HK1180673B

HK1180673B - Novel hydroxamic acid derivative

Info

Publication number: HK1180673B
Application number: HK13107775.1A
Authority: HK
Inventors: 高岛一; 鹤田理纱; 薮内哲也; 冈裕辅; 浦部洋树; 须贺洋一郎; 高桥正人; 宇根内史; 小坪弘典; 庄司宗生; 川口泰子
Original assignee: 大正制药株式会社; 富山化学工业株式会社
Priority date: 2010-04-20
Filing date: 2011-04-20
Publication date: 2016-11-18

Description

Novel hydroxamic acid derivatives

Technical Field

The present invention relates to a novel hydroxamic acid derivative or a salt thereof having an inhibitory activity against Uridine Diphosphate (UDP) -3-O-acyl-N-acetylglucosamine deacetylase (LpxC), and an antibacterial agent containing the same as an active ingredient.

Background

Gram-negative bacteria have an outer membrane formed of a lipid bilayer which gram-positive bacteria do not have, and therefore tend to have a stronger drug resistance than gram-positive bacteria in terms of the problem of drug permeability. In addition, gram-negative bacteria are known to have a number of drug efflux proteins, which are also associated with drug resistance (non-patent document 1). In addition, Lipopolysaccharide (LPS), which is one of the main components of the outer membrane, is strongly associated with toxicity as an endotoxin.

Among gram-negative bacteria, particularly pseudomonas aeruginosa is known to have a strong tendency to exhibit natural resistance to various antibacterial agents. Pseudomonas aeruginosa is a weakly toxic bacterium that widely exists in natural environments and living environments and does not normally exhibit pathogenicity to healthy normal persons. However, pseudomonas aeruginosa is one of the important bacteria causing opportunistic infection and nosocomial infection, because it is a causative bacterium of serious acute infection such as sepsis in patients suffering from serious basic diseases, patients who are called susceptible hosts to be used for transplantation or the like and who are subjected to medical practices such as medical catheters, tracheal intubation, surgery, and the like. In recent years, in the medical field, there have been clinically isolated pseudomonas aeruginosa resistant to a carbapenem, a quinolone drug, an aminoglycoside drug, or the like, which is originally expected to be effective against pseudomonas aeruginosa (non-patent document 2), and also isolated multidrug-resistant pseudomonas aeruginosa resistant to all of these 3 types of drugs (non-patent document 3). Since there is almost no effective therapeutic agent when multi-dose resistant Pseudomonas aeruginosa is infected, it is a worldwide problem as an intractable infectious disease, and development of a drug having a novel mechanism of action is urgently desired.

UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is an enzyme responsible for the synthesis of lipid A, the hydrophobic anchor of the constituent LPS of the outer membrane. Lipid a biosynthesis involves 10 steps of reaction, and LpxC catalyzes the 2 nd step of the biosynthesis reaction to remove the acetyl group of UDP-3-O-acyl-N-acetylglucosamine (non-patent document 4). Lipid a is an essential component for forming the outer membrane, and is consequently essential for the survival of gram-negative bacteria (non-patent document 5). LpxC is one of important enzymes that determine the reaction rate in the biosynthesis process of lipid a, and is an enzyme necessary for the biosynthesis of lipid a. Therefore, a drug inhibiting the activity of LpxC is highly expected to be an antibacterial agent effective against gram-negative bacteria including pseudomonas aeruginosa, and particularly, an antibacterial agent effective against drug-resistant pseudomonas aeruginosa because it has a mechanism of action different from that of conventional drugs.

Hitherto, patent documents 1 to 4 and non-patent documents 6 to 10 have been known as LpxC inhibitors having an amide structure, patent document 5 has been known as an inhibitor having a urea structure, and patent document 6 has been known as an inhibitor having an ether structure, but the present compound is not known to have LpxC inhibitory activity.

[ patent document 1 ] specification of International publication No. 04/062601

[ patent document 2 ] International publication No. 07/069020 Specification

[ patent document 3 ] International publication No. 08/154642 Specification

[ patent document 4 ] specification of International publication No. 10/031750

[ patent document 5 ] International publication No. 10/017060 Specification

[ patent document 6 ] International publication No. 10/032147 Specification

[ Nonpatent document 1 ] Antichronologically Resistence (2002) Mar1, 34, p.634-640.

[ Nonpatent document 2 ] J.Antimicrob.Chemother (2003) Jan14, 51, p.347-352.

[ Nonpatent document 3 ] Jpn.J. antibiotics (2006), 59(5), p.355-363.

[ Nonpatent document 4 ] J.biol.chem. (1995) Dec22, 270, p.30384-30391.

[ Nonpatent document 5 ] J.Bacteriol. (1987), 169, p.5408-5415

[ Nonpatent document 6 ] J.Med.chem. (2002), 45, p3112-3129.

[ Nonpatent document 7 ] Proc.Natl.Acad.Sci.USA (2007), 104, p18433-18438.

[ Nonpatent document 8 ] chem.biol. (2011), 18, p38-47.

[ Nonpatent document 9 ] Bioorg.Med.chem. (2011), 19, p852-860.

[ Nonpatent document 10 ] Bioorg.Med.chem.Lett. (2011), 21, p1155-1161.

Disclosure of Invention

The present invention addresses the problem of providing a novel compound which exhibits a strong antibacterial activity against gram-negative bacteria such as Pseudomonas aeruginosa and drug-resistant bacteria thereof by inhibiting LpxC and is useful as a pharmaceutical.

The present inventors have made intensive studies to find a compound having an LpxC inhibitory activity, and as a result, have found that a compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof can achieve the object, and have completed the present invention.

The present invention will be explained below.

The invention is a

(1) A compound represented by the general formula [1] or a pharmaceutically acceptable salt thereof,

[ CHEM 1]

(in the formula, wherein,

R¹and R²The same or different represent a hydrogen atom, C_1-6Alkyl radical, C_3-8Cycloalkyl or C_1-6Alkoxy (the C)_1-6Alkyl radical, C_1-6Alkoxy and C_3-8Cycloalkyl radicals may be chosen from "halogen atoms, hydroxy groups, C_3-8Cycloalkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkoxy, amino, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, -N (R)¹¹)COR¹²、-N(R¹¹)SO₂R¹²Cyano, carboxy, carbamoyl, -CON (R)¹³)(R¹⁴)、-SO₂N(R¹³)(R¹⁴)、C_1-6Alkylthio radical, C_1-6Alkylsulfonyl, aryloxy, aryl and heterocyclic groups "substituted with 1 to 3 substituents, which may be the same or different),

R¹¹、R¹²、R¹³and R¹⁴Same or different and represents a hydrogen atom or C_1-6An alkyl group, a carboxyl group,

R¹³and R¹⁴May be bonded to a nitrogen atom to form a nitrogen-containing compound which may further contain 1 or more nitrogen atoms,A saturated or unsaturated 5-or 6-membered ring of an oxygen atom or a sulfur atom,

R³represents a hydrogen atom or C_1-6Alkyl (the C)_1-6The alkyl group may be selected from "halogen atom, hydroxy group, C _1-6Alkoxy radical, C_3-8Cycloalkoxy, amino, C_1-6Alkylamino and di (C)_1-6Alkyl) amino "is substituted with 1 to 3 substituents which may be the same or different),

R⁴represents a hydrogen atom, a hydroxyl group, C_1-6Alkoxy radical, C_3-8Cycloalkoxy, amino, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, C_1-6Alkyl radical, C_3-8Cycloalkyl (the C)_1-6Alkyl and C_3-8Cycloalkyl radicals optionally substituted by halogen atoms, hydroxy groups, C_3-8Cycloalkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkoxy, amino, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, -N (R)⁴¹)COR⁴²、-N(R⁴¹)SO₂R⁴²Cyano, carboxy, -CON (R)⁴³)(R⁴⁴)、-SO₂N(R⁴³)(R⁴⁴)、C_1-6Alkylthio radical, C_1-6Alkylsulfonyl, aryl, aryloxy and heterocyclic groups (the aryl, aryloxy and heterocyclic groups may be selected from the group consisting of "halogen atom, C_1-6Alkyl radical, C_3-8Cycloalkyl, benzyl, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_2-8Alkoxyalkyl, hydroxy, C_1-6Alkoxy radical, C_3-8Cycloalkoxy, amino, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, -N (R)⁴⁵)COR⁴⁶、-N(R⁴⁵)SO₂R⁴⁶Cyano, carboxy, -CON (R)⁴⁷)(R⁴⁸)、-SO₂N(R⁴⁷)(R⁴⁸)、C_1-6Alkylthio and C_1-6Alkylsulfonyl "substituted with 1 to 3 substituents which may be the same or different)" may be substituted with 1 to 3 substituents which may be the same or different), an aryl group or a heterocyclic group (the aryl group and the heterocyclic group may be substituted with one or more substituents selected from the group consisting of "halogen atom, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C _1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_2-8Alkoxyalkyl, hydroxy, C_1-6Alkoxy radical, C_3-8Cycloalkoxy, amino, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, -N (R)⁴⁵)COR⁴⁶、-N(R⁴⁵)SO₂R⁴⁶Cyano, carboxy, -CON (R)⁴⁷)(R⁴⁸)、-SO₂N(R⁴⁷)(R⁴⁸)、C_1-6Alkylthio and C_1-6Alkylsulfonyl "substituted with 1 to 3 substituents, which may be the same or different),

R⁴¹、R⁴²、R⁴³、R⁴⁴、R⁴⁵、R⁴⁶、R⁴⁷and R⁴⁸Same or different and represents a hydrogen atom or C_1-6An alkyl group, a carboxyl group,

R⁴³and R⁴⁴May be linked together with the bound nitrogen atom to form a saturated or unsaturated 5-or 6-membered ring which may further contain 1 or more nitrogen atoms, oxygen atoms or sulfur atoms,

R⁴⁷and R⁴⁸May be linked together with the bound nitrogen atom to form a saturated or unsaturated 5-or 6-membered ring which may further contain 1 or more nitrogen atoms, oxygen atoms or sulfur atoms,

R³and R⁴May be linked together with the bound nitrogen atom to form a saturated or unsaturated 5-or 6-membered ring which may further contain 1 or more nitrogen atoms, oxygen atoms or sulfur atoms,

A¹represents a 2-valent aryl group, a 2-valent heterocyclic group or C_3-8Cycloalkylene (the 2-valent aryl group, the 2-valent heterocyclic group and C_3-8The cycloalkylene group may be selected from the following substituent group R^aAre the same or different and are substituted with 1 to 4 substituents),

substituent group R^aRepresents a halogen atom, a hydroxyl group, an amino group (the amino group may be substituted by C) _2-6Alkanoyl or 1 or 2C_1-6Alkyl-substituted), carboxy, carbamoyl, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_2-6Alkenyl and C_1-6Alkoxy (the C)_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_2-6Alkenyl and C_1-6Alkoxy groups may be selected from "halogen atoms, hydroxy groups, amino groups, carboxyl groups, C_1-6Alkylaminocarbonyl and C_1-6Alkoxycarbonyl "by 1 to 4 substituents which may be the same or different),

l represents-C.ident.C-, -C.ident.C- (CH)₂)_m-O-、-CH＝CH-、-CH＝CH-C≡C-、-C≡C-CH＝CH-、-O-、-S-、-NR⁵-、-CONR⁵-、-NR⁵CO-, 2-valent heterocyclic radical, - (CH)₂)_m-NR⁵-、-(CH₂)_m-O-、-NR⁵-(CH₂)_m-、-O-(CH₂)_m-、-ON＝CH-、C_1-4An alkylene group or a chemical bond,

R⁵represents a hydrogen atom, C_1-6Alkyl radical, C_3-8A cycloalkyl group or an aryl group, or a substituted cycloalkyl group,

m represents 1, 2 or 3,

A²represents a 2-valent aryl group, a 2-valent heterocyclic group, a 2-valent partially saturated condensed polycyclic hydrocarbon ring group, C_3-8Cycloalkylene radical, C_3-8Cycloalkenylene group, C_1-4Alkylene or C_2-4Alkenylene (the 2-valent aryl group, the 2-valent heterocyclic group, the 2-valent partially saturated condensed polycyclic hydrocarbon ring group, C_3-8Cycloalkenylene group, C_3-8Cycloalkylene radical, C_1-4Alkylene and C_2-4The alkenylene group may be substituted by a substituent group R selected from the group consisting of^bAre the same or different and are substituted with 1 to 4 substituents),

substituent group R^bRepresents a halogen atom, an optionally protected hydroxyl group, a mercapto group, a cyano group, a nitro group, an optionally protected amino group, an optionally protected formyl group, an optionally protected carboxyl group, a carbamoyl group, a sulfo group, a ureido group, a guanidino group, C _1-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-6Haloalkyl, C_1-6Hydroxy radicalAlkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, C_1-6Alkoxycarbonyl group, C_2-6An alkanoyl group and an aryl group,

w represents R⁶-X¹-、R⁶-X²-Y¹-X¹-、R⁶-X⁴-Y¹-X²-Y³-X³-、Q-X¹-Y²-X³-or Q-X¹-Y¹-X²-Y³-X³-，

Y²represents-O-, -NR⁷-、-CO-、-NR⁷CO-、-CONR⁷-、-S(O)_n-、-OCO-、-COO-、-NR⁷SO₂-、-SO₂NR⁷-、-OCOO-、-OCONR⁷-、-NR⁷CONR⁸-or a chemical bond,

Y¹and Y³The same or different, represent-O-, -NR⁷-、-CO-、-NR⁷CO-、-CONR⁷-、-S(O)_n-、-OCO-、-COO-、-NR⁷SO₂-、-SO₂NR⁷-、-OCOO-、-OCONR⁷-or-NR⁷CONR⁸-，

n represents 0, 1 or 2,

X¹and X³Same or different, represent C_1-10Alkylene radical, C_2-10Alkenylene radical, C_2-10Alkynylene, C_3-8Cycloalkylene, -C_1-6alkylene-C_3-8cycloalkylene-C_1-6Alkylene- (the C)_1-10Alkylene radical, C_2-10Alkenylene radical, C_2-10Alkynylene, C_3-8Cycloalkylene and-C_1-6alkylene-C_3-8cycloalkylene-C_1-6Alkylene-may be substituted by a substituent group R^cAre substituted with 1 to 4 substituents, which may be the same or different), or a chemical bond,

X²and X⁴Same or different, represent C_1-10Alkylene radical, C_2-10Alkenylene radical, C_2-10Alkynylene or-C_1-6alkylene-C_3-8cycloalkylene-C_1-6Alkylene- (the C)_1-10Alkylene radical, C_2-10Alkenylene radical, C_2-10Alkynylene and-C_1-6alkylene-C_3-8cycloalkylene-C_1-6Alkylene-may be substituted by a substituent group R^cAre the same or different and are substituted with 1 to 4 substituents),

q represents C_3-8Cycloalkyl, aryl or heterocyclic radical (C_3-8The cycloalkyl, aryl and heterocyclic groups may be selected from the following group of substituents R^cAre substituted by 1 to 4 substituents which may be the same or different and may be C between different carbon atoms in the heterocyclic ring _1-6Alkylene or-C_1-6alkylene-O-C_1-6Alkylene-bridged),

R⁶represents a hydrogen atom, a halogen atom, a hydroxyl group which may be protected, a mercapto group, a cyano group, a nitro group, an amino group which may be protected, a formyl group which may be protected, a carboxyl group which may be protected, a carbamoyl group, a sulfo group, a phosphoric acid group which may be protected, a ureido group, a guanidino group, R⁷-O-NR⁸-CO-、R⁸-ON＝CR⁹-、R⁸-ON＝CR⁹-NH-、R⁷-O-NR⁸-CH＝N-、(R⁷)(R⁸)N-N＝CH-、R⁸-O-NR⁸-、N≡C-NR⁸-or C_1-6Alkoxy (the C)_1-6Alkoxy groups may be substituted with 1 to 3 hydroxy groups),

R⁷and R⁸The same or different represent a hydrogen atom, C_1-6Alkyl radical, C_3-8Cycloalkyl, aryl or heterocyclic radical (C_1-6Alkyl radical, C_3-8The cycloalkyl, aryl and heterocyclic groups may be selected from the following group of substituents R^cAre the same or different and are substituted with 1 to 4 substituents),

R⁹represents a hydrogen atom, C_1-6Alkyl radical, C_3-8Cycloalkyl, amino or C_1-6An alkylamino group,

substituent groupGroup R^cRepresents a halogen atom, a hydroxyl group, a cyano group, a nitro group, or an amino group (the amino group may be substituted by C)_2-6Alkanoyl or 1 or 2C_1-6Alkyl substituted), carboxy, carbamoyl, ureido, guanidino, C_1-6Alkyl (the C)_1-6Alkyl may be substituted with a heterocyclic group), C_1-6Hydroxyalkyl radical, C_1-6Haloalkyl, C_3-8Cycloalkyl radical, C_1-6Alkoxy (the C)_1-6The alkoxy group may be selected from the group consisting of a hydroxyl group, a halogen atom, C_3-8Cycloalkyl radical, C_1-6Alkoxy, aryl and heterocyclic groups substituted with 1 to 3 substituents which may be the same or different), C _3-8Cycloalkoxy, C_1-6Alkoxycarbonyl group, C_1-6Alkoxycarbonylamino group, C_2-6Alkanoyl radical, C_1-6Alkylsulfonyl radical, C_1-6Alkylthio, aryl, heterocyclic groups (the aryl and heterocyclic groups may be selected from the group consisting of "halogen atom, hydroxy, cyano, nitro, amino, carboxyl and C_1-6Alkyl "identically or differently substituted with 1 to 4 substituents), C_1-6Alkylidene radical (such C_1-6The alkylene group may be substituted by C_1-6Alkoxy substituted), C_3-8Cycloalkylene, monocyclic saturated heterocyclylene (which may be substituted by 1 to 2C)_1-6Alkyl substituted) and hydroxyaminocarbonyl),

(2) the compound according to (1) or a pharmaceutically acceptable salt thereof, which is represented by the general formula [1],

[ CHEM 2 ]

(in the formula, wherein,

R¹and R²The same or different represent a hydrogen atom, C_1-6Alkyl radical, C_3-8Cycloalkyl or C_1-6Alkoxy (the C)_1-6Alkyl radical, C_1-6Alkoxy and C_3-8Cycloalkyl radicals may be chosen from "halogen atoms, hydroxy groups, C_3-8Cycloalkyl radical, C_1-6Alkoxy radical,C_3-8Cycloalkoxy, amino, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, -N (R)¹¹)COR¹²、-N(R¹¹)SO₂R¹²Cyano, carboxy, carbamoyl, -CON (R)¹³)(R¹⁴)、-SO₂N(R¹³)(R¹⁴)、C_1-6Alkylthio radical, C_1-6Alkylsulfonyl, aryloxy, aryl and heterocyclic groups "substituted with 1 to 3 substituents, which may be the same or different),

R¹¹、R¹²、R¹³and R¹⁴Same or different and represents a hydrogen atom or C _1-6An alkyl group, a carboxyl group,

R¹³and R¹⁴May be linked together with the bound nitrogen atom to form a saturated or unsaturated 5-or 6-membered ring which may further contain 1 or more nitrogen atoms, oxygen atoms or sulfur atoms,

R³represents a hydrogen atom or C_1-6Alkyl (the C)_1-6The alkyl group may be selected from "halogen atom, hydroxy group, C_1-6Alkoxy radical, C_3-8Cycloalkoxy, amino, C_1-6Alkylamino and di (C)_1-6Alkyl) amino "is substituted with 1 to 3 substituents which may be the same or different),

R⁴represents a hydrogen atom, a hydroxyl group, C_1-6Alkoxy radical, C_3-8Cycloalkoxy, amino, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, C_1-6Alkyl radical, C_3-8Cycloalkyl (the C)_1-6Alkyl and C_3-8Cycloalkyl radicals optionally substituted by halogen atoms, hydroxy groups, C_3-8Cycloalkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkoxy, amino, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, -N (R)⁴¹)COR⁴²、-N(R⁴¹)SO₂R⁴²Cyano, carboxy, -CON (R)⁴³)(R⁴⁴)、-SO₂N(R⁴³)(R⁴⁴)、C_1-6Alkylthio radical, C_1-6Alkylsulfonyl, aryl, aryloxy and heterocyclic group (theThe aryl, aryloxy and heterocyclic groups may be selected from the group consisting of "halogen atom, C_1-6Alkyl radical, C_3-8Cycloalkyl, benzyl, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_2-8Alkoxyalkyl, hydroxy, C_1-6Alkoxy radical, C_3-8Cycloalkoxy, amino, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, -N (R)⁴⁵)COR⁴⁶、-N(R⁴⁵)SO₂R⁴⁶Cyano, carboxy, -CON (R) ⁴⁷)(R⁴⁸)、-SO₂N(R⁴⁷)(R⁴⁸)、C_1-6Alkylthio and C_1-6Alkylsulfonyl "substituted with 1 to 3 substituents which may be the same or different)" may be substituted with 1 to 3 substituents which may be the same or different), an aryl group or a heterocyclic group (the aryl group and the heterocyclic group may be substituted with one or more substituents selected from the group consisting of "halogen atom, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_2-8Alkoxyalkyl, hydroxy, C_1-6Alkoxy radical, C_3-8Cycloalkoxy, amino, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, -N (R)⁴⁵)COR⁴⁶、-N(R⁴⁵)SO₂R⁴⁶Cyano, carboxy, -CON (R)⁴⁷)(R⁴⁸)、-SO₂N(R⁴⁷)(R⁴⁸)、C_1-6Alkylthio and C_1-6Alkylsulfonyl "substituted with 1 to 3 substituents, which may be the same or different),

R⁴⁷and R⁴⁸May be bonded to a nitrogen atom to form a structure which may further contain 1 or more nitrogen atoms or oxygen atomsOr a saturated or unsaturated 5-or 6-membered ring of a sulfur atom,

A¹represents a 2-valent aryl group, a 2-valent heterocyclic group or C _3-8Cycloalkylene (the 2-valent aryl group, the 2-valent heterocyclic group and C_3-8The cycloalkylene group may be selected from the following substituent group R^aAre the same or different and are substituted with 1 to 4 substituents),

substituent group R^aRepresents a halogen atom, a hydroxyl group, an amino group (the amino group may be substituted by C)_2-6Alkanoyl or 1 or 2C_1-6Alkyl-substituted), carboxy, carbamoyl, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_2-6Alkenyl and C_1-6Alkoxy (the C)_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_2-6Alkenyl and C_1-6Alkoxy groups may be selected from "halogen atoms, hydroxy groups, amino groups, carboxyl groups, C_1-6Alkylaminocarbonyl and C_1-6Alkoxycarbonyl "by 1 to 4 substituents which may be the same or different),

l represents-C.ident.C-, -C.ident.C-, -O-, -S-, -NR-, -⁵-、-CONR⁵-、-NR⁵CO-, 2-valent heterocyclic radical, - (CH)₂)_m-NR⁵-、-(CH₂)_m-O-、-NR⁵-(CH₂)_m-、-O-(CH₂)_m-、-ON＝CH-、C_1-4An alkylene group or a chemical bond,

m represents 1, 2 or 3,

A²represents a 2-valent aryl group, a 2-valent heterocyclic group, a 2-valent partially saturated condensed polycyclic hydrocarbon ring group, C_3-8Cycloalkylene radical, C_1-4Alkylene or C_2-4Alkenylene (the 2-valent aryl group, the 2-valent heterocyclic group, the 2-valent partially saturated condensed polycyclic hydrocarbon ring group, C_3-8Cycloalkylene radical, C_1-4Alkylene and C_2-4The alkenylene group may be substituted by a substituent group R selected from the group consisting of^bAre the same or different and are substituted with 1 to 4 substituents),

Substituent group R^bRepresents a halogen atom, an optionally protected hydroxyl group, a mercapto group, a cyano group, a nitro group, an optionally protected amino group, an optionally protected formyl group, an optionally protected carboxyl group, a carbamoyl group, a sulfo group, a ureido group, a guanidino group, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, C_1-6Alkoxycarbonyl group, C_2-6An alkanoyl group and an aryl group,

n represents 0, 1 or 2,

X¹and X³Same or different, represent C_1-10Alkylene radical, C_2-10Alkenylene radical, C_2-10Alkynylene (the C)_1-10Alkylene radical, C_2-10Alkenylene and C_2-10The alkynylene group may be selected from the following substituent group R^cAre substituted with 1 to 4 substituents, which may be the same or different), or a chemical bond,

q represents C_3-8Cycloalkyl, aryl or heterocyclic radical (C _3-8The cycloalkyl, aryl and heterocyclic groups may be selected from the following group of substituents R^cAre the same or different and are substituted with 1 to 4 substituents),

R⁶represents a hydrogen atom, a halogen atom, a hydroxyl group which may be protected, a mercapto group, a cyano group, a nitro group, an amino group which may be protected, a formyl group which may be protected, a carboxyl group which may be protected, a carbamoyl group, a sulfo group, a phosphoric acid group which may be protected, a ureido group, a guanidino group, R⁷-O-NR⁸-CO-、R⁸-ON＝CR⁹-、R⁸-ON＝CR⁹-NH-、R⁷-O-NR⁸-CH＝N-、(R⁷)(R⁸)N-N＝CH-、R⁸-O-NR⁸-or N ≡ C-NR⁸-，

substituent group R^cRepresents a halogen atom, a hydroxyl group, a cyano group, a nitro group, or an amino group (the amino group may be substituted by C)_2-6Alkanoyl or 1 or 2C_1-6Alkyl substituted), carboxy, carbamoyl, ureido, guanidino, C_1-6Alkyl (the C)_1-6Alkyl may be substituted with a heterocyclic group), C_1-6Hydroxyalkyl radical, C_1-6Haloalkyl, C_3-8Cycloalkyl radical, C_1-6Alkoxy (the C)_1-6Alkoxy may be substituted by 1 to 3 hydroxy groups), C_3-8Cycloalkoxy, C_1-6Alkoxycarbonyl group, C _1-6Alkoxycarbonylamino group, C_2-6Alkanoyl radical, C_1-6Alkylsulfonyl radical, C_1-6Alkylthio, aryl and heterocyclic groups (which may be selected from the group consisting of "halogen atom, hydroxy, cyano, nitro, amino, carboxy and C_1-6Alkyl "is substituted with 1 to 4 substituents, which may be the same or different)),

(3) the compound according to (1) or (2) or a pharmaceutically acceptable salt thereof, R¹Is a hydrogen atom or C_1-6Alkyl (the C)_1-6Alkyl groups may be substituted with 1 to 3 identical or different halogen atoms),

(4) the compound according to (3) or a pharmaceutically acceptable salt thereof, R¹Is C_1-6Alkyl (the C)_1-6Alkyl groups may be substituted with 1 to 3 identical or different halogen atoms),

(5) the compound according to (4) or a pharmaceutically acceptable salt thereof, R¹Is a methyl group, and the compound is,

(6) the compound according to any one of (1) to (5), or a pharmaceutically acceptable salt thereof, R²Is a hydrogen atom, and is a hydrogen atom,

(7) the compound according to any one of (1) to (5), or a pharmaceutically acceptable salt thereof, R²Is a methyl group, and the compound is,

(8) the compound according to any one of (1) to (7) or a pharmaceutically acceptable salt thereof,

R³is a hydrogen atom, and is a hydrogen atom,

R⁴is C_1-6Alkyl (the C)_1-6The alkyl group may be substituted with a phenyl group or a monocyclic aromatic heterocyclic group (the phenyl group and the monocyclic aromatic heterocyclic group may be substituted with a substituent selected from the group consisting of "halogen atom, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C _1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_2-8Alkoxyalkyl, hydroxy, C_1-6Alkoxy radical, C_3-8Cycloalkoxy, amino, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, -N (R)⁴⁵)COR⁴⁶、-CON(R⁴⁷)(R⁴⁸) "identically or differently substituted with 1 to 3 substituents)),

(9) the compound according to (8) or a pharmaceutically acceptable salt thereof, R³Is a hydrogen atom, R⁴Is a methyl group, and the compound is,

(10) the compound according to any one of (1) to (9) or a pharmaceutically acceptable salt thereof, A¹Is phenylene (which may be selected from the group consisting of "halogen atom, hydroxy, amino and C_1-6Alkyl "is substituted with 1 to 4 substituents which may be the same or different),

(11) the compound according to (10) or a pharmaceutically acceptable salt thereof, A¹Is a phenylene group, and the compound is,

(12) the compound as described in any one of (1) to (11), or a pharmaceutically acceptable salt thereof, wherein L is-C.ident.C-, -CH-C.ident.C-, -C.ident.C-CH-, ethylene or a chemical bond,

(13) the compound according to (12) or a pharmaceutically acceptable salt thereof, wherein L is a bond or-C.ident.C-,

(14) the compound according to (13) or a pharmaceutically acceptable salt thereof, L is a bond,

(15) the compound according to (13) or a pharmaceutically acceptable salt thereof, wherein L is-C.ident.C-,

(16) as in any of (1) to (15)Means a compound of the formula or a pharmaceutically acceptable salt thereof, A²Is a 2-valent aryl group (the 2-valent aryl group may be selected from the group consisting of "halogen atom, hydroxyl group, amino group and C _1-6Alkyl "substituted with the same or different 1 to 4 substituents), a 2-valent monocyclic aromatic heterocyclic group (the 2-valent monocyclic aromatic heterocyclic group contains 1 to 3 atoms as ring-constituting atoms selected from any of a nitrogen atom, an oxygen atom and a sulfur atom, and may be substituted with one or more substituents selected from a halogen atom, a hydroxyl group, an amino group and C_1-6Alkyl "substituted with the same or different 1 to 4 substituents), a 2-valent fused ring aromatic heterocyclic group, or a 2-valent fused ring heterocyclic group having a partially saturated monocyclic ring (the 2-valent fused ring aromatic heterocyclic group and the 2-valent fused ring heterocyclic group having a partially saturated monocyclic ring contain 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as ring-forming atoms, and at least one of the rings constituting the fused ring is a benzene ring or a pyridine ring, and may be substituted with one or more substituents selected from the group consisting of" halogen atom, hydroxyl group, amino group and C_1-6Alkyl "is substituted with 1 to 4 substituents which may be the same or different),

(17) the compound according to (16) or a pharmaceutically acceptable salt thereof, A²Is phenylene or of the formula [2]The 2-valent radical of the formula (I),

[ CHEM 3 ]

(in the formula, Z¹And Z²Same or different is-CH₂-、-O-、-NH-、-N(CH₃) -or-S-. Wherein Z is¹And Z²Are all-CH₂Except for the case of-is),

(18) the compound according to (16) or a pharmaceutically acceptable salt thereof, A ²Is phenylene, pyridyldiyl, pyrimidinediyl, 2, 4-furandiyl, pyrazolediyl, pyrroldiyl, a 2-valent fused ring aromatic heterocyclic group consisting of a 5-membered ring and a 6-membered ring, or a 2-valent fused ring heterocyclic group consisting of a 5-membered ring and a 6-membered ring and having a partially saturated monocyclic ring (the phenylene, pyridyldiyl group)The group "a pyrimidine diyl group, a 2, 4-furandiyl group, a pyrazole diyl group, a pyrrole diyl group, a 2-valent condensed ring aromatic heterocyclic group composed of a 5-membered ring and a 6-membered ring" and a 2-valent condensed ring heterocyclic group having a partially saturated monocyclic ring composed of a 5-membered ring and a 6-membered ring "may be selected from the group consisting of" a halogen atom, a hydroxyl group, an amino group and C_1-6Alkyl "is substituted with 1 to 4 substituents which may be the same or different),

(19) the compound according to any one of (1) to (18) or a pharmaceutically acceptable salt thereof,

w is R⁶-X¹-，

X¹Is a methylene group or a chemical bond,

R⁶is a hydrogen atom, a hydroxyl group which may be protected or R⁸-ON＝CR⁹-，

R⁸Is a hydrogen atom or C_1-6Alkyl (the C)_1-6The alkyl group may be substituted by a substituent group R^cAre the same or different and are substituted with 1 to 4 substituents),

R⁹is a hydrogen atom, C_1-6Alkyl radical, C_3-8Cycloalkyl, amino or C_1-6An alkylamino group,

substituent group R^cAre a halogen atom and a hydroxyl group,

(20) the compound according to any one of (1) to (18) or a pharmaceutically acceptable salt thereof,

W is R⁶-X²-Y¹-X¹-，

Y¹is-O-or-NR⁷-，

X¹Is methylene, ethylene (which may be substituted by 1 to 2 methyl groups), C_3-8A cycloalkylene group or a chemical bond,

X²is C_1-4Alkylene (the C)_1-4The alkylene group may be selected from the following substituent groups R^cPhase ofAnd the same or different 1 to 4 substituents),

R⁶is a hydrogen atom, a halogen atom, a hydroxyl group which may be protected or C_1-6An alkoxy group,

R⁷is a hydrogen atom, C_1-6Alkyl radical, C_3-8Cycloalkyl (the C)_1-6Alkyl radical, C_3-8The cycloalkyl group may be selected from the following substituent groups R^cAre the same or different and are substituted with 1 to 4 substituents),

substituent group R^cIs a halogen atom, a hydroxyl group and C_1-6An alkyl group, a carboxyl group,

(21) the compound according to any one of (1) to (18) or a pharmaceutically acceptable salt thereof,

w is Q-X¹-Y²-X³-，

Y²is-O-, -NR⁷-or a chemical bond,

X¹is C_1-4Alkylene (the C)_1-4The alkylene group may be selected from the following substituent groups R^cAre substituted with 1 to 4 substituents, which may be the same or different), or a chemical bond,

X³is methylene, ethylene (which may be substituted by 1 to 2 methyl groups), C_3-8A cycloalkylene group or a chemical bond,

q is C_3-8Cycloalkyl, aryl or heterocyclic radical (C_3-8The cycloalkyl, aryl and heterocyclic groups may be selected from the following group of substituents R^cAre the same or different and are substituted with 1 to 4 substituents),

substituent group R^cIs a halogen atom, a hydroxyl group, C_1-6Alkyl radical, C_1-6Hydroxyalkyl radical, C_1-6Haloalkyl, C_3-8Cycloalkyl radical, C_1-6Alkoxy (the C)_1-6Alkoxy may be substituted by 1 to 3 hydroxyl groups or halogen atoms), C_3-8Cycloalkoxy, C_2-6Alkanoyl radical, C_1-6Alkylidene radical (such C_1-6The alkylene group may be substituted by C_1-6Alkoxy substituted) and a hydroxyaminocarbonyl group,

(22) the compound according to any one of (1) to (18) or a pharmaceutically acceptable salt thereof,

w is a hydrogen atom, a halogen atom, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical (this C)_1-6Alkyl radical, C_1-6Alkoxy and C_1-6The alkylamino group may be selected from "halogen atom, hydroxy group, C_1-6Alkoxy and morpholino "substituted with 1 to 3 substituents which may be the same or different),

(23) a pharmaceutical composition comprising the compound of (1) to (22) or a pharmaceutically acceptable salt thereof,

(24) LpxC inhibitor containing the compound of (1) to (22) or a pharmaceutically acceptable salt thereof,

(25) an antibacterial agent comprising the compound of (1) to (22) or a pharmaceutically acceptable salt thereof.

