Fused heterocyclic compounds as ion channel modulators

Patent metadata

Field	Value
Publication number	US-9682998-B2
Application number	US-201615188701-A
Country	US
Kind code	B2
Filing date	Jun 21, 2016
Priority date	May 10, 2011
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

Abstract

The present disclosure relates to compounds that are sodium channel inhibitors and to their use in the treatment of various disease states, including cardiovascular diseases and diabetes. In particular embodiments, the structure of the compounds is given by Formula I:

wherein Q, R 1 , X 1 , X 2 , Y and R 2 are as described herein, to methods for the preparation and use of the compounds and to pharmaceutical compositions containing the same.

First claim

What is claimed is:

1. A compound of Formula:

wherein:
Y is —C(R 5 ) 2 — or —C(O)—;
Q is a covalent bond or C 2-4 alkynylene;
R 1 is aryl or heteroaryl;
wherein said aryl or heteroaryl are optionally substituted with trifluoromethoxy or trifluoromethyl;
R 2 is —R 6 , —C 1-6 alkylene-R 6 , —C 2-6 alkenylene-R 6 , —C 2-6 alkynylene-R 6 , -L-R 6 , -L-C 1-6 alkylene-R 6 , —C 1-6 alkylene-L-R 6 or —C 1-6 alkylene-L-C 1-6 alkylene-R 6 ;
L is —O—, —S—, —C(O)—, —S(O) 2 —, —NR 20 S(O) 2 —, —S(O) 2 NR 20 —, —C(O)NR 20 — or —NR 20 C(O)—;
provided that when Y is —C(R 5 ) 2 —, then L is —C(O)— or —S(O) 2 —, and R 2 is -L-R 6 , -L-C 1-6 alkylene-R 6 , —C 1-6 alkylene-L-R 6 or —C 1-6 alkylene-L-C 1-6 alkylene-R 6 ;
each R 3 is independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl or heterocyclyl;
wherein said C 1-6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, —NO 2 , C 3-6 cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R 20 )(R 22 ), —C(O)—R 20 , —C(O)—OR 20 , —C(O)—N(R 20 )(R 22 ), —CN and —O—R 20 ;
wherein said C 3-6 cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, —NO 2 , C 1-6 alkyl, aralkyl, C 3-6 cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R 20 )(R 22 ), —C(O)—R 20 , C(O)—OR 20 , —C(O)—N(R 20 )(R 22 ), —CN and —O—R 20 ; and
wherein said C 1-6 alkyl, aralkyl, C 3-6 cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, —NO 2 , —N(R 20 )(R 22 ), —C(O)—R 20 , —C(O)—OR 20 , —C(O)—N(R 20 )(R 22 ), —CN and —O—R 20 ;

R 4 is hydrogen, C 1-6 alkyl, C 1-4 alkoxy, —C(O)—OR 20 , —C(O)—N(R 20 )(R 22 ), —N(R 20 )—S(O) 2 —R 20 , C 3-6 cycloalkyl, aryl, heteroaryl or heterocyclyl;
wherein said C 1-6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, —NO 2 , C 3-6 cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R 20 )(R 22 ), —C(O)—R 20 , —C(O)—OR 20 , —C(O)—N(R 20 )(R 22 ), —CN and —O—R 20 ;
wherein said C 3-6 cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, —NO 2 , C 1-6 alkyl, aralkyl, C 3-6 cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R 20 )(R 22 ), —C(O)—R 20 , C(O)—OR 20 , —C(O)—N(R 20 )(R 22 ), —CN, and —O—R 20 ; and
wherein said C 1-6 alkyl, aralkyl, C 3-6 cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, —NO 2 , —N(R 20 )(R 22 ), —C(O)—R 20 , —C(O)—OR 20 , —C(O)—N(R 20 )(R 22 ), —CN and —O—R 20 ;

