Triazole pyridyl compounds as agonists of the APJ receptor

Patent metadata

Field	Value
Publication number	US-10689367-B2
Application number	US-201716347970-A
Country	US
Kind code	B2
Filing date	Nov 3, 2017
Priority date	Nov 16, 2016
Publication date	Jun 23, 2020
Grant date	Jun 23, 2020

Abstract

Compounds of Formula I and Formula II, pharmaceutically acceptable salt thereof, stereoisomers of any of the foregoing, or mixtures thereof are agonists of the APJ Receptor and may have use in treating cardiovascular and other conditions. Compounds of Formula I and Formula II have the structures where the definitions of the variables are provided herein.

First claim

What is claimed:

1. A compound of Formula I or Formula II:

or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, or a mixture thereof,
wherein:
R 1 is a pyridyl group that is unsubstituted or is substituted with 1, 2, or 3 R 1a substituents;
R 1a in each instance is independently selected from —F, —Cl, —Br, —I, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —(C 1 -C 6 alkyl)-OH, —(C 1 -C 6 haloalkyl)-OH, —(C 1 -C 6 perhaloalkyl)-OH, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —CN, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —C 2 -C 6 alkenyl, —O—(C 1 -C 6 alkyl)-OH, —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl)-OH, —O—(C 1 -C 6 haloalkyl)-O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 perhaloalkyl)-OH, —O—(C 1 -C 6 perhaloalkyl)-O—(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —C(═O)—(C 1 -C 6 alkyl), —C(═O)OH, —C(═O)—O—(C 1 -C 6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1 -C 6 alkyl), —C(═O)N(C 1 -C 6 alkyl) 2 , —S(═O) 2 —(C 1 -C 6 alkyl), —S(═O) 2 NH 2 , —S(═O) 2 NH(C 1 -C 6 alkyl), or —S(═O) 2 N(C 1 -C 6 alkyl) 2 ;
R 2 is selected from —H, or C 1 -C 4 alkyl or is absent in the compounds of Formula II;
R 3 is selected from an unsubstituted C 1 -C 10 alkyl, a C 1 -C 10 alkyl substituted with 1, 2, or 3 R 3a substituents, a group of formula —(CR 3b R 3c )-Q, a group of formula NH—(CR 3b R 3c )-Q, a group of formula —(CR 3b R 3c )—C(═O)-Q, a group of formula —(CR 3d R 3e )—(CR 3f R 3g )-Q, a group of formula —(CR 3b ═CR 3c )-Q, or a group of formula -(heterocyclyl)-Q, wherein the heterocyclyl of the -(heterocyclyl)-Q has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms selected from N, O, or S and is unsubstituted or is substituted with 1, 2, or 3 R 3h substituents;
R 3a in each instance is independently selected from —F, —Cl, —CN, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —O—(C 1 -C 6 alkyl)-OH, —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ;
R 3b and R 3c are independently selected from —H, —F, —Cl, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —O—(C 1 -C 6 alkyl)-OH, —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ;
R 3d and R 3e are independently selected from —H, —F, —Cl, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —O—(C 1 -C 6 alkyl)-OH, —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ;
R 3f and R 3g are independently selected from —H, —F, —Cl, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —O—(C 1 -C 6 alkyl)-OH, —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ;
R 3h in each instance is independently selected from —F, —Cl, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —O—(C 1 -C 6 alkyl)-OH, —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , or oxo;
Q is a monocyclic or bicyclic C 6 -C 10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms selected from N, O, or S, a C 3 -C 8 cycloalkyl group, or a 3 to 7 membered heterocyclyl group containing 1, 2, or 3 heteroatoms selected from N, O, or S, wherein the C 6 -C 10 aryl group, the heteroaryl group, the cycloalkyl group, and the heterocyclyl group are unsubstituted or are substituted with 1, 2, 3, or 4 R Q substituent;