The compound and the pharmaceutically acceptable salt thereof have a strong LpxC inhibitory action and a strong antibacterial activity against gram-negative bacteria such as pseudomonas aeruginosa, and therefore are useful as a pharmaceutical composition and an antibacterial agent against bacteria.

Detailed Description

The present invention is described in more detail below.

First, the words used in this specification will be described.

In the present invention, "n-" means normal, "i-" means iso, "s-" means secondary, "t-" means tertiary, "c-" means ring, "o-" means ortho, "m-" means meta, and "p-" means para.

"halogen atom" means fluorine atom, chlorine atom, bromine atom and iodine atom.

“C_1-6The "alkyl group" refers to a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an isopropyl group, an isobutyl group, a t-butyl group, an s-butyl group, an isopentyl group, a neopentyl group, a t-pentyl group and a 1, 2-dimethylpropyl group.

“C_1-6Hydroxyalkyl "means" C "as defined above_1-6As the alkyl group "which has 1 or more of the hydrogen atoms substituted with a hydroxyl group, there may be exemplified hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 1-hydroxypentyl, 5-hydroxypentyl, 1-hydroxyhexyl, 6-hydroxyhexyl, 2-hydroxymethyl-1-hydroxypropyl, 2-dihydroxymethyl-1-hydroxypropyl and 2-hydroxymethyl-1-hydroxypentyl groups.

“C_1-6Haloalkyl "means" C "as defined above_1-6The alkyl group in which 1 or more of the hydrogen atoms of the alkyl group "are substituted with a halogen atom may be exemplified by fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2, 2, 2-trifluoroethyl group, 2, 2, 2-trichloroethyl group, pentafluoroethyl group, 3, 3, 3-trifluoropropyl group, perfluoropropyl group, 4-fluorobutyl group, 4-chlorobutyl group and 4-bromobutyl group.

“C_2-8The "alkoxyalkyl group" means an alkoxyalkyl group having 2 to 8 carbon atoms in total, and examples thereof include a methoxymethyl group, a 1-methoxyethyl group, a 1-methoxypropyl group, a 2-methoxypropyl group, a 1-methoxybutyl group, a 1-methoxypentyl group, a 1-ethoxyethyl group, a 1-ethoxypropyl group, a 1-ethoxybutyl group, a 1-propoxyethyl group, a 1-isopropoxyethyl group and a 1-propoxypropyl group.

“C_3-8The "cycloalkyl group" means a cycloalkyl group having 3 to 8 carbon atoms, and is exemplified by c-propyl, c-butyl, c-pentyl, c-hexyl, c-heptyl and c-octyl。

“C_2-6Alkenyl "is as defined above for" C_1-6Examples of the "alkyl group" which may be a linear or branched alkenyl group having 2 to 6 carbon atoms and having 1 or more double bonds at any position include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 2-butenyl, 1, 3-butadienyl, 2-pentenyl, 3-pentenyl and 2-hexenyl.

“C_2-6Alkynyl "means at" C "above_1-6The "alkyl group" may have 1 or more triple bonds at any position, and may have a linear or branched alkynyl group having 2 to 6 carbon atoms, and examples thereof include an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 3-butynyl group, a 1-pentynyl group, a 4-pentynyl group, a 1-hexynyl group and a 5-hexynyl group.

“C_3-8Cycloalkenyl is as defined above for "C_3-8Cycloalkyl groups "cycloalkyl groups having 3 to 8 carbon atoms and 1 or more double bonds at any position thereof are exemplified by c-butenyl, c-pentenyl, c-hexenyl, c-hexadienyl, c-heptenyl and c-octenyl.

“C_1-6The "alkoxy group" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, and may, for example, be a methoxy group, an ethoxy group, a 1-propoxy group, an isopropoxy group, a 1-butoxy group, a 1-methyl-1-propoxy group, a t-butoxy group or a 1-pentyloxy group.

“C_3-8The cycloalkoxy group "means a cycloalkoxy group having 3 to 8 carbon atoms, and may, for example, be a c-propoxy group, a c-butoxy group, a c-pentyloxy group or a c-hexyloxy group.

“C_1-6The "alkylthio group" refers to a straight-chain or branched-chain alkylthio group having 1 to 6 carbon atoms, and examples thereof include a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, an s-butylthio group, a t-butylthio group, a 1, 1-dimethylpropylthio group, an n-pentylthio group, an isopentylthio group and an n-hexylthio group.

“C_1-6The "alkylamino group" refers to a linear or branched alkylamino group having 1 to 6 carbon atoms, and may, for example, be methylaminomethaneA group selected from the group consisting of an ethylamino group, an n-propylamino group, an isopropylamino group, an n-butylamino group, an s-butylamino group, a t-butylamino group, a 1, 1-dimethylpropylamino group, an n-pentylamino group, an isopentylamino group and an n-hexylamino group.

' two (C)_1-6Alkyl) amino "refers to a dialkylamino group having 2 linear or branched alkyl groups having 1 to 6 carbon atoms, and examples thereof include a dimethylamino group, a diethylamino group, a di (n-propyl) amino group, a diisopropylamino group, a di (n-butyl) amino group, a di (s-butyl) amino group, a di (t-butyl) amino group, a di (1, 1-dimethylethyl) amino group, a di (n-pentyl) amino group, a diisopentylamino group, and a di (n-hexyl) amino group.

“C_2-6The "alkanoyl group" is a linear or branched alkanoyl group having 2 to 6 carbon atoms, and may, for example, be an acetyl group, a propionyl group, a butyryl group or a pivaloyl group.

“C_1-6The "alkoxycarbonyl group" is a carbonyl group having a linear or branched alkoxy group having 1 to 6 carbon atoms, and may include, for example, a methoxycarbonyl group, an ethoxycarbonyl group and an isopropoxycarbonyl group.

“C_1-6The "alkylaminocarbonyl group" refers to a carbonyl group having a linear or branched alkylamino group having 1 to 6 carbon atoms, and examples thereof include a methylaminocarbonyl group, an ethylaminocarbonyl group and an isopropylaminocarbonyl group.

“C_1-6Alkoxycarbonylamino "is a compound having C_1-6The amino group of the alkoxycarbonyl group is exemplified by methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino and t-butoxycarbonylamino.

“C_1-6The "alkylsulfonyl group" refers to a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms, and includes, for example, methylsulfonyl group, ethylsulfonyl group and propylsulfonyl group.

The "aryl group" means a monocyclic to 4-membered aromatic carbocyclic group having 6 to 18 carbon atoms, and may be exemplified by phenyl, naphthyl, anthryl, phenanthryl, tetracenyl (tetracenyl) and pyrenyl (pyrenyl).

The "aryloxy group" refers to a group having an oxy group bonded to the above-mentioned "aryl group", and is exemplified by phenoxy and naphthoxy.

The "fused polycyclic hydrocarbon ring group" means a 2-to 4-membered carbocyclic group having 6 to 18 carbon atoms, and examples thereof include 2-to 4-membered aryl groups such as naphthyl, anthryl, phenanthryl, tetracenyl and pyrenyl, and further include fluorenyl, indenyl and acenaphthenyl.

The "partially saturated condensed polycyclic hydrocarbon ring group" means a condensed polycyclic hydrocarbon ring group which is partially hydrogenated, and can be exemplified by indanyl and acenaphthenyl.

The "heterocyclic group" means a "monocyclic heterocyclic group", "fused ring heterocyclic group" or "spiro heterocyclic group" containing 1 to 5 atoms, optionally selected from a nitrogen atom, an oxygen atom and a sulfur atom, as ring-constituting atoms. When the hetero atom is a sulfur atom, the dioxide thereof is also included in the present invention.

The "monocyclic heterocyclic group" means a monocyclic heterocyclic group consisting of 3 to 8 atoms in the ring in the above-mentioned "heterocyclic group", and includes "monocyclic saturated heterocyclic group", "monocyclic aromatic heterocyclic group" and "partially saturated monocyclic aromatic heterocyclic group".

The "fused ring heterocyclic group" means a fused ring heterocyclic group composed of 6 to 14 atoms in the ring in the above-mentioned "heterocyclic group", and includes "fused ring saturated heterocyclic group", "fused ring aromatic heterocyclic group" and "fused ring heterocyclic group having a partially saturated single ring".

The "spiro heterocyclic group" means a heterocyclic group consisting of 6 to 14 total atoms in the ring and having 2 rings sharing one spiro carbon atom, and may be substituted with 1 to 3 oxo groups. There may be exemplified, for example, a 2-oxa-6-azaspiro [3.3] heptyl group, a 1-oxa-6-azaspiro [3.3] heptyl group, a 6-oxa-1-azaspiro [3.3] heptyl group, a 1-oxo-2, 8-diazaspiro [4.5] decyl group, a 1, 4-dioxa-8-azaspiro [4.5] decyl group, a 2-azaspiro [3.3] heptyl group, a 7-oxa-2-azaspiro [3.5] nonyl group, a 5, 8-oxa-2-azaspiro [3.4] octyl group, a 1, 4-dioxa-8-azaspiro [4.5] decyl group and a 1-oxaspiro [4.5] decyl group.

The "monocyclic saturated heterocyclic group" means a monocyclic heterocyclic group which forms a ring only through a saturated bond and may be substituted with 1 to 2 oxo groups. Examples thereof include aziridinyl, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, piperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl (the sulfur atom in the ring may also be oxidized), homopiperazinyl, homomorpholinyl (oxazepanyl), imidazolidinyl, pyrazolidinyl, oxazolidinyl, 2-oxo-1, 3-oxazolidin-3-yl, isoxazolidinyl, 2, 3-dioxopiperazinyl, oxetan-2-yl, oxetan-3-yl, 1, 3-dioxolanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydro-2H-thiopyranyl, ditholanyl and thiolan.

Examples of the "monocyclic aromatic heterocyclic group" may include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl and tetrazolyl.

The "partially saturated monocyclic aromatic heterocyclic group" means a monocyclic aromatic heterocyclic group in which a part of the bonds constituting the ring are saturated, and includes a group substituted with 1 or 2 oxo groups. There may be exemplified 4, 5-dihydro-1H-imidazolyl, 1, 2, 3, 6-tetrahydropyridinyl, 4H-1, 3-oxazinyl and 5, 6-dihydro-4H-1, 3-oxazinyl.

The "fused ring-type saturated heterocyclic group" means a fused ring-type heterocyclic group having a ring formed only by a saturated bond, and may be substituted with 1 to 3 oxo groups. octahydro-1H-isoindolyl, decahydroquinolinyl, decahydroisoquinolinyl, hexahydro-2H- [1, 4] dioxa [2, 3-c ] pyrrolyl, and 3-azabicyclo [3.1.0] hex-3-yl are exemplified.

Examples of the "condensed ring aromatic heterocyclic group" may include a quinolyl group, an isoquinolyl group, a naphthyridinyl group (e.g., 1, 6-naphthyridinyl group, 1, 7-naphthyridinyl group, 1, 8-naphthyridinyl group), a quinazolinyl group, a benzofuranyl group, a benzothienyl group, an indolyl group, a benzoxazolyl group, a benzisoxazolyl group (e.g., benzo [ c ] isoxazolyl group, benzo [ d ] isoxazolyl group), a 1H-indazolyl group, a 2H-indazolyl group, a benzimidazolyl group, a benzooxadiazolyl group (e.g., benzo [1, 2, 5] oxadiazolyl group, benzo [1, 2, 3] oxadiazolyl group, a benzo [2, 1, 3] oxadiazolyl group), a benzothiazolyl group, a benzothiadiazolyl group (e.g., [1, 2, 5] thiadiazolyl group, a benzo [1, 2, 3] thiadiazolyl group), a indolizinyl group, a benzofuroyl group (benzofuranyl group), Thienopyridinyl (e.g., thieno [2, 3-b ] pyridinyl, [3, 2-b ] pyridinyl), pyrazolopyridinyl, imidazopyridinyl (e.g., imidazo [1, 5-a ] pyridinyl, imidazo [1, 2-a ] pyridinyl, 3H-imidazo [4, 5-b ] pyridinyl), imidazopyrazinyl (e.g., imidazo [1, 5-a ] pyrazinyl, imidazo [1, 2-a ] pyrazinyl), pyrazolopyrimidinyl (e.g., pyrazolo [1, 5-a ] pyrimidinyl, pyrazolo [1, 5-c ] pyrimidinyl), triazolopyrimidinyl (e.g., [1, 2, 3] triazolo [1, 5-a ] pyrimidinyl, [1, 2, 3] triazolo [1, 5-c ] pyrimidinyl, [1, 2, 4] triazolo [1, 5-a ] pyrimidinyl, [1, 2, 4] triazolo [1, 5-c ] pyrimidinyl), thienothienyl (e.g., thieno [2, 3-b ] thienyl, thieno [3, 2-b ] thienyl), and imidazothiazolyl (e.g., imidazo [2, 1-b ] thiazolyl, imidazo [5, 1-b ] thiazolyl).

The "fused ring heterocyclic group having a partially saturated single ring" means a fused ring aromatic heterocyclic group having a single ring in which a part of the bonds constituting the ring are saturated, and may be substituted with 1 to 3 oxo groups. Examples thereof include 1, 3-dihydrobenzimidazol-2-onyl (onyl), 2-benzoxazolonyl, octahydroisoindolyl, 2H-pyrido [3, 2-b ] -1, 4-oxazin-3 (4H) -one-yl, 3-oxo-3, 4-dihydro-2H-pyrido [3, 2-b ] [1, 4] oxazin-6-yl, [1, 3] dioxanone (dioxolo) [4, 5-b ] pyridyl, 2, 3-dihydrobenzo [ b ] thienyl, 2, 3-dihydro-1-benzofuran-5-yl, 2, 3-dihydro-1-benzofuran-6-yl, 1, 3-dihydro-2-benzofuran-5-yl, 2, 3-dihydro-1H-indol-5-yl, 1, 3-benzodioxol-5-yl, 2, 3-dihydro-1, 4-benzodioxine-2-yl, 2, 3-dihydro-1, 4-benzodioxine-6-yl, 3-oxo-3, 4-dihydro-2H-1, 4-benzoxazin-6-yl, 1, 4-benzodioxanyl, 2H-benzo [ b ] [1, 4] oxazin-3 (4H) -one-yl, 3, 4-dihydro-2H-benzo [ b ] [1, 4] dioxepanyl, indolinyl, 2H-isoindolinyl, chromanyl, Chromonyl, isochroman, and 1, 2, 3, 4-tetrahydroisoquinolinyl.

The "4 to 7-membered nitrogen-containing saturated heterocyclic group" means a monocyclic saturated heterocyclic group consisting of 4 to 7 ring atoms in the above-mentioned "monocyclic saturated heterocyclic group" and having 1 or 2 nitrogen atoms in the ring. May contain 1 or 2 oxygen atoms as ring-forming atoms, and may be substituted with 1 or 2 oxo groups. There may be exemplified azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperazinyl, homomorpholinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl and 2, 3-dioxopiperazinyl.

The "nitrogen-containing saturated spiro ring group" refers to a spiro ring heterocyclic group consisting of 7 to 11 total atoms in the ring and containing 1 or 2 nitrogen atoms in the ring, and may be substituted with 1 to 2 oxo groups. There may be exemplified, for example, 2-oxa-6-azaspiro [3.3] heptyl, 1-oxo-2, 8-diazaspiro [4.5] decyl, 1, 4-dioxa-8-azaspiro [4.5] decyl, 2-azaspiro [3.3] heptyl, 7-oxa-2-azaspiro [3.5] nonyl, 5, 8-oxa-2-azaspiro [3.4] octyl and 1, 4-dioxa-8-azaspiro [4.5] decyl.

“C_1-4The "alkylene group" is a linear or branched alkylene group having 1 to 4 carbon atoms, and may, for example, be-CH ₂-、-(CH₂)₂-、-(CH₂)₃-、-CH₂-CH(CH₃)-、-C(CH₃)₂-、-(CH₂)₄-、-(CH₂)₂-CH(CH₃)-、-CH₂-CH(CH₃)-CH₂-and-CH (CH)₃)-(CH₂)₂-。

“C_1-6The term "alkylene" refers to a linear or branched alkylene group having 1 to 6 carbon atoms, excluding the above-mentioned "C_1-4Specific examples of the "alkylene group" may include- (CH)₂)₅-、-(CH₂)₃-CH(CH₃)-、-(CH₂)₂-CH(C₂H₅)-、-(CH₂)₆-、-(CH₂)₃-CH(CH₃)-CH₂-and-CH₂-CH(CH₃)-(CH₂)₃-。

“C_1-10The term "alkylene" refers to a linear or branched alkylene group having 1 to 10 carbon atoms, excluding the above-mentioned "C_1-6Specific examples of the "alkylene group" may include- (CH)₂)₇-、-(CH₂)₅-CH(CH₃)-、-(CH₂)₄-CH(C₂H₅)-、-(CH₂)₈-、-(CH₂)₆-CH(CH₃)-CH₂-and-CH₂-CH(CH₃)-(CH₂)₇-。

“C_3-8The "cycloalkylene group" refers to a group having a valence of 2 obtained by removing any 2 hydrogen atoms from a cycloalkane having 3 to 8 carbon atoms, and examples thereof include 1, 1-c-propylene, 1, 2-c-propylene, 1-c-butylene, 1, 2-c-butylene, 1, 3-c-butylene, 1, 2-c-pentylene, 1-c-hexylene, 1, 2-c-hexylene, 1, 3-c-hexylene, 1, 4-c-hexylene and 1, 3-c-heptylene.

“C_2-4The "alkenylene group" refers to a linear or branched alkenylene group having 1 or 2 or more double bonds in the chain and having 2 to 4 carbon atoms, and may include, for example, -CH-CH₂-、-CH₂-CH＝CH-、-CH＝C(CH₃)-、-(CH₂)₂-CH＝CH-、-CH(CH₃)-CH＝CH-、-CH₂-CH＝CH-CH₂-and-CH-.

“C_2-6The "alkenylene group" refers to a linear or branched alkenylene group having 2 to 6 carbon atoms and having 1 or 2 or more double bonds in the chain, excluding the above-mentioned "C_2-4Specific examples of "alkenylene" may include- (CH) ₂)₃-CH＝CH-、-(CH₂)₂-CH＝C(CH₃)-、-(CH₂)₄-CH ═ CH-and- (CH)₂)₂-CH＝C(C₂H₅)-。

“C_2-10The "alkenylene group" refers to a linear or branched alkenylene group having 2 to 10 carbon atoms and having 1 or 2 or more double bonds in the chain, excluding the above-mentioned "C_2-6Specific examples of "alkenylene" may include- (CH)₂)₅-CH＝CH-、-(CH₂)₅-CH＝C(CH₃)-、-(CH₂)₆-CH ═ CH-and- (CH)₂)₆-CH＝C(C₂H₅)-。

“C_3-8Cycloalkenyl is as defined above for "C_3-8The cycloalkylene group "may be a cycloalkylene group having 3 to 8 carbon atoms and 1 or more double bonds at any position, and may, for example, be a c-butenylene group, a c-pentenylene group, a c-hexenylene group, a c-hexadienylene group, a c-heptenylene group or a c-octenylene group.

“C_2-10The "alkynylene group" is a linear or branched alkynylene group having 2 to 10 carbon atoms and having 1 or 2 or more triple bonds in the chain, and may be exemplified by the above-mentioned "C_2-10The carbon atom of the double bond portion of alkenylene "further removes a hydrogen atom to obtain a triple-bonded 2-valent group.

“-C_1-6alkylene-C_3-8cycloalkylene-C_1-6Alkylene- "means C_1-6Alkylene radical, C_3-8Cycloalkylene radical, C_1-6Examples of the 2-valent group to which an alkylene group is bonded may include those of the formula [3]The 2-valent radical of the formula.

[ CHEM 4 ]

“C_1-6The "alkylidene group" refers to a linear or branched alkylidene group having 1 to 6 carbon atoms, and may include, for example, a methine group, an ethylidene group, an n-propylidene group, an n-butylidene group, an isopropylidene group, an n-pentylidene group and an n-hexylidene group.

“C_3-8The cycloalkylene group means a cycloalkylene group having 3 to 8 carbon atoms, and may, for example, be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or a cyclooctyl group.

"monocyclic saturated heterocyclic subunit" means a group having a valence of 2 resulting from further removing 1 hydrogen atom bonded to a carbon atom having a free valence from the monocyclic saturated heterocyclic group, and is exemplified by azetidin-3-subunit, pyrrolidin-3-subunit, piperidin-4-subunit, homopiperidin-4-subunit, tetrahydrofuran-3-subunit and tetrahydropyran-4-subunit.

The "aryl group having a valence of 2" refers to a group having a valence of 2 obtained by removing any 2 hydrogen atoms from a monocyclic, 2-ring, 3-ring or 4-ring aromatic carbocyclic ring having 6 to 18 carbon atoms, and may include, for example, a group having a valence of 2 obtained by removing any 2 hydrogen atoms from benzene, naphthalene, cyclopenta cycloheptene, fluorene, phenanthrene, anthracene or pyrene.

The "partially saturated condensed polycyclic hydrocarbon ring group having a valence of 2" means a group having a valence of 2 obtained by further removing any 1 hydrogen atom from the above-mentioned "partially saturated condensed polycyclic hydrocarbon ring group", and examples thereof include a group having a valence of 2 obtained by removing any 1 hydrogen atom from an indanyl group, an acenaphthylene group and the like.

The "heterocyclic group having a valence of 2" means a 2-valent group obtained by further removing any 1 hydrogen atom from the above-mentioned "heterocyclic group", and includes "monocyclic heterocyclic group having a valence of 2", "condensed ring heterocyclic group having a valence of 2", and "spiro heterocyclic group having a valence of 2".

The "monocyclic heterocyclic group having a valence of 2" means a 2-valent group obtained by further removing any 1 hydrogen atom from the above-mentioned "monocyclic heterocyclic group", and includes "monocyclic saturated heterocyclic group having a valence of 2", "monocyclic aromatic heterocyclic group having a valence of 2", and "partially saturated monocyclic aromatic heterocyclic group having a valence of 2".

The "2-valent condensed ring-type heterocyclic group" means a 2-valent group obtained by further removing any 1 hydrogen atom from the above-mentioned "condensed ring-type heterocyclic group", and includes "a 2-valent condensed ring-type saturated heterocyclic group", "a 2-valent condensed ring-type aromatic heterocyclic group", and "a 2-valent condensed ring-type heterocyclic group having a partially saturated monocyclic ring".

The "spiro heterocyclic group having a valence of 2" means a 2-valent group obtained by further removing any 1 hydrogen atom from the above-mentioned "spiro heterocyclic group", examples thereof include 2-valent groups obtained by removing any 1 hydrogen atom from a 2-oxa-6-azaspiro [3.3] heptyl group, a 1-oxo-2, 8-diazaspiro [4.5] decyl group, a 1, 4-dioxa-8-azaspiro [4.5] decyl group, a 2-azaspiro [3.3] heptyl group, a 7-oxa-2-azaspiro [3.5] nonyl group, a 5, 8-oxa-2-azaspiro [3.4] octyl group, a 1, 4-dioxa-8-azaspiro [4.5] decyl group and a 1-oxaspiro [4.5] decyl group.

The "monocyclic saturated heterocyclic group having a valence of 2" means a group having a valence of 2 obtained by removing any 1 hydrogen atom from the above-mentioned "monocyclic saturated heterocyclic group", and examples thereof include aziridinyl, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, piperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl (the sulfur atom in the ring may be oxidized), homopiperazinyl, homomorpholinyl (oxoazanyl)), imidazolidinyl, pyrazolidinyl, oxazolidinyl, 2-oxo-1, 3-oxazolidin-3-yl, isoxazolidinyl, 2, 3-dioxopiperazinyl, oxetan-2-yl, oxetan-3-yl, 1, 3-dioxolanyl, tetrahydrofuranyl, tetrahydropyranyl group, tetrahydro-2H-thiopyranyl, dithiolan and thiolan are 2-valent groups obtained by removing any 1 hydrogen atom.

The "monocyclic aromatic heterocyclic group having a valence of 2" means a group having a valence of 2 obtained by removing any 1 hydrogen atom from the above-mentioned "monocyclic aromatic heterocyclic group", and examples thereof include groups having a valence of 2 obtained by removing any 1 hydrogen atom from a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a thienyl group, a pyrrolyl group, a thiazolyl group, an isothiazolyl group, a pyrazolyl group, an imidazolyl group, a furyl group, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group, a 1, 3, 4-thiadiazolyl group, a 1, 2, 3-triazolyl group and a 1, 2, 4-triazolyl group.

The "partially saturated monocyclic aromatic heterocyclic group having a valence of 2" means a 2-valent group obtained by further removing any 1 hydrogen atom from the above-mentioned "partially saturated monocyclic aromatic heterocyclic group", and there may be exemplified 2-valent groups obtained by removing any 1 hydrogen atom from a 4, 5-dihydro-1H-imidazolyl group, a 1, 2, 3, 6-tetrahydropyridinyl group, a 4H-1, 3-oxazinyl group and a 5, 6-dihydro-4H-1, 3-oxazinyl group.

The "fused ring-type saturated heterocyclic group having a valence of 2" means a group having a valence of 2 obtained by further removing any 1 hydrogen atom from the above-mentioned "fused ring-type saturated heterocyclic group", and examples thereof include groups having a valence of 2 obtained by removing any 1 hydrogen atom from octahydro-1H-isoindolyl, decahydroquinolinyl, decahydroisoquinolinyl, hexahydro-2H- [1, 4] dioxa [2, 3-c ] pyrrolyl and 3-azabicyclo [3.1.0] hex-3-yl.

The "2-valent fused ring-type aromatic heterocyclic group" refers to a 2-valent group obtained by further removing any 1 hydrogen atom from the above-mentioned "fused ring-type aromatic heterocyclic group", and may be exemplified by quinolyl, isoquinolyl, naphthyridinyl (e.g., 1, 6-naphthyridinyl, 1, 7-naphthyridinyl, 1, 8-naphthyridinyl), quinazolinyl, benzofuranyl, benzothienyl, indolyl, benzoxazolyl, benzisoxazolyl (e.g., benzo [ c ] isoxazolyl, benzo [ d ] isoxazolyl), 1H-indazolyl, 2H-indazolyl, benzimidazolyl, benzooxadiazolyl (e.g., benzo [1, 2, 5] oxadiazolyl, benzo [1, 2, 3] oxadiazolyl, benzo [2, 1, 3] oxadiazolyl), benzothiazolyl, benzothiadiazolyl (e.g., [1, 2, 5] thiadiazolyl, benzo [1, 2, 3] thiadiazolyl), indolizinyl, benzofuroazinyl, thienopyridinyl (e.g., thieno [2, 3-b ] pyridinyl, [3, 2-b ] pyridinyl), pyrazolopyridyl, imidazopyridinyl (e.g., imidazo [1, 5-a ] pyridinyl, imidazo [1, 2-a ] pyridinyl, 3H-imidazo [4, 5-b ] pyridinyl), imidazopyrazinyl (e.g., imidazo [1, 5-a ] pyrazinyl, imidazo [1, 2-a ] pyrazinyl), pyrazolopyrimidinyl (e.g., pyrazolo [1, 5-a ] pyrimidinyl, pyrazolo [1, 5-c ] pyrimidinyl), triazolopyrimidinyl (e.g., [1, 2, 3] triazolo [1, 5-a ] pyrimidinyl, triazolo [1, 5-a ] pyrimidinyl, [1, 2, 3] triazolo [1, 5-c ] pyrimidinyl, [1, 2, 4] triazolo [1, 5-a ] pyrimidinyl, [1, 2, 4] triazolo [1, 5-c ] pyrimidinyl), thienothienyl (e.g., thieno [2, 3-b ] thienyl, thieno [3, 2-b ] thienyl), and imidazothiazolyl (e.g., imidazo [2, 1-b ] thiazolyl, imidazo [5, 1-b ] thiazolyl) are 2-valent groups resulting from the removal of any 1 hydrogen atom.

The "2-valent fused ring-type aromatic heterocyclic group composed of 5-and 6-membered rings" means a 2-valent aromatic heterocyclic group composed of a fused ring of 5-and 6-membered rings in the above "2-valent fused ring-type aromatic heterocyclic group", and examples thereof include benzofuranyl, benzothienyl, indolyl, benzoxazolyl, benzisoxazolyl (e.g., benzo [ c ] isoxazolyl, benzo [ d ] isoxazolyl), 1H-indazolyl, 2H-indazolyl, benzimidazolyl, benzooxadiazolyl (e.g., benzo [1, 2, 5] oxadiazolyl, benzo [1, 2, 3] oxadiazolyl, benzo [2, 1, 3] oxadiazolyl), benzothiazolyl, benzothiadiazolyl (e.g., [1, 2, 5] thiadiazolyl, benzo [1, 2, 3] thiadiazolyl), indolizinyl, benzofurozinyl, benzothiazolyl, benzothiadiazolyl, Thienopyridinyl (e.g., thieno [2, 3-b ] pyridinyl, [3, 2-b ] pyridinyl), pyrazolopyridinyl, imidazopyridinyl (e.g., imidazo [1, 5-a ] pyridinyl, imidazo [1, 2-a ] pyridinyl, 3H-imidazo [4, 5-b ] pyridinyl), imidazopyrazinyl (e.g., imidazo [1, 5-a ] pyrazinyl, imidazo [1, 2-a ] pyrazinyl), pyrazolopyrimidinyl (e.g., pyrazolo [1, 5-a ] pyrimidinyl, pyrazolo [1, 5-c ] pyrimidinyl), and triazolopyrimidinyl (e.g., [1, 2, 3] triazolo [1, 5-a ] pyrimidinyl, [1, 2, 3] triazolo [1, 5-c ] pyrimidinyl, [1, 2, 4] triazolo [1, 5-a ] pyrimidinyl, 1, 2, 4] triazolo [1, 5-c ] pyrimidinyl) from any 1 hydrogen atom.

The "fused ring heterocyclic group having a partially saturated monocyclic ring having a valence of 2" means a group having a valence of 2 obtained by further removing any 1 hydrogen atom from the above-mentioned "fused ring heterocyclic group having a partially saturated monocyclic ring", and is exemplified by groups having a valence of 2, which are obtained by further removing 1 hydrogen atom from 1, 3-dihydrobenzimidazol-2-one group (-onyl), 2-benzoxazolinone group, octahydroisoindolyl, 2H-pyrido [3, 2-b ] -1, 4-oxazin-3 (4H) -one-yl, 3-oxo-3, 4-dihydro-2H-pyrido [3, 2-b ] [1, 4] oxazin-6-yl, [1, 3] dioxolo [4, 5-b ] pyridyl, 2, 3-dihydrobenzo [ b ] thienyl, 2, 3-dihydro-1-benzofuran-5-yl, 2, 3-dihydro-1-benzofuran-6-yl, 1, 3-dihydro-2-benzofuran-5-yl, 2, 3-dihydro-1H-indol-5-yl, 1, 3-benzodioxol-5-yl, 2, 3-dihydro-1, 4-benzodioxin-2-yl, 2, 3-dihydro-1, 4-benzodioxin-6-yl, 3-oxo-3, 4-dihydro-2H-1, 4-benzoxazin-6-yl, 1, 4-benzodioxin, 2H-benzo [ b ] [1, 4] oxazin-3 (4H) -one-yl, 3, 4-dihydro-2H-benzo [ b ] [1, 4] dioxepin yl (dioxapinyl), indolinyl, 2H-isoindolinyl, chromanyl, chromonyl, isochromanyl and 1, 2, 3, 4-tetrahydroisoquinolinyl, excluding any 1 hydrogen atom, to give a 2-valent group.

