selected from OH,

R 8 , at each occurrence, is independently selected from H, F, Cl, Br, —OCH 3 , —OCF 3 , ═O, CN, CH 3 , CF 3 , —C(═O)NH 2 , —(CH 2 ) n -aryl substituted with 0-3 R e , —(CH 2 ) n —C 3-6 cycloalkyl substituted with 0-3 R e , and —(CH 2 ) n -heterocyclyl substituted with 0-3 R e ;
R 8a , at each occurrence, is independently selected from H, CH 3 , aryl substituted with 0-3 R e , and 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 , —(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 e , at each occurrence, is independently selected from F, Cl, Br, CN, NO 2 , ═O, CO 2 H, C 1-6 alkyl (optionally substituted with F and Cl), —OH, —OCH 3 , —OCF 3 , —(CH 2 ) n —C 3-6 cycloalkyl, —(CH 2 ) n —C 4-6 heterocyclyl, —(CH 2 ) n -aryl, —(CH 2 ) n -heteroaryl, and —(CH 2 ) n OC 1-4 alkyl; and
n, at each occurrence, is independently selected from zero, 1, 2, and 3.

4. The pharmaceutical composition according to claim 1 comprising a pharmaceutically acceptable carrier and a compound of Formula (II), or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
R 1 , at each occurrence, is independently selected from F, Cl, —OH, —CH 2 CH 3 , —OCH 3 , and —OCD 3 ;
R 2 is independently selected from

Assignees

• Bristol Myers Squibb Co

Inventors

• Pi Zulan
• Bilder Donna M
• Brigance Robert Paul
• Finlay Heather
• Jiang Wen
• Johnson James A
• Lawrence R Michael
• Meng Wei
• Myers Michael C
• Phillips Monique
• Tora George O
• Zhang Xiaojun

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title