Flap modulators

Patent metadata

Field	Value
Publication number	US-9745328-B2
Application number	US-201414765556-A
Country	US
Kind code	B2
Filing date	Jan 31, 2014
Priority date	Feb 4, 2013
Publication date	Aug 29, 2017
Grant date	Aug 29, 2017

Abstract

The present invention relates to compounds of Formula (I), or a form thereof wherein ring A 1 , R 1 , R 2 , R 3 , R 3 ′, L, W, and V 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 —, —SO 2 —, —CH 2 —SO 2 —, —SO 2 —CH 2 —, —SO 2 —NR—,

—SO 2 —NR—CH 2 —, —CH 2 —SO 2 —NR—, —NR—, —NR—SO 2 —, —NR—SO 2 —NR—, —S—, —S—CH 2 —, —CH 2 —S—,
—C(═O)—, —C(═O)—O—, —O—, —O—CH 2 —, —NR—C(═O)—, —NR—C(═O)—NR—, or —C(═O)—NR—, wherein R is H,
C 1-2 alkyl, C 1-2 alkyl-OH or cyclopropyl;
R 1 is H, halo, methyl, CF 3 , —O—CF 3 , or —O—CH 3 ;
R 2 is H, cyano, halo, —SO 2 —CH 3 , 2-(trimethylsilyl)ethoxy, phenyl, C 1-6 alkyl, heteroaryl, heterocyclyl, C 3-9 cycloalkyl, provided R 2 is not H if L is a bond, and wherein said phenyl, C 1-6 alkyl, heteroaryl, heterocyclyl or C 3-9 cycloalkyl is optionally and independently substituted with 1-4 substituents selected from the group consisting of:

methyl, ethyl, oxo, fluoro, hydroxyl, cyano, amino, methoxy, tert-butoxy, acetyl, cyclopropyl, cyclobutyl, cyclohexyl, phenyl, azetidin-1-yl, azetidin-3-yl, pyrrolidin-1-yl, 2,4-dihydro-3H-1,2,4-triazol-3-one-4-yl, 1H-imidazol-4-yl, pyrazin-2-yl, pyrimidin-2-yl, 1,3-oxazolidin-2-one-5-yl, N-benzamide, benzo[d]imidazol-2(3H)-one, 4-methylpiperazin-1-yl, morpholin-4-yl, CF 3 , —SO 2 —CH 3 , —C(═O)-cyclopropyl, —SO 2 -cyclohexyl, —NHCH 3 , —N(CH 3 ) 2 , —NHAc, —NHCO 2 t-Bu, —CH 2 —NH 2 , —C(═O)—NH 2 , —C(═O)—N(ethyl) 2 , —NH—C(═O)—NH 2 , —NH—C(═O)—CH 3 , —C(═O)—(C 1 -C 4 alkyl), —C(═O)—OH, —C(═O)—NH(C 1 -C 4 alkyl)-(CH 2 ) n —OH, and —(CH 2 ) n —CN, wherein n is 1 or 2;
V is CH, CR′, or N, wherein R′ is methyl or F;
W is CR″ or N, wherein R″ is H, F, hydroxyl, amino, CH 3 or —O—CH 3 ;
ring A is selected from the group consisting of:

R 3 is H, F, methyl, or —O—CH 3 ;
R 3 ′ is H or F;
R 4 is H, methyl, cyano, amino, halo, —COOH, or —O—CH 3 ;
R 5 is H, methyl, cyano, or —CF 3 ;
R 6 is H, cyano, amino, halo, or —CF 3 ; and
R 7 is halo, amino, —CONH 2 , cyano, —O—CH 3 , —CF 3 , or —COO-ethyl;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein
L is a bond, —O—, —SO 2 —NH—, —NH—SO 2 —, —SO 2 —, —S—, —C(═O)—, fluoro or —C(═O)—NH—;
R 1 is H, bromo or CF 3 ;
R 2 is H, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclohexyl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, tetrahydro-2H-thiopyran-4-yl, morpholin-2-yl, morpholin-4-yl, thiomorpholin-4-yl, pyrazin-2-yl, pyrimidin-2-yl, or pyrimidin-4-yl, provided R 2 is not H if L is a bond, and wherein R 2 is optionally substituted with hydroxyl, fluoro, amino, oxo, methyl, or —CH 2 —NH 2 ;
V is CH or N;
W is CR″ or N, wherein R″ is H or F;
ring A is