The "fused ring heterocyclic group having a partially saturated monocyclic ring and having a valence of 2 consisting of 5-membered and 6-membered rings" means a heterocyclic group having a valence of 2 consisting of a fused ring of 5-membered and 6-membered rings in the above-mentioned "fused ring heterocyclic group having a partially saturated monocyclic ring and is exemplified by 1, 3-dihydrobenzimidazol-2-one group (-onyl), 2-benzoxazolonyl group, octahydroisoindolyl, [1, 3] dioxolo [4, 5-b ] pyridyl, 2, 3-dihydrobenzo [ b ] thienyl, 2, 3-dihydro-1-benzofuran-5-yl, 2, 3-dihydro-1-benzofuran-6-yl, 1, 3-dihydro-2-benzofuran-5-yl, 1, 3-dihydrobenzo [ b ] thienyl, 2, 3-dihydro-1-benzofuran-5-yl, 2, 3-dihydro-2-benzofuran-5-yl, 2-, 2-valent groups derived from 2, 3-dihydro-1H-indol-5-yl, 1, 3-benzodioxol-5-yl, indolinyl and 2H-isoindolinyl by removal of any 1 hydrogen atom.

Examples of the "saturated or unsaturated 5-or 6-membered ring which may be bonded to the bonded nitrogen atom to form a ring which may further contain 1 or more nitrogen atom, oxygen atom or sulfur atom" include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and 1, 2, 3, 6-tetrahydropyridinyl.

"hydroxy group which may be protected" means an unprotected or protected hydroxy group.

"protected hydroxy" refers to a hydroxy group protected by a "protecting group for the hydroxy group".

The "protecting group for hydroxyl group" includes all groups which can be usually used as protecting groups for hydroxyl group, and examples thereof include P.G.M.Wuts et al, protective group organic Synthesis 4 th edition, 2006, John Wiley&Sons, inc. For example, can be C_1-6Alkoxy-substituted C_1-6Alkyl (methyl, methoxymethyl, t-butoxymethyl, etc.), benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, which may be selected from "halogen atom, C_1-6Benzyl (benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl and the like) substituted with a substituent of alkoxy and nitro ", C which may be substituted with 1 to 3 substituents selected from" halogen atom and aryl group_1-6Alkoxycarbonyl (methoxycarbonyl, t-butoxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl and the like), benzoyl, C which may be substituted by 1 to 3 halogen atoms_2-6Alkanoyl (acetyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, pivaloyl, and the like), and a compound having an amino group selected from the group consisting of "C_1-6Alkyl and aryl "silyl groups of the same or different 3 substituents (trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, etc.).

"amino group which may be protected" means an unprotected or protected amino group.

"protected amino" refers to an amino group protected by a "protecting group for an amino group".

The "protecting group for amino group" includes all groups which can be usually used as protecting groups for amino group, and examples thereof include P.G.M.Wuts, and the like, protective group organic Synthesis 4 th edition, 2006, John Wiley&Sons, inc. For example, may be selected from "halogen atom, C_1-6Benzyl (benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl and the like) substituted with a substituent of alkoxy and nitro ", C which may be substituted with 1 to 3 substituents selected from" halogen atom and aryl group_1-6Alkoxycarbonyl (methoxycarbonyl, t-butoxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl and the like), allyl, dialkylaminoalkyl (N, N-dimethylaminomethylene, N-diethylaminomethylene and the like), formyl, C which may be substituted by 1 to 3 halogen atoms_2-6Alkanoyl (acetyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, pivaloyl, and the like) and benzoyl.

"carboxyl group which may be protected" means an unprotected or protected carboxyl group.

"protected carboxy" refers to a carboxy group protected by a "protecting group for the carboxy group".

The "protecting group for carboxyl group" includes all groups which can be usually used as protecting groups for carboxyl group, and examples thereof include P.G.M.Wuts, and the like, protective group organic Synthesis 4 th edition, 2006, John Wiley&Sons, inc. May be exemplified by_1-6Alkoxy-substituted C_1-6Alkyl (methyl, ethyl, t-butyl, methoxymethyl, t-butoxymethyl, etc.) and optionally substituted with one or more substituents selected from the group consisting of "halogen atom, C_1-6Alkoxy and nitro "(or the like) benzyl (p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl, and the like).

"phosphate group which may be protected" means an unprotected or protected phosphate group.

"protected phosphate group" refers to a phosphate group protected by a "phosphate group protecting group".

The "protecting group for a phosphate group" includes all groups which can be usually used as a protecting group for a phosphate, and examples thereof include P.G.M.Wuts et al, protective group organic Synthesis 4 th edition, 2006, John Wiley&Sons, inc. There may be exemplified C which may be substituted by cyano_1-6Alkyl groups (methyl, ethyl, t-butyl, 2-cyanoethyl, etc.) and benzyl groups (benzyl, p-chlorophenylmethyl, p-nitrobenzyl, etc.) which may be substituted with a substituent selected from the group consisting of a "halogen atom and a nitro group".

"formyl group which may be protected" means a formyl group which may be unprotected or protected.

"protected formyl" includes all formyl groups commonly used as protecting groups for formyl, and examples thereof include those described in P.G.M.Wuts et al, protective group organic Synthesis 4 th edition, 2006, John Wiley & Sons, INC. For example, 1, 1-dimethoxymethyl, 1, 1-diethoxymethyl, 1, 3-dioxane, 1, 3-dioxolane, 1, 3-dithiane and 1, 3-dithiolanyl.

"protecting group for ethynyl" includes all groups which can be generally used as protecting groups for ethynyl, and is exemplified by P.G.M.Wuts et al, protective group organic Synthesis 4 th edition, 2006, John Wiley&Sons, inc. For example, having a structure selected from "C_1-6Alkyl and aryl "silyl groups having 3 substituents which may be the same or different (trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, etc.).

The "leaving group" may be exemplified by a halogen atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group and a p-toluenesulfonyloxy group.

"antibacterial agent" means a substance which acts on gram-positive bacteria or gram-negative bacteria and has the ability to inhibit the proliferation or sterilization thereof. Or a substance which inhibits the growth of bacteria or kills a part of the bacteria to reduce the number of the bacteria. Examples of the gram-positive bacteria include Staphylococcus (such as Staphylococcus aureus and Staphylococcus epidermidis), Streptococcus (such as Streptococcus pyogenes, group B streptococcus and Streptococcus pneumoniae), enterococcus (such as enterococcus faecalis and enterococcus faecium). Examples of the gram-negative bacterium include Pseudomonas (e.g., Pseudomonas aeruginosa), Escherichia (e.g., Escherichia coli), Klebsiella (e.g., Klebsiella pneumoniae and Klebsiella oxytoca), Haemophilus (e.g., influenza bacteria and parainfluenza bacteria), Bordetella (e.g., pertussis bacteria and bronchial septicemia bacteria), Serratia (e.g., Serratia marcescens), Proteus (Proteus mirabilis), Enterobacter (e.g., Enterobacter cloacae), Campylobacter (e.g., Campylobacter jejuni), Aciditis (e.g., Campylobacter jejuni), Vibrio (e.g., Vibrio enteritis and cholera), Morganella (e.g., Morganella morganii), Salmonella (e.g., Salmonella typhi), Shigella (e.g., Acinetobacter), and Acinetobacter (e.g., Acinetobacter), Haemophilus (Acinetobacter) and Acinetobacter (e.g., Acinetobacter) and Acinetobacter (Acinetobacter) and calcium acetate, Legionella (Legionella pneumophila (Legionelnemenuophila), etc.), Bacteroides (Bacteroides fragilis, etc.), Neisseria (gonococcus, meningococcus, etc.), Moraxella (Moraxella catarrhalis), etc.), Chlamydomonas (Chlamydiathromyces trachomatis), Chlamydia psittaci (Chlamydia psittaci, etc.), and helicobacter (helicobacter pylori, etc.).

Preferred modes of the compounds of the present invention are as follows.

Preferred R¹Is a hydrogen atom or C_1-6Alkyl (the C)_1-6Alkyl groups may be substituted with 1 to 3 halogen atoms which may be the same or different). More preferred R¹Is C_1-6Alkyl (the C)_1-6Alkyl groups may be substituted with 1 to 3 halogen atoms which may be the same or different), enhancement of antibacterial activity in vitro (invitro) or in vivo (invivo), and improvement of water solubility can be expected. Further preferred R¹Is methyl or ethyl, most preferably R¹Is methyl.

Preferred R²Is a hydrogen atom or a methyl group, more preferably R²Is methyl.

Preferred R³Is a hydrogen atom.

Preferred R⁴Is C_1-6Alkyl (the C)_1-6The alkyl group may be substituted with a phenyl group or a monocyclic aromatic heterocyclic group (the phenyl group and the monocyclic aromatic heterocyclic group may be substituted with a substituent selected from the group consisting of "halogen atom, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_2-8Alkoxyalkyl, hydroxy, C_1-6Alkoxy radical, C_3-8Cycloalkoxy, amino, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, -N (R)⁴⁵)COR⁴⁶、-CON(R⁴⁷)(R⁴⁸) "the same or different 1 to 3 substituents substituted) with a substituent), more preferred R⁴Is methyl (the methyl group may be a monocyclic aromatic heterocyclic group (the monocyclic aromatic heterocyclic group may be the same or different by 1 to 3C _1-6Alkyl substituted), the most preferred R⁴Is methyl.

Preferred A¹Is phenylene (which may be selected from the group consisting of "halogen atom, hydroxy, amino and C_1-6Alkyl "identically or differently substituted with 1 to 4 substituents), more preferred A¹Is phenylene. Among them, phenylene is preferably represented by the following formula [4]That is combined.

[ CHEM 5 ]

In the formula, R^eIs a halogen atom, a hydroxyl group, an amino group or C_1-6Alkyl, e is 0, 1, 2, 3 or 4.

Preferred L are-C ≡ C-, -C ≡ C-, -CH ≡ CH-C-, -C-CH ≡ CH-, ethylene or a chemical bond, and more preferred L is-C ≡ C-or a chemical bond.

Preferred A²Is a 2-valent aryl group (the 2-valent aryl group may be selected from the group consisting of "halogen atom, hydroxyl group, amino group and C_1-6Alkyl "substituted with the same or different 1 to 4 substituents), a 2-valent monocyclic aromatic heterocyclic group (the 2-valent monocyclic aromatic heterocyclic group contains 1 to 3 atoms as ring-constituting atoms selected from any of a nitrogen atom, an oxygen atom and a sulfur atom, and may be substituted with one or more substituents selected from a halogen atom, a hydroxyl group, an amino group and C_1-6Alkyl "substituted with the same or different 1 to 4 substituents), a 2-valent fused ring aromatic heterocyclic group, or a 2-valent fused ring heterocyclic group having a partially saturated monocyclic ring (the 2-valent fused ring aromatic heterocyclic group and the 2-valent fused ring heterocyclic group having a partially saturated monocyclic ring contain 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as ring-forming atoms, and at least one ring constituting the fused ring is a benzene ring or a pyridine ring, and may be substituted with one or more substituents selected from the group consisting of" a halogen atom, a hydroxyl group, an amino group and C _1-6Alkyl "is substituted with 1 to 4 substituents, which may be the same or different).

More preferred A²Is phenylene or of the formula [5 ]]The 2-valent functional group represented by (a),

[ CHEM 6 ]

(in the formula, Z¹And Z²Same or different is-CH₂-、-O-、-NH-、-N(CH₃) -or-S-. Wherein Z is¹And Z²Are all-CH₂Except for cases of

More preferred A²Or a phenylene group, a pyridyldiyl group, a pyrimidyldiyl group, a 2, 4-furandiyl group, a pyrazolediyl group, a pyrroldiyl group, a 2-valent condensed ring-type aromatic heterocyclic group composed of a 5-membered ring and a 6-membered ring, or a 2-valent aromatic heterocyclic group composed of a 5-membered ring and a 6-membered ringThe condensed ring-type heterocyclic group having a partially saturated monocyclic ring of (the phenylene group, pyridyldiyl group, pyrimidinediyl group, 2, 4-furandiyl group, pyrazolediyl group, pyrrolediyl group, "a 2-valent condensed ring-type aromatic heterocyclic group composed of a 5-membered ring and a 6-membered ring" and "a 2-valent condensed ring-type heterocyclic group having a partially saturated monocyclic ring composed of a 5-membered ring and a 6-membered ring" may be selected from the group consisting of "a halogen atom, a hydroxyl group, an amino group and C_1-6Alkyl "identically or differently substituted with 1 to 4 substituents), the most preferred A²Is phenylene or 2, 4-furandiyl.

One preferred mode of W is a hydrogen atom, a halogen atom, C_1-6Alkyl radical, C_1-6Alkoxy radical, C _1-6Alkylamino radical (this C)_1-6Alkyl radical, C_1-6Alkoxy and C_1-6The alkylamino group may be selected from "halogen atom, hydroxy group, C_1-6Alkoxy and morpholino "substituted with 1 to 3 substituents, which may be the same or different).

Another preferred mode of W is R⁶-X¹-，

Wherein, X¹Is a methylene group or a chemical bond,

substituent group R^cHalogen atom and hydroxyl group.

Another preferred mode of W is R⁶-X²-Y¹-X¹-，

Wherein, Y¹is-O-or-NR⁷-，

X¹Is methylene, ethylene (the methylene and ethylene can be selected from methyl and C)_3-8Cycloalkyl substituted with the same or different 1 to 2 substituents), a cyclopropyl group or a chemical bond,

X²is C_1-4Alkylene (the C)_1-4The alkylene group may be selected from the following substituent groups R^cAre the same or different and are substituted with 1 to 4 substituents),

R⁷is a hydrogen atom, C_1-6Alkyl or C_3-8Cycloalkyl (the C)_1-6Alkyl radical, C_3-8The cycloalkyl group may be selected from the following substituent groups R^cAre the same or different and are substituted with 1 to 4 substituents),

Substituent group R^cIs a halogen atom, a hydroxyl group and C_1-6An alkyl group.

Another preferred mode of W is Q-X¹-Y²-X³-，

Wherein, Y²is-O-, -NR⁷-or a chemical bond,

X³methylene, ethylene (which may be substituted with 1 to 2 methyl groups), cyclopropyl or a bond,

substituent group R^cIs a halogen atom, a hydroxyl group, C_1-6Alkyl radical, C_1-6Hydroxyalkyl radical, C_1-6Haloalkyl, C_3-8Cycloalkyl radical, C_1-6Alkoxy (the C)_1-6Alkoxy may be substituted by 1 to 3 hydroxyl groups or halogen atoms), C_3-8Cycloalkoxy, C_2-6Alkanoyl radical, C_1-6Alkylidene radical (such C_1-6The alkylene group may be substituted by C_1-6Alkoxy substituted) and hydroxyaminocarbonyl.

W is Q-X¹-Y²-X³When, more preferably in one way

Y²Is a chemical bond and is characterized in that,

X¹is a chemical bond and is characterized in that,

q is a heterocyclic group (the heterocyclic group may be selected from the following substituent group R^cAre the same or different and are substituted with 1 to 4 substituents),

wherein the heterocyclic group is a 4-to 7-membered nitrogen-containing saturated heterocyclic group represented by the following formula [6] or a nitrogen-containing saturated spiro group represented by the following formula [7 ].

[ CHEM 7]

(wherein n1 represents 0, 1, 2, 3 or 4, R^cAs described above)

[ CHEM 8 ]

W is Q-X¹-Y²-X³When, more preferably, another way is

Y²represents-NR⁷-，

q is C_3-8Cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, oxazolyl or isoxazolyl (C) _3-8Cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, oxazolyl and isoxazolyl groups can be selected from the following group of substituents R^cAre the same or different and are substituted with 1 to 4 substituents),

Preferred modes of the compounds of the present invention are as follows.

[ CHEM 9]

In the formula, R¹、R²、R³、R⁴、L、R^e、R^fE, f and W are as defined above and in a preferred manner.

Preferred alternative embodiments of the compounds of the present invention are described below.

[ CHEM 10 ]

In the formula, R¹、R²、R³、R⁴、L、R^eThe definitions and preferred modes of definition of e and W are as described above,

R^his a halogen atom, a hydroxyl group, an amino group or C_1-6An alkyl group, a carboxyl group,

h is 0, 1, 2 or 3.

Among them, W in the formula [9] is particularly preferably W

(1)R⁶-X¹-

(wherein, X¹Is a methylene group or a chemical bond,

R⁶is a hydrogen atom, a hydroxyl group which may be protected or R ⁸-ON＝CH-，

substituent group R^cA halogen atom and a hydroxyl group),

(2)R⁶-X²-Y¹-X¹-

(wherein, Y¹is-O-or-NH-,

X¹is a methylene group or an ethylene group,

X²is C_1-4Alkylene (the C)_1-4The alkylene groups may be substituted by the same or different 1 to 4 halogen atoms),

R⁶is a hydrogen atom, a halogen atom, a hydroxyl group which may be protected or C_1-6An alkoxy group),

(3)Q-X¹-Y²-X³-

(wherein, Y²is-O-or-NH-,

X¹is C_1-4An alkylene group or a chemical bond,

q is C_3-8Cycloalkyl (the C)_3-8The cycloalkyl group may be selected from the following substituent groups R^cAre the same or different and are substituted with 1 to 4 substituents),

substituent group R^cIs a halogen atom, a hydroxyl group, C_1-6Alkyl radical, C_1-6Hydroxyalkyl radical, C_1-6Haloalkyl, C_3-8Cycloalkyl radical, C_1-6Alkoxy (the C)_1-6Alkoxy may be substituted by 1 to 3 hydroxyl groups or halogen atoms), C_3-8Cycloalkoxy, C_2-6Alkanoyl radical, C_1-6Alkylidene radical (such C_1-6The alkylene group may be substituted by C_1-6Alkoxy substituted) and hydroxyaminocarbonyl), or

(4)Q-X¹-Y²-X³-

(wherein, Y²Is a chemical bond and is characterized in that,

X¹is a chemical bond and is characterized in that,

wherein the heterocyclic group is a 4-to 7-membered nitrogen-containing saturated heterocyclic group represented by the following formula [6 ].

[ CHEM 11 ]

(wherein n1 represents 0, 1, 2, 3 or 4, R^cAs described above)).

Examples of the preferable compound in the present invention include

(2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

(2S) -N-hydroxy-N', 2-dimethyl-2- (methyl { [4- ({4- [ (oxetan-3-ylamino) methyl ] phenyl } ethynyl) phenyl ] carbonyl } amino) malonamide,

(2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { [4- (2-oxa-6-azaspiro [3.3] hept-6-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

(2S) -N-hydroxy-2- { [ (4- { [5- (methoxymethyl) furan-3-yl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N', 2-dimethylmalonamide,

(2S) -2- [ { [4- ({4- [ (3-ethoxyazetidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

(2S) -N-hydroxy-2- [ { [4- ({4- [ (3-methoxyazetidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N', 2-dimethylmalonamide,

(2S) -2- [ { [4- ({5- [ (cyclopropylamino) methyl ] furan-3-yl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide.

The compound represented by the formula [1] of the present invention has a chiral carbon. The compounds of the present invention may be used as racemic compounds or as specific enantiomers. Among them, as the specific enantiomer, a compound represented by the following formula [10] is preferable.

[ CHEM 12 ]

In the formula, R¹、R²、R³、R⁴、A¹、A²L and W are as defined above and in a preferred manner.

The compounds of the present invention may exist as stereoisomers such as tautomers and geometric isomers, and optical isomers, and the present invention also includes these isomers. In addition, various hydrates, solvates and polymorphic substances of the compound of the present invention and a salt thereof are also included.

In the present invention, pharmaceutically acceptable salts refer to salts used in chemotherapy and prevention of bacterial infections. Examples of the salts include salts with acids such as acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethylsuccinic acid, malonic acid, lactobionic acid, gluconic acid, glucoheptonic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid (Tosicacid), lauryl sulfuric acid, malic acid, aspartic acid, glutamic acid, adipic acid, cysteine, N-acetylcysteine, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid, picric acid, thiocyanic acid, undecanoic acid, acrylic acid polymers and carboxyvinyl polymers, salts with inorganic bases such as lithium salts, sodium salts, potassium salts, magnesium salts and calcium salts, salts with organic amines such as morpholine and piperidine, and amino acids.

The compounds of the present invention also include compounds that function as prodrugs when administered. Compounds that function as prodrugs are preferably R⁶Is a phosphate group. The group of compounds that function as prodrugs preferably has the following characteristics.

(1) The prodrug compound itself may also, but need not, have LpxC enzyme inhibitory or antibacterial activity.

(2) After administration, a functional group functioning as a prodrug is cleaved by an appropriate enzyme in vivo, and is converted into a compound exhibiting desired pharmacological activity. In this case, if the prodrug itself has an antibacterial activity and is not cleaved by an enzyme in vivo, the prodrug compound can also exhibit a drug effect as it is. In addition, the prodrug compound and the compound cleaved by an enzyme in vivo may be present in admixture.

(3) By making a prodrug, it is expected to increase water solubility, enhance or sustain pharmacodynamic action, reduce side effects or toxicity, improve stability, and the like. In particular, an increase in water solubility is expected. For example, when a prodrug is used as an injection or infusion solution, improvement of administration conditions such as reduction of the amount of an administration solution becomes possible, and increase in the amount of an active ingredient or increase in blood concentration is expected to enhance drug efficacy.

The compounds of the present invention may be combined with one or more pharmaceutically acceptable carriers, excipients or diluents to make pharmaceutical formulations. Examples of the carrier, excipient and diluent include various oils such as water, lactose, glucose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, water syrup, methyl cellulose, polyvinylpyrrolidone, alkyl p-hydroxy benzoate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil and the like. Further, the carrier, excipient or diluent may be mixed with additives such as a thickener, a binder, a disintegrant, a pH adjuster, and a dissolving agent, which are generally used, as needed, and the mixture may be formulated into an oral or non-oral drug such as a tablet, a pill, a capsule, a granule, a powder, a solution, an emulsion, a suspension, an ointment, an injection, and a skin patch by a conventional preparation technique.

The compound can be used for 1 time of administration of 1-5000 mg of 1 for adult patients by oral or non-oral administration for 1 or several times per day. The dose can be increased or decreased as appropriate depending on the type of disease to be treated, the age, weight, and symptoms of the patient. In addition, the compounds of the present invention may also be used in combination with other drugs.

The compound of the present invention can be synthesized, for example, by the following method, but the method for producing the compound of the present invention is not limited thereto.

(scheme 1)

[ CHEM 13 ]

The general formula (1a) (wherein R is^1aA protecting group for carboxyl group, other symbols being as defined above) with hydroxylamine in the presence or absence of a base such as sodium methoxide to obtain a compound represented by the general formula [1 ]]The compound shown in the specification.

(scheme 2)

[ CHEM 14 ]

The general formula (2a) (wherein R is^2aThe other symbols are the same as those described above) and a deprotection reaction is carried out under appropriate conditions depending on the type of the carboxyl-protecting group to obtain a compound represented by the general formula (2b) (wherein the symbols are the same as those described above). Then, the compound represented by the general formula (2b) is reacted with the general formula (2c) (wherein R is R in the presence of a condensing agent, in the presence or absence of a base ^2bA hydroxyl-protecting group or a hydrogen atom) to obtain a compound represented by the general formula (2d) (wherein the symbols are as defined above), or reacting an acid chloride or acid anhydride of a compound represented by the general formula (2b) with a hydroxylamine compound represented by the general formula (2c) in the presence or absence of a base to obtain a compound represented by the general formula (2 d). And, R^2bWhen the protecting group is a hydroxyl group, deprotection reaction is carried out under appropriate conditions depending on the type of the protecting group, whereby general formula [1 ] can be obtained]The compound shown in the specification.

The compounds represented by the general formulae (1a), (2a) and (2d) can be obtained, for example, by the methods described in schemes 3, 4a, 4b, 5a, 5b, 6 or 7.

(scheme 3)

[ CHEM 15 ]

The general formula (3a) (wherein R is^3aBeing a protected carboxyl group OR-CONH-OR^3b(in the formula, R^3bA protecting group for a hydroxyl group), and the other symbols have the same meanings as described above), with a compound represented by the general formula (3b) (wherein the symbols have the same meanings as described above) in the presence of a condensing agent in the presence or absence of a base to obtain a compound represented by the general formula (3c) (wherein the symbols have the same meanings as described above), or with an acid chloride or acid anhydride of a compound represented by the general formula (3b) in the presence or absence of a base to obtain a compound represented by the general formula (3 c).

The compound represented by the general formula [1] can be obtained from the compound represented by the general formula [ 3c ] by the method of the scheme 1 or 2.

(scheme 4a)

[ CHEM 16 ]

Reacting a compound of the general formula (4aa) (wherein R is^4aaBeing a protected carboxyl group OR-CONH-OR^4ab(in the formula, R^4abA protecting group for a hydroxyl group), the other symbols being as defined above) and a compound represented by the general formula (4ab) (wherein X is^4aaThe other symbols are the same as those described above) in the presence of a condensing agent in the presence or absence of a base to obtain a compound represented by the general formula (4ac) (wherein the symbols are the same as those described above), or a compound represented by the general formula (4ab)The acid chloride or acid anhydride of the compound (4) may be reacted with the compound represented by the general formula (4aa) in the presence or absence of a base to obtain the compound represented by the general formula (4 ac). Then, the compound represented by the general formula (4ac) and the compound represented by the general formula (4ad) (wherein the symbols are as defined above) are subjected to a coupling reaction in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium or (1, 3-bis (2, 6-diisopropylphenyl) imidazolium) (3-chloropyridyl) palladium (II) dichloride in the presence or absence of a base and in the presence or absence of a ligand to obtain a compound represented by the general formula (4ae) (wherein the symbols are as defined above).

The compound represented by the general formula (4ae) can be obtained by the method according to scheme 1 or 2, wherein the compound is represented by the general formula [1 ].

(scheme 4b)

[ CHEM 17 ]

Reacting a compound of the formula (4ba) (wherein R is^4baBeing a protected carboxyl group OR-CONH-OR^4bb(in the formula, R^4bbA protecting group for a hydroxyl group), and the other symbols have the same meanings as described above, with a compound represented by the general formula (4bb) (wherein the symbols have the same meanings as described above) in the presence or absence of a base in the presence of a condensing agent to obtain a compound represented by the general formula (4bc) (wherein the symbols have the same meanings as described above), or with a diboron compound such as dipentacyldiboron (bis pinacolato) in the presence or absence of a base in the presence or absence of a catalyst such as bis (triphenylphosphine) palladium (II) dichloride in the presence or absence of a base to obtain a compound represented by the general formula (4 bc). A compound represented by the general formula (4bc) is reacted with a compound represented by the general formula (4bd) (wherein X is^4baIs a leaving groupThe group and other symbols have the same meanings as described above), in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium or (1, 3-bis (2, 6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) dichloride, in the presence or absence of a base, in the presence or absence of a ligand, to give a compound represented by the general formula (4be) (wherein the symbols have the same meanings as described above).

The compound represented by the general formula [1] can be obtained from the compound represented by the general formula (4be) by the method of the scheme 1 or 2.

(scheme 5a)

[ CHEM 18 ]

Reacting a compound of the general formula (5aa) (wherein R is^5aaBeing a protected carboxyl group OR-CONH-OR^5ab(in the formula, R^5abA protecting group for a hydroxyl group), the other symbols being as defined above) and a compound represented by the general formula (5ab) (wherein X is^5aaThe other symbols are the same as those described above) in the presence of a condensing agent in the presence or absence of a base to obtain a compound represented by the general formula (5ac) (wherein the symbols are the same as those described above), or an acid chloride or acid anhydride of the general formula (5ab) is reacted with the general formula (5aa) in the presence or absence of a base to obtain a compound represented by the general formula (5 ac). Then, a compound represented by the general formula (5ac) and a compound represented by the general formula (5ad) (wherein the symbols are as defined above) are subjected to a coupling reaction in the presence of a catalyst such as bis (triphenylphosphine) palladium dichloride and copper iodide, in the presence or absence of a base, and in the presence or absence of a ligand, to obtain a compound represented by the general formula (5ae) (wherein the symbols are as defined above).

The compound represented by the general formula (5ae) can be obtained by the method according to scheme 1 or 2, wherein the compound is represented by the general formula [1 ].

(scheme 5b)

[ CHEM 19 ]

Reacting a compound of the formula (5ba) (wherein R is^5baBeing a protected carboxyl group OR-CONH-OR^5bb(in the formula, R^5bbA protecting group for a hydroxyl group), the other symbols being as defined above) and a compound represented by the general formula (5bb) (wherein R is^5bcThe other symbols are the same as those described above) in the presence of a base in the presence of a condensing agent to obtain a compound represented by the general formula (5bc) (wherein the symbols are the same as those described above), or by reacting an acid chloride or acid anhydride of the general formula (5bb) with the general formula (5ba) in the presence or absence of a base to obtain a compound represented by the general formula (5bc) (wherein the symbols are the same as those described above), or by using a compound represented by the general formula (5ac) shown in scheme 5a, in the presence of a catalyst such as bis (triphenylphosphine) palladium dichloride and copper iodide, in the presence or absence of a base, in the presence or absence of a ligand^5bcProtected acetylene is reacted to give a compound represented by the general formula (5 bc). The compound represented by the general formula (5bc) is allowed to react depending on the kind of the protecting group R ^5bcThe deprotection reaction is carried out under appropriate conditions to obtain a compound represented by the general formula (5bd) (wherein the symbols are as defined above), and further the compound is reacted with a compound represented by the general formula (5be) (wherein X is^5baOther symbols having the same meanings as described above as leaving groups) to obtain a compoundA compound represented by the formula (5bf) (wherein the symbols have the same meanings as defined above).

A compound represented by the general formula [1] can be obtained from the compound represented by the general formula (5bf) by the method of the scheme 1 or 2.

(scheme 6)

[ CHEM 20 ]

For the general formula (6a) (wherein X^6aIs a leaving group, R^6aBeing a protected carboxyl group OR-CONH-OR^6b(in the formula, R^6bA protecting group for a hydroxyl group), and the other symbols are the same as those described above), and a compound represented by the general formula (6b) (wherein X is^6bThe other symbols being as defined above for the leaving group) in the presence of a base to obtain a compound represented by the general formula (6 c).

The compound represented by the general formula [1] can be obtained from the compound represented by the general formula (6c) by the method of scheme 4a or 5 a.

(scheme 7)

[ CHEM 21 ]

The general formula (7a) (wherein R is^7aAnd R^7bThe same or different protecting groups for carboxyl groups, and the same other symbols as those described above) with a compound represented by the general formula (7b) (wherein the symbols are the same as those described above) in the presence of a condensing agent in the presence or absence of a base to obtain a compound represented by the general formula (7c) (wherein the symbols are the same as those described above). Allowing the compound represented by the general formula (7c) to exist or not to exist in the presence of a baseThen, the reaction with a compound represented by the general formula (7d) (wherein the symbols have the same meanings as those described above) gives a compound represented by the general formula (7e) (wherein the symbols have the same meanings as those described above). Or, 2 carboxyl protecting groups R of the compound represented by the general formula (7c)^7aとR^7bUnder appropriate conditions, carrying out R alone^7bThe deprotection reaction of (2) to produce a monocarboxylic acid compound represented by the general formula (7f) (wherein the symbols are as defined above), and then reacting the monocarboxylic acid compound with a compound represented by the general formula (7d) in the presence of a condensing agent in the presence or absence of a base to obtain a compound represented by the general formula (7 e). For example, R ^7aAnd R^7bIn the case of all ethyl groups, the reaction can be carried out in an absolute ethanol solvent using 1 equivalent of potassium hydroxide as described in the literature (bioorg. med. chem. (2007), 15, p63-76), whereby only R can be reacted^7bDeprotection is carried out.

On the other hand, a compound represented by the general formula (7c) is reacted with a compound represented by the general formula (7g) (wherein X is^7aThe other symbols are the same as those described above) in the presence of a base to obtain a compound represented by the general formula (7h) (wherein the symbols are the same as those described above). The compound represented by the general formula (7h) is reacted with the compound represented by the general formula (7d) in the presence or absence of a base to obtain a compound represented by the general formula (7i) (wherein the symbols are as defined above). A protecting group R for 2 carboxyl groups of the compound represented by the general formula (7h)^7aAnd R^7bOf the kind of (1) to R only under appropriate conditions^7bThe compound represented by the general formula (7i) can be obtained by subjecting the compound to deprotection reaction to obtain a monocarboxylic acid compound, and then reacting the compound represented by the general formula (7d) with a compound represented by the general formula (7d) in the presence of a condensing agent in the presence or absence of a base, or reacting a compound represented by the general formula (7e) with a compound represented by the general formula (7g) in the presence of a base to obtain a compound represented by the general formula (7 i).

A compound represented by the general formula [1] can be obtained from the compound represented by the general formula (7e) or (7i) by the method of the scheme 1 or 2.

The compounds represented by the general formulae (3a), (4aa), (4ba), (5aa), (5ba) and (7a) can be obtained, for example, by the method described in scheme 8, 9, 10 or 11.

(scheme 8)

[ CHEM 22 ]

The general formula (8a) (wherein, X^8aIs a leaving group, R^8aAnd R^8bA protecting group for carboxyl group, which may be the same or different), with a compound represented by the general formula (8b) in the presence or absence of a base to obtain a compound represented by the general formula (8c) (wherein the symbols are the same as those in the above description) and a compound represented by the general formula (8d) (wherein the symbols are the same as those in the above description). The compound represented by the general formula (8c) is reacted with the compound represented by the general formula (8e) in the presence or absence of a base to obtain a compound represented by the general formula (8f) (wherein the symbols are as defined above). Or a protecting group R for 2 carboxyl groups of the compound represented by the general formula (8a)^8aAnd R^8bOf the kind of (1) to R only under appropriate conditions^8bThe compound represented by the general formula (8f) can be obtained by subjecting the compound to deprotection reaction to obtain a monocarboxylic acid compound, and then reacting the compound with the compound represented by the general formula (8e) in the presence of a condensing agent in the presence or absence of a base.

