Compounds for use in preparing heterocyclic triazole agonists of the APJ receptor

Patent metadata

Field	Value
Publication number	US-10150760-B2
Application number	US-201815945852-A
Country	US
Kind code	B2
Filing date	Apr 5, 2018
Priority date	May 3, 2016
Publication date	Dec 11, 2018
Grant date	Dec 11, 2018

Abstract

Compounds of Formula V, salts thereof, tautomers thereof, and salts of the tautomers have the following structure and are useful compounds in preparing small molecule agonists of the APJ Receptor:

where the definitions of the variables are provided herein.

First claim

What is claimed:

1. A compound of Formula V, a salt thereof, a tautomer thereof, or a salt of the tautomer:

wherein:
R 1 is a 3-, 4-, 5-, 6-, 7-, or 8-membered saturated or partially saturated heterocyclic group that includes 1, 2, or 3 heteroatoms independently selected from N, O, or S 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)-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 , —NHS(═O) 2 —(C 1 -C 6 alkyl), or —S(═O) 2 —(C 1 -C 6 alkyl), wherein R 1a may also be oxo unless R 1 is a 6-membered heterocyclic group that includes one N atom and includes at least one double bond, and further wherein two R 1a substituents on adjacent carbon atoms or on an adjacent carbon atom and an adjacent N atom of a 5- or 6-membered heterocyclic R 1 group may join to form a 6 membered ring that may be saturated, partially saturated, or aromatic and may include 0, 1, or 2 N atoms and may further optionally be substituted with 1 or 2 R 1a′ substituent and may include an oxo substituent if the ring is not an aromatic ring;
R 1a′ is in each instance independently selected from —F, —Cl, —Br, —I, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 perhaloalkyl, C 3 -C 8 cycloalkyl —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —CN, —OH, —O—(C 1 - 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 or —S(═O) 2 —(C 1 -C 6 alkyl);
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 —(CR 3d R 3e )—(CR 3f R 3g )-Q, a group of formula —(CR 3d R 3e )—(CR 3f R 3g )—C(═O)-Q, a group of formula —(CR 3d R 3e )—(CR 3f R 3g )—CH(OH)-Q, a group of formula —(CR 3d R 3e )—(CR 3f R 3g )—(CR 3f R 3g )-Q, a group of formula —(C 3 -C 8 cycloalkyl)-Q, a group of formula -(heterocyclyl)-Q, or -Q, wherein the heterocyclyl of the -(heterocyclyl)-Q group has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms independently selected from N, O, or S and is unsubstituted or is substituted with 1, 2, or 3 R 3h substituents, and further wherein the C 3 -C 8 cycloalkyl of the —(C 3 -C 8 cycloalkyl)-Q group is unsubstituted or is substituted with 1 or 2 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, —(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 1 -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 ;
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 , —C(═O)—(C 1 -C 6 alkyl), —C(═O)—(C 3 -C 6 cycloalkyl), —C(═O)—O—(C 1 -C 6 alkyl), oxo, or —C(═O)—(heterocyclyl), wherein the heterocyclyl group of the R h —C(═O)-(heterocyclyl) has 5 or 6 ring members of which 1 or 2 are heteroatoms independently selected from N, or S or has 3 or 4 ring members of which 1 is a heteroatom selected from N, O, or S;
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, —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 , —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, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-NH 2 , —(C 1 -C 6 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

Assignees

• Amgen Inc

Inventors

• Chen Xiaoqi
• Cheng Alan C
• Connors Richard V
• Debenedetto Mikkel V
• Dransfield Paul John
• Fu Zice
• Harvey James S
• Heath Julie Anne
• Houze Jonathan
• Judd Ted C
• Kopecky David John
• Lai Su-Jen
• Ma Zhihua
• Nishimura Nobuko
• Olson Steven H
• Pattaropong Vatee
• Wang Xiaodong

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07D405/04

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

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title