FLAP modulators

Patent metadata

Field	Value
Publication number	US-9732093-B2
Application number	US-201414765552-A
Country	US
Kind code	B2
Filing date	Jan 31, 2014
Priority date	Feb 4, 2013
Publication date	Aug 15, 2017
Grant date	Aug 15, 2017

Abstract

The present invention relates to compounds of Formula (I), or a form thereof, wherein ring A, R 1 , L and R 2 are as defined herein, useful as FLAP modulators. The invention also relates to pharmaceutical compositions comprising compounds of Formula (I). Methods of making and using the compounds of Formula (I) are also within the scope of the invention.

First claim

The invention claimed is:

1. A compound of Formula (I)

wherein
L is a bond, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 NH—, —CH 2 C(═O)NH—, —CH 2 C(OH)(H)CH 2 —, or —CH 2 C(OH)(H)CH 2 NH—;
R 1 is halo, C 1-5 alkyl, C 3-6 cycloalkyl, or cyclohexylmethyl;
R 2 is H, C 1-4 alkyl, hydroxyl, amino, cyano, —CH 2 C(═O)O-(tert-butyl), —CH 2 C(═O)O-(ethyl), —CH 2 C(═O)OH, —NHS(═O) 2 CH 3 , tert-butyl(dimethyl)silyl, —NHCH 3 , —N(CH 3 ) 2 , —NH-(isopropyl), optionally substituted phenyl, optionally substituted 5-membered or 6-membered heteroaryl, C 3-6 cycloalkyl, or optionally substituted heterocyclyl;
wherein the 5-membered or 6-membered heteroaryl, the heterocyclyl, or the phenyl is optionally and independently substituted with 1-4 substituents selected from the group consisting of:
C 1-4 alkyl, —CH 2 -methoxy, —C(═O)OH, —CH 2 C(═O)OH, —C(═O)—O—CH 2 CH 3 , —C(═O)—O—CH 3 , —C(═O)—O-(tert-butyl), —NH 2 , —N(CH 3 ) 2 , —NH-(isobutyl), —NH(CH 2 ) 2 NHC(═O)—O-tert-butyl, —NH(CH 2 ) 2 NH 2 , —NH(CH 2 ) 2 N(CH 3 ) 2 , —C(═O)NH 2 , —C(═O)CH 3 , oxo, halo, hydroxyl, methoxy, trifluoromethyl, trifluoromethoxy, methoxymethyl, —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NH(CH 3 ), —S(═O) 2 N(CH 3 ) 2 , —S—CH 3 , cyano, 1H-tetrazol-5-yl, thiophen-2-yl, cyclopropyl, azetidin-1-yl, phenyl, 4′-(trifluoromethyl) phenyl, benzyl, 1,5-dioxa-9-azaspiro[5.5]undecan-9-yl, 5-pyrimidinyl-2-amine, and pentafluoro-lambda˜6˜-sulfanyl;
ring A is selected from the group consisting of:

R 3 is H, cyano, methyl, methoxy, halo, or —NH 2 and R 4 is H, or methyl;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein
L is a bond or —CH 2 —;
R 1 is tert-butyl or cyclobutyl;
R 2 is optionally substituted phenyl or an optionally substituted 6-membered heteroaryl;
wherein the substitution of the phenyl or the 6-membered heteroaryl is selected from a group consisting of:
hydroxyl, fluoro, methoxy, cyano, amino, —C(═O)—NH 2 , and pentafluoro-lambda˜6˜-sulfanyl;
ring A is

 and
R 3 is H or cyano;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , wherein
L is a bond or —CH 2 —;
R 1 is tert-butyl or cyclobutyl;
R 2 is optionally substituted substituted phenyl, optionally substituted pyridine or optionally substituted pyrimidine;
wherein the substitution of the phenyl, the pyridine or the pyrimidine is selected from a group consisting of:
hydroxyl, fluoro, methoxy, cyano, amino, —C(═O)—NH 2 , and pentafluoro-lambda˜6˜-sulfanyl; and
ring A is

or a pharmaceutically acceptable salt thereof.