A compound represented by the general formula [1] can be obtained from the compound represented by the general formula (8d) or (8f) by the method according to scheme 3, 4a, 4b, 5a or 5 b.

(scheme 9)

[ CHEM 23 ]

The compound represented by the general formula (9a) (wherein the symbols have the same meanings as those described above) is reacted with benzaldehyde in the presence of a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride, in the presence or absence of a metal salt such as zinc chloride, to obtain a compound represented by the general formula (9b) (wherein the symbols have the same meanings as those described above). Then, the compound represented by the general formula (9b) is reacted with the general formula (9c) (wherein X is^9aIs a leaving group, R^9aAnd R^9bThe same or different carboxyl-protecting groups) to obtain a compound represented by the general formula (9d) (wherein the symbols have the same meanings as defined above). The compound represented by the general formula (9d) is reacted with a compound represented by the general formula (9e) (wherein the symbols are as defined above) in the presence or absence of a base to obtain a compound represented by the general formula (9f) (wherein the symbols are as defined above), or a compound represented by the general formula (9d) wherein R is a protective group for 2 carboxyl groups ^9aAnd R^9bOf the kind of (1) to R only under appropriate conditions^9bThe compound represented by the general formula (9f) can be obtained by subjecting the compound to deprotection reaction to obtain a monocarboxylic acid compound, and then reacting the compound with the compound represented by the general formula (9h) in the presence or absence of a base in the presence of a condensing agent. The compound represented by the general formula (9f) is subjected to debenzylation in the presence of a catalyst such as palladium on carbon or palladium hydroxide in the presence of hydrogen or formic acid to obtain a compound represented by the general formula (9g) (wherein the symbols are as defined above).

Further, as for the compound represented by the general formula (9f), the general formula (9h) (wherein, X is^9bThe other symbols are the same as those described above) in the presence of a base to obtain a compound represented by the general formula (9i) (wherein the symbols are the same as those described above). A compound represented by the general formula (9i) is reacted with hydrogen or methyl in the presence of a catalyst such as palladium on carbon or palladium hydroxideDebenzylation in the presence of an acid can provide a compound represented by the general formula (9j) (wherein the symbols are as defined above).

A compound represented by the general formula [1] can be obtained from the compound represented by the general formula (9g) or (9j) by the method according to scheme 3, 4a, 4b, 5a or 5 b.

(scheme 10)

[ CHEM 24 ]

The general formula (10a) (wherein R is as defined in scheme 9) obtained by the method of scheme 9^10aAnd R^10bSame or different carboxyl-protecting groups, Bn is benzyl, and other symbols are the same as those described above), in the presence of a catalyst such as palladium on carbon or palladium hydroxide, in the presence of hydrogen or formic acid, and then, depending on the type of amino-protecting group (t-butoxycarbonyl, etc.), the amino-protecting reaction is carried out under appropriate conditions to give a compound of the general formula (10b) (wherein R is R^10cA protecting group for amino group, and the other symbols have the same meanings as described above). The compound represented by the general formula (10b) is reacted with the compound represented by the general formula (10c) (wherein the symbols are as defined above) in the presence or absence of a base to obtain a compound represented by the general formula (10d) (wherein the symbols are as defined above), or a compound represented by the general formula (10b) wherein R is a protective group for 2 carboxyl groups^10aAnd R^10bOf the kind of (1) to R only under appropriate conditions^10bThe compound represented by the general formula (10d) can be obtained by subjecting the compound to deprotection reaction to obtain a monocarboxylic acid compound, and then reacting the compound with the compound represented by the general formula (10c) in the presence of a condensing agent in the presence or absence of a base. Deprotection reaction is carried out under appropriate conditions according to the kind of the protecting group of the amino group of the compound represented by the general formula (10d) to obtain the general formula (10e) (wherein the symbol is as defined above and the symbol is as defined above The same as defined above).

Further, as for the compound represented by the general formula (10d), the general formula (10f) (wherein, X is^10bThe other symbols are the same as those described above) in the presence of a base to obtain a compound represented by the general formula (10g) (wherein the symbols are the same as those described above). Depending on the type of the amino-protecting group of the compound represented by the general formula (10g), a deprotection reaction may be carried out under appropriate conditions to obtain a compound represented by the general formula (10h) (wherein the symbols are as defined above).

A compound represented by the general formula [1] can be obtained from the compound represented by the general formula (10e) or (10h) by the method according to scheme 3, 4a, 5b, 5a or 5 b.

(scheme 11)

[ CHEM 25 ]

The general formula (11a) (wherein R is R) obtained by the method according to scheme 8, 9 or 10^11aThe protecting group for carboxyl group, the other symbols being as defined above) and the amino protecting group of the compound represented by the formula (11b) (wherein R is as defined above) under appropriate conditions to obtain the compound^11bA protecting group for amino group, and the other symbols have the same meanings as described above). Depending on the kind of the carboxyl-protecting group of the compound represented by the general formula (11b), deprotection reaction may be carried out under appropriate conditions, followed by reaction with the compound represented by the general formula (11c) (wherein R is R in the formula ^11cA protecting group for a hydroxyl group) to obtain a compound represented by the general formula (11d) (wherein the symbols have the same meanings as defined above). Next, deprotection reaction is carried out under appropriate conditions according to the kind of the amino-protecting group of the compound represented by the general formula (11d) to obtain the general formula (11e) (wherein the symbols are as defined above)The same as above).

A compound represented by the general formula [1] can be obtained from the compound represented by the general formula (11e) by any of the methods shown in schemes 3, 4a, 4b, 5a and 5 b.

The compounds represented by the general formulae (3b), (4ad), (4bb), (5ad) and (7b) can be obtained, for example, by the method described in scheme 12a or 12 b.

(case 12a)

[ CHEM 26 ]

Reacting a compound of the general formula (12aa) (in the formula, X^12aaOther symbols are the same as those described above) in the presence of a catalyst such as 1, 1' -bis (diphenylphosphino) ferrocene dichloropalladium, in the presence or absence of a base, in the presence or absence of a ligand, and in the presence or absence of a ligand, to obtain a compound represented by the general formula (12ab) (wherein the symbols are the same as those described above). Then, the general formula (12ac) (wherein X is ^12abIs a leaving group, R^12aA carboxyl group, a protected carboxyl group or a cyano group, and the other symbols have the same meanings as described above) with a compound represented by the general formula (12ab) or a compound represented by the general formula (12ad) (the symbols in the formula are the same as described above) in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium, in the presence or absence of a base, in the presence or absence of a ligand, and the like, to obtain a compound represented by the general formula (12ae) (the symbols in the formula are the same as described above). Further, R in the compound represented by the general formula (12ae)^12aaIn the case of a carboxyl-protecting group or a cyano group, a compound represented by the general formula (12af) (wherein the symbols are as defined above) can be obtained by hydrolysis under basic or acidic conditions. Further, the order of reaction may be changed to the general formula (12ac)The compound represented by the formula (12af) is obtained by converting the compound represented by the formula (12af) into a boronic acid ester and then reacting the boronic acid ester with the compound represented by the formula (12 aa).

A compound represented by the general formula [1] can be obtained from a compound represented by the general formula (12ab) or (12af) by any of the methods shown in schemes 3, 4a, 4b and 7.

(scheme 12b)

[ CHEM 27 ]

Reacting a compound of the formula (12ba) (wherein X^12baThe other symbols being as defined above for the leaving group) with a compound represented by the general formula (12bb) (wherein R is R in the formula^12baProtecting group for ethynyl group), according to the protecting group R^12baThe deprotection reaction is carried out under an appropriate condition to obtain a compound represented by the general formula (12bc) (wherein the symbols are as defined above). Further reacting a compound represented by the general formula (12bc) with the general formula (12bd) (wherein X is^12bbIs a leaving group, R^12bbA carboxyl group, a protected carboxyl group or a cyano group, and the other symbols have the same meanings as described above), in the presence of a catalyst such as bis (triphenylphosphine) palladium dichloride and copper iodide, in the presence or absence of a base, and in the presence or absence of a ligand, to obtain a compound represented by the general formula (12be) (wherein the symbols have the same meanings as described above). R of the compound represented by the general formula (12be) ^12bbIn the case of a carboxyl-protecting group or a cyano group, a compound represented by the general formula (12bf) (wherein the symbols are as defined above) can be obtained by hydrolysis under basic or acidic conditions. In addition, the reaction can also be modifiedThe compound represented by the general formula (12bd) is converted into an acetylene compound, and then the compound represented by the general formula (12ba) is reacted to obtain a compound represented by the general formula (12 bf).

A compound represented by the general formula [1] can be obtained from a compound represented by the general formula (12bc) or (12bf) by any of the methods shown in schemes 3, 5a, 5b and 7.

The compounds described in schemes 1 to 12 can also be obtained by the methods described in schemes 13 to 23, for example.

(scheme 13)

[ CHEM 28 ]

The method according to scheme 2, 3, 4a, 4b, 5a, 5b or 7, wherein X is represented by the general formula (13a) (in the formula^13aIs a leaving group, R^13aIs carboxy, protected carboxy OR-CONH-OR^13b(in the formula, R^13bA protecting group for a hydroxyl group), the other symbols being as defined above) and a compound represented by the general formula (13b) (wherein R is^13cIs R⁹-X²-、R⁹-X⁴-Y¹-X²-、Q-X¹-or Q-X¹-Y¹-X²-, the other symbols have the same meanings as those described above) in the presence or absence of a catalyst, in the presence or absence of a base, and in the presence or absence of a ligand, to obtain a compound represented by the general formula (13c) (wherein the symbols have the same meanings as those described above).

The compound represented by the general formula [1] can be obtained from the compound represented by the general formula (13c) by the method of the scheme 1 or 2.

(scheme 14)

[ CHEM 29 ]

The general formula (14a) (wherein, X^14aAnd X^14bA leaving group, other symbols being as defined above) and a compound represented by the general formula (14b) (wherein R is^14aIs R⁹-X²-、R⁹-X⁴-Y¹-X²-、Q-X¹-or Q-X¹-Y¹-X²-, the other symbols have the same meanings as those described above) in the presence or absence of a catalyst, in the presence or absence of a base, and in the presence or absence of a ligand, to obtain a compound represented by the general formula (14c) (wherein the symbols have the same meanings as those described above).

A compound represented by the general formula [1] can be obtained from the compound represented by the general formula (14c) by the method according to scheme 4b, 5b, 12a or 12 b.

(scheme 15)

[ CHEM 30 ]

Reacting a compound of the general formula (15a) (wherein X is as defined in scheme 12a or 12 b) obtained by the process of scheme 12a or 12b^15aAre linked together with adjacent methylene groups to form-X¹-or-X²-Y³-X³A group of (A), R^15aA protected carboxyl group or cyano group, and the other symbols have the same meanings as described above) and a compound of the formula (15b) (wherein X is^15bis-X²-or-X⁴-, the other symbols are as defined above) in the presence of a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride, in the presence or absence of a metal salt such as zinc chloride, to give a compound represented by the general formula (15c) (wherein the symbol and the symbol are as defined above) The same as defined above). Then, the compound represented by the general formula (15c) is subjected to a hydrolysis reaction under basic or acidic conditions to obtain a compound represented by the general formula (15d) (wherein the symbols are as defined above).

The compound represented by the general formula [1] can be obtained from the compound represented by the general formula (15d) by the method according to scheme 3 or 7.

(scheme 16)

[ CHEM 31 ]

Reacting a compound of the general formula (16a) (wherein X is as defined in scheme 12a or 12 b) obtained by the process of scheme 12a or 12b^16aAre linked together with adjacent methylene groups to form-X¹-or-X²-Y³-X³A group of (A), R^16aThe other symbols of the formula (i) are as defined above for the protected carboxyl group or cyano group) with a compound represented by the general formula (16b) (the symbols in the formula are as defined above), in the presence of a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride, in the presence or absence of a metal salt such as zinc chloride, to give a compound represented by the general formula (16c) (the symbols in the formula are as defined above). Wherein formula (16b) represents a 4-to 7-membered nitrogen-containing saturated heterocyclic group (wherein q is 0, 1, 2, 3 or 4, and the other symbols are as defined above).

[ CHEM 32 ]

Then, the compound represented by the general formula (16c) is subjected to hydrolysis reaction under basic or acidic conditions to obtain a compound represented by the general formula (16d) (wherein the symbols are as defined above).

The compound represented by the general formula [1] can be obtained from the compound represented by the general formula (16d) by the method of the scheme 3 or 7.

(scheme 17)

[ CHEM 33 ]

The general formula (17a) (wherein, X^17aAre linked together with adjacent methylene groups to form-X¹-or-X²-Y³-X³A group of (A) X^17bA leaving group, other symbols being as defined above) and a compound represented by the general formula (17b) (wherein X is^17cis-X²-or-X⁴-, the other symbols have the same meanings as described above) in the presence of a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride, in the presence or absence of a metal salt such as zinc chloride, to obtain a compound represented by the general formula (17c) (wherein the symbols have the same meanings as described above).

A compound represented by the general formula [1] can be obtained from the compound represented by the general formula (17c) by the method according to scheme 4b, 5b, 12a or 12 b.

(scheme 18)

[ CHEM 34 ]

The general formula (18a) (wherein X is as defined in the description) obtained by the method according to the scheme 2, 3, 4a, 4b, 5a, 5b or 7^18ais-X¹-or-X²-Y³-X³-，X^18bIs a leaving group, R^18aA protecting group for a hydroxyl group, other symbols being as defined above) and a compound represented by the general formula (18b) (wherein X is^18cis-X²-or-X ⁴-, the other symbols have the same meanings as described above) in the presence or absence of a base to obtain a compound represented by the general formula (18c) (wherein the symbols have the same meanings as described above).

The compound represented by the general formula [1] can be obtained from the compound represented by the general formula (18c) by the method of scheme 2.

(scheme 19)

[ CHEM 35 ]

The general formula (19a) (wherein X is as defined in the description) obtained by the method according to the scheme 2, 3, 4a, 4b, 5a, 5b or 7^19ais-X¹-Y²-X³-or-X¹-Y¹-X²-Y³-X³-，X^19bIs a leaving group, R^19aThe other symbols are the same as those described above as protecting groups for hydroxyl groups) with a compound represented by the general formula (19b) (wherein the symbols are the same as those described above) in the presence or absence of a base, to obtain a compound represented by the general formula (19c) (wherein the symbols are the same as those described above).

The compound represented by the general formula [1] can be obtained from the compound represented by the general formula (19c) by the method of scheme 2.

(scheme 20)

[ CHEM 36 ]

The general formula (20a) (wherein X is as defined in the description) obtained by the method according to the scheme 2, 3, 4a, 4b, 5a, 5b or 7^20aAre linked together with adjacent methylene groups to form-X¹-or-X²-Y³-X³A group of (A), R^20aIs carboxy, protected carboxy OR-CONH-OR ^20b(in the formula, R^20bA protecting group for a hydroxyl group), and the other symbols have the same meanings as described above) with a compound represented by the general formula (20b) (wherein the symbols have the same meanings as described above), in the presence of a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride, in the presence or absence of a metal salt such as zinc chloride, to obtain a compound represented by the general formula (20c) (wherein the symbols have the same meanings as described above).

The compound represented by the general formula [1] can be obtained from the compound represented by the general formula (20c) by the method of the scheme 1 or 2.

(scheme 21)

[ CHEM 37 ]

The general formula (21a) (wherein X is as defined in the description) obtained by the method according to the scheme 2, 3, 4a, 4b, 5a, 5b or 7^21aAre linked together with adjacent methylene groups to form-X¹-or-X²-Y³-X³A group of (A), R^21aIs carboxy, protected carboxy OR-CONH-OR^21b(in the formula, R^21bA protecting group for a hydroxyl group), the other symbols being as defined above) and a compound represented by the general formula (21b) (wherein X is^21bis-X²-or-X⁴-, the other symbols have the same meanings as described above) in the presence of a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride, in the presence or absence of a metal salt such as zinc chloride, to obtain a compound represented by the general formula (21c) (wherein the symbols have the same meanings as described above). A compound represented by the general formula (21c) can be obtained by the method of scheme 1 or 2 to obtain the general formula [1 ]The compound shown in the specification.

(scheme 22)

[ CHEM 38 ]

Reacting a compound of the general formula (22a) (wherein X is as defined in scheme 12a or 12 b) obtained by the process of scheme 12a or 12b^22ais-X¹-or-X²-Y³-X³-，X^22bIs a leaving group, R^22aA protected carboxyl group or cyano group, and the other symbols have the same meanings as described above) and a compound represented by the general formula (22b) (wherein X is^22cis-X²-or-X⁴-, the other symbols have the same meanings as described above) in the presence or absence of a base to obtain a compound represented by the general formula (22c) (wherein the symbols have the same meanings as described above). Then, the compound represented by the general formula (22c) is subjected to hydrolysis reaction under basic or acidic conditions to obtain a compound represented by the general formula (22d) (wherein the symbols are as defined above).

The compound represented by the general formula [1] can be obtained from the compound represented by the general formula [ 22d ] by the method according to scheme 3 or 7.

(scheme 23)

[ CHEM 39 ]

Reacting a compound of the general formula (23a) (wherein X is as defined in scheme 12a or 12 b) obtained by the process of scheme 12a or 12b^23ais-X¹-Y²-X³-or-X¹-Y¹-X²-Y³-X³-，X^23bIs a leaving group, R^23aProtected carboxyl group or cyano group, the other symbols being as defined above) and a compound represented by the general formula (23b) (wherein the symbols are as defined above) are reacted in the presence or absence of a base Accordingly, a compound represented by the general formula (23c) (wherein the symbols have the same meanings as described above) can be obtained. Then, the compound represented by the general formula (23c) is subjected to hydrolysis reaction under basic or acidic conditions to obtain a compound represented by the general formula (23d) (wherein the symbols are as defined above).

The compound represented by the general formula [1] can be obtained from the compound represented by the general formula (23d) by the method of the scheme 3 or 7.

In the synthetic methods shown above, the order of the reaction steps may be changed as necessary. When an amino group, a hydroxyl group, a formyl group, and a carboxyl group are present in the compound obtained in each step of the reaction and an intermediate thereof, the protecting group thereof may be deprotected or appropriately recombined to perform the reaction.

Unless otherwise specified, examples of the base in the case of using a base in the above reaction include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium amide, sodium methoxide, potassium t-butoxide, sodium hydride, lithium hydride, triethylamine, diisopropylethylamine, dimethylaniline, diethylaniline, pyridine, pyrrolidine and N-methylmorpholine.

Examples of the acid include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and polyphosphoric acid, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid and acetic acid.

Examples of the condensing agent include O- (7-azobenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide, carbonyldiimidazole, 2-chloro-1-methylpyridinium iodide salt, 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholine chloride salt, O- (7-azobenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate, and the like.

Examples of the activating agent used in the method using an acid chloride or acid anhydride include thionyl chloride, oxalyl chloride, phosphorus oxychloride, acetic anhydride, and chloroformates.

Examples of the catalyst include palladium acetate, palladium chloride, bis (triphenylphosphine) palladium (II) dichloride, tetrakis (triphenylphosphine) palladium, bis (acetonitrile) dichloropalladium, bis (benzonitrile) dichloropalladium, tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium, 1' -bis (diphenylphosphino) ferrocene dichloropalladium, bis (tricyclohexylphosphine) dichloropalladium, bis (tri-o-tolylphosphine) dichloropalladium, bis (tri-t-butylphosphino) dichloropalladium, (1, 3-bis (2, 6-diisopropylphenyl) imidazolium) (3-chloropyridyl) palladium (II) dichloride, palladium on carbon, palladium hydroxide and copper iodide.

Examples of the ligand include tri-t-butylphosphine, tricyclohexylphosphine, triphenylphosphine, tritolylphosphine, tributylphosphite, tricyclohexylphosphite, triphenylphosphite, 1 ' -bis (diphenylphosphino) ferrocene, 2 ' -bis (diphenylphosphino) -1, 1 ' -binaphthyl, 2-dicyclohexylphosphino-2 ', 6 ' -dimethoxybiphenyl, 2-dicyclohexylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl, 2- (di-t-butylphosphino) -2 ', 4 ', 6 ' -triisopropylbiphenyl, and 2- (di-t-butylphosphino) biphenyl.

Examples of the oxidizing agent include potassium permanganate, chromium oxide, potassium dichromate, hydrogen peroxide, m-chloroperoxybenzoic acid, urea hydroperoxide adduct/phthalic anhydride, t-butyl hydroperoxide, cumene hydroperoxide and other inorganic and organic peroxides, selenium dioxide, lead (IV) acetate, t-butyl hypochlorite, sodium hypochlorite, and 1, 1, 1-triacetoxy-1, 1-dihydro-1, 2-phenyliodoxy-3 (1H) -one.

Examples of the reducing agent include hydrogen complexes such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, and diisobutylaluminum hydride, and borane-based compounds, sodium amalgam-based compounds, and sodium amalgam-based compounds.

Examples of the metal salt include zinc chloride, zirconium chloride, indium chloride, and magnesium chloride.

The solvent is not particularly limited as long as it is stable under the reaction conditions, inert, and does not interfere with the reaction, and examples thereof include a polar solvent (for example, an alcohol solvent such as water, methanol, ethanol, and isopropyl alcohol), an inert solvent (for example, a halogenated hydrocarbon solvent such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride, an ether solvent such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1, 4-dioxane, and dimethoxyethane, an aprotic solvent such as dimethylformamide, dimethyl sulfoxide, ethyl acetate, tert-butyl acetate, acetonitrile, and propionitrile, an aromatic solvent such as benzene, toluene, and anisole, a hydrocarbon such as cyclohexane, and a mixed solvent of these solvents.

The reaction may be carried out at a temperature selected from-78 ℃ to the boiling point of the solvent used in the reaction, under normal pressure or under pressure, under microwave irradiation, or the like.

The present invention will be described in further detail below with reference to intermediate synthesis examples, and test examples. The compounds of the present invention are not limited to the compounds described in the following examples.

Unless otherwise specified, silicA gel 60N, CHROMATOREXNH-DM1020, Fuji silicon chemical LTD, and ODS-A-AA12S50, YMC, were used as the carrier for the silicA gel chromatography, NH-type silicA gel chromatography, and Kanto chemical corporation, respectively. Silica gel thin layer chromatography for separation Using PLC plate silica gel 60F manufactured by Merck₂₅₄. Cellpure uses products from advanced minerals. Phaseparator used Biotage corporation. The NMR spectrum indicated proton NMR, and the internal standard substance used tetramethylsilane, values were expressed in ppm.

LC-MS and HPLC were measured by Agilent1100, and MS (ESI) was measured by MicroMassPlatformLC. The columns, solvents and assay conditions used are as follows.

Column: waters, SunAire^TMC18，2.5um，4.6x50mmColumn

Solvent: CH (CH)₃CN(0.10％CF₃COOH)，H₂O(0.10％CF₃COOH)

The measurement conditions were as follows: 0 to 0.5 minute (10% CH)₃CN) → 5.5 min (80% CH)₃CN) → 6.0 to 6.3 minutes (99% CH)₃CN) gradient elution

LC-separation Using GILSONpreparative HPLCsystem. The column, solvent and assay conditions used for LC-separation are as follows.

Column: waters, SunAire^TMPrepC18，OBD^TM5.0um，30x50mmColumn

Solvent: CH (CH)₃CN(0.1％CF₃COOH)，H₂O(0.1％CF₃COOH)

The measurement conditions were as follows: 0 to 2 minutes (10% CH)₃CN) → 11 min (80% CH) ₃CN) → 13.5 min (95% CH)₃CN) gradient elution

In addition, the abbreviated symbols in the embodiments are as follows.

(+) -CSA: (+) -10-Camphorsulfonic acid

AcOEt: ethyl acetate

AcOBu: acetic acid n-butyl ester

APCI: atmospheric pressure chemical ionization method

aq.: aqueous solution

Boc: t-butoxycarbonyl radical

Bn: benzyl radical

Bu: butyl radical

DEAD: azodicarboxylic acid diethyl ester

DIPEA: n, N-diisopropylethylamine

DMF: n, N-dimethylformamide

DMSO-d₆: 6 heavy hydrogenation of dimethyl sulfoxide

ESI: electrospray ionization method

Et: ethyl radical

HATU: o- (7-azobenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate

HOBt·H₂O: 1-hydroxybenzotriazole monohydrate

IPA: isopropanol (I-propanol)

IPE: diisopropyl ether

LC: liquid chromatography

LDA: lithium diisopropylamide

Me: methyl radical

NMP: 1-methyl-2-pyrrolidone

PEPSI: (1, 3-bis (2, 6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) dichloride

PdCl₂(dppf)·CH₂Cl₂: 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane complex

PdCl₂(PPh₃)₂: bis (triphenylphosphine) palladium (II) dichloride

PPTS: 4-Methylbenzenesulfonic acid pyridine salt

(p-Tol)₃P: tris (4-methylphenyl) phosphine

p-TsOH·H₂O: p-toluenesulfonic acid monohydrate

TBAF: tetra-n-butylammonium fluoride

TEA: triethylamine

TFA: trifluoroacetic acid

THF: tetrahydrofuran (THF)

THP: tetrahydropyranyl group

TMS: trimethylsilyl group

TIPS: triisopropylsilyl radical

TsCl; 4-Methylbenzenesulfonyl chloride

WSC & HCl: 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride

s: single peak

br.s.: broad peak (broad single peak)

d: double peak

dd: double doublet

dt: double triplet

m: multiple peaks

t: triplet peak

td: triplet peak

tt: triplet peak

q: quartet peak

And (3) quin: quintuple peak

First, a method for synthesizing a common intermediate used in synthesizing the compound of the present invention is described. The scheme for intermediate synthesis is shown in the following figure.

[ CHEM 40 ]

Synthesis of intermediate 1-1

[ benzyl (methyl) amino ] malonic acid diethyl ester

[ CHEM 41 ]

The same procedures as described in the literature (Tetrahedron 2005, vol. 61, p. 8722-8739) were carried out using diethyl bromomalonate (8.5g) to give diethyl [ phenylmethyl (methyl) amino ] malonate (intermediate 1-1, colorless oily substance) (6.7g, 67%).

MS(ESI)：280(M+H)⁺

¹HNMR (600MHz, chloroform-d) ppm1.25-1.35(6H, m), 2.46(3H, s), 3.82(2H, s), 4.16(1H, s), 4.21-4.31(4H, m), 7.22-7.41(5H, m)

Synthesis of intermediate 1-2

[ benzyl (methyl) amino ] malonic acid dimethyl ester

[ CHEM 42 ]

To a solution of N-methylbenzylamine (15mL) in acetonitrile (60mL), a solution of dimethyl bromomalonate (12g) in acetonitrile (10mL) was added dropwise at room temperature, and the mixture was stirred at room temperature for 6 hours. Toluene (0.20L) was added, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. Toluene (0.10L) and OH-type silica gel (6.0g) were added to the residue, and the mixture was stirred at room temperature for 20 minutes, then filtered, and the filtrate was concentrated under reduced pressure to give dimethyl [ phenylmethyl (methyl) amino ] malonate (yellowish oil) (14g, 96%).

¹HNMR (400MHz, chloroform-d) ppm2.46(3H, s), 3.60-4.00(2H, m), 3.79(6H, br.s.), 4.20(1H, s), 7.20-7.50(5H, m)

Synthesis of intermediate 2-2

({ [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) amino } methyl) benzene

[ CHEM 43 ]

To a solution of dimethyl [ phenylmethyl (methyl) amino ] malonate (intermediate 1-2, 13g) in methanol (39mL) was added a 9 mol/L-methylamine-methanol solution (14mL) at room temperature, and the mixture was stirred at room temperature for 26 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added to the resulting residue, and the organic layer was separated. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was distilled off under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (hexane/ethyl acetate 50/50 → chloroform/acetone 95/5) to give ({ [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) amino } methyl) benzene (yellowish oil) (7.1g, 56%).

¹HNMR (400MHz, chloroform-d) ppm2.37(3H, s), 2.87(3H, d, J ═ 5.1Hz), 3.60-3.85(2H, m), 3.81(3H, s), 3.98(1H, s), 6.90-7.00(1H, m), 7.20-7.40(5H, m)

Synthesis of intermediate 3-1 (1)

[ (t-Butoxycarbonyl) (methyl) amino ] malonic acid diethyl ester

[ CHEM 44 ]

TEA (0.25L) and di-t-butyl dicarbonate (0.18kg) were added to a chloroform (1.7L) solution of diethyl (methylamino) malonate (0.17kg) obtained by the same synthesis method as described in the literature (tetrahedron, 2005, volume 61, page 8722-8739), and the mixture was stirred at room temperature for 14 hours, followed by concentration of the reaction mixture. The obtained residue was purified by OH silica gel column chromatography (gradient elution from hexane/ethyl acetate: 97/3 → 80/20) to obtain diethyl [ (t-butoxycarbonyl) (methyl) amino ] malonate (intermediate 3-1, yellow oil) (0.21kg, 82%).

MS(ESI)：312(M+Na)⁺

¹HNMR (600MHz, chloroform-d) ppm1.27-1.34(6H, m), [ 1.44%]，1.48(9H，s)，2.95(3H，s)，4.23-4.31(4H，m)，[5.11]，5.51(1H，s)

Synthesis of intermediate 3-1 (2)

[ (t-Butoxycarbonyl) (methyl) amino ] malonic acid diethyl ester

[ CHEM 45 ]

To a solution of diethyl [ phenylmethyl (methyl) amino ] malonate (intermediate 1-1, 0.55kg) in ethanol (5.3L) were added 10% Pd — C (0.16kg) and di-tert-butyl dicarbonate (0.42kg), and the mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere, filtered through celite, and the solvent was distilled off under reduced pressure. To a solution of the obtained residue in ethanol (3.5L), 10% Pd-C (71g) was added, and the mixture was further stirred at room temperature for 6 hours under a hydrogen atmosphere. The mixture was filtered through celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by OH silica gel column chromatography (gradient elution from hexane/ethyl acetate: 98/2 → 60/40) to obtain diethyl [ (t-butoxycarbonyl) (methyl) amino ] malonate (intermediate 3-1, colorless oil) (0.42kg, 74%).

MS(ESI)：312(M+Na)⁺，288(M-H)^-

¹HNMR (600MHz, chloroform-d) ppm1.27-1.34(6H, m), [ 1.44%]，1.48(9H，s)，2.95(3H，s)，4.19-4.32(4H，m)，[5.11]，5.51(1H，s)

Synthesis of intermediate 4-2

N²- (t-butoxycarbonyl) -N, N²O-trimethyl-3-oxoSubstituted serine amides

[ CHEM 46 ]

At [ (t-butoxycarbonyl) (methyl) amino group]To a solution of diethyl malonate (intermediate 3-1, 0.21kg) in methanol (2.1L) was added 40% methylamine-methanol solution (67mL), and the mixture was stirred at room temperature for 19 hours. A40% methylamine-methanol solution (23mL) was added thereto, and after stirring at the same temperature for 4 days, ethyl acetate (0.30L) was added, citric acid monohydrate (81g) was slowly added under ice-cooling, and stirring was carried out under ice-cooling for 30 minutes. The precipitated solid was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (gradient elution of hexane/ethyl acetate 75/25 → 15/85) to obtain N²- (t-butoxycarbonyl) -N, N²O-trimethyl-3-oxoserine amide (intermediate 4-2, yellow oil) (63g, 34%).

MS(ESI)：283(M+Na)⁺

¹HNMR (600MHz, chloroform-d) ppm1.44(9H, br.s.), 2.86(3H, br.s.), 2.99(3H, br.s.), 3.80(3H, s), [4.64]，5.11(1H，br.s.)，[6.85]，7.13(1H，br.s.)

Synthesis of intermediate 5-2 (1)

N，N²O-trimethyl-3-oxoserine amide hydrochloride

[ CHEM 47 ]

In N²- (t-butoxycarbonyl) -N, N ²O-trimethyl-3-oxoserine amide (intermediate 4-2, 62g) in ethyl acetate (0.19L) was added to a solution of 4.0 mol/L-hydrochloric acid-ethyl acetate (0.13L) at room temperatureStirred for 24 hours. The precipitated solid was filtered and washed with ethyl acetate to obtain N, N²O-trimethyl-3-oxoserine amide hydrochloride (intermediate 5-2, white solid) (39g, 84%).

MS(ESI)：161(M+H)⁺

¹HNMR(600MHz，DMSO-d₆)ppm2.71(3H，d，J＝4.58Hz)，3.34(3H，s)，3.79(3H，s)，4.81(1H，s).8.97(1H，br.s.)，9.69(1H，br.s.)

Synthesis of intermediate 5-2 (2)

N，N²O-trimethyl-3-oxoserine amide hydrochloride

[ CHEM 48 ]

In ({ [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl)]To a solution of (methyl) amino } methyl) benzene (intermediate 2-2, 7.1g) in methanol (50mL) were added di-tert-butyl dicarbonate (19mL) and 20% palladium hydroxide-carbon (1.4g), and the mixture was stirred at room temperature for 3.5 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was concentrated under reduced pressure. To a solution of the obtained residue in THF (20mL) was added dropwise a solution of 5.7 mol/L-hydrochloric acid-1, 4-dioxane (50mL) under water cooling, and the mixture was stirred at room temperature for 1 hour and 15 minutes. IPE (0.15L) was added thereto, the mixture was stirred for 15 minutes under ice-cooling, and the precipitated solid was filtered and washed with a mixed solvent of ethyl acetate-IPE (1: 2) to obtain N, N²O-trimethyl-3-oxosersamine hydrochloride (slightly orange solid) (4.9g, 88%).

