Biphenyl compound or salt thereof

Patent metadata

Field	Value
Publication number	US-10723742-B2
Application number	US-201615776548-A
Country	US
Kind code	B2
Filing date	Nov 25, 2016
Priority date	Nov 27, 2015
Publication date	Jul 28, 2020
Grant date	Jul 28, 2020

Abstract

A compound or a salt thereof represented by Formula (I). An LSD1 inhibitor containing the compound or a salt thereof as an active ingredient. A pharmaceutical composition containing the compound or salt thereof. An antitumor agent containing the compound or a salt thereof as an active ingredient.

First claim

The invention claimed is:

1. A compound represented by Formula (I) or a salt thereof:

wherein
ring A represents a monocyclic, bridged cyclic, or spirocyclic 4- to 14-membered nitrogen-containing saturated heterocyclic group having 1 to 3 nitrogen atoms, 0 to 1 sulfur atoms, and 0 to 2 oxygen atoms as heteroatoms,
ring B represents monocyclic or bicyclic 5- to 14-membered unsaturated hydrocarbon or a monocyclic or bicyclic 5- to 14-membered unsaturated heterocyclic group that may be substituted with oxo, that has 0 to 4 nitrogen atoms, 0 to 2 sulfur atoms, and 0 to 3 oxygen atoms as heteroatoms, and that has at least one of nitrogen, sulfur, and oxygen, and
X represents O or S,
R1 represents nitro or cyano,
R2 represents halogen,
R3 represents amino, mono- or di(C1-C6 alkyl)amino, (C3-C7 cycloalkyl)amino, or C1-C6 alkyl,
R4 is selected from the group consisting of halogen, nitro, cyano, carboxy, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkyl, mono- or di(C1-C6 alkyl)amino, and substituted or unsubstituted carbamoyl, wherein when two or more R4 are present they may be identical or different,
wherein when R4 is selected from the group consisting of substituted C1-C8 alkyl, substituted C2-C6 alkenyl, substituted C1-C6 alkoxy, substituted C3-C7 cycloalkyl, and substituted carbamoyl, the substituent is selected from the group consisting of halogen, carboxy, C1-C6 alkoxy, hydroxy, C1-C6 alkyl that is unsubstituted or substituted with hydroxy, monocyclic 5- to 10-membered unsaturated hydrocarbon, carbamoyl that is unsubstituted or substituted with C1-C6 alkyl or monocyclic 5- to 10-membered unsaturated hydrocarbon, (C2-C7 acyl)oxy, amino that is unsubstituted or substituted with C1-C6 alkyl or C2-C7 acyl, C3-C7 cycloalkyl that is unsubstituted or substituted with hydroxy, and (C1-C6 alkoxy)(C1-C6 alkyl), wherein when two or more of the substituents are present, the substituents may be identical or different,

l is an integer of 0 to 2,
m is an integer of 0 to 2, and
n is an integer of 0 to 5,
wherein when l is 2, two R2s may be identical or different, when m is 2, two R3s may be identical or different, and when n is 2 to 5, two to five R4s may be identical or different.

2. The compound or a salt thereof according to claim 1 , which satisfies the following conditions in Formula (I):
ring A represents pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl,

2,7-diazaspiro[3.4]octanyl, 3,7-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,8-diazaspiro[3.5]nonanyl, 3,7-diazaspiro[3.5]nonanyl, 3,8-diazaspiro[4.4]nonanyl, 3,8-diazaspiro[4.5]decanyl, or 9-oxa-diazaspiro[3.5]nonanyl, and
R3 represents amino, methylamino, ethylamino, isopropylamino, dimethylamino, cyclobutylamino, or methyl, wherein when two or more R3s are present, R3s may be identical or different.

3. The compound or a salt thereof according to claim 1 , which satisfies the following conditions in Formula (I):
R4 represents halogen, nitro, cyano, carboxy, C1-C8 alkyl that may be substituted with halogen, amino, hydroxyl, carboxy, carbamoyl, (C1-C6 alkyl)carbamoyl, (C1-C6 alkyl)carbonylamino, C1-C6 alkoxy, (C1-C6 alkyl)carbonyl, C3-C7 cycloalkyl, hydroxyl(C3-C7 cycloalkyl), or (C1-C6 alkyl)carbonyloxy, C2-C6 alkenyl, C1-C6 alkoxy that may be substituted with hydroxyl or monocyclic 5- to 10-membered unsaturated hydrocarbon, C3-C7 cycloalkyl that may be substituted with hydroxyl, hydroxyl(C1-C4 alkyl), (C1-C4 alkoxy)(C1-C4 alkyl), hydroxyl(C3-C7 cycloalkyl), or (C6-C14 aromatic hydrocarbon)-substituted carbamoyl, mono- or di(C1-C6 alkyl)amino, or carbamoyl that may be substituted with C1-C6 alkyl, wherein when two or more R4s are present, R4s may be identical or different.