each R 5 is independently hydrogen or C 1-6 alkyl;
R 6 is C 3-6 cycloalkyl, aryl, heteroaryl or heterocyclyl;
wherein said C 3-6 cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C 1-6 alkyl, C 2-4 alkynyl, halo, —NO 2 , C 3-6 cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R 20 )(R 22 ), —N(R 20 )—S(O) 2 —R 20 , —N(R 20 )—C(O)—R 22 , —C(O)—R 20 , —C(O)—OR 20 , —C(O)—N(R 20 )(R 22 ), —S(O) 2 —R 20 , —CN and —O—R 20 ;
wherein said C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, —NO 2 , C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R 20 )(R 22 ), —C(O)—R 20 , —C(O)—OR 20 , —C(O)—N(R 20 )(R 22 ), —CN and —O—R 20 ; and
wherein said C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of C 1-6 alkyl, halo, aryl, —NO 2 , —CF 3 , —N(R 20 )(R 22 ), —C(O)—R 20 , —C(O)—OR 20 , —C(O)—N(R 20 )(R 22 ), —CN, —S(O) 2 —R 20 and —O—R 20 ;

R 20 and R 22 are in each instance independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, heterocyclyl, aryl or heteroaryl; and
wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C 1-4 alkyl, aralkyl, —N(R 26 )(R 28 ), aminoacyl, —NO 2 , —S(O) 2 —R 26 , —CN, C 1-3 alkoxy, —CF 3 , —OCF 3 , —OCH 2 CF 3 , —C(O)—NH 2 , —C(O)—R 26 , —C(O)—OR 26 , aryl, C 3-6 cycloalkyl, heterocyclyl, aryl and heteroaryl;
wherein said aralkyl, heterocyclyl or heteroaryl is optionally further substituted with C 1-4 alkyl, —CF 3 , aryl or C 3-6 cycloalkyl; or

when R 20 and R 22 are attached to a common nitrogen atom R 20 and R 22 may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, alkyl, aralkyl, aryl, aryloxy, aralkyloxy, heteroaryloxy, substituted amino, aminoacyl, —NO 2 , —S(O) 2 —R 26 , —CN, C 1-3 alkoxy, hydroxymethyl, —CF 3 , —OCF 3 , aryl, heteroaryl and C 3-6 cycloalkyl; and
R 26 and R 28 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 3-6 cycloalkyl, aryl and heteroaryl; and
wherein the C 1-6 alkyl, C 3-6 cycloalkyl, aryl or heteroaryl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, C 1-4 alkoxy, —CF 3 , —OCF 3 and C 3-6 cycloalkyl;

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

2. The compound of claim 1 , wherein Q is a bond.

3. The compound of claim 1 , wherein R 2 is —R 6 , —C 1-6 alkylene-R 6 , -L-R 6 , -L-C 1-6 alkylene-R 6 or —C 1-6 alkylene-L-R 6 ;
L is —O—, —C(O)—, —S(O) 2 —, —S(O) 2 NR 20 — or —C(O)NR 20 —; provided that when Y is —C(R 5 ) 2 —, then L is —C(O)— or —S(O) 2 —, and R 2 is -L-R 6 , -L-C 1-6 alkylene-R 6 or —C 1-6 alkylene-L-R 6 ; and
R 6 is cycloalkyl, aryl, heteroaryl or heterocyclyl;
wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C 1-6 alkyl, halo, cycloalkyl, aryl, heteroaryl, —N(R 20 )(R 22 ), —C(O)—OR 20 , —S(O) 2 —R 20 , —CN and —O—R 20 ;
wherein said C 1-6 alkyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, cycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)—OR 20 and —O—R 20 ; and
wherein said heteroaryl is optionally further substituted with one, two or three C 1-6 alkyl.

4. The compound of claim 3 , wherein R 2 is

Assignees

• Gilead Sciences Inc

Inventors

• Corkey Britton Kenneth
• Elzein Elfatih
• Graupe Michael
• Guerrero Juan
• Jiang Robert H
• Kalla Rao V
• Kobayashi Tetsuya
• Koltun Dmitry
• Li Xiaofen
• Martinez Ruben
• Notte Gregory
• Parkhill Eric Q
• Perry Thao
• Venkataramani Chandrasekar
• Zablocki Jeff

Classifications

• A61P9/04

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

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · 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