¹HNMR(400MHz，D₂0)ppm2.63(3H，s)，2.70(3H，s)，3.75(3H，s)

Synthesis of intermediate 6-2

1-iodo-4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } benzene

[ CHEM 49 ]

In the presence of 4-iodobenzoyl chloride (13g), N²O-trimethyl-3-oxoserine amide hydrochloride (intermediate 5-2, 10g) was added to a chloroform (0.20L) suspension, DIPEA (27mL) was added thereto under ice-cooling, and the mixture was stirred at room temperature for 4 hours, followed by concentration of the reaction mixture. The resulting residue was purified by OH-type silica gel column chromatography (gradient elution from hexane/ethyl acetate 70/30 → 0/100) to give 1-iodo-4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl](methyl) carbamoyl } benzene (intermediate 6-2, white solid) (14g, 68%).

MS(ESI)：391(M+H)⁺，389(M-H)^-

¹HNMR (200MHz, chloroform-d) ppm2.88(3H, d, J ═ 4.8Hz), 3.11(3H, s), 3.84(3H, s), 5.45(1H, br.s), 7.16-7.34(3H, m), 7.71-7.86(2H, m)

Synthesis of intermediate 7-1

N- (t-Butoxycarbonyl) -O-ethyl-N-methyl-3-oxoserine

[ CHEM 50 ]

To a solution of diethyl [ (t-butoxycarbonyl) (methyl) amino ] malonate (intermediate 3-1, 1.0g) in ethanol (2.0mL) was added an ethanol solution (4.0mL) of potassium hydroxide (0.19g) prepared under ice-cooling, and the mixture was stirred at room temperature for 23 hours. The reaction mixture was concentrated under reduced pressure, and 1.0mol/L aqueous sodium hydrogencarbonate solution was added to conduct extraction with ethyl acetate. The aqueous layer was cooled with ice water, potassium hydrogensulfate was added thereto, the pH was adjusted to 2, and extraction with chloroform was performed. The extract was dried over anhydrous sodium sulfate, and after removing the drying agent by filtration, the solvent was distilled off under reduced pressure to give N- (t-butoxycarbonyl) -O-ethyl-N-methyl-3-oxoserine (intermediate 7-1, pale yellow oil) (0.26g, 29%).

MS(ESI)：284(M+Na)⁺，260(M-H)^-

¹HNMR(600MHz，DMSO-d₆)ppm1.18-1.23(3H，m)，[1.35]，1.42(9H，s)，[2.81]，2.84(3H，s)，4.14-4.20(2H，m)，[5.01]，5.23(1H，s)

Synthesis of intermediate 8-2

N²- (t-butoxycarbonyl) -N, N²O, 2-tetramethyl-3-oxoserine amide

[ CHEM 51 ]

In N²- (t-butoxycarbonyl) -N, N²O-trimethyl-3-oxoserine amide (intermediate 4-2, 2.0g) was dissolved in acetonitrile (5.0mL), methyl iodide (1.4mL) and potassium carbonate (1.6g) were added, and the mixture was stirred under a sealed condition at room temperature for 20 hours. Methyl iodide (2.8mL) was added thereto, and the mixture was stirred at room temperature for 3 days under a sealed condition. Further, methyl iodide (2.8mL) was added thereto, and the mixture was stirred under a sealed condition at room temperature for 1 day and then at 50 ℃ for 9 hours. After stirring at room temperature for 14 hours, potassium carbonate was removed by filtration, and the reaction solution was concentrated after washing with ethyl acetate. The obtained residue was purified by OH-type silica gel column chromatography (gradient elution of hexane/ethyl acetate 70/30 → 100/0) to obtain N²- (t-butoxycarbonyl) -N, N²O, 2-tetramethyl-3-oxoserine amide (intermediate 8-2, yellow oil) (1.5g, 78%).

MS(ESI)：275(M+H)⁺，297(M+Na)⁺

¹HNMR (200MHz, chloroform-d) ppm1.40(9H, s))，1.64(3H，s)，2.85(3H，d，J＝4.8Hz)，3.04(3H，s)，3.74(3H，s)8.02(1H，br.s.)

Synthesis of intermediate 9-1

O-ethyl-N, N²2-trimethyl-3-oxoserine amides

[ CHEM 52 ]

To a solution of diethyl bromo (methyl) malonate (3.0g) in THF (9.0mL) was added a 2.0 mol/L-methylamine-THF solution (21mL) under ice-cooling, and the mixture was stirred under a closed condition at room temperature for 16 hours. The precipitated solid was removed by filtration, and the filtrate was concentrated. The obtained residue was purified by OH silica gel column chromatography (chloroform/methanol gradient 100/0 → 93/7) to obtain O-ethyl-N, N ²2-trimethyl-3-oxoserine amide (intermediate 9-1, yellow oil) (2.0g, 89%).

MS(ESI)：189(M+H)⁺

¹HNMR (600MHz, chloroform-d) ppm1.27-1.32(3H, m), 1.51(3H, s), 2.30(3H, s), 2.82(3H, d, J ═ 5.0Hz), 4.13-4.33(2H, m), 7.17-7.25(1H, m)

Synthesis of intermediate 9-2

N，N²O, 2-tetramethyl-3-oxoserine amide hydrochloride

[ CHEM 53 ]

In N²- (t-butoxycarbonyl) -N, N²O, 2-tetramethyl-3-oxoserine amide (intermediate 8-2, 1.5g) in dioxane (5.0mL) was added 4.0 mol/L-dioxahexakis hydrochloride under ice-coolingRing (5.0mL), stirred at room temperature for 18 hours, and concentrated to give N, N²O, 2-tetramethyl-3-oxoserine amide hydrochloride (intermediate 9-2, white solid) (1.1g, 98%).

MS(ESI)：175(M+H)⁺

¹HNMR (200MHz, chloroform-d) ppm1.75(3H, s), 2.46(3H, s), 2.68(3H, d, J ═ 4.4Hz), 3.80(3H, s)8.60-8.67(1H, m), 9.85(1H, br.s.)

Synthesis of intermediate 10-1

1- { [ 1-ethoxy-2-methyl-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } -4-iodobenzene

[ CHEM 54 ]

In the presence of O-ethyl-N, N²2-trimethyl-3-oxoserine amide (intermediate 9-1, 0.25g) in chloroform (2.3mL) was added DIPEA (0.34mL) and 4-iodobenzoyl chloride (0.13g) under ice-cooling, and the reaction mixture was stirred at room temperature for 40 minutes and concentrated. The obtained residue was purified by NH silica gel column chromatography (gradient elution from hexane/ethyl acetate 70/30 → 35/65) to give 1- { [ 1-ethoxy-2-methyl-3- (methylamino) -1, 3-dioxopropan-2-yl ](methyl) carbamoyl } -4-iodobenzene (intermediate 10-1, yellow oil) (0.20g, 72%).

MS(ESI)：419(M+H)⁺，417(M+H)^-

¹HNMR (600MHz, chloroform-d) ppm1.21-1.28(3H, m), 1.75(3H, s), 2.88(3H, d, J ═ 4.5Hz), 3.13(3H, s), 4.13-4.29(2H, m), 7.18-7.24(2H, m), 7.72-7.81(2H, m), 8.09-8.23(1H, m)

Synthesis of intermediate 10-2

1- { [ 1-methoxy-2-methyl-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } -4-iodobenzene

[ CHEM 55 ]

To a solution of 1-iodo-4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } benzene (intermediate 6-2, 2.6g) in DMF (25mL) was added methyl iodide (1.7 mL). Potassium carbonate (1.4g) was added under water cooling, and the mixture was stirred at room temperature for 1.5 hours. Methyl iodide (0.40mL) and potassium carbonate (0.46g) were added thereto, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added, insoluble matter was removed by filtration, water was added to the filtrate, the pH was adjusted to 5 with 1 mol/L-hydrochloric acid, and the organic layer was separated. The extract was washed with water and saturated brine in this order, dried over anhydrous magnesium sulfate, filtered to remove the drying agent, and the solvent was distilled off under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (gradient elution of chloroform/acetone: 100/0 → 80/20) and then by OH-type silica gel column chromatography (gradient elution of chloroform/acetone: 196/4 → 175/25), to give 1- { [ 1-methoxy-2-methyl-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } -4-iodobenzene (colorless oil) (2.3g, 82%).

¹HNMR (400MHz, chloroform-d) ppm1.75(3H, s), 2.88(3H, d, J ═ 4.9Hz), 3.13(3H, s), 3.75(3H, s), 7.21-7.25(2H, m), 7.74-7.80(2H, m), 8.09-8.19(1H, m)

Synthesis of intermediate 11

1- { [ 2-carboxy-1- (methylamino) -1-oxopropan-2-yl ] (methyl) carbamoyl } -4-iodobenzene

[ CHEM 56 ]

To a solution of 1- { [ 1-methoxy-2-methyl-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } -4-iodobenzene (intermediate 10-2, 0.12g) in THF (1.0mL) -MeOH (1.0mL) was added 1.7mol/L aqueous potassium hydroxide (0.55mL) and the mixture was stirred at room temperature for 3 hours. Adjusting pH to 5 with 10% citric acid aqueous solution, and extracting with chloroform-methanol mixture. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and then the solvent was distilled off under reduced pressure to give 1- { [ 2-carboxy-1- (methylamino) -1-oxopropan-2-yl ] (methyl) carbamoyl } -4-iodobenzene (intermediate 11, orange solid). (91mg, 80%)

MS(ESI)：413(M+Na)⁺

¹HNMR (200MHz, chloroform-d) ppm1.80(3H, s), 2.84(3H, d, J ═ 4.8Hz)3.22(3H, s), 7.12-7.37(3H, m), 7.69-7.82(2H, m)

Synthesis of intermediate 12

2- [ (4-iodobenzoyl) (methyl) amino ] -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide

[ CHEM 57 ]

To a solution of 1- { [ 2-carboxy-1- (methylamino) -1-oxopropan-2-yl ] (methyl) carbamoyl } -4-iodobenzene (intermediate 11, 81mg) and HATU (120mg) in DMF (5.0mL) were added DIPEA (0.11mL) and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (24mg) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water was added, extraction was performed with chloroform, and then the organic layer was washed with saturated brine, dried over magnesium sulfate, and the drying agent was removed by filtration, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (gradient elution of chloroform/methanol 100/0 → 95/5) to give 2- [ (4-iodobenzoyl) (methyl) amino ] -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (intermediate 12, pale yellow oil) (59mg, 57%).

MS(ESI)：512(M+Na)⁺，488(M-H)^-

¹HNMR (600MHz, chloroform-d) ppm1.50-1.99(6H, m), [ 1.80%]，1.81(3H，s)，2.76-2.92(3H，m)，[3.14]，3.17(3H，s)，3.51-3.70(1H，m)，3.80-4.06(1H，m)，4.89-5.03(1H，m)，7.18-7.31(2H，m)，[6.97]，7.61(1H，br.s.)7.72-7.83(2H，m)，[10.04]，10.46(1H，s)

Isolation of intermediate 13-1

1- { [ (2S) -1-ethoxy-2-methyl-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } -4-iodobenzene

[ CHEM 58 ]

1- { [ 1-ethoxy-2-methyl-3- (methylamino) -1, 3-dioxopropan-2-yl](methyl) carbamoyl } -4-iodobenzene (intermediate 10-1, 0.26kg) was isolated and purified by Supercritical Fluid Chromatography (SFC). In (separation conditions: column: CHIRALCELOZ-H, column size: 3cmI.D.x25cmL, mobile phase: CO ₂Ethanol/acetonitrile 80/16/4<v/v/v>Flow rate: 85mL/min, column temperature: 25 ℃, detection wavelength: 240nm) to obtain 1- { [ (2S) -1-ethoxy-2-methyl-3- (methylamino) -1, 3-dioxopropan-2-yl](methyl) carbamoyl } -4-iodobenzene (intermediate 13-1, light yellow oil) (0.12 kg).

[α]_D: -37.4 (C: 0.10, chloroform)

Synthesis of intermediate 14

1- { [ (2S) -2-carboxy-1- (methylamino) -1-oxopropan-2-yl ] (methyl) carbamoyl } -4-iodobenzene

[ CHEMICAL 59 ]

To a solution of 1- { [ (2S) -1-ethoxy-2-methyl-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } -4-iodobenzene (intermediate 13-1, 36g) in THF (72mL) and methanol (36mL) was added dropwise a solution of potassium hydroxide (15g) in water (54mL) at room temperature, and stirred at room temperature for 30 minutes. To a mixture of water (0.36L) and 12 mol/L-hydrochloric acid (36mL) was added dropwise the reaction mixture at room temperature, and the mixture was stirred under ice-cooling for 30 minutes. The precipitate was filtered and washed with ice-cold water. The resulting suspension of solid ethyl acetate (75mL) and water (25mL) was stirred for 30 min, filtered and washed with ethyl acetate to give 1- { [ (2S) -2-carboxy-1- (methylamino) -1-oxopropan-2-yl ] (methyl) carbamoyl } -4-iodobenzene (intermediate 14, white solid) (21g, 62%).

MS(ESI)：413(M+Na)⁺，389(M-H)^-

¹HNMR (400MHz, chloroform-d) pm1.82(3H, s), 2.87(3H, d, J ═ 4.9Hz), 3.26(3H, s), 6.70-6.85(1H, m), 7.22-7.26(2H, m), 7.76-7.82(2H, m)

Synthesis of intermediate 15

(2S) -2- [ (4-iodobenzoyl) (methyl) amino ] -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide

[ CHEM 60 ]

To a solution of 1- { [ (2S) -2-carboxy-1- (methylamino) -1-oxopropan-2-yl ] (methyl) carbamoyl } -4-iodobenzene (intermediate 14, 4.0g) and O- (tetrahydropyran-2-yl) hydroxylamine (1.6g) in DMF (16mL) was added DIPEA (5.3mL) and HATU (5.9g) under water cooling. The mixture was stirred under ice-cooling for 2 hours and at room temperature for 1 hour. Water and ethyl acetate were added in this order, and the organic layer was separated. The extract was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. OH type silica gel (4.0g) was added thereto, stirred at room temperature for 10 minutes, filtered, and the solvent was distilled off under reduced pressure. To the residue was added a mixed solvent of IPE and ethyl acetate 10: 1, and the supernatant was removed. After repeating this operation 2 times, a mixed solvent of ethyl acetate (6.0mL) and IPA (6.0mL) was added to the obtained residue, and the solid was collected by filtration to obtain (2S) -2- [ (4-iodobenzoyl) (methyl) amino ] -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (intermediate 15, white solid) (1.3g, 26%). The residue obtained from the filtrate was purified by OH silica gel column chromatography (ethyl acetate/hexane 50/50 → gradient elution of chloroform/acetone 100/0 → 85/15) to give (2S) -2- [ (4-iodobenzoyl) (methyl) amino ] -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (intermediate 15, white solid) (1.7g, 34%).

MS(ESI)：512(M+Na)⁺，488(M-H)^-

¹HNMR (400MHz, chloroform-d) ppm1.50-2.00(6H, m) [1.83 ]]，1.84(3H，s)，2.85-2.90(3H，m)，[3.18]，3.20(3H，s)，3.55-3.72(1H，m)，3.85-4.10(1H，m)，4.95-5.05(1H，m)，[7.01]，7.66(1H，br.s.)，7.25-7.32(2H，m)，7.81(2H，d，J＝8.3Hz)，[10.10]，10.52(1H，s)

Synthesis of intermediate 16

[ (4-iodobenzoyl) (methyl) amino ] (methyl) malonic acid diethyl ester

[ CHEM 61 ]

To a solution of diethyl bromo (methyl) malonate (81g) in THF (0.23L) was added a 2.0 mol/L-methylamine-THF solution (0.51L) under ice-cooling, and the mixture was stirred under a closed condition at room temperature for 16 hours. The precipitated solid was removed by filtration, and the filtrate was concentrated. The obtained residue was purified by OH silica gel column chromatography (gradient elution of chloroform/methanol 100/0 → 92/8) to obtain a yellow oil (38 g). DIPEA (86mL) and 4-iodobenzoyl chloride (53g) were added to a chloroform (0.53L) solution of the yellow oil (38g) under ice-cooling, and the mixture was stirred at room temperature for 1 hour, followed by concentration of the reaction mixture. The obtained residue was purified by NH silica gel column chromatography (gradient elution of hexane/ethyl acetate: 30/70 → 0/100), IPE was added thereto, and the precipitated solid was collected by filtration and purified by OH silica gel column chromatography (gradient elution of chloroform/methanol: 100/0 → 95/5) to obtain diethyl [ (4-iodobenzoyl) (methyl) amino ] (methyl) malonate (intermediate 16-1, white solid) (3.3g, 1.1% yield in 2 steps).

¹HNMR (600MHz, chloroform-d) ppm1.30(6H, t, J ═ 7.0Hz), 1.81(3H, s), 2.93(3H, s), 4.17-4.36(4H, m), 7.20-7.28(2H, m), 7.71-7.81(2H, m)

The following examples are provided to describe the preparation of the compounds of the present invention in detail.

Example 1

2- [ (Biphenyl-4-ylcarbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide (Compound 1)

[ CHEM 62 ]

(1) In N, N²O-trimethyl-3-oxoserine amide hydrochloride (intermediate 5-2, 2.02g) and triethylamine (2.18g) in chloroform (20mL) were added in small amounts to 4-phenylbenzoyl chloride (2.23g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, warmed to room temperature and stirred for 1 hour. Water was added to the reaction solution, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate, filtered to remove the drying agent, and the solvent was distilled off under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (gradient elution of chloroform/methanol 98/2 → 90/10) to give 4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl group](methyl) carbamoyl } biphenyl (yellow solid) (3.0g, 86%).

MS(ESI)：363(M+Na)⁺，339(M-H)^-

¹HNMR (600MHz, chloroform-d) ppm2.90(3H, d, J ═ 4.58Hz), 3.20(3H, s), 3.85(3H, s), [5.14]，5.50(1H，br.s.)，7.18-7.23(1H，m)，7.39(1H，d，J＝7.34Hz)，7.46(2H，t，J＝7.79Hz)，7.55-7.69(6H，m)

[ CHEM 63 ]

(2) To a solution of 4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } biphenyl (30mg) obtained in example 1- (1) in THF (0.25mL) and ethanol (0.20mL) was added 50% aqueous hydroxylamine solution (0.20mL), and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by separation with silica gel thin layer chromatography (chloroform/methanol ═ 8/1), IPE was added, and the precipitated solid was filtered and dried to obtain 2- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide (compound 1, pale yellow solid) (17mg, 59%).

MS(ESI)：364(M+Na)⁺，340(M-H)^-

¹HNMR (600MHz, chloroform-d) ppm2.88(3H, br.s.), 3.06(3H, br.s.), 5.16]，5.59(1H，br.s.)，7.30-7.73(9H，m)，10.87(1H，br.s.)

Example 2

N-hydroxy-N '-methyl-2- (methyl { [ 4' - (methylamino) biphenyl-4-yl ] carbonyl } amino) malonamide (Compound 2)

[ CHEM 64 ]

(1) To a solution of tert-butyl (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) carbamate (2.0g) in DMF (6.OmL) were added 60% sodium hydride (0.55g) and methyl iodide (1.2mL), and the mixture was stirred at room temperature for 18 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The extract was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was distilled off under reduced pressure. Hexane was added to the residue, and the precipitated solid was collected by filtration to give tert-butyl methyl (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) carbamate (white solid) (1.46g, 70%).

¹HNMR (400MHz, chloroform-d) ppm1.34(12H, s), 1.45(9H, s), 3.27(3H, s), 7.24(2H, d, J ═ 8.4Hz), 7.76(2H, d, J ═ 8.4Hz)

[ CHEM 65 ]

(2) To a solution of tert-butyl methyl (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) carbamate (846mg) obtained in example 2- (1) and 4-iodobenzoic acid (420mg) in DMF (17mL) was added PdCl ₂(PPh₃)₂(119mg), triphenylphosphine (89mg), potassium phosphate (1.44g) and water (1.7mL) were stirred at 90 ℃ for 3.5 hours under a nitrogen atmosphere. After the reaction solution was allowed to cool, ethyl acetate and water were added, the pH was adjusted to 3 with 1 mol/L-hydrochloric acid, the organic layer was separated, and the extract was washed with water and saturated brine in this order. After drying over anhydrous magnesium sulfate, silica gel (10.0g) was added and stirred at room temperature for 15 minutes. After the drying agent and the silica gel were removed by filtration,the solvent was distilled off under reduced pressure. Hexane was added to the residue, and the precipitated solid was collected by filtration and washed with a mixed solvent of IPE/hexane 1/1. IPE was added to the resulting solid, and after stirring at room temperature for 15 minutes, the residual solid was collected by filtration to give 4' - ((t-butoxycarbonyl) (methyl) amino) biphenyl-4-carboxylic acid (pale brown solid) (396mg, 71%).

¹HNMR(400MHz，DMSO-d₆)ppm1.42(9H，s)，3.23(3H，s)，7.41(2H，d，J＝8.5Hz)，7.72(2H，d，J＝8.5Hz)，7.80(2H，d，J＝8.3Hz)，8.01(2H，d，J＝8.3Hz)，12.80-13.14(1H，br.s.)

[ CHEM 66 ]

(3) To a solution of 4' - ((t-butoxycarbonyl) (methyl) amino) biphenyl-4-carboxylic acid (0.10g) obtained in example 2- (2) in DMF (2.0mL) was added N, N²O-trimethyl-3-oxoserine amide hydrochloride (intermediate 5-2, 90mg), HATU (0.17g) and DIPEA (0.16mL) were stirred at room temperature for 16 hours. To the reaction mixture were added ethyl acetate and water, the organic layer was separated, and the extract was washed with water and saturated brine in this order. After drying over anhydrous sodium sulfate and removing the drying agent by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate ═ 1/3) to give 4- ((t-butoxycarbonyl) (methyl) amino) -4' - ((((2-methoxy-1- ((methylamino) carbonyl) -2-oxoethyl) (methyl) amino) carbonyl) biphenyl (white foamy substance) (73mg, 51%).

¹HNMR (400MHz, chloroform-d) ppm1.48(9H, s), 2.90(3H, d, J ═ 4.9Hz), 3.20(3H, s), 3.31(3H, s), 3.85(3H, s), 5.49(1H, s), 7.16-7.23(1H, m), 7.34(2H, d, J ═ 8.3Hz), 7.52-7.67(6H, m)

[ CHEM 67 ]

(4) To a solution of 4- ((t-butoxycarbonyl) (methyl) amino) -4' - (((2-methoxy-1- ((methylamino) carbonyl) -2-oxoethyl) (methyl) amino) carbonyl) biphenyl (60mg) obtained in example 2- (3) in anisole (1.0mL) was added TFA (1.0mL), and the mixture was stirred at room temperature for 1 hour. IPE was added to the reaction solution, the supernatant was removed, and a 50% aqueous hydroxylamine solution (1.5mL) was added to a methanol (2.0mL) solution of the obtained residue, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, the reaction mixture was adjusted to pH6 with 6 mol/L-hydrochloric acid, ethyl acetate was added thereto, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by separation using silica gel thin layer chromatography (chloroform/methanol ═ 5/1) to give N-hydroxy-N '-methyl-2- (methyl { [ 4' - (methylamino) biphenyl-4-yl ] carbonyl } amino) malonamide (compound 2, pale yellow solid) (20mg, 42%).

MS(ESI)：393(M+Na)⁺，369(M-H)^-

¹HNMR(400MHz，CD₃OD)ppm2.80(6H，br.s.)，3.12(3H，s)，6.69(2H，d，J＝8.6Hz)，7.35-7.69(6H，m)

Example 3

N-hydroxy-2- [ { [4 '- (methoxymethyl) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N' -methylmalonamide (Compound 4)

[ CHEM 68 ]

(1) To a solution of 1-bromo-4- (bromomethyl) benzene (5.0g) in methanol (40mL) was added 28% sodium methoxide-methanol solution (5.0g) at room temperature, and the mixture was stirred at room temperatureStirring for 21 hours. Water was added to the reaction mixture, and after extraction with diethyl ether, the organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. To a DMSO solution (40mL) of the resulting residue were added 4, 4, 4 ', 4 ', 5, 5, 5 ', 5 ' -octamethyl-2, 2 ' -bis-1, 3, 2-dioxaborane (7.6g), PdCl₂(dppf)·CH₂Cl₂(0.82g) and potassium acetate (5.9g), and the mixture was stirred at 100 ℃ for 4 hours. After cooling, water (0.10L) and ethyl acetate (0.10L) were added to the mixture, and insoluble matter precipitated was removed by filtration, and the filtrate was extracted with ethyl acetate. Filtering to remove desiccant, distilling off solvent under reduced pressure, and purifying the obtained residue by OH-type silica gel chromatography (gradient elution of hexane/ethyl acetate: 90/10 → 80/20) to obtain 2- [4- (methoxymethyl) phenyl]4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane (pale green solid) (4.1g, 82%).

MS(ESI)：249(M+H)⁺

¹HNMR (200MHz, chloroform-d) ppm1.34(12H, s), 3.38(3H, s), 4.48(2H, s), 7.30-7.38(2H, m), 7.76-7.83(2H, m)

[ CHEM 69 ]

(2) To a solution of 2- [4- (methoxymethyl) phenyl ] -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane (4.1g) obtained in example 3- (1) in ethanol (0.10L) were added ethyl 4-iodobenzoate (5.5g), tetrakis (triphenylphosphine) palladium (1.2g) and cesium carbonate (9.8g), and after stirring at 80 ℃ for 30 minutes, the solvent was distilled off under reduced pressure. The obtained residue was purified by OH silica gel chromatography (hexane/ethyl acetate ═ 85/15) to give ethyl 4' - (methoxymethyl) biphenyl-4-carboxylate (pale yellow solid) (3.5g, 80%).

MS(ESI/APCIDual)：271(M+H)⁺

¹HNMR (200MHz, chloroform-d) ppm1.43(3H, t, J ═ 7.0Hz), 3.43(3H, s), 4.42(2H, q, J ═ 7.0Hz), 4.51(2H, s), 7.41-7.45(2H, m), 7.57-7.70(4H, m), 8.06-8.15(2H, m)

[ CHEM 70 ]

(3) To a solution of ethyl 4' - (methoxymethyl) biphenyl-4-carboxylate (3.5g) obtained in example 3- (2) in THF (20mL) was added ethanol (20mL) and a 2.0mol/L aqueous solution of sodium hydroxide (10mL), and the mixture was stirred at 80 ℃ for 1 hour. Water was added to the reaction solution, and after neutralization with an aqueous hydrochloric acid solution, the precipitate was collected by filtration to give 4' - (methoxymethyl) biphenyl-4-carboxylic acid (gray solid) (3.0g, 96%).

MS(ESI/APCIDual)：241(M-H)^-

¹HNMR(600MHz，DMSO-d₆)ppm3.32(3H，s)，4.46(2H，s)，7.41-7.43(2H，m)，7.69-7.72(4H，m)，7.97-8.01(2H，m)

[ CHEM 71 ]

(4) To a solution of 4' - (methoxymethyl) biphenyl-4-carboxylic acid (0.36g) obtained in example 3- (3) in DMF (6.0mL) were added intermediate 5-2(0.39g), HATU (0.57g), and DIPEA (0.80mL), and the mixture was stirred at 80 ℃ for 30 minutes, followed by addition of saturated saline to the reaction mixture, extraction with ethyl acetate, and drying of the organic layer over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by NH-type silica gel chromatography (gradient elution of hexane/ethyl acetate: 50/50 → 0/100) to give 4- (methoxymethyl) -4' - { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } biphenyl (yellow oil) (0.40g, 69%).

MS(ESI/APCIDual)：385(M+H)⁺，407(M+Na)⁺，383(M-H)^-

¹HNMR (600MHz, chloroform-d) ppm2.88(3H, d, J ═ 4.6Hz), 3.19(3H, s), 3.43(3H, s), 3.84(3H, s), 4.51(2H, s), 5.52(1H, s), 7.27(1H, br.s.), 7.43-7.44(2H, m), 7.56-7.67(6H, m)

[ CHEM 72 ]

(5) To a tetrahydrofuran (5.0mL) solution of 4- (methoxymethyl) -4 ' - { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } biphenyl (0.40g) obtained in example 3- (4) was added ethanol (5.0mL) and a 50% aqueous hydroxylamine solution (5.0mL), and the mixture was stirred at room temperature for 2 hours, followed by concentrating the reaction mixture under reduced pressure, purifying the resulting product by separation with silica gel thin layer chromatography (chloroform/methanol ═ 85/15), adding IPE, collecting the precipitated solid by filtration, and drying the solid to obtain N-hydroxy-2- [ { [4 ' - (methoxymethyl) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N ' -methylmalonamide (compound 4, peach solid) (0.18g, 46%).

MS(ESI/APCIDual)：408(M+Na)⁺，384(M-H)^-

¹HNMR(600MHz，CD₃OD)ppm2.83(3H，br.s.)，3.12(3H，s)，3.40(3H，s)，4.51(2H，s)，7.44(2H，d，J＝8.25Hz)，7.57-7.78(6H，m)

Compounds 3, 5, 6, 8, 40, 43, 52, 56, 58, 61, 94, 112, 114, 115, 153, 165, 169, 176, 179-185, 187-192, 195-197, 199-203, 208, 211-216, 220, 222-224, 226-231, 233, 236-241, 243, 244, 246-248, 251-262, 265, 266, 269-271, 278, 279, 281, 282, 285-287, 290, 291, 298, 299, 308-312, 344, 347, 352, 442-452, 456-460, 462, 463, 467-470, 474, 475, 479, 480, 499, 502 and 519 were synthesized by the same method as in example 3 using the corresponding starting materials.

Example 4

N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [3- (morpholin-4-yl) propoxy ] biphenyl-4-yl } carbonyl) amino ] malonamide (Compound 7)

N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [3- (morpholin-4-yl) propoxy ] biphenyl-4-yl } carbonyl) amino ] malonamide 4-methylbenzenesulfonate (Compound 7b)

[ CHEM 73 ]

(1) To a solution of 4' -hydroxybiphenyl-4-carbonitrile (10g) in DMF (0.10L) were added 2- (3-chloropropyloxy) tetrahydro-2H-pyran (11g), potassium carbonate (11g) and potassium iodide (4.4g), and the mixture was stirred at 100 ℃ for 5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, and then the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure. To a solution of the obtained residue in ethanol (0.10L) was added PPTS (1.3g), and the mixture was stirred at 60 ℃ for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by OH-type silica gel chromatography (gradient elution of hexane/ethyl acetate: 80/20 → 20/80) to give 4' - (3-hydroxypropoxy) biphenyl-4-carbonitrile (white solid) (12g, 88%).

MS(ESI/APCIDual)：434(M+H)⁺，456(M+Na)⁺，432(M-H)^-

¹HNMR (600MHz, chloroform-d) ppm2.09(2H, quin, J ═ 6.0Hz), 3.87-3.91(2H, m), 4.19(2H, t, J ═ 6.0Hz), 7.00-7.03(2H, m), 7.52-7.55(2H, m), 7.63-7.65(2H, m), 7.68-7.70(2H，m)

[ CHEM 74 ]

(2) To a chloroform (0.1L) solution of 4' - (3-hydroxypropoxy) biphenyl-4-carbonitrile (5.1g) obtained in example 4- (1) was added TsCl (12g) and pyridine (10mL), and the mixture was stirred at room temperature overnight. Chloroform was added to the reaction mixture, and the mixture was washed with a 1.0mol/L aqueous hydrochloric acid solution and a 1.0mol/L aqueous sodium hydrogencarbonate solution, and the organic layer was dried over anhydrous magnesium sulfate, and then the drying agent was removed by filtration, and the solvent was distilled off under reduced pressure. IPE was added to the obtained residue, and the precipitated solid was collected by filtration, followed by addition of ethanol (40mL) and morpholine (8.8mL), followed by stirring at 80 ℃ for 1 hour. The reaction solution was distilled off under reduced pressure, and the obtained residue was purified by OH-type silica gel chromatography (gradient elution from hexane/ethyl acetate: 50/50 → 90/10) to give 4' - [3- (morpholin-4-yl) propoxy ] biphenyl-4-carbonitrile (pale brown solid) (5.1g, 79%)

MS(ESI/APCIDual)：323(M+H)⁺

¹HNMR (200MHz, chloroform-d) ppm1.93-2.07(2H, m), 2.44-2.59(6H, m), 3.69-3.76(4H, m), 4.08(2H, t, J ═ 6.7H2), 6.95-7.04(2H, m), 7.48-7.57(2H, m), 7.60-7.72(4H, m)

[ CHEM 75 ]

(3) To a solution of 4' - [3- (morpholin-4-yl) propoxy ] biphenyl-4-carbonitrile (5.1g) obtained in example 4- (2) in ethanol (0.12L) was added an aqueous 8.0 mol/L-potassium hydroxide solution (40mL), and the mixture was refluxed for 12 hours. The solvent was distilled off under reduced pressure, and water (0.20L) was added to the obtained residue, followed by addition of concentrated hydrochloric acid (25mL) and a 1.0mol/L aqueous solution of potassium hydrogensulfate (30mL) under ice-cooling to neutralize the residue. The precipitated solid was collected by filtration and washed with water to give 4' - [3- (morpholin-4-yl) propoxy ] biphenyl-4-carboxylic acid (white solid) (5.5g, 100%)

MS(ESI/APCIDual)：283(M-H)^-

¹HNMR(600MHz，DMSO-d₆)ppm2.12-2.24(2H，m)，2.91-3.61(6H，m)，3.75-4.04(4H，m)，4.13(2H，t，J＝6.0Hz)，7.05-7.09(2H，m)，7.69-7.72(2H，m)，7.74-7.77(2H，m)，7.98-8.00(2H，m)

[ CHEM 76 ]

(4) 4' - [3- (morpholin-4-yl) propoxy ] obtained in example 4- (3)]To a solution of biphenyl-4-carboxylic acid (0.34g) in DMF (5.0mL) were added intermediate 5-2(0.24g), WSC. HCl (0.29g), HOBt. H₂O (0.20g) and DIPEA (0.27mL) were stirred at room temperature for 2 hours, and then an aqueous sodium hydrogencarbonate solution was added to the reaction mixture to extract it with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered to remove the drying agent, and the solvent was distilled off under reduced pressure. The obtained residue was purified by NH-type silica gel chromatography (gradient elution from hexane/ethyl acetate: 50/50 → 0/100) to give 4- {3- [ (4' - { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl) ](methyl) carbamoyl } biphenyl-4-yl) oxy]Propyl morpholine (colorless oil) (0.11g, 23%).