R Q in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —C(═O)—(C 1 -C 6 alkyl), —C(═O)OH, —C(═O)—O—(C 1 -C 6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1 -C 6 alkyl), —C(═O)N(C 1 -C 6 alkyl) 2 , —S(═O) 2 —(C 1 -C 6 alkyl), phenyl, or a heteroaryl group, and the Q heterocyclyl group may be substituted with 1 oxo R Q substituent;
R 4 is selected from a monocyclic C 3 -C 8 cycloalkyl group, a C 5 -C 10 polycyclic cycloalkyl group, or a straight or branched chain C 1 -C 6 alkyl group, wherein the C 3 -C 8 cycloalkyl R 4 group group is unsubstituted or is substituted with 1, 2, 3, or 4 R 4a substituents, wherein the C 5 -C 10 polycyclic cycloalkyl R 4 group is unsubstituted or is substituted with 1, 2, 3, or 4 R 4b substituents, and further wherein the straight or branched chain C 1 -C 6 alkyl R 4 group is unsubstituted or is substituted with 1, 2, or 3 R 4c substituents;
R 4a in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —(C 1 -C 6 alkyl)-OH, oxo, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , NH(C 1 -C 6 alkyl-OH), —N(C 1 -C 6 alkyl-OH) 2 , —C(═O)—(C 1 -C 6 alkyl), —C(═O)OH, —C(═O)—O—(C 1 -C 6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1 -C 6 alkyl), —C(═O)N(C 1 -C 6 alkyl) 2 , —S(═O) 2 —(C 1 -C 6 alkyl), or a 3 to 6 membered cycloalkyl group, wherein the 3 to 6 membered cycloalkyl R 4a group is unsubstituted or is substituted with 1 or 2 R 4aa substituents, and further wherein two R 4a substituents on the same carbon atom of the C 3 -C 8 cycloalkyl R 4 group may join together with the carbon atom to which they are attached to form a 3 to 6-membered heterocyclyl group containing 1 or 2 heteroatoms selected from N, O, or S which is unsubstituted or is substituted with 1 or 2 R 4aa substituents;
R 4b in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —(C 1 -C 6 alkyl)-OH, oxo, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —NH 2 , —NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , NH(C 1 -C 6 alkyl-OH), —N(C 1 -C 6 alkyl-OH) 2 , —C(═O)—(C 1 -C 6 alkyl), —C(═O)OH, —C(═O)—O—(C 1 -C 6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1 -C 6 alkyl), or —C(═O)N(C 1 -C 6 alkyl) 2 ;
R 4c in each instance is selected from —F, —Cl, —Br, —I, —CN, —OH, oxo, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —S—(C 1 -C 6 alkyl), —S—(C 1 -C 6 haloalkyl), —S—(C 1 -C 6 perhaloalkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , NH(C 1 -C 6 alkyl-OH), —N(C 1 -C 6 alkyl-OH) 2 , —C(═O)—(C 1 -C 6 alkyl), —C(═O)OH, —C(═O)—O—(C 1 -C 6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1 -C 6 alkyl), —C(═O)N(C 1 -C 6 alkyl) 2 , —C(═O)NH(C 3 -C 6 cycloalkyl), —C(═O)N(C 1 -C 6 alkyl)(C 3 -C 6 cycloalkyl), —C(═O)N(C 3 -C 6 cycloalkyl) 2 , —S(═O)—(C 1 -C 6 alkyl), —S(═O) 2 —(C 1 -C 6 alkyl), a 3 to 6 membered cycloalkyl group, a 3 to 6 membered heterocyclyl group containing 1 or 2 heteroatoms selected from N, O, or S, a phenyl group, or a 5 or 6 membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from N, O, or S, wherein the a 3 to 6 membered cycloalkyl R 4c group, the 3 to 6 membered heterocyclyl R 4c group, the phenyl R 4c group, or the a 5 or 6 membered hete

Assignees

• Amgen Inc

Inventors

• Chen Yinhong
• Cheng Alan C
• Debenedetto Mikkel V
• Dransfield Paul John
• Harvey James S
• Houze Jonathan
• Khakoo Aarif Yusuf
• Lai Su-Jen
• Ma Zhihua
• Pattaropong Vatee
• Swaminath Gayathri
• Kreiman Charles
• Moebius David C
• Sharma Ankit

Classifications

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• A61P9/04

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

• C07D417/14

  containing three or more hetero rings · CPC title