R 3 is H;
R 3 ′ is H;
R 4 is H or cyano; and
R 5 is H or cyano;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein
L is a bond, —O—, —SO 2 —NH—, —NH—SO 2 —, —SO 2 —, —S—, or —C(═O)—;
R 1 is H or CF 3 ;
R 2 is H, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclohexyl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, tetrahydro-2H-thiopyran-4-yl, morpholin-2-yl, morpholin-4-yl, thiomorpholin-4-yl, pyrazin-2-yl, pyrimidin-2-yl, or pyrimidin-4-yl, provided R 2 is not H if L is a bond, and wherein R 2 is optionally substituted with hydroxyl, fluoro, amino, oxo, methyl, or —CH 2 —NH 2 ;
V is CH or N;
W is CR″ or N, wherein R″ is H or F;
ring A is

R 3 is H; and
R 3 ′ is H;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein the compound is selected from:
5-(3-fluoro-2′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine,
N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methanesulfonamide,
6-Amino-3-[3-fluoro-2′-(methylsulfonyl)biphenyl-4-yl]pyrazine-2-carbonitrile,
4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,
4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide,
4′-(5-Aminopyrazin-2-yl)-N-cyclohexyl-3′-fluorobiphenyl-2-sulfonamide,
4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-methylpropyl)biphenyl-2-sulfonamide,
4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2,2,2-trifluoro-1-methylethyl)biphenyl-2-sulfonamide (racemic),
4′-(5-Aminopyrazin-2-yl)-N-(cyclobutylmethyl)-3′-fluorobiphenyl-2-sulfonamide,
(endo)-4′-(5-Aminopyrazin-2-yl)-N-bicyclo[2.2.1]hept-2-yl-3′-fluorobiphenyl-2-sulfonamide (racemic),
4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(1-methylcyclobutyl)biphenyl-2-sulfonamide,
4′-(5-Aminopyrazin-2-yl)-N-(1,1-dimethylpropyl)-3′-fluorobiphenyl-2-sulfonamide,
4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2,2,2-trifluoro-1,1-dimethylethyl)biphenyl-2-sulfonamide,
4′-(5-Aminopyrazin-2-yl)-N-cyclopentyl-3′-fluorobiphenyl-2-sulfonamide,
4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-methylbiphenyl-2-sulfonamide,
4′-(5-Aminopyrazin-2-yl)-N-ethyl-3′-fluorobiphenyl-2-sulfonamide,
4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-phenylethyl)biphenyl-2-sulfonamide,
(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]biphenyl-2-sulfonamide,
(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-phenylethyl]biphenyl-2-sulfonamide,
(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]biphenyl-2-sulfonamide,
4′-(5-Aminopyrazin-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)-3′-fluorobiphenyl-2-sulfonamide,
(S)-4′-(5-Aminopyrazin-2-yl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-3′-fluorobiphenyl-2-sulfonamide,
(R)-4′-(5-Aminopyrazin-2-yl)-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-3′-fluorobiphenyl-2-sulfonamide,
(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-1-phenylethyl]biphenyl-2-sulfonamide,
(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide,
4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-phenylbiphenyl-2-sulfonamide,
(S)-4′-(5-Aminopyrazin-2-yl)-N-[(3S)-1-ethyl-2-oxoazepan-3-yl]-3′-fluorobiphenyl-2-sulfonamide,
(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(3S)-2-oxoazepan-3-yl]biphenyl-2-sulfonamide,
(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(3S)-1-methyl-2-oxoazepan-3-yl]biphenyl-2-sulfonamide,
4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)biphenyl-2-sulfonamide,
4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-pyridin-3-ylbiphenyl-2-sulfonamide,
4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide,
N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfamide,
N-(4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1, 1′-biphenyl]-2-yl)propane-2-sulfonamide,
N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]ethanesulfonamide,
N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]propane-1-sulfonamide,
N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-2-methylpropane-1-sulfonamide,
N-(4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)cyclopropanesulfonamide,
N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]hexane-1-sulfonamide,
N-(4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)cyclobutanesulfonamide,
N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-1,1,1-trifluoromethanesulfonamide,
4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N,N-dimethylbiphenyl-2-sulfonamide,
5-[3-Fluoro-2′-(piperidin-1-ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Bacani Genesis M
• Eccles Wendy
• Fitzgerald Anne E
• Goldberg Steven D
• Hack Michael D
• Hawryluk Natalie A
• Jones William M
• Keith John M
• Krawczuk Paul
• Lebsack Alec D
• Lee-Dutra Alice
• Liu Jing
• Mcclure Kelly J
• Meduna Steven P
• Pippel Daniel J
• Rosen Mark D
• Sales Zachary S

Classifications

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/04

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