MS(ESI/APCIDual)：484(M+H)⁺，506(M+Na)⁺，482(M-H)^-

¹HNMR (600MHz, chloroform-d) ppm2.01(2H, quin, J ═ 6.8Hz), 2.48-2.50(4H, m), 2.55(2H, t, J ═ 6.8Hz), 2.91(3H, d, J ═ 5.0Hz), 3.20(3H, br.s.), 3.73-3.75(4H, m), 3.85(3H, s), 4.09(2H, t, J ═ 6.8Hz), 5.48(1H, s), 6.99-7.00(2H, m), 7.17-7.18(1H, m), 7.53-7.63(6H, m)

[ CHEM 77 ]

(5) To a solution of 4- {3- [ (4' - { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } biphenyl-4-yl) oxy ] propyl } morpholine (0.11g) obtained in example 4- (4) in THF (1.0mL) were added ethanol (1.0mL) and a 50% aqueous hydroxylamine solution (1.0mL), and the mixture was stirred at room temperature for 2 hours, followed by concentrating the reaction mixture under reduced pressure. The obtained residue was purified by separation using silica gel thin layer chromatography (chloroform/methanol ═ 90/10), and then recrystallized from ethyl acetate/hexane to give N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [3- (morpholin-4-yl) propoxy ] biphenyl-4-yl } carbonyl) amino ] malonamide (compound 7, light brown solid) (43mg, 39%).

MS(ESI/APCIDual)：485(M+H)⁺，507(M+Na)⁺，483(M-H)^-

¹HNMR(600MHz，DMSO-d₆)ppm1.84-1.92(2H，m)，2.33-2.40(4H，m)，2.41-2.46(2H，m)，2.67(3H，br.s.)，2.98(3H，s)，3.54-3.61(4H，m)，4.03-4.10(2H，m)，5.36，[5.84](1H，br.s.)，7.01-7.06(2H，m)，7.32-7.74(6H，m)，8.14(1H，br.s.)，9.04(1H，br.s.)，10.85(1H，br.s.)

[ CHEM 78 ]

(6) N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [3- (morpholin-4-yl) propoxy) group obtained in example 4- (5) ]Biphenyl-4-yl } carbonyl) amino]To a suspension of malonamide (compound 7, 24mg) in THF (1.0mL) was added p-TsOH. H₂O (9.5mg), and after stirring at room temperature for 10 minutes, the precipitate was collected by filtration to give N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [3- (morpholin-4-yl) propoxy)]Biphenyl-4-Yl } carbonyl) amino]Malonamide 4-methylbenzenesulfonate (compound 7b, white solid) (26mg, 79%).

MS(ESI/APCIDual)：485(M+H)⁺，483(M-H)^-

¹HNMR(600MHz，CD₃OD)ppm2.18-2.29(2H，m)，2.36(3H，s)，2.83(3H，br.s.)，3.12(3H，br.s.)，3.17-3.40(8H，m)，3.90(2H，br.s.)，4.12-4.19(2H，m)，7.04(2H，d，J＝8.7Hz)，7.22(2H，d，J＝8.3Hz)，7.54-7.77(8H，m)

Example 5

N-hydroxy-N' -methyl-2- [ methyl (4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } benzoyl) amino ] malonamide (compound 168)

[ CHEM 79 ]

(1) To a solution of ethyl 4-iodobenzoate (20g) in THF (0.25L) were added 4-ethynylbenzaldehyde (10g) and PdCl, which were obtained according to the same method as the synthesis method described in the literature (tetrahedron letters, 2007, vol. 48(33), page 5817-₂(PPh₃)₂(3.4g), CuI (1.5g), and triethylamine (32mL) were stirred at room temperature for 3 hours, and then the reaction mixture was concentrated. The obtained residue was purified by OH-type silica gel chromatography (gradient elution from hexane/chloroform: 80/20 → 0/100) to obtain 4- [ (4-formylphenyl) ethynyl group]Ethyl benzoate (yellow solid) (16g, 69%).

¹HNMR (600MHz, chloroform-d) ppm1.41(3H, t, J ═ 7.3Hz), 4.40(2H, q, J ═ 7.3Hz), 7.62(2H, d, J ═ 8.7Hz), 7.70(2H, d, J ═ 7.8Hz), 7.89(2H, d, J ═ 7.8Hz), 8.05(2H, d, J ═ 8.7Hz), 10.04(1H, s)

[ CHEM 80 ]

(2) To a chloroform (20mL) solution of ethyl 4- [ (4-formylphenyl) ethynyl ] benzoate (2.1g) obtained in example 5- (1) was added 1, 4-oxoazalane hydrochloride (1.6g) and acetic acid (0.90mL), and the mixture was stirred at room temperature for 3.5 hours, followed by stirring at 60 ℃ for 2 hours, followed by addition of sodium triacetoxyborohydride (2.7g) and stirring at room temperature for 16 hours. After a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH silica gel chromatography (chloroform/methanol gradient 100/0 → 93/7) to give ethyl 4- { [4- (1, 4-oxoazanan-4-ylmethyl) phenyl ] ethynyl } benzoate (yellow solid) (1.5g, 52%).

MS(ESI)：364(M+H)⁺

¹HNMR (600MHz, chloroform-d) ppm1.41(3H, t, J ═ 6.9Hz), 1.85-1.94(2H, m), 2.64-2.75(4H, m), 3.67(2H, s), 3.70-3.75(2H, m), 3.80-3.86(2H, m), 4.39(2H, q, J ═ 6.9Hz), 7.36(2H, d, J ═ 7.8Hz), 7.45-7.61(4H, m), 7.99-8.05(2H, m)

[ CHEMICAL 81 ]

(3) To a solution of ethyl 4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } benzoate (1.5g) obtained in example 5- (2) in THF (15mL), ethanol (15mL) and water (10mL) was added a 10% aqueous sodium hydroxide solution (6.6mL), and the mixture was stirred at room temperature for 3 hours and then neutralized with acetic acid (5.0 mL). The reaction mixture was concentrated, water was added, and the precipitated solid was filtered and dried to give 4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } benzoic acid (white solid) (0.92g, 67%).

MS(ESI)：336(M+H)⁺，334(M+H)^-

¹HNMR(600MHz，DMSO-d6)ppm1.77-1.84(2H，m)，2.58-2.67(4H，m)，3.58-3.73(6H，m)，7.40(2H，d，J＝8.3Hz)，7.54(2H，d，J＝8.3Hz)，7.63(2H，d，J＝8.3Hz)，7.95(2H，d，J＝8.3Hz)

[ CHEM 82 ]

(4) 4- { [4- (1, 4-Oxoazepan-4-ylmethyl) phenyl group obtained in example 5- (3) was used]Ethynyl } benzoic acid (0.25g), N²O-trimethyl-3-oxoserinamide hydrochloride (intermediate 5-2, 0.18g) was reacted with the same example 4- (4) to give 4- {4- [ (4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl)](methyl) carbamoyl } phenyl) ethynyl]Benzyl } -1, 4-oxoazadecane (white solid) (0.11g, 30%).

MS(ESI)：478(M+H)⁺，476(M+H)^-

¹HNMR (600MHz, chloroform-d) ppm1.85-1.97(2H, m), 2.64-2.77(4H, m), 2.90(3H, d, J ═ 4.6Hz), 3.12-3.18(3H, m), 3.66-3.78(4H, m), 3.80-3.87(5H, m), 5.46(1H, s), 7.12-7.22(1H, m), 7.36(2H, d, J ═ 6.9Hz), 7.41-7.67(6H, m)

[ CHEM 83 ]

(5) The same procedures used in example 4- (5) were repeated except for using 4- {4- [ (4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } phenyl) ethynyl ] benzyl } -1, 4-oxoazacane (0.11g) obtained in example 5- (4) to give N-hydroxy-N' -methyl-2- [ methyl (4- { [4- (1, 4-oxoazanan-4-ylmethyl) phenyl ] ethynyl } benzoyl) amino ] malonamide (compound 168, white solid) (40mg, 37%).

MS(ESI)：479(M+H)⁺，477(M-H)^-

¹HNMR (600MHz, chloroform-d) ppm1.90-1.99(2H, m), 2.65-2.81(4H, m), 2.90(3H, d, J ═ 5.0Hz), 3.01(3H, s), 3.68-3.78(4H, m), 3.81-3.86(2H, m), 5.58(1H, br.s.), 7.38(2H, d, J ═ 7.3Hz), 7.50(2H, d, J ═ 7.8Hz), 7.53-7.63(4H, m)

Example 6

2- ({ [4- (4-Cyclopropylbut-1, 3-diyn-1-yl) phenyl ] carbonyl } (methyl) amino) -N-hydroxy-N' -methylmalonamide (Compound 507)

[ CHEM 84 ]

(1) To a solution of methyl 4- (bromoethynyl) benzoate (0.65g) obtained by the method described in patent (WO2008/154642) in THF (6.5mL) was added PdCl under water cooling in a nitrogen atmosphere₂(PPh₃)₂(95mg), CuI (52mg), diisopropylamine (1.5mL), and ethynylcyclopropane (0.30mL), and stirred for 1.5 hours. Ethyl acetate and water were added, the pH was adjusted to 5 with 6 mol/L-hydrochloric acid, and the organic layer was separated. The extract was dried over anhydrous magnesium sulfate, and then dried by filtration to remove the drying agent, the solvent was distilled off under reduced pressure, the obtained residue was purified by OH-type silica gel column chromatography (gradient elution of hexane/ethyl acetate: 95/5 → 92/8), hexane was added to the obtained solid, and filtration was performed to obtain methyl 4- (4-cyclopropylbut-1, 3-diyn-1-yl) benzoate (pale brown solid) (0.31g, 51%).

¹HNMR (400MHz, chloroform-d) ppm0.82-0.95(4H, m), 1.37-1.47(1H, m), 3.91(3H, s), 7.51(2H, d, J ═ 8.2Hz), 7.96(2H, d, J ═ 8.2Hz)

[ CHEM 85 ]

(2) To methyl 4- (4-cyclopropylbut-1, 3-diyn-1-yl) benzoate (0.31g) obtained in example 6- (1) were added methanol (3.0mL), 1, 4-dioxane (3.0mL) and a 20% aqueous solution of sodium hydroxide (1.5mL), and the mixture was stirred at room temperature for 2.5 hours. Ethyl acetate and water were added, the pH was adjusted to 3 with 6 mol/L-hydrochloric acid, and the organic layer was separated. The extract was dried over anhydrous magnesium sulfate, filtered to remove the drying agent, and the solvent was distilled off under reduced pressure to give 4- (4-cyclopropylbut-1, 3-diyn-1-yl) benzoic acid (dark brown solid) (0.28g, 94%).

¹HNMR(400MHz，DMSO-d₆)ppm0.70-1.05(4H，m)，1.50-1.65(1H，m)，7.63(2H，d，J＝8.3Hz)，7.92(2H，d，J＝8.3Hz)，13.21(1H，br.s.)

[ CHEM 86 ]

(3) To a solution of 4- (4-cyclopropylbut-1, 3-diyn-1-yl) benzoic acid (0.42g) obtained in example 6- (2) in DMF (4.0mL) were added HATU (1.1g) and DIPEA (1.0mL), and the mixture was stirred at room temperature for 2.5 hours, followed by addition of N, N²O-trimethyl-3-oxoserine amide hydrochloride (intermediate 5-2, 0.59g) was stirred at 70 to 80 ℃ for 40 minutes. The reaction solution was cooled to room temperature, ethyl acetate and water were added, the organic layer was separated, and the extract was washed with water and saturated brine in this order. Drying with anhydrous magnesium sulfate, filtering to remove the drying agent, and distilling under reduced pressure to remove the solvent to obtain 1- (4-cyclopropylbut-1, 3-diyne-1 -yl) -4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl](methyl) carbamoyl } benzene (brown oil) (0.81 g).

¹HNMR (400MHz, chloroform-d) ppm0.81-0.95(4H, m), 1.37-1.51(1H, m), 2.88(3H, d, J ═ 4.8Hz), 3.11(3H, s), 3.83(3H, s), 5.44(1H, s), 7.15-7.35(1H, m), 7.35-7.57(4H, m)

[ CHEM 87 ]

(4) To a solution of 1- (4-cyclopropylbut-1, 3-diyn-1-yl) -4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } benzene (0.81g) obtained in example 6- (3) in methanol (2.0mL) was added a 50% aqueous hydroxylamine solution (1.0mL) under ice-cooling, and after stirring for 30 minutes under ice-cooling, the mixture was stirred for 2.5 hours under water-cooling. A50% aqueous hydroxylamine solution (1.0mL) was added thereto, and the mixture was stirred for 30 minutes under water cooling. Ethyl acetate and water were added to the reaction mixture, and after adjusting the pH to 5 with 6 mol/L-hydrochloric acid, the organic layer was separated. The extract was washed with water and saturated brine in this order, dried over anhydrous magnesium sulfate, filtered to remove the drying agent, and the solvent was distilled off under reduced pressure. To the obtained residue were added chloroform and IPE, followed by filtration, and the obtained solid was purified by OH-type silica gel column chromatography (chloroform/methanol ═ 10/1), whereby 2- ({ [4- (4-cyclopropylbut-1, 3-diyn-1-yl) phenyl ] carbonyl } (methyl) amino) -N-hydroxy-N' -methylmalonamide (compound 507, white solid) (0.16g, yield in 2 steps: 20%) was obtained.

MS(ESI)：376(M+Na)⁺，352(M-H)^-

¹HNMR(400MHz，CD₃OD)ppm0.73-0.80(2H，m)，0.87-0.95(2H，m)，1.41-1.50(1H，m)，2.80(3H，s)，3.04(3H，s)，7.30-7.57(4H，m)

Compounds 476, 484, 492, 493, 500, 509, 511, and 529 were synthesized by the same method as in example 3 using the corresponding starting materials.

Example 7

2- [ (Biphenyl-4-ylcarbonyl) (methyl) amino ] -N-hydroxy-N' - [ (5-methyl-1, 2-oxazol-3-yl) methyl ] malonamide (Compound 172)

[ CHEM 88 ]

(1) N- (t-butoxycarbonyl) -O-ethyl-N-methyl-3-oxoserine (intermediate 7-1, 2.3g), 1- (5-methyl-1, 2-oxazol-3-yl) methylamine (1.0g), WSC & HCl (2.4g), HOBt & H₂O (1.9g) and chloroform (24mL) were stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added to the reaction mixture, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate, the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by OH-type silica gel column chromatography (gradient elution with chloroform/methanol: 98/2 → 92/8) to give 3- ({ [ N- (t-butoxycarbonyl) -O-ethyl-N-methyl-3-oxoseryl aminoacyl)]Amino } methyl) -5-methyl-1, 2-oxazole (light yellow oil) (2.1g, 67%).

MS(ESI)：378(M+Na)⁺，354(M-H)^-

¹HNMR (600MHz, chloroform-d) ppm1.24-1.34(3H, m), [ 1.38%]，1.48(9H，br.s.)，2.39(3H，s)，2.96-3.06(3H，m)，4.21-4.30(2H，m)，4.44-4.57(2H，m)，[4.63]，5.01(1H，br.s.)，6.00(1H，s)，7.57，[7.81](1H，br.s.)

[ CHEM 89 ]

(2) To a solution of 3- ({ [ N- (t-butoxycarbonyl) -O-ethyl-N-methyl-3-oxoseryl ] amino } methyl) -5-methyl-1, 2-oxazole (0.30g) obtained in example 7- (1) in ethyl acetate (2.0mL) was added 4.0 mol/L-hydrochloric acid-ethyl acetate (1.0mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and chloroform (2.0mL), TEA (0.27g), and 4-phenylbenzoyl chloride (0.18g) were added to the resulting residue under water-cooling, followed by stirring at room temperature overnight. The reaction solution was purified by OH-type silica gel column chromatography (chloroform/methanol gradient 98/2 → 96/4) to give 3- ({ [ N- (biphenyl-4-ylcarbonyl) -O-ethyl-N-methyl-3-oxoserinyl ] amino } methyl) -5-methyl-1, 2-oxazole (colorless oil) (0.15g, 40%).

MS(ESI)：458(M+Na)⁺，434(M-H)^-

¹HNMR(600MHz，DMSO-d₆)ppm1.22-1.30(m，3H)，2.39(3H，s)，2.97-3.04(3H，m)，4.17-4.24(2H，m)，4.38(2H，d，J＝5.0Hz)，[5.01]，5.64(1H，br.s)，6.10-6.18(1H，m)，7.36-7.82(10H，m)

[ CHEM 90 ]

(3) The same procedures used in example 4- (5) were repeated except for using 3- ({ [ N- (biphenyl-4-ylcarbonyl) -O-ethyl-N-methyl-3-oxoseryl ] amino } methyl) -5-methyl-1, 2-oxazole (0.15g) obtained in example 7- (2) to give 2- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N-hydroxy-N' - [ (5-methyl-1, 2-oxazol-3-yl) methyl ] malonamide (compound 172, white solid) (63mg, 45%)

MS(ESI)：445(M+Na)⁺，421(M-H)^-

¹HNMR(600MHz，DMSO-d₆)ppm2.38(3H，s)，3.00(3H，s)，4.35(2H，br.s.)[4.75]，5.45(1H，br.s.)，6.19(1H，br.s.)，7.36-7.61(5H，m)，7.67-7.80(4H，m)，8.85(1H，br.s.)，9.10(1H，br.s.)，10.93(1H，br.s.)

Compounds 116, 118 to 126, 128 to 147, 149 to 152, 155 to 158, 170 to 173, 175, 177 and 178 were synthesized by the same method as in example 7 using the corresponding starting materials.

Example 8

2- [ (Biphenyl-4-ylcarbonyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide (Compound 164)

[ CHEM 91 ]

(1) To a solution of diethyl aminomalonate hydrochloride (4.3g) and TEA (8.4mL) in chloroform (80mL) was added 4-phenylbenzoyl chloride (4.3g) in small amounts under ice-cooling, and the mixture was stirred at the same temperature for 3 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate, and after removing the drying agent by filtration, the solvent was distilled off under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (chloroform/methanol-20/1) to obtain diethyl [ (biphenyl-4-ylcarbonyl) amino ] malonate (white solid) (6.7g, 95%).

MS(ESI)：356(M+H)⁺，378(M+Na)⁺

¹HNMR (600MHz, chloroform-d) ppm1.35(6H, t, J ═ 7.2Hz), 4.28-4.39(4H, m), 5.38(1H, d, J ═ 6.6Hz), 7.16(1H, d, J ═ 6.6Hz), 7.41(1H, tt, J ═ 7.5, 1.3Hz), 7.48(2H, t, J ═ 7.5Hz), 7.63(2H, dd, J ═ 7.5, 1.3Hz), 7.70(2H, d, J ═ 8.5Hz), 7.94(2H, d, J ═ 8.5Hz)

[ CHEM 92 ]

(2) Methyl iodide (0.18g) was added to a suspension of diethyl [ (biphenyl-4-ylcarbonyl) amino ] malonate (0.36g) obtained in example 8- (1) and potassium carbonate (0.20g) in acetonitrile (5.0mL), and the mixture was stirred at room temperature for 14 hours under a sealed condition. Water was added to the reaction solution, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate, and after removing the drying agent by filtration, the solvent was distilled off under reduced pressure. The obtained residue was purified by OH silica gel column chromatography (gradient elution of hexane/ethyl acetate 80/20 → 50/50) to obtain diethyl [ (biphenyl-4-ylcarbonyl) amino ] (methyl) malonate (white solid) (0.24g, 66%).

MS(ESI)：370(M+H)⁺

¹HNMR (600MHz, chloroform-d) ppm1.27(6H, t, J ═ 7.1Hz), 1.88(3H, s), 4.24-4.33(4H, m), 7.38(1H, tt, J ═ 7.7, 1.2Hz), 7.46(2H, t, J ═ 7.7Hz), 7.58(1H, br.s), 7.61(2H, dd, J ═ 7.7, 1.2Hz), 7.67(2H, d, J ═ 8.4Hz), 7.89(2H, d, J ═ 8.4Hz)

[ CHEM 93 ]

(3) To a solution of diethyl [ (biphenyl-4-ylcarbonyl) amino ] (methyl) malonate (0.24g) obtained in example 8- (2) in methanol (3.0mL) was added 40% methylamine-methanol solution (61mg), and the mixture was stirred under sealed conditions at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (gradient elution from hexane/ethyl acetate: 50/50 → 30/70) to give 4- { [ 1-methoxy-2-methyl-3- (methylamino) -1, 3-dioxopropan-2-yl ] carbamoyl } biphenyl (white solid) (70mg, 31%).

MS(ESI)：341(M+Na)⁺，375(M+Cl)^-

¹HNMR (600MHz, chloroform-d) ppm1.92(3H, s),2.89-2.92(3H，m)，3.79(3H，s)，6.34-6.39(1H，m)，7.37-7.41(1H，m)，7.45-7.49(2H，m)，7.60-7.64(2H，m)，7.66-7.70(2H，m)，7.89(1H，br.s)，7.91-7.94(2H，m)

[ CHEM 94 ]

(4) Using 4- { [ 1-methoxy-2-methyl-3- (methylamino) -1, 3-dioxopropan-2-yl ] carbamoyl } biphenyl (70mg) obtained in example 8- (3), the same procedures as in example 4- (5) were carried out to give 2- [ (biphenyl-4-ylcarbonyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide (compound 164, white solid) (10mg, 15%)

MS(ESI)：364(M+Na)⁺，340(M-H)^-

¹HNMR(600MHz，DMSO-d₆)ppm1.66(3H，s)，2.63(3H，d，J＝4.6Hz)，7.40-7.44(1H，m)，7.48-7.54(2H，m)，7.75(2H，d，J＝8.7Hz)，7.80(2H，d，J＝8.3Hz)，7.96(2H，d，J＝8.3Hz)，8.16(1H，br.s.)，8.90(1H，br.s.)，10.89(1H，br.s.)

Example 9

2- [ (Biphenyl-4-ylcarbonyl) (cyclopropyl) amino ] -N-hydroxy-N' -methylmalonamide (Compound 127)

[ CHEM 95 ]

(1) To a solution of diethyl bromomalonate (1.0g) in acetonitrile (10mL) was added cyclopropylamine (0.30mL), and the mixture was stirred at room temperature for 16 hours. The precipitated solid was removed by filtration, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by OH-type silica gel column chromatography (gradient elution of hexane/ethyl acetate: 90/10 → 70/30) to obtain (cyclopropylamino) diethyl malonate (colorless oil) (0.57g, 63%).

MS(ESI)：216(M+H)⁺，214(M+H)^-

¹HNMR (600MHz, chloroform-d) ppm0.37-0.52(4H, m), 1.22-1.34(6H, m), 2.15-2.22(1H, m), 4.17-4.28(4H, m), 4.82(1H, s)

[ CHEM 96 ]

(2) To a solution of diethyl (cyclopropylamino) malonate (0.20g) obtained in example 9- (1) in methanol (2.0mL) was added a 40% methylamine-methanol solution (86 μ L), and after stirring at room temperature for 5 days, the reaction solution was concentrated. The obtained residue was purified by OH silica gel column chromatography (gradient elution of chloroform/methanol 100/0 → 95/5) 2 times to obtain N²cyclopropyl-N, O-dimethyl-3-oxoserine amide (colorless oil) (58mg, 31%).

MS(ESI)：201(M+H)⁺

¹HNMR (600MHz, chloroform-d) ppm0.29-0.34(1H, m), 0.42-0.53(3H, m), 2.14-2.20(1H, m), 2.80-2.83(3H, m), 3.83(3H, s), 4.00(1H, s), 6.94(1H, br.s.)

[ CHEM 97 ]

(3) N obtained in example 9- (2)²To a chloroform (0.70mL) solution of cyclopropyl-N, O-dimethyl-3-oxoserine amide (70mg) was added DIPEA (0.11mL) and 4-phenylbenzoyl chloride (78mg) under ice-cooling, and the mixture was stirred at room temperature for 15 hours and ice-cooling for 4.5 hours, followed by concentrating the reaction mixture.The obtained residue was purified 2 times by OH-type silica gel column chromatography (chloroform/methanol gradient 100/0 → 95/5) to give 4- { cyclopropyl [ 1-ethoxy-3- (methylamino) -1, 3-dioxopropan-2-yl group ]Carbamoyl } biphenyl and 4- { cyclopropyl [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl]Carbamoyl } biphenyl (34mg, 26%) as a yellow oil.

MS(ESI)：403(M+Na)⁺，379(M-H)-，389(M+Na)⁺，365(M-H)^-

¹HNMR (600MHz, chloroform-d) ppm0.41-0.70(4H, m), 1.24-1.36(3H, m), 2.13-2.21(1H, m), [ 2.80%]，2.89(3H，d，J＝5.0Hz)，[3.81，[3.82]](3H，s)，4.21-4.33(2H，m)，4.61，[4.65](1H，s)，7.35-7.49(3H，m)，7.58-7.95(7H，m)

[ CHEM 98 ]

(4) The same procedures used in example 4- (5) were repeated except for using a mixture (34mg) of 4- { cyclopropyl [ 1-ethoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] carbamoyl } biphenyl obtained in example 9- (3) and 4- { cyclopropyl [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] carbamoyl } biphenyl to give 2- [ (biphenyl-4-ylcarbonyl) (cyclopropyl) amino ] -N-hydroxy-N' -methylmalonamide (compound 127, white solid) (3.2mg, 10%).

MS(ESI)：390(M+Na)⁺，366(M-H)^-

¹HNMR (600MHz, chloroform-d) ppm0.44-0.69(4H, m), 2.88(3H, d, J ═ 4.6Hz), 3.07-3.13(1H, m), 5.18(1H, s), 7.02-7.19(1H, m), 7.36-7.42(1H, m), 7.44-7.50(2H, m), 7.60-7.70(4H, m), 7.76(2H, d, J ═ 8.3Hz), 10.92(1H, br.s.)

Compounds 154 and 198 were synthesized in the same manner as in example 9 using the corresponding starting materials.

Example 10

2- [ { [4- ({4- [ (cyclopropylamino) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -n-hydroxy-n' -methylmalonamide (compound 301)

[ CHEM 99 ]

(1) 4-ethynylbenzaldehyde (14g) and PdCl obtained from ethyl 4-iodobenzoate (30g) and according to the synthetic method described in the literature (tetrahedron letters, 2007, vol. 48(33), p. 5817-₂(PPh₃)₂TEA (46mL) was added to a suspension of (3.9g) and CuI (2.1g) in THF (0.40L), and the mixture was stirred at 45 ℃ for 4 hours. After cooling, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was distilled off under reduced pressure. After hexane/ethyl acetate (1: 1(v/v)) was added to the obtained residue and stirred, a precipitate was collected by filtration and dried. The filtrate was concentrated and the same operation was carried out to give 4- [ (4-formylphenyl) ethynyl group]Ethyl benzoate (yellow solid) (27g, 88%).

MS(ESI/APCIDual)：279(M+H)⁺

¹HNMR (200MHz, chloroform-d) ppm1.41(3H, t, J ═ 7.3Hz), 4.40(2H, q, J ═ 7.3Hz), 7.52-7.78(4H, m), 7.81-8.18(4H, m), 10.04(1H, s)

[ CHEM 100 ]

(2) Trimethyl orthoformate (51g) and (+) -CSA (2.3g) were added to a methanol (0.40L) -chloroform (0.10L) mixture of ethyl 4- [ (4-formylphenyl) ethynyl ] benzoate (27g) obtained in example 10- (1), and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, followed by extraction with chloroform. After drying the organic layer over anhydrous magnesium sulfate, the drying agent was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH silica gel chromatography (hexane/ethyl acetate gradient 95/5 → 80/20) to give ethyl 4- { [4- (dimethoxymethyl) phenyl ] ethynyl } benzoate (white solid) (21g, 67%).

MS(ESI/APCIDual)：325(M+H)⁺

¹HNMR(200MHz，DMSO-d₆)ppm1.33(3H，t，J＝7.2Hz)，3.26(6H，s)，4.33(2H，q，J＝7.2Hz)，5.43(1H，s)，7.36-7.78(6H，m)，7.91-8.07(2H，m)

[ CHEM 101 ]

(3) To a solution of ethyl 4- { [4- (dimethoxymethyl) phenyl ] ethynyl } benzoate (21g) obtained in example 10- (2) in THF (0.25L) -methanol (0.25L) was added a 2.0 mol/L-aqueous sodium hydroxide solution (0.10L), and the mixture was stirred at room temperature for 3 hours. After the solvent was distilled off, water and acetic acid were added to the residue to adjust the pH to 4, and the precipitate was collected by filtration and dried. Hexane/ethyl acetate (3: 1(v/v)) was added, and after stirring for a short time, the precipitate was collected by filtration and dried to give 4- { [4- (dimethoxymethyl) phenyl ] ethynyl } benzoic acid (white solid) (15g, 75%).

MS(ESI/APCIDual)：295(M-H)^-

¹HNMR(200MHz，DMSO-d₆)ppm3.26(6H，s)，5.43(1H，s)，7.36-7.67(6H，m)，7.85-8.00(2H，m)

[ CHEM 102 ]

(4) 4- { [4- (dimethoxymethyl) phenyl group obtained in example 10- (3)]To a solution of ethynyl } benzoic acid (5.0g) and HATU (9.6g) in DMF (50mL) were added DIPEA (8.8mL), N²O-trimethyl-3-oxoserine amide hydrochloride (intermediate 5-2, 3.3g) was stirred at 80 ℃ for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered to remove the drying agent, and the solvent was distilled off under reduced pressure. The residue obtained is purified by chromatography on silica gel type NH (gradient hexane/ethyl acetate 50/50 → 0/100) to yield 1- (dimethoxymethyl) -4- [ (4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl) ](methyl) carbamoyl } phenyl) ethynyl]Benzene (yellow oil) (6.6g, 89%).

MS(ESI/APCIDual)：439(M+H)⁺，461(M+Na)⁺，437(M-H)^-

¹HNMR(200MHz，DMSO-d₆)ppm2.69(3H，d，J＝4.4Hz)，2.93(3H，s)，3.26(6H，s)，3.72(3H，s)，5.43(1H，s)，5，58(1H，s)，7.24-7.73(8H，m)，8.50(1H，br.d，J＝4.4Hz)

[ CHEM 103 ]

(5) To a solution of 1- (dimethoxymethyl) -4- [ (4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } phenyl) ethynyl ] benzene (6.5g) obtained in example 10- (4) in acetone (50mL) was added 1.0mol/L aqueous hydrochloric acid (4.0mL) under ice-cooling, and the mixture was stirred at room temperature for 15 hours. After the solvent was distilled off, hexane/AcOEt (20: 1(v/v)) was added to the residue, and after stirring for a short time, the precipitate was collected by filtration and dried to give 1-formyl-4- [ (4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } phenyl) ethynyl ] benzene (white solid) (4.6g, 79%).

MS(ESI/APCIDual)：393(M+H)⁺，415(M+Na)⁺，391(M-H)^-

¹HNMR (200MHz, chloroform-d) ppm2.90(3H, d, J ═ 4.8Hz), 3.15(3H, s), 3.86(3H, s), 5.47(1H, br.s), 7.20(1H, br.s.), 7.44-7.97(8H, m), 10.03(1H, s)

[ CHEM 104 ]

(6) To a chloroform (20mL) solution of 1-formyl-4- [ (4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } phenyl) ethynyl ] benzene (1.0g) obtained in example 10- (5) were added cyclopropylamine (0.15g) and acetic acid (0.16g), and the mixture was stirred at room temperature for 2.5 hours, then sodium triacetoxyborohydride (0.89g) was added, and the mixture was stirred at room temperature for 15 hours. After a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was distilled off under reduced pressure. The obtained residue was purified by OH silica gel chromatography (gradient elution from hexane/ethyl acetate 34/66 → 1/100) to give 1- [ (cyclopropylamino) methyl ] -4- [ (4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } phenyl) ethynyl ] benzene (colorless foam) (0.84g, 74%).