4. A compound selected from the group consisting of:
5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine,
3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol,
5-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)benzyl]oxy}phenyl)pyrazin-2-amine,
5-(4-Cyclobutyl-2-fluoro-3-{[3-(trifluoromethyl)benzyl]oxy}phenyl)pyrazin-2-amine,
5-(4-Cyclobutyl-2-fluoro-3-{[2-(trifluoromethyl)benzyl]oxy}phenyl)pyrazin-2-amine,
3-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzoic acid,
4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzoic acid,
5-(4-Cyclobutyl-2-fluoro-3-{[3-(methylsulfonyl)benzyl]oxy}phenyl)pyrazin-2-amine,
5-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfonyl)benzyl]oxy}phenyl)pyrazin-2-amine,
5-(4-Cyclobutyl-2-fluoro-3-{[2-(trifluoromethoxy)benzyl]oxy}phenyl)pyrazin-2-amine,
5-(4-Cyclobutyl-2-fluoro-3-{[3-(trifluoromethoxy)benzyl]oxy}phenyl)pyrazin-2-amine,
5-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)pyrazin-2-amine,
5-(3-{[4-Chloro-2-(methylsulfonyl)benzyl]oxy}-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine,
1-(4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-methyl}phenyl)-ethanone,
5-[4-Cyclobutyl-2-fluoro-3-(pyridin-3-ylmethoxy)phenyl]pyrazin-2-amine,
5-[4-Cyclobutyl-2-fluoro-3-(pyridin-4-ylmethoxy)phenyl]pyrazin-2-amine,
4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile,
3-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile,
3-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzamide,
2-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile,
2-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzamide,
5-(4-Cyclobutyl-2-fluoro-3-{[4-(1H-tetrazol-5-yl)benzyl]oxy}phenyl)pyrazin-2-amine,
5-(4-Cyclobutyl-2-fluoro-3-{[3-(1H-tetrazol-5-yl)benzyl]oxy}phenyl)pyrazin-2-amine,
5-(4-Cyclobutyl-2-fluoro-3-{[2-(1H-tetrazol-5-yl)benzyl]oxy}phenyl)pyrazin-2-amine,
(4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}phenyl)acetic acid,
5-[4-Cyclobutyl-2-fluoro-3-(pyridin-2-ylmethoxy)phenyl]pyrazin-2-amine,
4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-N,N-dimethyl-benzenesulfonamide,
4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-methyl}-benzenesulfonamide,
4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-N-methylbenzenesulfonamide,
5-{4-Cyclobutyl-2-fluoro-3-[(4-fluorobenzyl)oxy]phenyl}pyrazin-2-amine,
5-{4-Cyclobutyl-2-fluoro-3-[(3-fluorobenzyl)oxy]phenyl}pyrazin-2-amine,
5-{4-Cyclobutyl-2-fluoro-3-[(2-fluorobenzyl)oxy]phenyl}pyrazin-2-amine,
5-{4-Cyclobutyl-3-[(2,6-difluorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine,
5-{4-Cyclobutyl-3-[(2,3-difluorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine,
5-{4-Cyclobutyl-3-[(3,4-difluorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine,
5-{3-[(2-Chlorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine,
5-{3-[(3-Chlorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine,
5-{3-[(4-Chlorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine,
5-{4-Cyclobutyl-3-[(2,6-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine,
5-{4-Cyclobutyl-3-[(2,5-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine,
5-{4-Cyclobutyl-3-[(2,3-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine,
5-{4-Cyclobutyl-3-[(2,4-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine,
5-{4-Cyclobutyl-3-[(3,4-dimethylbenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine,
5-(3-{[2-Chloro-3-(trifluoromethyl)benzyl]oxy}-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine,
5-(3-{[5-Chloro-2-(trifluoromethyl)benzyl]oxy}-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine,
5-(4-Cyclobutyl-2-fluoro-3-{[4-fluoro-2-(trifluoromethyl)benzyl]oxy}phenyl)pyrazin-2-amine,
5-{3-[(2-Chloro-5-fluorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine,
2-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzoic acid,
5-{4-Cyclobutyl-2-fluoro-3-[(1-methyl-1H-pyrazol-3-yl)methoxy]phenyl}pyrazin-2-amine,
5-{4-Cyclobutyl-3-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)methoxy]-2-fluorophenyl}pyrazin-2-amine,
tert-Butyl [3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]acetate, [3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]acetic acid,
(racemic) 1-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)pyridin-2(1H)-one,
(racemic) 3-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)pyrimidin-4(3H)-one,
(racemic) 2-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)pyridazin-3(2H)-one,
(racemic) 1-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)pyrazin-2(1H)-one,
(racemic) 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(pyrimidin-5-ylamino)propan-2-ol,
(racemic) 1-(3-(5-Aminopyrazin-2-yl)-6-cycl

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Eccles Wendy
• Fitzgerald Anne E
• Hack Michael D
• Hawryluk Natalie A
• Jones William M
• Keith John M
• Krawczuk Paul
• Lebsack Alec D
• Liu Jing
• Mani Neelakandha S
• Mcclure Kelly J
• Meduna Steven P
• Rosen Mark D

Classifications

• A61P35/04

  specific for metastasis · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title