Fused heterocyclic compounds as ion channel modulators

Patent metadata

Field	Value
Publication number	US-9598435-B2
Application number	US-201514872787-A
Country	US
Kind code	B2
Filing date	Oct 1, 2015
Priority date	Jul 1, 2011
Publication date	Mar 21, 2017
Grant date	Mar 21, 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 Z 1 , Z 2 , Z 3 , Z 4 , X, Y, R 2 , R 3 and R 4 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 XII:

Z 1 , Z 2 and Z 4 are each independently selected from the group consisting of CR 7 and N;
provided that one of Z 1 , Z 2 and Z 4 is N; and provided that only one of Z 1 , Z 2 and Z 4 is N;
n is 0, 1, 2, 3, 4 or 5;
R 2 is —C 1-6 alkylene-R 5 ,-L-R 5 , -L-C 1-6 alkylene-R 5 , —C 1-6 alkylene-L-R 5 or -C 1-6 alkylene-L-C 1-6 alkylene-R 5 ;
wherein each —C 1-6 alkylene is optionally substituted by one substituent independently selected from the group consisting of C 2-4 alkynyl, halo, —NO 2 , —CN, —O—R 20 , —N(R 20 )(R 22 ), —C(O)—R 20 , —C(O)—OR 26 , —C(O)—N(R 20 )(R 22 ), —N(R 20 )—S(O) 2 —R 20 , cycloalkyl, aryl, heteroaryl or heterocyclyl; and
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, C 2-4 alkynyl, halo, —NO 2 , 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 ;

L is —O—, —S—, —C(O)—, —NHS(O) 2 —, —S(O) 2 NH—, —C(O)NH— or —NHC(O)—, provided that when R 2 is -L-R 5 or -L-C 1-6 alkylene-R 5 , then L is not —O—, —S—, —NHS(O) 2 — or —NHC(O)—;
R 5 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, C 2-4 alkynyl, halo, —NO 2 , 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 ), —CN and —O—R 20 ;
wherein said C 1-6 alkyl, 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, 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, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of 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 —OR 20 ;

each R 10 is independently selected from the group consisting of halo, —NO 2 , —CN, —SF 5 , —Si(CH 3 ) 3 , —O—R 20 , —S—R 20 , —C(O)—R 20 , —C(O)—OR 20 , —N(R 20 )(R 22 ), —C(O)—N(R 20 )(R 22 ), —N(R 20 )—C(O)—R 22 , —N(R 20 )—C(O)—OR 22 , —N(R 20 —S(O) 2 —R 26 , —S(O) 2 —R 20 , —O—S(O) 2 —R 20 , —S(O) 2 —N(R 20 )(R 22 ), C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and
wherein said C 1-6 alkyl, C 2 - 4 alkenyl, C 2 - 4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, —NO 2 , aryl, heterocyclyl, heteroaryl, C 1-3 haloalkyl, C 1-6 alkyl, cycloalkyl, —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 7 is hydrogen, halo or C 1-6 alkyl;
R 20 and R 22 are in each instance independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C 1-4 alkyl, acylamino, oxo, —NO 2 , —S(O) 2 R 26 , —CN, C 1-3 alkoxy, —CF 3 , —OCF 3 , —OCH 2 CF 3 , —C(O)—NH 2 , aryl, cycloalkyl and heteroaryl; and
wherein said heteroaryl is optionally further substituted with C 1-4 alkyl or 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, C 1-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO 2 , —S(O) 2 R 26 , —CN, C 1-3 alkoxy, —CF 3 , —OCF 3 , aryl, heteroaryl and cycloalkyl; and
each R 26 is independently selected from the group consisting of hydrogen, C 1-4 alkyl, aryl and cycloalkyl;
wherein the C 1-4 alkyl, aryl and cycloalkyl 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 and —OCF 3 ;

or a pharmaceutically acceptable salt, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.

2. The compound of claim 1 , wherein R 2 is

3. The compound of claim 1 , wherein n is 0 or 1; and R 10 is 4-trifluoromethyl or 4-trifluoromethoxy.

4. A compound selected from the group consisting of:
4-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one (XII-1)

4-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[2,3-f][1,4]oxazepin-5(2H)-one (XII-2)

4-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydropyrido[2,3-f][1,4]oxazepin-5(2H)-one (XII-3)

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one (XII-5)

4-((4-methylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one (XII-8)

4-(cyclopropylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one (XII-9)

4-((3-methoxypyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazenin-5(2H)-one (XII-10)

4-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one (XII-11)

 and
4-((4-methoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5 (2H)-one (XII-14)

or a pharmaceutically acceptable salt, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.

5. The compound of claim 1 , wherein n is 0 or 1;
R 10 is —O—R 20 or C 1-4 alkyl;
wherein the alkyl is optionally substituted with three halo; and
R 20 is C 1 —C 15 alkyl; and wherein the alkyl is optionally substituted with one, two or three halo.

6. The compound of claim 1 , wherein R 2 is —C 1-6 alkylene-R 5 or -C 1-6 alkylene-L-C 1-6 alkylene-R 5 .

7. The compound of claim 1 ,

Assignees

• Gilead Sciences Inc

Inventors

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

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P5/48

  of the pancreatic hormones · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · 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