MS(ESI/APCIDual)：434(M+H)⁺，456(M+Na)⁺，432(M-H)^-

¹HNMR (200MHz, chloroform-d) ppm0.34-0.49(4H, m), 2.10-2.20(1H, m), 2.89(3H, d, J ═ 4.8Hz), 3.14(3H, s), 3.84(3H, s), 3.86(2H, s), 5.48(1H, s)，7.23-7.34(3H，m)，7.48-7.60(6H，m)

[ CHEM 105 ]

(7) The same procedures used in example 4- (5) were repeated except for using 1- [ (cyclopropylamino) methyl ] -4- [ (4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } phenyl) ethynyl ] benzene (0.84g) obtained in example 10- (6) to give 2- [ { [4- ({4- [ (cyclopropylamino) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide (Compound 301, white solid) (0.56g, 84%)

MS(ESI/APCIDual)：435(M+H)⁺，457(M+Na)⁺，433(M-H)^-

¹HNMR(600MHz，CD₃OD)ppm0.38-0.41(2H，m)，0.46-0.49(2H，m)，2.14(1H，tt，J＝6.9，3.6Hz)，2.82(3H，br.s.)，3.08(3H，s)，3.83(2H，s)，7.38-7.39(2H，m)，7.42-7.64(6H，m)

Compounds 300, 302 to 305, 313 to 318, 321 to 323, 325 to 334, 336, 337, 353 to 356, 359 to 363, 365, 366, 368 to 374, 378, 383, 384, 386 to 388, 391 to 393, 482, 485, 486, 489, 490, 494, 495, 497, 505, 510, 512, 513, 515, 522, 524, 525, 527, 530, 532, 533, 535, 537 to 540, 542, 543, 546, 551 and 552 were synthesized in the same manner as in example 10 using the corresponding starting materials.

Example 11

2- { [ (4- { [4- (2, 3-dihydroxypropoxy) phenyl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide (Compound 320)

[ CHEM 106 ]

(1) Methyl 4-ethynylbenzoate (0.95g) and PdCl (PdCl) obtained by the same method as the synthesis method described in the document (journal of organic chemistry (transaction of Zhu Huanale organic chemical Khimii), 2002, 38(2), pp. 213-219) were added to a THF (35mL) solution of 3- (4-iodophenoxy) propane-1, 2-diol (1.8g) obtained by the same method as the synthesis method described in the document (journal of American chemical society, 2010, pp. 132(30), 10391-10397)₂(PPh₃)₂(0.21g), CuI (0.11g), and TEA (2.5mL) were stirred at room temperature for 2 hours. The reaction mixture was concentrated, ethyl acetate-chloroform was added, and the precipitated solid was filtered and dried to obtain 4- { [4- (2, 3-dihydroxypropoxy) phenyl group]Ethynyl } benzoic acid methyl ester (orange solid) (0.92g, 47%).

MS(ESI)：349(M+Na)⁺，361(M+Cl)^-

¹HNMR(200MHz，DMSO-d₆)ppm3.45(2H，t，J＝5.7Hz)，3.73-4.14(6H，m)，4.62-4.74(1H，m)，4.98(1H，d，J＝4.8Hz)，7.01(2H，d，J＝8.8Hz)，7.44-7.72(4H，m)，7.98(2H，d，J＝8.8Hz)

[ CHEM 107 ]

(2) To a solution of methyl 4- { [4- (2, 3-dihydroxypropoxy) phenyl ] ethynyl } benzoate (0.92g) obtained in example 11- (1) in THF (25mL) and MeOH (15mL) was added a 10% aqueous sodium hydroxide solution (5.5mL), and the mixture was stirred at room temperature for 3.5 hours and then neutralized with acetic acid (1.2 mL). The reaction mixture was concentrated, water was added, and the precipitated solid was filtered and dried to give 4- { [4- (2, 3-dihydroxypropoxy) phenyl ] ethynyl } benzoic acid (pale green solid) (0.80g, 91%).

MS(ESI)：335(M+Na)⁺，311(M-H)^-

¹HNMR(200MHz，DMSO-d₆)ppm3.42-3.53(3H，m)，3.65-4.17(4H，m)，6.80-7.98(8H，m)

[ CHEMICAL 108 ]

(3) 4- { [4- (2, 3-dihydroxypropoxy) phenyl group obtained in example 11- (2)]To a solution of ethynyl } benzoic acid (0.20g) in DMF (2.0mL) was added N, N²O-trimethyl-3-oxoserine amide hydrochloride (intermediate 5-2, 0.13g), HATU (0.17g) and DIPEA (0.33mL) was stirred at 80 ℃ for 1 hour. After a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered to remove the drying agent, and the solvent was distilled off under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (gradient elution with ethyl acetate/methanol 99/1 → 88/12) to give 1- (2, 3-dihydroxypropoxy) -4- [ (4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl group](methyl) carbamoyl } phenyl) ethynyl]Benzene (white solid) (23mg, 8.0%).

MS(ESI)：477(M+Na)⁺，453(M-H)^-

¹HNMR (600MHz, chloroform-d) ppm2.86-2.93(3H, m), 3.15(3H, s), 3.83(3H, br.s.), 4.01-4.18(5H, m), 5.45(1H, s), 6.85-6.95(2H, m), 7.17-7.23(1H, m), 7.42-7.59(6H, m)

[ CHEM 109 ]

(4) The same procedures used in example 4- (5) were repeated except for using 1- (2, 3-dihydroxypropoxy) -4- [ (4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } phenyl) ethynyl ] benzene (23mg) obtained in example 11- (3) to give 2- { [ (4- { [4- (2, 3-dihydroxypropoxy) phenyl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide (compound 320, white solid) (3.0mg, 14%).

MS(ESI)：478(M+Na)⁺，454(M-H)^-

¹HNMR(600MHz，CD₃OD)ppm2.82(3H，br.s.)，3.08(3H，s)，3.61-3.73(2H，m)，3.93-4.05(2H，m)，4.06-4.14(1H，m)，6.98(2H，d，J＝9.2Hz)，7.40-7.65(6H，m)

Compound 335 was synthesized using the corresponding starting materials in the same manner as in example 11.

Example 12

2- [ (Biphenyl-4-ylcarbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide (Compound 324)

[ CHEM 110 ]

(1) In the presence of O-ethyl-N, N²2-trimethyl-3-oxoserine amide (intermediate 9-1, 0.69g) in chloroform (10mL) was added DIPEA (1.0mL) and 4-phenylbenzoyl chloride (0.50g) in this order, and the mixture was stirred at room temperature for 5 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, followed by extraction with chloroform. After drying the organic layer over anhydrous magnesium sulfate, the drying agent was removed by filtration, and the solvent was distilled off under reduced pressure. The residue obtained is purified by chromatography on silica gel type OH (hexane/ethyl acetate gradient 60/40 → 25/75) to give 4- { [ 1-ethoxy-2-methyl-3- (methylamino) -1, 3-dioxopropan-2-yl](methyl) carbamoyl } biphenyl (colorless oil)Material) (0.79g, 66%).

MS(ESI/APCIDual)：391(M+Na)⁺

¹HNMR (600MHz, chloroform-d) ppm1.28(3H, t, J ═ 7.1Hz), 1.78(3H, s), 2.90(3H, d, J ═ 5.0Hz), 3.19(3H, s), 4.13-4.32(2H, m), 7.33-7.50(3H, m), 7.52-7.70(6H, m), 8.14-8.24(1H, m)

[ CHEM 111 ]

(2) 4- { [ 1-ethoxy-2-methyl-3- (methylamino) -1, 3-dioxopropan-2-yl ] obtained in example 12- (1) ]To a solution of (methyl) carbamoyl } biphenyl (0.30g) in ethanol (3.0mL) -THF (3.0mL) was added a 0.84mol/L aqueous solution of potassium hydroxide (3.0mL), and the mixture was stirred at room temperature for 4.5 hours. Under ice-cooling conditions, water and a 2.0mol/L aqueous solution of potassium hydrogensulfate were added to adjust the pH to 7, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the drying agent was removed by filtration, and the solvent was distilled off under reduced pressure to give 4- { [ 2-carboxy-1- (methylamino) -1-oxopropan-2-yl](methyl) carbamoyl } biphenyl (orange solid) (0.29g, 82%). MS (ESI/APCIDual): 363(M + Na)⁺，295(M-CO²-H)^-

¹HNMR (600MHz, chloroform-d) ppm1.85(3H, s), 2.89(3H, d, J ═ 4.6Hz), 3.34(3H, s), 6.68(1H, br.s.), 7.34-7.51(3H, m), 7.53-7.70(6H, m)

[ CHEM 112 ]

(3) To a DMF (5.0mL) solution of 4- { [ 2-carboxy-1- (methylamino) -1-oxopropan-2-yl ] (methyl) carbamoyl } biphenyl (0.23g) obtained in example 12- (2) were added DIPEA (0.30mL), HATU (0.35g) and O-benzylhydroxylamine hydrochloride (0.14g) in this order under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 3 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the drying agent was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by OH silica gel chromatography (hexane/ethyl acetate gradient 70/30 → 0/100) and chloroform/methanol gradient 98/2 → 95/5) to give N- (benzyloxy) -2- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N', 2-dimethylmalonamide (light brown oil) (0.22g, 75%).

MS(ESI/APCIDual)：468(M+Na)⁺，444(M-H)^-

¹HNMR (600MHz, chloroform-d) ppm1.78(3H, s), 2.84(3H, d, J ═ 4.6Hz), 3.21(3H, s), [4.84]，4.94(2H，s)，7.14-7.23(1H，m)，7.28-7.54(10H，m)，7.57-7.66(4H，m)，10.14(1H，s)

[ CHEM 113 ]

(4) To a solution of N- (benzyloxy) -2- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N', 2-dimethylmalonamide (0.10g) obtained in example 12- (3) in methanol (3.0mL) was added 10% Pd-C (36mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. After filtration through celite, the solvent was distilled off, and the residue was purified by separation with silica gel thin layer chromatography (chloroform/methanol-14/1) to give 2- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide (compound 324, yellow solid) (38mg, 48%).

MS(ESI/APCIDual)：378(M+Na)⁺，394(M+K)⁺，354(M-H)^-

¹HNMR(600MHz，CD₃OD)ppm1.76(3H，s)，2.78(3H，s)，3.20(3H，s)，7.33-7.38(1H，m)，7.42-7.47(2H，m)，7.59-7.66(4H，m)，7.71(2H，d，J＝8.7Hz)

Compounds 342, 348 to 350 and 521 were synthesized by the same method as in example 12 using the corresponding starting materials.

Example 13

(2S) -2- [ (Biphenyl-4-ylcarbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide (Compound 341)

[ CHEM 114 ]

(1) N- (benzyloxy) -2- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N', 2-dimethylmalonamide (80mg) obtained in example 12- (3) was isolated and purified by using a chiral column. Purification was carried out under the conditions (separation conditions: column: CHIRALPAKAD, column size: 2cmI.D.x25cmL, mobile phase: hexane/IPA 50/50< v/v >, flow rate: 10mL/min, column temperature: 25 ℃ C., detection wavelength: 254nm) to give (2S) -N- (benzyloxy) -2- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N', 2-dimethylmalonamide (white solid) (29mg, 36%).

[α]_D(ii) a +26.8 (C: 0.10, chloroform)

¹HNMR (600MHz, chloroform-d) ppm1.78(3H, s), 2.84(3H, d, J ═ 4.6Hz), 3.21(3H, s), [4.84]，4.94(2H，s)，7.16-7.23(1H，m)，7.28-7.67(14H，m)，10.10-10.17(1H，m)

[ CHEM 115 ]

(2) To a solution of (2S) -N- (benzyloxy) -2- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N', 2-dimethylmalonamide (21mg) obtained in example 13- (1) in methanol (2.6mL) was added 10% Pd — C (7.0mg), and the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere, filtered through celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by separation using silica gel thin layer chromatography (chloroform/methanol ═ 6/1) to give (2S) -2- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide (compound 341, white solid) (4.2mg, 27%).

[α]_D(ii) a +8.3 (C: 0.17, methanol)

MS(ESI)：378(M+Na)⁺，354(M-H)^-

¹HNMR (600MHz, chloroform-d) ppm1.84(3H, s), 2.86(3H, d, J ═ 5.0Hz), 3.27(3H, s), 6.72-6.77(1H, m), 7.36-7.42(1H, m), 7.44-7.50(2H, m), 7.58-7.63(4H, m), 7.63-7.68(2H, m), 10.56-10.67(1H, m)

Example 14

2- [ { [4- ({4- [1- (cyclopropylamino) ethyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide (compound 357)

[ CHEM 116 ]

(1) To a solution of 1- (4-iodophenyl) ethanone (1.2g) in chloroform (20mL) were added cyclopropylamine (0.85g), acetic acid (0.89g), and sodium triacetoxyborohydride (3.2g), and the mixture was stirred at room temperature under a nitrogen atmosphere for 24 hours. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and then the organic layer was washed with a saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the drying agent was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by OH type silica gel chromatography (hexane/ethyl acetate ═ 80/20) to give N- [1- (4-iodophenyl) ethyl ] cyclopropylamine (colorless oil) (1.3g, 95%).

MS(ESI/APCIDual)：288(M+H)⁺

¹HNMR (200MHz, chloroform-d) ppm0.22-0.41(4H, m), 1.34(3H, d, J ═ 6.6Hz), 1.88-2.00(1H, m), 3.82(1H, q, J ═ 6.6Hz), 7.03-7.12(2H, m), 7.59-7.68(2H, m)

[ CHEM 117 ]

(2) N- [1- (4-iodophenyl) ethyl ] obtained in example 14- (1)]To a solution of cyclopropylamine (0.23g) in chloroform (5.0mL) was added ethynyl (trimethyl) silane (80mg), PdCl₂(PPh₃)₂(29mg), CuI (16mg), and TEA (0.25g) were stirred at room temperature under a nitrogen atmosphere for 24 hours. After stirring at 45 ℃ for 2 hours, PdCl was added₂(PPh₃)₂(29mg), the reaction mixture was refluxed for 5 hours under a nitrogen atmosphere and then concentrated. The obtained residue was purified by OH type silica gel chromatography (hexane/ethyl acetate ═ 85/15) to give N- (1- {4- [ (trimethylsilyl) ethynyl group]Phenyl } ethyl) cyclopropylamine (brown oil) (0.14g, 66%).

MS(ESI/APCIDual)：258(M+H)⁺

¹HNMR (600MHz, chloroform-d) ppm0.21-0.39(4H, m), 0.25(9H, s), 1.34(3H, d, J ═ 6.9Hz), 1.91-1.94(1H, m), 3.84(1H, q, J ═ 6.9Hz), 7.24-7.25(2H, m,), 7.41-7.43(2H, m) })

[ CHEM 118 ]

(3) To a solution of N- (1- {4- [ (trimethylsilyl) ethynyl ] phenyl } ethyl) cyclopropylamine (0.12g) obtained in example 14- (2) in methanol (3.0mL) was added potassium carbonate (96mg), and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. The reaction mixture was filtered to remove solids and concentrated. The obtained residue was purified by OH type silica gel chromatography (hexane/ethyl acetate ═ 95/5) to give N- [1- (4-ethynylphenyl) ethyl ] cyclopropylamine (colorless oil) (85mg, 100%).

MS(ESI/APCIDual)：186(M+H)⁺

¹HNMR (200MHz, chloroform-d) ppm0.20-0.42(4H, m), 1.36(3H, d, J ═ 6.9Hz), 1.88-2.00(1H, m), 3.04(1H, s), 3.85(1H, q, J ═ 6.9Hz), 7.23-7.30(2H, m), 7.42-7.49(2H, m)

[ CHEM 119 ]

(4) N- [1- (4-ethynylphenyl) ethyl group obtained in example 14- (3)]To a solution of cyclopropylamine (51mg) in chloroform (5.0mL) were added intermediate 6-2(0.11g), PdCl₂(PPh₃)₂(10mg), CuI (5.0mg), and TEA (28mg) were stirred at room temperature under a nitrogen atmosphere for 2 hours, and then the reaction mixture was concentrated. The obtained residue was purified by OH type silica gel chromatography (ethyl acetate) to obtain 1- [1- (cyclopropylamino) ethyl group]-4- [ (4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl](methyl) carbamoyl } phenyl) ethynyl]Benzene (light yellow bubbles) (0.10g, 85%).

MS(ESI/APCIDual)：448(M+H)⁺，470(M+Na)⁺，446(M-H)^-

¹HNMR (200MHz, chloroform-d) ppm0.25-0.42(4H, m), 1.38(3H, d, J ═ 6.6Hz), 1.90-2.02(1H, m), 2.89(3H, d, J ═ 4.8Hz), 3.14(3H, br.s), 3.84(3H, s), 3.88(1H, q, J ═ 6.6Hz), 5.48(1H, br.s), 7.24-7.36(3H, m), 7.48-7.60(6H, m)

[ CHEM 120 ]

(5) The same procedures used in example 4- (5) were repeated except for using 1- [1- (cyclopropylamino) ethyl ] -4- [ (4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } phenyl) ethynyl ] benzene (98mg) obtained in example 14- (4) to give 2- [ { [4- ({4- [1- (cyclopropylamino) ethyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide (compound 357, white solid) (42mg, 89%).

MS(ESI/APCIDual)：449(M+H)⁺，471(M+Na)⁺，447(M-H)^-

¹HNMR(600MHz，CD₃OD)ppm0.31-0.42(4H，m)，1.39(3H，d，J＝6.9Hz)，1.96(1H，m)，2.82(3H，br.s.)，3.08(3H，s)，3.90(1H，q，J＝6.9Hz)，7.39-7.62(8H，m)

Compounds 358, 367, 375, 379, 381, 382, 385, 407, 455, 461, 464, 465, 471 to 473, 483, 487, 488, 491, 496, 498, 501, 503, 504, 506, 508, 514, 516 to 518, 523, 536, 544, 545, 547, 562 to 564, 568, 572 to 574, and 579 to 582 were synthesized in the same manner as in example 14 using the corresponding starting materials.

Example 15

N-hydroxy-N', 2-dimethyl-2- { [ (4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide (Compound 380)

[ CHEM 121 ]

(1) A40% methylamine-methanol solution (0.80mL) was added to a methanol (90mL) solution of diethyl { [ (4-iodophenyl) carbonyl ] amino } malonate (4.1g) obtained according to the same method as the synthesis method described in the literature (Organic & biomolecular chemistry, 2005, Vol. 3(19), p. 3531-3539), and the mixture was stirred at room temperature for 19 hours. Then, 40% methylamine-methanol solution (0.24mL) was added thereto, and the mixture was stirred at the same temperature for 19 hours, followed by concentration of the reaction mixture. The resulting residue was purified by OH silica gel column chromatography (chloroform/ethanol gradient 95/5 → 90/10) to give 1-iodo-4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] carbamoyl } benzene (white solid) (1.5g, 39%).

MS(ESI)：377(M+H)⁺，411(M+Cl)^-

¹HNMR (600MHz, chloroform-d) ppm2.90(3H, d, J ═ 5.2Hz), 3.84(3H, s), 5.19(1H, d, J ═ 6.2Hz), 6.44-6.50(1H, m), 7.38-7.44(1H, m), 7.58(2H, d, J ═ 8.7Hz), 7.82(2H, d, J ═ 8.7Hz)

[ CHEM 122 ]

(2) Methyl iodide (0.35mL) was added to a suspension of 1-iodo-4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] carbamoyl } benzene (1.5g) obtained in example 15- (1), potassium carbonate (0.81g) in acetonitrile (40mL) and DMF (16mL), and the mixture was stirred at room temperature for 4 days under a sealed condition. Water was added to the reaction solution, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate, and after removing the drying agent by filtration, the solvent was distilled off under reduced pressure. The resulting residue was purified by OH silica gel column chromatography (hexane/ethyl acetate gradient 45/55 → 14/86) to give 1-iodo-4- { [ 1-methoxy-2-methyl-3- (methylamino) -1, 3-dioxopropan-2-yl ] carbamoyl } benzene (colorless oil) (1.3g, 82%).

MS(ESI)：391(M+H)⁺，425(M+Cl)^-

¹HNMR (600MHz, chloroform-d) ppm1.89(3H, s), 2.96(3H, s), 3.77(3H, s), 6.34(1H, br.s.), 7.53-7.59(2H, m), 7.78-7.83(2H, m), 7.85(1H, s)

[ CHEM 123 ]

(3) 1, 4-Oxoazalkane hydrochloride (1.0g) and TEA (1.1mL) were added to a chloroform (20mL) solution of 4-ethynylbenzaldehyde (1.0g) obtained by the same synthesis method as described in literature (tetrahedron letters, 2007, volume 48(33), page 5817-5820), followed by stirring at room temperature for 30 minutes, adding acetic acid (0.45mL), stirring at room temperature for 1 hour, then adding sodium triacetoxyborohydride (2.4g), and stirring at room temperature for 15 hours. After a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was distilled off under reduced pressure. The resulting residue was purified by NH-type silica gel chromatography (gradient hexane/ethyl acetate 90/10 → 60/40) to give 4- (4-ethynylbenzyl) -1, 4-oxoazadecane (yellow solid) (1.4g, 87%).

MS(ESI)：216(M+H)⁺

¹HNMR (200MHz, chloroform-d) ppm1.78-1.99(2H, m), 2.58-2.75(4H, m), 3.05(1H, s), 3.60-3.75(4H, m), 3.77-3.91(2H, m), 7.26-7.50(4H, m)

[ CHEM 124 ]

(4) 1-iodo-4- { [ 1-methoxy-2-methyl-3- (methylamino) -1, 3-dioxopropan-2-yl obtained in example 15- (2)]To a solution of carbamoyl } benzene (0.16g) in THF (2.0mL) was added 4- (4-ethynylbenzyl) -1, 4-oxoazacane (79mg) obtained in example 15- (3), PdCl₂(PPh₃)₂(14mg), CuI (9.0mg), and TEA (0.16mL) were stirred at room temperature for 2 hours, and then the reaction mixture was concentrated. The residue obtained is purified by chromatography on silica gel type OH (hexane/ethyl acetate gradient 57/43 → 3/97) to give 4- {4- [ (4- { [ 1-methoxy-2-methyl-3- (methylamino) -1, 3-dioxopropan-2-yl)]Carbamoyl } phenyl) ethynyl]Benzyl } -1, 4-oxoazalane (yellow bubbles) (0.12g, 65%).

MS(ESI)：478(M+H)⁺，512(M+Cl)^-

¹HNMR (600MHz, chloroform-d) ppm1.56(3H, s), 1.87-1.93(2H, m), 2.66-2.74(4H, m), 2.90(3H, d, J ═ 4.5Hz), 3.67(2H, s), 3.70-3.74(2H, m), 3.77(3H, s), 3.80-3.88(2H, m), 6.32(1H, d, J ═ 4.5Hz), 7.36(2H, d, J ═ 7.8Hz), 7.50(2H, d, J ═ 7.8Hz), 7.60(2H, d, J ═ 8.3Hz), 7.83(2H, d, J ═ 8.3Hz)

[ CHEM 125 ]

(5) The same procedures used in example 4- (5) were repeated except for using 4- {4- [ (4- { [ 1-methoxy-2-methyl-3- (methylamino) -1, 3-dioxopropan-2-yl ] carbamoyl } phenyl) ethynyl ] benzyl } -1, 4-oxoazacane (74mg) obtained in example 15- (4) to give N-hydroxy-N', 2-dimethyl-2- { [ (4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide (Compound 380, white solid) (6.2mg, 8.0%).

MS(ESI)：479(M+H)⁺，477(M-H)^-

¹HNMR(600MHz，CD₃OD)ppm1.77(3H，s)，1.88-1.95(2H，m)，2.68-2.75(4H，m)，2.77(3H，s)，3.69-3.75(4H，m)，3.79-3.84(2H，m)，7.41(2H，d，J＝8.3Hz)，7.51(2H，d，J＝8.3Hz)，7.62(2H，d，J＝8.7Hz)，7.92(2H，d，J＝8.7Hz)

Example 16

(2S) -N-hydroxy-N', 2-dimethyl-2- [ methyl (4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } benzoyl) amino ] malonamide (Compound 376)

[ CHEM 126 ]

(1) At (2S) -2- [ (4-iodobenzoyl) (methyl) amino]-N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (intermediate 15, 12g), 4-ethynylbenzaldehyde (4.1g), PdCl₂(PPh₃)₂To a mixture of (0.85g), CuI (0.46g) and THF (60mL), TEA (10mL) was added dropwise at room temperature under nitrogen, and the mixture was stirred at room temperature for 2 hours and 15 minutes. Ethyl acetate (0.20L), OH-type silica gel (12g), Cellpure (5.9g) and activated carbon (0.60g) were added to the solution, and insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (ethyl acetate/hexane 50/50, followed by gradient elution with chloroform/acetone 100/0 → 80/20), and ethyl acetate and IPE were added to the obtained solid, followed by filtration and washing with IPE to obtain (2S) -2- [ {4- [ (4-formylphenyl) ethynyl group ]Benzoyl } (methyl) amino]-N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (tan solid) (9.0g, 76%).

MS(ESI)：514(M+Na)⁺，490(M-H)^-

¹HNMR (400MHz, chloroform-d) ppm1.50-2.00(6H, m) [1.82 ]]，1.83(3H，s)，2.84-2.90(3H，m)，[3.17]，3.20(3H，s)，3.52-3.70(1H，m)，3.80-4.10(1H，m)，4.94-5.02(1H，m)，[6.95-7.05]，7.47-7.57(1H，m)，7.52-7.58(2H，m)，7.58-7.64(2H，m)，7.69(2H，d，J＝8.0Hz)，7.89(2H，d，J＝8.1Hz)，10.03(1H，s)，[10.07]，10.49(1H，s)

[ CHEM 127 ]

(2) To a solution of (2S) -2- [ {4- [ (4-formylphenyl) ethynyl ] benzoyl } (methyl) amino ] -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (3.7g) obtained in example 16- (1) and homomorpholine hydrochloride (1.6g) in chloroform (13mL) were added TEA (1.6mL) and acetic acid (0.8mL), and under a nitrogen atmosphere, sodium triacetoxyborohydride (2.6g) was added in portions under ice-cooling, followed by stirring at room temperature for 3.5 hours. Water and ethyl acetate were added, the pH was adjusted to 7.5 with a 1mol/L aqueous solution of sodium hydroxide, and then the organic layer was separated. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH silica gel column chromatography (chloroform/acetone gradient 100/0 → 60/40 followed by chloroform/methanol 90/10) to give (2S) -N, 2-dimethyl-2- [ methyl (4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } benzoyl) amino ] -N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (pale yellow solid) (3.0g, 69%).

¹HNMR (400MHz, chloroform-d) ppm1.50-2.00(8H, m) [1.81 ]]，1.82(3H，s)，2.66-2.74(4H，m)，2.83-2.89(3H，m)，[3.17]，3.20(3H，s)，3.50-4.10(8H，m)，4.93-5.03(1H，m)，[6.95-7.05]，7.60-7.70(1H，m)，7.35(2H，d，J＝8.0Hz)，7.46-7.55(4H，m)，7.57(2H，d，J＝8.0Hz)，[10.09]，10.50(1H，s)

[ CHEM 128 ]

(3) To a suspension of (2S) -N, 2-dimethyl-2- [ methyl (4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } benzoyl) amino ] -N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (3.0g) obtained in example 16- (2) in 1, 4-dioxane (6.0mL) was added dropwise a 1 mol/L-aqueous sulfuric acid solution (16mL) under water cooling, and the mixture was stirred at room temperature for 2 hours and 50 minutes. Water and ethyl acetate were added, and the aqueous layer was separated. After adjusting to pH7 with 20% sodium hydroxide and saturated aqueous sodium bicarbonate, ethyl acetate and sodium chloride were added, and the organic layer was separated. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was distilled off under reduced pressure. The obtained residue was purified by OH silica gel column chromatography (chloroform/acetone gradient 100/0 → 60/40 followed by chloroform/methanol gradient 98/2 → 90/10) to give (2S) -N-hydroxy-N', 2-dimethyl-2- [ methyl (4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } benzoyl) amino ] malonamide (compound 376, a yellowish solid) (1.7g, 65%).

MS(ESI)：493(M+H)⁺，491(M-H)^-

¹HNMR(600MHz，CD₃OD)ppm1.77(3H，s)，1.89-1.95(2H，m)，2.69-2.76(4H，m)，2.79(3H，s)，3.17(3H，s)，3.71(2H，s)，3.71-3.75(2H，m)，3.81(2H，t，J＝6.0Hz)，7.36-7.62(8H，m)

Compounds 396, 397, 409, 414, 416, 417, 419, 421, 427, 429 to 432, 439 to 441, 531, 534, 541, 548, 549, 553 to 561, 565 to 567, 569 to 571, 577 to 578, 587, 591, 594, 598, 607, 610, 611, 613 to 615, 617 to 620, 625, 631 and 634 were synthesized using the corresponding starting materials in the same manner as in example 16.

Example 16-1

(2S) -2- [ ({4- [ (4- { [3- (2-fluoroethoxy) azetidin-1-yl ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide (Compound 559)

[ CHEM 129 ] to

(1) To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (0.52g) in DMF (5.0mL) was added 60% sodium hydride (0.18g) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Under ice-cooling conditions, 1-bromo-2-fluoroethane (0.45mL) was added, and after stirring at room temperature for 2 hours, the mixture was stirred at 50 ℃ for 1.5 hours, and further at 70 ℃ for 1.5 hours. The reaction solution was cooled to room temperature, ethyl acetate and a saturated aqueous ammonium chloride solution were added, and the organic layer was separated. The extract was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was distilled off under reduced pressure. The obtained residue was purified by OH silica gel column chromatography (gradient elution from hexane/ethyl acetate 80/20 → 70/30) to obtain tert-butyl 3- (2-fluoroethoxy) azetidine-1-carboxylate (colorless oil) (0.30g, 46%).

¹HNMR (400MHz, chloroform-d) ppm1.44(9H, s), 3.58-3.64(1H, m), 3.65-3.72(1H, m), 3.82-3.92(2H, m), 4.03-4.14(2H, m), 4.24-4.33(1H, m), 4.46-4.53(1H, m), 4.59-4.65(1H, m)

[ CHEM 130 ]

(2) To a solution of tert-butyl 3- (2-fluoroethoxy) azetidine-1-carboxylate (0.30g) obtained in example 16-1- (1) in 1, 4-dioxane (0.9mL) was added methanol (0.15mL) followed by 4.0mol/L-HCl-1, 4-dioxane solution (1.7mL) and the mixture was stirred at room temperature for 3 hours. IPE (10mL) was added to the reaction mixture and the supernatant was removed, and this procedure was repeated 3 times to give 3- (2-fluoroethoxy) azetidine hydrochloride (colorless oil) (0.20g, 94%).

¹HNMR(600MHz，D₂O)ppm3.58-3.63(1H，m)，3.67-3.71(1H，m)，3.90-3.98(2H，m)，4.17-4.25(2H，m)，4.40-4.50(2H，m)，4.52-4.56(1H，m)

[ CHEM 131 ]

(3) To a solution of (2S) -2- [ {4- [ (4-formylphenyl) ethynyl ] benzoyl } (methyl) amino ] -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (0.15g) obtained in example 16- (1) and 3- (2-fluoroethoxy) azetidine hydrochloride (63mg) obtained in example 16-1- (2) in NMP (1.5mL) was added sodium triacetoxyborohydride (0.10g) under ice-cooling in a nitrogen atmosphere, and the mixture was stirred at room temperature for 40 minutes. Water and ethyl acetate were added, the pH was adjusted to 7.5 with a saturated aqueous sodium bicarbonate solution, and the organic layer was separated. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was distilled off under reduced pressure. The obtained residue was purified by OH silica gel column chromatography (gradient elution of chloroform/acetone 80/20 → 50/50) to give (2S) -2- [ {4- [ (4- { [3- (2-fluoroethoxy) azetidin-1-yl ] methyl } phenyl) ethynyl ] benzoyl } (methyl) amino ] -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (yellow oil) (0.14g, 81%).

¹HNMR (400MHz, chloroform-d) ppm1.40-1.95(6H, m), [1.81]，1.82(3H，s)，2.80-2.90(3H，m)，2.95-3.05(2H，m)，[3.17]，3.20(3H，s)，3.50-3.80(7H，m)，3.80-4.10(1H，m)，4.15-4.25(1H，m)，4.45-4.65(2H，m)，4.90-5.05(1H，m)，[6.95-7.05]，7.60-7.70(1H，m)，7.25-7.40(2H，m)，7.45-7.60(6H，m)，[10.09]，10.50(1H，br.s.)

[ CHEM 132 ]

(4) From (2S) -2- [ {4- [ (4- { [3- (2-fluoroethoxy) azetidin-1-yl ] methyl } phenyl) ethynyl ] benzoyl } (methyl) amino ] -N, 2-dimethyl-N '- (tetrahydro-2H-pyran-2-yloxy) malonamide (0.14g) obtained in example 16-1- (3), in the same manner as in example 16- (3), there were obtained (2S) -2- [ ({4- [ (4- { [3- (2-fluoroethoxy) azetidin-1-yl ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N', 2-Dimethylmalonamide (Compound 559, yellow solid) (77mg, 60%).

MS(ESI)：512(M+H)⁺，510(M-H)^-

¹HNMR(400MHz，CD₃OD)ppm1.77(3H，s)，2.79(3H，s)，3.08-3.14(2H，m)，3.16(3H，s)，3.56-3.74(4H，m)，3.70(2H，s)，4.16-4.25(1H，m)，4.40-4.45(1H，m)，4.52-4.57(1H，m)，7.25-7.40(2H，m)，7.45-7.65(6H，m)

Example 16-2

(2S) -2- [ { [4- ({4- [ (3-ethoxyazetidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide (Compound 557)

[ CHEM 133 ]

(1) From (2S) -2- [ {4- [ (4-formylphenyl) ethynyl ] benzoyl } (methyl) amino ] -N, 2-dimethyl-N '- (tetrahydro-2H-pyran-2-yloxy) malonamide (0.30g) obtained in example 16- (1) and 3-ethoxyazetidine hydrochloride (0.11g), according to the same manner as in example 16-1- (3), there was obtained (2S) -2- { [4- ({4- [ (3-ethoxyazetidin-1-yl) methyl ] phenyl } ethynyl) benzoyl ] (methyl) amino } -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (yellow solid) (0.26g, 74%).