4. The compound represented by Formula (I) or a salt thereof according to claim 1 ,
wherein
ring A represents pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl,

2,7-diazaspiro[3.4]octanyl, 3,7-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,8-diazaspiro[3.5]nonanyl, 3,7-diazaspiro[3.5]nonanyl, 3,8-diazaspiro[4.4]nonanyl, 3,8-diazaspiro[4.5]decanyl, or 9-oxa-diazaspiro[3.5]nonanyl, ring B represents phenyl, naphthyl, pyridyl, pyrazolopyridyl, pyrazolopyrimidinyl, indolyl, indolinyl, 2-oxo-indolinyl, indazolyl, benzoimidazolyl, benzoisoxazolyl, benzothiazolyl, benzotriazolyl, imidazopyridinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 1,3-dihydroisobenzofuranyl, dihydrobenzooxazinyl, benzodioxolyl, dihydrobenzodioxynyl, or 2-oxo-2,3-dihydrobenzo[d]thiazolyl,
X represents O or S,
R1 represents nitro or cyano,
R2 represents fluorine, and is present at the ortho position relative to R1 on the phenyl,
R3 represents amino, methylamino, ethylamino, isopropylamino, dimethylamino, cyclobutylamino, or methyl, wherein when two or more R3s are present, R3s may be identical or different, and
R4 represents fluorine, chlorine, bromine, iodine, nitro, cyano, carboxy, methyl, ethyl, n-propyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, fluoroethyl, aminoethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxydimethylethyl, hydroxymethylpropyl, hydroxymethylbutyl, hydroxyethylbutyl, carboxymethyl, carbamoylmethyl, methylcarbamoylmethyl, di methylcarbamoylmethyl, acetylaminoethyl, methoxyethyl, hydroxycyclopropylmethyl, hydroxycyclopropylethyl, hydroxycyclobutylmethyl, methylcarbonyloxyethyl, isobutenyl, methoxy, hydroxypropoxy, cyclopropyl, hydroxymethyl cyclopropyl, methoxymethyl cyclopropyl, hydroxycyclopropyl cyclopropyl, phenylcarbamoyl cyclopropyl, benzyloxy, dimethylamino, carbamoyl, methylcarbamoyl, or dimethylcarbamoyl, wherein when two or more R4s are present, R4s may be identical or different, and
n is an integer of 0 to 3, wherein when n is 2 to 3, two to three R4s may be identical or different.

5. A compound selected from the group consisting of compounds (1) (24) (1) 4-[5-[(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile,
(2) 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile,
(3) 4-[5-[(3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile,
(4) (S)-5′-(3-aminopyrrolidine-1-carbonyl)-3-fluoro-2′-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indol-5-yl)-[1,1′-biphenyl]-4-carbonitrile,
(5) 5′-((3-endo)-3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2′-(6,7-difluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1′-biphenyl]-4-carbonitrile,
(6) 5′-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2″,3-difluoro-4″-(2-hydroxy-2-methylpropyl)-[1,1′:2′,1″-terphenyl]-4-carbonitrile-isomer-B,
(7) 5′-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2′-(6,7-difluoro-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-fluoro-[1,1′-biphenyl]-4-carbonitrile-isomer-B,
(8) 5′-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-3-fluoro-2′-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-[1,1′-biphenyl]-4-carbonitrile-isomer-B,
(9) 5′-((1S,2S,4R)-rel-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonyl)-2′-(6,7-difluor

Assignees

• Taiho Pharmaceutical Co Ltd

Inventors

• Yamashita Satoshi
• Ogawa Takahiro
• Komatani Hideya

Classifications

• C07D401/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D451/04

  with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system · CPC title

• C07D207/14 Primary

  Nitrogen atoms not forming part of a nitro radical · CPC title

• A61K31/4184

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title