Triazole agonists of the APJ receptor

Patent metadata

Field	Value
Publication number	US-9745286-B2
Application number	US-201615297487-A
Country	US
Kind code	B2
Filing date	Oct 19, 2016
Priority date	May 20, 2015
Publication date	Aug 29, 2017
Grant date	Aug 29, 2017

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 have use in treating cardiovascular and other conditions. Compounds of Formula I and Formula II have the following structures:

where the definitions of the variables are provided herein.

First claim

What is claimed:

1. A method of treating a cardiovascular condition, the method comprising: administering to a subject having a cardiovascular condition an effective amount of 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 the cardiovascular condition is heart failure or hypertension, and further wherein the compound of Formula I or Formula II has the structure:

wherein:
R 1 is an unsubstituted pyridyl, pyridonyl, or pyridine N-oxide, or is a pyridyl, pyridonyl, or pyridine N-oxide substituted with 1, 2, 3, or 4 R 1a substituents;
R 1a 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, —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 , phenyl, —C(═O)-(heterocyclyl), or a heterocyclyl group, wherein the heterocyclyl group of the —C(═O)-(heterocyclyl) or heterocyclyl group is a 3 to 7 membered ring containing 1, 2, or 3 heteroatoms selected from N, O, or S;
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 substituent;
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 group, the heteroaryl group, or the heterocyclyl group are unsubstituted or are substituted with 1, 2, or 3 R 4a 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, —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), or —C(═O)N(C 1 -C 6 alkyl) 2 , and the heterocyclyl R 4 group may be further substituted with 1 oxo substituent; and
further wherein:
if R 4 is an unsubstituted or substituted phenyl ring and R 3 is a group of formula —(CR 3b ═CR 3c )-Q, then at least one of the following is true:
a) R 4 is substituted with at least one —O—(C 1 -C 6 alkyl) group;
b) Q is not an oxadiazole;
c) R 3b is not —H;
d) R 3c is not —H;
e) R 1 is not a 2-pyridyl group; or
f) R 4 is substituted with two or more —O—(C 1 -C 6 alkyl) groups.

2. The method of claim 1 , wherein the cardiovascular condition is heart failure.

3. The method of claim 1 , wherein the cardiovascular condition is heart failure with reduced ejection fraction.

4. The method of claim 1 , wherein the cardiovascular condition is heart failure with preserved ejection fraction.

5. The method of claim 1 , wherein the cardiovascular condition is hypertension.

6. The method of claim 1 , wherein the method includes administering at least one additional therapeutic agent to the subject, wherein the additional therapeutic agent is selected from an α-blocker, a β-blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.

7. The method of claim 1 , wherein the method includes administering at least one additional therapeutic agent to the subject, wherein the additional therapeutic agent is selected from an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB).

8. A method of improving cardiac contractility in a subject suffering from a cardiovascular condition, the method comprising: administerin

Assignees

• Amgen Inc

Inventors

• Chen Ning
• Chen Xiaoqi
• Chen Yinhong
• Cheng Alan C
• Connors Richard V
• Deignan Jeffrey
• Dransfield Paul John
• Du Xiaohui
• Fu Zice
• Heath Julie Anne
• Horne Daniel B
• Houze Jonathan
• Kaller Matthew R
• Khakoo Aarif Yusuf
• Kopecky David John
• Lai Su-Jen
• Ma Zhihua
• Mcgee Lawrence R
• Medina Julio C
• Mihalic Jeffrey T
• Nishimura Nobuko
• Olson Steven H
• Pattaropong Vatee
• Swaminath Gayathri
• Wang Xiaodong
• Yang Kevin
• Yeh Wen-Chen
• Debenedetto Mikkel V
• Farrell Robert P
• Hedley Simon J
• Judd Ted C
• Kayser Frank

Classifications

• C07D241/24

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• A61P9/04

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

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D413/04

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

• C07F7/08

  Compounds having one or more C—Si linkages · CPC title