Flap modulators

Patent metadata

Field	Value
Publication number	US-10047101-B2
Application number	US-201715667420-A
Country	US
Kind code	B2
Filing date	Aug 2, 2017
Priority date	Feb 4, 2013
Publication date	Aug 14, 2018
Grant date	Aug 14, 2018

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 selected from:

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 —, and —CH 2 C(OH)(H)CH 2 NH—;
R 1 is selected from: halo, C 1-5 alkyl, C 3-6 cycloalkyl, and cyclohexylmethyl;
R 2 is selected from: 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-oxy, —NHCH 3 , —N(CH 3 ) 2 , —NH-(isopropyl), optionally substituted phenyl, optionally substituted 5-membered or 6-membered heteroaryl, C 3-6 cycloalkyl, and 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-tent-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-pyrimidine-2-amine, and pentafluoro-lambda˜6˜-sulfanyl;
ring A is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 , wherein the compound isselected from the group consisting of:
6-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-3H-imidazo[4,5-b]pyridine,
7-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,
6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol,
7-[3-(Benzyloxy)-4-cyclobutyl-2-fluorophenyl]-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,
3-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzonitrile,
7-(4-Cyclobutyl-2-fluoro-3-{[3-(methylsulfonyl)benzyl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,
7-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfonyl)benzyl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,
4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzonitrile,
7-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,
3-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzamide,
4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzamide,
7-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,
(4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}phenyl)acetic acid,
4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzoic acid,
3-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-7H-pyrrolo[2,3-c]pyridazine,
5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine,
6-Cyclobutyl-3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-fluorophenol,
6-Cyclobutyl-2-fluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenol,
6-Cyclobutyl-2-fluoro-3-(7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol,
7(4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,
2(6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy)pyrimidin-4-amine,
7(4-Cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,
5(4-Cyclobutyl-2-fluoro-3-((6-methoxypyrim id in-4-yl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridine,
5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine,
2-[6-Cyclobutyl-2-fluoro-3-(7H-pyrrolo[2,3-c]pyridazin-3-yl)phenoxy]pyrimidin-4-amine, and
5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]-1H-pyrrolo[2,3-b]pyridine, and
and their pharmaceutically acceptable salts thereof.

3. A pharmaceutical composition comprising at least one compound of claim 1 and at least one pharmaceutically acceptable carrier.

4. The pharmaceutical composition of claim 3 comprising at least one compound of claim 2 .

5. A process for making a pharmaceutical composition comprising admixing any of the compounds according to claim 1 and a pharmaceutically acceptable carrier.

Assignees

• Janssen Pharmaceutica Nv
• Janssen Pharmaceautica 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

• A61P43/00

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

• A61P37/08

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

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/04

  specific for metastasis · CPC title