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

Patent metadata

Field	Value
Publication number	US-10106528-B2
Application number	US-201715468230-A
Country	US
Kind code	B2
Filing date	Mar 24, 2017
Priority date	Mar 24, 2016
Publication date	Oct 23, 2018
Grant date	Oct 23, 2018

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 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 alkylene substituted with 0-5 R e ;
ring B is independently selected from C 3-6 cycloalkyl, C 3-6 cycloalkenyl, aryl, bicyclic carbocyclyl, and 6-membered heteroaryl;
R 1 , at each occurrence, 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 1-10 alkyl substituted with 0-3 R e ; C 2-5 alkenyl substituted with 0-3 R e , aryl substituted with 0-3 R e , heteroaryl substituted with 0-3 R e , and C 3-6 cycloalkyl substituted with 0-3 R e ; provided when R 2 is C 1-10 alkyl, the carbon atoms and the groups attached thereto except the carbon atom attached to the pyrimidine ring may be replaced by O, N, and S;
R 3 is independently selected from H and C 1-5 alkyl:
R 4 is independently selected from —(CR 7 R 7 ) n —R 6 , —(CR 7 R 7 ) n OR 6 , —(CR 7 R 7 ) n S(O) p R 6 , —(CR 7 R 7 ) n C(═O)R 6 , —(CR 7 R 7 ) n NR a R 6 , —(CR 7 R 7 ) n NR a C(═O)R 6 , —(CR 7 R 7 ) n S(O) p NR a R 6 , and —(CR 7 R 7 ) n NR a S(O) p R 6 ;
alternatively, R 3 and R 4 together with the nitrogen atom to which they are both attached form a heterocyclic ring or a spiro heterocyclic ring comprising carbon atoms and additional 1 to 4 heteroatoms selected from NR 5a , O, and S and substituted with 0-5 R 5 ;
R 5 , at each occurrence, is independently selected from OH, halogen, —(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 , at each occurrence, 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 —C 3-10 carbocyclyl 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, halogen, —(CH 2 ) n OR b , ═O, (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 , 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 F, Cl, Br, CN, NO 2 , ═O, CO 2 H, 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, —(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, F, Cl, Br, CN, OH, 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, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; 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 diastereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
R 1 , at each occurrence, 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 , heteroaryl substituted with 0-3 R e , C 3-6 cycloalkyl, —(CH 2 ) 1-4 OC 1-5 alkyl, —(CH 2 ) 1-4 NHC 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 or a spiro 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 , at each occurrence, 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 , —NHC(═O)OR b , 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

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• 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

• A61P9/04

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