Cycloalkyl substituted triazole compounds as agonists of the APJ receptor

Patent metadata

Field	Value
Publication number	US-11020395-B2
Application number	US-201716347942-A
Country	US
Kind code	B2
Filing date	Nov 3, 2017
Priority date	Nov 16, 2016
Publication date	Jun 1, 2021
Grant date	Jun 1, 2021

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 following structures: (I) (II) 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 thereof, a stereoisomer thereof, or a mixture thereof,
wherein:
R 1 is an unsubstituted monocyclic C 3 -C 8 cycloalkyl, an unsubstituted C 5 -C 8 polycyclic cycloalkyl, an unsubstituted monocyclic C 4 -C 8 cycloalkenyl, a monocyclic C 3 -C 8 cycloalkyl substituted with 1, 2, 3, or 4 R 1a substituents, a C 5 -C 8 polycyclic cycloalkyl substituted with 1, 2, or 3 R 1a substituents, or a monocyclic C 4 -C 8 cycloalkenyl substituted with 1, 2, or 3 R 1a substituents;
R 1a in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —OH, ═O, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), perhaloalkyl), —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —C 2 -C 4 alkenyl, ═CH 2 , ═CH—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-OH, alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl)-OH, haloalkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 perhaloalkyl)-OH, perhaloalkyl)-O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 alkyl)-OH, 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, 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 , —NHS(═O) 2 —(C 1 -C 6 alkyl), —S(═O) 2 —(C 1 -C 6 alkyl), a phenyl group, or a monocyclic heteroaryl group with 5 or 6 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the R 1a phenyl and R 1a heteroaryl groups are unsubstituted or are substituted with 1, 2, or 3, R 1a′ substituents; and further wherein two R 1a groups on a single carbon atom of a monocyclic C 3 -C 8 cycloalkyl R 1 group may join together with the carbon atom to which they are attached to form a heterocyclic ring having 3 to 6 members of which 1 or 2 are heteroatoms independently selected from O, N, and S;
R 1a′ is in each instance, independently selected from —F, —Cl, —Br, —I, —CN, —OH, O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, —C 2 -C 4 alkenyl, —(C 1 -C 6 alkyl)-OH, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl)-OH, —(C 1 -C 6 haloalkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 perhaloalkyl)-OH, —(C 1 -C 6 perhaloalkyl)-O—(C 1 -C 6 alkyl), —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)NH2, —C(═O)NH(C 1 -C 6 alkyl), —C(═O)N(C 1 -C 6 alkyl) 2 , —NHS(═O) 2 —(C 1 -C 6 alkyl), or —S(═O) 2 —(C 1 -C 6 alkyl);
R 2 is selected from —H, or C 1 -C 4 alkyl or is absent in the compounds of Formula II;
R 3 is a group of formula —(CR 3d R 3e )—(CR 3f R 3g -Q;
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, —(C 1 -C 6 alkyl)-OH, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl)-phenyl, —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 6 perhaloalkyl, —OH, —(C 1 -C 6 alkyl)-OH, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 perhaloalkyl), —O—(C 2 -C 6 alkenyl), —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 ;
wherein at least one of R 3d , R 3e , R 3f , and R 3f is not —H
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 independently selected from N, O, or S, a C 3 -C 8 cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the C 6 -C 10 aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R Q substituents; and further wherein the Q heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the Q heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom;
R Q in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, perhaloalkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 haloalkyl), perhaloalkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(═O)(C 1 -C 6 alkyl), —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), —(C 1 -C 6 alkyl)-OH, alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-NH 2 , alkyl)-NH—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-N—(C 1 -C 6 alkyl) 2 , phenyl, a heterocyclyl group, a —(C 1 -C 6 alkyl)heterocyclyl group, or a heteroaryl group with 5 or 6 ring members and 1, 2, or 3, heteroatoms independently selected from N, O, or S, wherein the heterocyclyl groups of the R Q heterocyclyl and —(C 1 -C 6 alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 are heteroatoms independently selected from N, O, or S, and further wherein the heterocyclyl and the heterocyclyl of the —(C 1 -C 6 alkyl)heterocyclyl R Q groups may be further substituted with one or two oxo substituents and a substituent selected from —F, —Cl, —Br, —I, —CN, —OH, —C 1 -C 6 alkyl, or —C(═O)—(C 1 -C 6 alkyl);
R 4 is selected from 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 independently selected from N, O, or S, or a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, wherein the C 6 -C 10 aryl, the heteroaryl, and the heterocyclyl R 4 group are unsubstituted or are substituted with 1, 2, 3, or 4 R 4a substituents; and
R 4a in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, perhaloalkyl, alkyl)-OH, alkyl)-O—(C 1 -C 6 alkyl), —OH, —O—(C 1 -C 6 alkyl), haloalkyl), 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 , phenyl, —S(═O) 2 —(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-heterocyclyl, or heterocyclyl wherein the heterocyclyl of the —(C 1 -C 6 alkyl)-heterocyclyl and heterocyclyl R′ groups is a 3-6 membered ring comprising 1 or 2 heteroatoms independently selected from N, O, or S, and is unsaturated or partially unsaturated and is optionally substituted with 1 or 2 oxo substituents, and further wherein the heterocyclyl of the R 4 group may be further substituted with 1 oxo substituent.

2. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer thereof, the stereoisomer thereof, or the mixture thereof, wherein
R 3d and R 3e are independen

Assignees

• Amgen Inc

Inventors

• Chen Yinhong
• Dransfield Paul John
• Harvey James S
• Heath Julie Anne
• Houze Jonathan
• Khakoo Aarif Yusuf
• Kopecky David J
• Lai Su-Jen
• Ma Zhihua
• Nishimura Nobuko
• Pattaropong Vatee
• Swaminath Gayathri
• Yeh Wen-Chen
• Ramsden Philip Dean

Classifications

• C07D249/14

  Nitrogen atoms · CPC title

• A61K31/4196

  1,2,4-Triazoles · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• C07D413/04

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

• C07D403/14

  containing three or more hetero rings · CPC title