¹HNMR (400MHz, chloroform-d) ppm1.20(3H, t, J ═ 7.1Hz), 1.35-1.95(6H, m), [1.81]，1.82(3H，s)，2.80-2.90(3H，m)，2.95-3.00(2H，m)，[3.17]，3.20(3H，s)，3.40-3.45(2H，m)，3.49(2H，s)，3.50-3.70(3H，m)，3.80-4.05(1H，m)，4.10-4.20(1H，m)，4.90-5.05(1H，m)，[6.95-7.05]，7.60-7.70(1H，m)，7.25-7.35(2H，m)，7.45-7.60(6H，m)，[10.08]，10.49(1H，br.s.)

[ CHEM 134 ]

(2) From (2S) -2- { [4- ({4- [ (3-ethoxyazetidin-1-yl) methyl ] phenyl } ethynyl) benzoyl ] (methyl) amino } -N, 2-dimethyl-N '- (tetrahydro-2H-pyran-2-yloxy) malonamide (0.26g) obtained in example 16-2- (1), according to the same manner as in example 16- (3), there was obtained (2S) -2- [ { [4- ({4- [ (3-ethoxyazetidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide (compound 557, yellow solid) (0.14g, 62%).

MS(ESI)：493(M+H)⁺，491(M-H)^-

¹HNMR(400MHz，CD₃OD)ppm1.16(3H，t，J＝7.0Hz)，1.77(3H，s)，2.79(3H，s)，3.06-3.12(2H，m)，3.16(3H，s)，3.35-3.50(2H，m)，3.58-3.76(4H，m)，4.08-4.20(1H，m)，7.25-7.40(2H，m)，7.45-7.70(6H，m)

Examples 16 to 3

(2S) -N-hydroxy-2- [ { [4- ({4- [ (3-Methoxyazetidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N', 2-dimethylmalonamide (Compound 567)

[ CHEM 135 ]

(1) From (2S) -2- [ {4- [ (4-formylphenyl) ethynyl ] benzoyl } (methyl) amino ] -N, 2-dimethyl-N '- (tetrahydro-2H-pyran-2-yloxy) malonamide (0.50g) obtained in example 16- (1) and 3-methoxyazetidine hydrochloride (0.16g), according to the same manner as in example 16-1- (3), there was obtained (2S) -2- { [4- ({4- [ (3-methoxyazetidin-1-yl) methyl ] phenyl } ethynyl) benzoyl ] (methyl) amino } -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (yellow solid) (0.39g, 68%).

¹HNMR (400MHz, chloroform-d) ppm1.55-1.95(6H, m), [1.81]，1.82(3H，s)，2.80-2.90(3H，m)，2.90-3.00(2H，m)，[3.17]，3.20(3H，s)，3.26(3H，s)，3.50-3.70(5H，m)，3.80-4.15(2H，m)，4.90-5.05(1H，m)，[6.95-7.05]，7.60-7.70(1H，m)，7.20-7.30(2H，m)，7.45-7.60(6H，m)，[10.08]，10.49(1H，br.s.)

[ CHEM 136 ]

(2) From (2S) -2- { [4- ({4- [ (3-methoxyazetidin-1-yl) methyl ] phenyl } ethynyl) benzoyl ] (methyl) amino } -N, 2-dimethyl-N '- (tetrahydro-2H-pyran-2-yloxy) malonamide (0.39g) obtained in example 16-3- (1), according to the same manner as in example 16- (3), there was obtained (2S) -N-hydroxy-2- [ { [4- ({4- [ (3-methoxyazetidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N', 2-dimethylmalonamide (compound 567, white solid) (0.26g, 79%).

MS(ESI)：479(M+H)⁺，477(M-H)^-

¹HNMR(400MHz，CD₃OD)ppm1.77(3H，s)，2.79(3H，s)，3.02-3.12(2H，m)，3.16(3H，s)，3.25(3H，s)，3.56-3.64(2H，m)，3.69(2H，s)，4.02-4.13(1H，m)，7.32(2H，d，J＝8.3Hz)，7.45-7.65(6H，m)

Examples 16 to 4

(2S) -2- [ { [4- ({4- [ (cyclopropylamino) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide (compound 553)

[ CHEM 137 ]

(1) From (2S) -2- [ {4- [ (4-formylphenyl) ethynyl ] benzoyl } (methyl) amino ] -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide obtained in example 16- (1) (0.30g) and cyclopropylamine (0.19mL), according to the same manner as in example 16- (2), (2S) -2- { [4- ({4- [ (cyclopropylamino) methyl ] phenyl } ethynyl) benzoyl ] (methyl) amino } -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (white solid) (0.20g, 62%) was obtained.

¹HNMR (400MHz, chloroform-d) ppm0.35-0.40(4H, m), 1.40-1.95(6H, m), [ 1.82%]，1.83(3H，s)，2.10-2.20(1H，m)，2.80-2.90(3H，m)，[3.17]，3.20(3H，s)，3.86(2H，br.s.)，3.90-4.15(2H，m)，4.90-5.05(1H，m)，7.20-7.35(2H，m)，7.40-7.60(6H，m)

[ CHEM 138 ]

(2) From (2S) -2- { [4- ({4- [ (cyclopropylamino) methyl ] phenyl } ethynyl) benzoyl ] (methyl) amino } -N, 2-dimethyl-N '- (tetrahydro-2H-pyran-2-yloxy) malonamide (0.20g) obtained in example 16-4- (1), (2S) -2- [ { [4- ({4- [ (cyclopropylamino) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide (compound 553, yellow solid) (0.11g, 68%) was obtained in the same manner as in example 16- (3).

MS(ESI)：450(M+H)⁺，448(M-H)^-

¹HNMR(400MHz，CD₃OD)ppm0.35-0.50(4H，m)，1.77(3H，s)，2.08-2.17(1H，m)，2.79(3H，s)，3.17(3H，s)，3.82(2H，s)，7.38(2H，d，J＝8.5Hz)，7.46-7.61(6H，m)

Examples 16 to 5

(2S) -N-hydroxy-2- [ { [4- ({4- [ (4-methoxypiperidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N', 2-dimethylmalonamide (Compound 565)

[ CHEM 139 ]

(1) From (2S) -2- [ {4- [ (4-formylphenyl) ethynyl ] benzoyl } (methyl) amino ] -N, 2-dimethyl-N '- (tetrahydro-2H-pyran-2-yloxy) malonamide (0.15g) obtained in example 16- (1) and 4-methoxypiperidine hydrochloride (60mg), according to the same manner as in example 16-1- (3), there were obtained (2S) -2- { [4- ({4- [ (4-methoxypiperidin-1-yl) methyl ] phenyl } ethynyl) benzoyl ] (methyl) amino } -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (yellow solid) (0.13g, 74%).

¹HNMR (400MHz, chloroform-d) ppm1.50-1.95(10H, m), [1.81]，1.82(3H，s)，2.05-2.20(2H，m)，2.65-2.75(2H，m)，2.80-2.90(3H，m)，3.15-3.25(1H，m)，[3.17]，3.20(3H，s)，3.34(3H，br.s.)，3.45-3.75(3H.m)，3.80-4.10(1H，m)，4.90-5.05(1H，m)，[6.95-7.05]，7.60-7.70(1H，m)，7.30-7.35(2H，m)，7.45-7.60(6H，m)，[10.08]，10.50(1H，br.s.)

[ CHEM 140 ]

(2) From (2S) -2- { [4- ({4- [ (4-methoxypiperidin-1-yl) methyl ] phenyl } ethynyl) benzoyl ] (methyl) amino } -N, 2-dimethyl-N '- (tetrahydro-2H-pyran-2-yloxy) malonamide (0.13g) obtained in example 16-5- (1), according to the same manner as in example 16- (3), there was obtained (2S) -N-hydroxy-2- [ { [4- ({4- [ (4-methoxypiperidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N', 2-dimethylpropanimidamide (compound 565, yellow solid) (49mg, 42%).

MS(ESI)：507(M+H)⁺，505(M-H)^-

¹HNMR(400MHz，CD₃OD)ppm1.51-1.64(2H，m)，1.77(3H，s)，1.86-1.96(2H，m)，2.18-2.32(2H，m)，2.65-2.85(2H，m)，2.79(3H，s)，3.17(3H，s)，3.20-3.35(1H，m)，3.28(3H，s)，3.56(2H，s)，7.35-7.40(2H，m)，7.45-7.65(6H，m)

Examples 16 to 6

(2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { [4- ({ [ (3-methyloxetan-3-yl) methyl ] amino } methyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide (Compound 578)

[ CHEM 141 ]

(1) From (2S) -2- [ {4- [ (4-formylphenyl) ethynyl ] benzoyl } (methyl) amino ] -N, 2-dimethyl-N '- (tetrahydro-2H-pyran-2-yloxy) malonamide (0.15g) obtained in example 16- (1) and [ (3-methyloxetan-3-yl) methyl ] amine (63mg), according to the same manner as in example 16- (2), there was obtained (2S) -N, 2-dimethyl-2- [ methyl (4- { [4- ({ [ (3-methyloxetan-3-yl) methyl ] amino } methyl) phenyl ] ethynyl } benzoyl) amino ] -N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (yellow color) Solid) (0.13g, 73%).

¹HNMR (400MHz, chloroform-d) ppm1.32(3H, s), 1.40-1.95(9H, m), 2.63(2H, s), 2.80-2.90(3H, m), [ 3.17%]，3.20(3H，s)，3.50-3.70(1H，m)，3.80-4.10(1H，m)，3.85(2H，s)，4.30-4.60(4H，m)，4.90-5.05(1H，m)，7.15-7.40(2H，m)，7.45-7.70(6H，m)

[ CHEM 142 ]

(2) From (2S) -N, 2-dimethyl-2- [ methyl (4- { [4- ({ [ (3-methyloxetan-3-yl) methyl ] amino } methyl) phenyl ] ethynyl } benzoyl) amino ] -N '- (tetrahydro-2H-pyran-2-yloxy) malonamide (0.13g) obtained in example 16-6- (1), according to the same procedure as in example 16- (3), there was obtained (2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { [4- ({ [ (3-methyloxetan-3-yl) methyl ] amino } methyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide (compound 578), yellow solid) (62mg, 55%).

MS(ESI)：493(M+H)⁺，491(M-H)^-

¹HNMR(400MHz，CD₃OD)ppm1.32(3H，s)，1.77(3H，s)，2.77(2H，s)，2.79(3H，s)，3.17(3H，s)，3.83(2H，s)，4，33(2H，d，J＝5.9Hz)，4.45(2H，d，J＝5.9Hz)，7.35-7.45(2H，m)，7.45-7.65(6H，m)

Examples 16 to 7

(2S) -N-hydroxy-2- [ ({4- [ (4- { [3- (2-methoxyethoxy) azetidin-1-yl ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N', 2-dimethylmalonamide (Compound 577)

[ CHEM 143 ]

(1) From (2S) -2- [ {4- [ (4-formylphenyl) ethynyl ] benzoyl } (methyl) amino ] -N, 2-dimethyl-N '- (tetrahydro-2H-pyran-2-yloxy) malonamide (0.12g) obtained in example 16- (1) and 3- (2-methoxyethoxy) azetidine hydrochloride (60mg), according to the same manner as in example 16-1- (3), there was obtained (2S) -2- [ {4- [ (4- { [3- (2-methoxyethoxy) azetidin-1-yl ] methyl } phenyl) ethynyl ] benzoyl } (methyl) amino ] -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) propyloxy) in the same manner as in example 16-1- (3) Diamide (yellow oil) (0.10g, 69%).

¹HNMR (400MHz, chloroform-d) ppm1.40-1.95(6H, m), [1.81]，1.82(3H，s)，2.80-2.90(3H，m)，2.95-3.05(2H，m)，[3.17]，3.20(3H，s)，3.35(3H，s)，3.45-3.70(9H，m)，3.75-4.10(1H，m)，4.15-4.25(1H，m)，4.90-5.05(1H，m)，[6.95-7.05]，7.60-7.70(1H，m)，7.20-7.30(2H，m)，7.45-7.60(6H，m)，[10.10]，10.51(1H，br.s.)

[ CHEM 144 ]

(2) From (2S) -2- [ {4- [ (4- { [3- (2-methoxyethoxy) azetidin-1-yl ] methyl } phenyl) ethynyl ] benzoyl } (methyl) amino ] -N, 2-dimethyl-N '- (tetrahydro-2H-pyran-2-yloxy) malonamide (0.10g) obtained in example 16-7- (1), according to the same manner as in example 16- (3), (2S) -N-hydroxy-2- [ ({4- [ (4- { [3- (2-methoxyethoxy) azetidin-1-yl ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N', 2-Dimethylmalonamide (Compound 577, yellow solid) (61mg, 69%).

MS(ESI)：523(M+H)⁺，521(M-H)^-

¹HNMR(400MHz，CD₃OD)ppm1.77(3H，s)，2.79(3H，s)，3.16(3H，s)，3.35(3H，s)，3.44-3.62(6H，m)，3.88-3.96(2H，m)，4.00(2H，s)，4.24-4.32(1H，m)，7.39(2H，d，J＝8.3Hz)，7.52-7.65(6H，m)

Examples 16 to 8

(2S) -N-hydroxy-N', 2-dimethyl-2- (methyl { [4- ({4- [ (oxetan-3-ylamino) methyl ] phenyl } ethynyl) phenyl ] carbonyl } amino) malonamide (Compound 396)

[ CHEM 145 ]

(1) The same procedures used in example 16- (2) were repeated except for using (2S) -2- [ {4- [ (4-formylphenyl) ethynyl ] benzoyl } (methyl) amino ] -N, 2-dimethyl-N '- (tetrahydro-2H-pyran-2-yloxy) malonamide (0.25g) obtained in example 16- (1) and oxetan-3-amine (44mg) to give (2S) -N, 2-dimethyl-2- { methyl [4- ({4- [ (oxetan-3-ylamino) methyl ] phenyl } ethynyl) benzoyl ] amino } -N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (light yellow foam) (0.24g, 85%).

MS(ESI)：549(M+H)⁺，547(M-H)^-

¹HNMR (600MHz, chloroform-d) ppm1.56-1.91(9H, m), 2.82-2.89(3H，m)，[3.17]，3.20(3H，s)，3.53-3.70(1H，m)，3.77(2H，s)，3.83-4.05(2H，m)，4.39-4.45(2H，m)，4.79(2H，t，J＝6.8Hz)，4.92-5.03(1H，m)，6.99(1H，br.s.)，7.31(2H，d，J＝8.3Hz)，7.46-7.60(6H，m)，7.60-7.66(1H，m)

[ CHEM 146 ]

(2) (2S) -N, 2-dimethyl-2- { methyl [4- ({4- [ (oxetan-3-ylamino) methyl ] obtained in example 16-8- (1)]Phenyl } ethynyl) benzoyl]To a solution of amino } -N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (97mg) in methanol (2.0mL) was added p-TsOH. H₂O (43mg) was stirred at room temperature for 1.5 hours. After a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, the mixture was extracted with chloroform. After drying the organic layer over anhydrous sodium sulfate, the drying agent was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by OH silica gel chromatography (gradient elution of chloroform/methanol: 98/2 → 86/14), and then IPE was added thereto, and the precipitated solid was collected by filtration and dried to obtain (2S) -N-hydroxy-N', 2-dimethyl-2- (methyl { [4- ({4- [ (oxetan-3-ylamino) methyl ] amide]Phenyl } ethynyl) phenyl]Carbonyl } amino) malonamide (compound 396, light yellow solid) (45mg, 55%).

MS(ESI)：465(M+H)⁺，463(M-H)^-

¹HNMR(600MHz，CD₃OD)ppm1.77(3H，s)，2.79(3H，s)，3.14-3.19(3H，m)，3.72(2H，s)，3.95-4.04(1H，m)，4.39-4.48(2H，m)，4.66-4.73(2H，m)，7.37(2H，d，J＝8.3Hz)，7.51(2H，d，J＝8.3Hz)，7.54-7.64(4H，m)

Examples 16 to 9

(2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { [4- (2-oxa-6-azaspiro [3.3] hept-6-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide (Compound 416)

[ CHEM 147 ]

(1) The same procedures used in example 16- (2) were repeated except for using (2S) -2- [ {4- [ (4-formylphenyl) ethynyl ] benzoyl } (methyl) amino ] -N, 2-dimethyl-N '- (tetrahydro-2H-pyran-2-yloxy) malonamide (0.12g) obtained in example 16- (1) and oxalate salt of 2-oxa-6-azaspiro [3.3] heptane (71mg) to give (2S) -N, 2-dimethyl-2- [ methyl (4- { [4- (2-oxa-6-azaspiro [3.3] hept-6-ylmethyl) phenyl ] ethynyl } benzoyl) amino ] -N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (yellow oily substance) Material) (95mg, 68%).

MS(ESI)：575(M+H)⁺，573(M-H)^-

¹HNMR(600MHz，CHLOROFORM-d)ppm1.61-1.90(9H，m)，2.84-2.87(3H，m)，[3.17]，3.20(3H，s)，3.36-3.39(4H，m)，3.51-3.70(3H，m)，3.83-4.07(1H，m)，4.72-4.77(4H，m)，4.93-5.01(1H，m)，6.96-7.03(1H，m)，7.24(2H，d，J＝7.8Hz)，7.44-7.59(6H，m)，7.62(1H，br.s.)

[ CHEM 148 ]

(2) The same procedures used in example 16-8- (2) were repeated except for using (2S) -N, 2-dimethyl-2- [ methyl (4- { [4- (2-oxa-6-azaspiro [3.3] hept-6-ylmethyl) phenyl ] ethynyl } benzoyl) amino ] -N '- (tetrahydro-2H-pyran-2-yloxy) malonamide (95mg) obtained in example 16-9- (1) to give (2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { [4- (2-oxa-6-azaspiro [3.3] hept-6-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide (compound 416, pale yellow solid) (23mg, 28%).

MS(ESI)：491(M+H)⁺，489(M-H)^-

¹HNMR(600MHz，CD₃OD)ppm1.77(3H，s)，2.79(3H，s)，3.17(3H，s)，3.43-3.50(4H，m)，3.61(2H，s)，4.71-4.75(4H，m)，7.31(2H，d，J＝8.3Hz)，7.50(2H，d，J＝8.3Hz)，7.54-7.63(4H，m)

Examples 16 to 10

(2S) -2- [ ({4- [ (4- { [ (furan-2-ylmethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide (Compound 417)

[ CHEM 149 ]

(1) The same procedures used in example 16- (2) were repeated except for using (2S) -2- [ {4- [ (4-formylphenyl) ethynyl ] benzoyl } (methyl) amino ] -N, 2-dimethyl-N '- (tetrahydro-2H-pyran-2-yloxy) malonamide (0.12g) obtained in example 16- (1) and 1- (furan-2-yl) methylamine (34mg) to give (2S) -2- [ {4- [ (4- { [ (furan-2-ylmethyl) amino ] methyl } phenyl) ethynyl ] benzoyl } (methyl) amino ] -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (yellow oily substance) (93mg, 67%).

MS(ESI)：573(M+H)⁺，571(M-H)^-

¹HNMR(600MHz，CHLOROFORM-d)ppm1.57-1.91(9H，m)，2.83-2.88(3H，m)，[3.17]，3.20(3H，s)，3.53-3.68(1H，m)，3.77-4.04(5H，m)，4.92-5.03(1H，m)，6.17-6.21(1H，m)，6.30-6.36(1H，m)，6.99(1H，br.s.)，7.31-7.40(3H，m)，7.46-7.60(6H，m)，7.61-7.67(1H，m)

[ CHEM 150 ]

(2) The same procedures used in example 16-8- (2) were repeated except for using (2S) -2- [ {4- [ (4- { [ (furan-2-ylmethyl) amino ] methyl } phenyl) ethynyl ] benzoyl } (methyl) amino ] -N, 2-dimethyl-N '- (tetrahydro-2H-pyran-2-yloxy) malonamide (93mg) obtained in example 16-10- (1) to give (2S) -2- [ ({4- [ (4- { [ (furan-2-ylmethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide (compound 417, pale yellow solid) (26mg, 33%).

MS(ESI)：489(M+H)⁺，487(M-H)^-

¹HNMR(600MHz，CD₃OD)ppm1.77(3H，s)，2.79(3H，s)，3.17(3H，s)，3.71-3.83(4H，m)，6.23-6.41(2H，m)，7.37(2H，d，J＝7.8Hz)，7.43-7.68(7H，m)

Example 17

(2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide (Compound 376)

[ CHEM 151 ]

(1) At 2- [ (4-iodobenzoyl) (methyl) amino group]-N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (intermediate 12, 1.0g), PdCl₂(PPh₃)₂To a suspension of (73mg) and CuI (40mg) in THF (50mL), TEA (0.87mL) and 4- (4-ethynylbenzyl) -1, 4-oxoazanane (0.45g) obtained in example 15- (3) were added in THF (0.45g) under ice-cooling5.0mL) and stirred for 2 hours. Addition of PdCl₂(PPh₃)₂(73mg), CuI (40mg), and TEA (0.87mL), 4- (4-ethynylbenzyl) -1, 4-oxoazanane (0.45g) obtained in example 15- (3) and THF (5.0mL) were added at 60 ℃ and the mixture was stirred for 1.5 hours, followed by concentration of the reaction mixture. The obtained residue was purified by NH-type silica gel chromatography (ethyl acetate → gradient elution of chloroform/methanol-100/0 → 95/5) to give N, 2-dimethyl-2- { methyl [ (4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] methyl]Ethynyl } phenyl) carbonyl]Amino } -N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (light brown foam) (1.1g, 93%).

MS(ESI/APCIDual)：577(M+H)⁺，599(M+Na)⁺，575(M-H)^-

[ CHEM 152 ]

(2) N, 2-dimethyl-2- { methyl [ (4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] obtained in example 17- (1)]Ethynyl } phenyl) carbonyl]To a solution of amino } -N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (0.80g) in methanol (10mL) was added p-TsOH. H ₂O (0.32g), and the mixture was stirred at room temperature for 4 hours. After the reaction solution was concentrated, a saturated aqueous sodium bicarbonate solution was added, extraction was performed with chloroform, and an organic layer was separated by a phase separator (phaseseparator) and distilled under reduced pressure. The obtained residue was purified by NH-type silica gel chromatography (gradient elution of chloroform/methanol-100/0 → 90/10) to give N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] amino acid ester]Ethynyl } phenyl) carbonyl]Amino } malonamide (yellow solid) (0.48g, 71%).

MS(ESI/APCIDual)：493(M+H)⁺，491(M-H)^-

[ CHEM 153 ]

(3) N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide (0.39g) obtained in example 17- (2) was isolated and purified by using a chiral column. Purification was carried out under the conditions (separation conditions: column: CHIRALPAKAD-H, column size: 2cmI.D.x25cmL, mobile phase: hexane/isopropanol 60/40< v/v >, flow rate: 10mL/min, column temperature: 40 ℃ C., detection wavelength: 254nm), and the obtained crude crystal was washed with IPE and dried to give (2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide (compound 376, yellow solid) (0.13 g).

[α]_D(ii) a +6.2 (C: 0.10, methanol)

MS(ESI/APCIDual)：493(M+H)⁺，491(M-H)^-

Example 18

(2S) -N-hydroxy-2- { [ (4- { [5- (methoxymethyl) furan-3-yl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N', 2-dimethylmalonamide (Compound 550)

[ CHEM 154 ]

(1) Sodium borohydride (0.32g) was added to a solution of 4-bromofuran-2-carbaldehyde (3.0g) in ethanol (15mL) in portions under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Acetone, ethyl acetate and water were added in this order, and the solvent was distilled off under reduced pressure. To the obtained residue was added ethyl acetate, and the organic layer was separated. The extract was washed with water and saturated brine in this order, dried over anhydrous magnesium sulfate, filtered to remove the drying agent, and the solvent was distilled off under reduced pressure to give (4-bromofuran-2-yl) methanol (brown oil) (3.1g, 100%).

¹HNMR(400MHz，CHLOROFORM-d)ppm1.80-1.87(1H，m)，4.58(2H，d，J＝5.4Hz)，6.36(1H，s)，7.40(1H，br.s.)

[ CHEM 155 ]

(2) To a solution of (4-bromofuran-2-yl) methanol (3.0g) obtained in example 18- (1) in DMF (15mL) was added iodomethane (1.6 mL). Under ice-cooling conditions, 60% sodium hydride (0.82g) was added in portions, and the mixture was stirred at room temperature for 1 hour and 40 minutes. Ethyl acetate and water were added and the organic layer was separated. The extract was washed with water and saturated brine in this order, dried over anhydrous magnesium sulfate, filtered to remove the drying agent, and the solvent was distilled off under reduced pressure to obtain a crude purified product (yellow oily substance) (3.9g) of 4-bromo-2- (methoxymethyl) furan.

¹HNMR(400MHz，CHLOROFORM-d)ppm3.36(3H，s)，4.36(2H，s)，6.38(1H，s)，7.39-7.43(1H，m)

[ CHEM 156 ]

(3) The crude purified 4-bromo-2- (methoxymethyl) furan (1.9g) obtained in example 18- (2), AcOBu (16mL), CuI (0.33g), and PdCl were added to the reaction solution₂(PPh₃)₂(0.60g), Triisopropylsilylacetylene (9.6mL), and TEA (12mL) under a nitrogen atmosphereStirred at 110 ℃ for 7.5 hours. After cooling, ethyl acetate (0.10L), OH-type silica gel (1.9g), Cellpure (0.95g) and activated carbon (10mg) were added thereto, and insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by OH silica gel column chromatography (gradient elution of hexane/ethyl acetate 100/0 → 80/20) to obtain a yellow oil (1.7 g). THF (4.0mL) was added to the oily substance (0.80g), a 1mol/L-TBAF-THF solution (4.1mL) was added dropwise under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling and then stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by OH-type silica gel column chromatography (gradient elution of hexane/ethyl acetate: 100/0 → 90/10) to give 4-ethynyl-2- (methoxymethyl) furan (yellow oil) (0.24 g).

¹HNMR(400MHz，CHLOROFORM-d)ppm3.04(1H，s)，3.36(3H，s)，4.37(2H，s)，6.40(1H，s)，7.63(1H，s)

[ CHEM 157 ]

(4) 4-ethynyl-2- (methoxymethyl) furan (0.24g) and (2S) -2- [ (4-iodobenzoyl) (methyl) amino group obtained in example 18- (3) ]To a solution of (E) -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (intermediate 15, 0.51g) in THF (7.0mL) was added PdCl₂(PPh₃)₂(70mg), CuI (38mg), and TEA (1.5mL) were stirred at room temperature under nitrogen for 5.5 hours. Ethyl acetate (30mL), OH-type silica gel (1.9g), Cellpure (0.95g) and activated charcoal (50mg) were added to the solution, and insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by OH silica gel column chromatography (gradient elution of ethyl acetate/hexane: 75/25 → 100/0 followed by gradient elution of chloroform/acetone: 100/0 → 70/30) to obtain (2S) -2- [ (4- { [5- (methoxymethyl) furan-3-yl group]Ethynyl } benzoyl) (methyl) amino]-N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (yellow solid) (0.43g, 84%).

¹HNMR(400MHz，CHLOROFORM-d)ppm1.50-1.95(6H，m)，[1.81]，1.82(3H，s)，2.82-2.88(3H，m)，[3.17]，3.20(3H，s)，3.38(3H，s)，3.51-3.70(1H，m)，3.80-4.08(1H，m)，4.40(2H，s)，4.93-5.03(1H，m)，6.46(1H，d，J＝0.5Hz)，[7.00]，7.63(1H，br.s.)，7.46-7.56(4H，m)，7.66-7.70(1H，m)，[10.10]，10.51(1H，br.s.)

[ CHEM 158 ]

(5) To a solution of (2S) -2- [ (4- { [5- (methoxymethyl) furan-3-yl ] ethynyl } benzoyl) (methyl) amino ] -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (0.43g) obtained in example 18- (4) in 1, 4-dioxane (4.0mL) was added dropwise a 1 mol/L-aqueous sulfuric acid solution (2.6mL) under water cooling, and the mixture was stirred at room temperature for 3 hours and 45 minutes. Ethyl acetate and water were added, the pH was adjusted to 6 with a saturated aqueous sodium bicarbonate solution, sodium chloride was added, and the organic layer was separated. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was distilled off under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (gradient elution of chloroform/methanol ═ 100/0 → 80/20) to give (2S) -N-hydroxy-2- { [ (4- { [5- (methoxymethyl) furan-3-yl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N', 2-dimethylmalonamide (compound 550, white solid) (0.25g, 68%).

MS(ESI)：436(M+Na)⁺，412(M-H)^-

¹HNMR(400MHz，CHLOROFORM-d)ppm1.80(3H，s)，2.83(3H，d，J＝4.6Hz)，3.17(3H，s)，3.38(3H，s)，4.39(2H，s)，6.45(1H，s)，6.80-7.00(1H，m)，7.30-7.60(5H，m)，7.68(1H，br.s.)，10.54(1H，br.s.)

Compounds 403, 410, 418, 420, 422, 424, 428, 433, 435, 436, 438, 528, 575, 576, 588, 589, 593, 599, 600, 602 to 605, 609, 612, 616, 622, 630 and 633 were synthesized by the same method as in example 18 using the corresponding starting materials.

Example 19

(2S) -N-hydroxy-N ', 2-dimethyl-2- [ methyl ({ 4' - [2- (morpholin-4-yl) ethoxy ] biphenyl-4-yl } carbonyl) amino ] malonamide (Compound 437)

[ CHEM 159 ]

(1) To a solution of 4-iodophenol (1.0g), 2-morpholinoethanol (0.72g) and triphenylphosphine (1.4g) in THF (30mL) was added 40% DEAD/toluene (2.5mL) under ice-cooling, and the mixture was stirred at room temperature for 17 hours. After the solvent was distilled off, the obtained residue was purified by NH type silica gel chromatography (gradient elution of hexane/ethyl acetate: 90/10 → 60/40) to give 4- [2- (4-iodophenoxy) ethyl ] morpholine (colorless oil) (1.4g, 93%).

MS(ESI/APCIDual)：334(M+H)⁺

¹HNMR(200MHz，CHLOROFORM-d)ppm2.47-2.64(4H，m)，2.79(2H，t，J＝5.7Hz)，3.64-3.81(4H，m)，4.07(2H，t，J＝5.7Hz)，6.59-6.77(2H，m)，7.46-7.63(2H，m)

[ CHEM 160 ]

(2) The 4- [2- (4-iodophenoxy) ethyl group obtained in example 19- (1) was added]Morpholine (0.49g), 4, 4, 4 ', 4 ', 5, 5, 5 ', 5 ' -octamethyl-2, 2 ' -bis-1, 3, 2-dioxaborane (0.56g), PdCl₂(dppf)·CH₂Cl₂A suspension of (0.12g) potassium acetate (0.43g) in DMSO (5.0mL) was stirred at 90 ℃ for 4 hours. Water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered to remove the drying agent, and the solvent was distilled off under reduced pressure. The obtained residue was purified by NH-type silica gel chromatography (gradient elution of hexane/ethyl acetate ═ 90/10 → 70/30) to give 4- {2- [4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy ] was ]Ethyl } morpholine (colourless bubbles) (0.63 g).

MS(ESI/APCIDual)：334(M+H)⁺

¹HNMR(200MHz，CHLOROFORM-d)ppm1.33(12H，s)，2.50-2.65(4H，m)，2.80(2H，t，J＝5.7Hz)，3.65-3.80(4H，m)，4.14(2H，t，J＝5.7Hz)，6.83-6.95(2H，m)，7.67-7.81(2H，m)

[ CHEM 161 ]

(3) A suspension of 4- {2- [4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenoxy ] ethyl } morpholine (0.55g), 1- { [ (2S) -1-ethoxy-2-methyl-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } -4-iodobenzene (intermediate 13-1, 0.43g), PEPSI (83mg), potassium carbonate (0.51g) obtained in example 19- (2) in dioxane (3.0mL) was stirred at 90 ℃ for 8 hours. PEPSI (83mg) was added thereto, and the mixture was stirred at 110 ℃ for 2 hours. Water was added thereto, and the mixture was extracted with chloroform. The organic layer was separated by a phase separator (Phaseseparator), and the solvent was distilled off under reduced pressure. The resulting residue was purified by NH-type silica gel chromatography (gradient hexane/ethyl acetate 50/50 → 0/100) to give 4- {2- [ (4' - { [ (2S) -1-ethoxy-2-methyl-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } biphenyl-4-yl) oxy ] ethyl } morpholine as a pale yellow oil (96mg, 19% over 2 steps).

MS(ESI/APCIDual)：498(M+H)⁺，520(M+Na)^-

¹HNMR(200MHz，CHLOROFORM-d)ppm1.17-1.38(3H，m)，1.78(3H，s)，2.52-2.68(4H，m)，2.76-2.96(5H，m)，3.19(3H，s)，3.65-3.83(4H，m)，4.05-4.35(4H，m)，6.90-7.07(2H，m)，7.44-7.66(6H，m)，8.07-8.29(1H，m)

[ CHEM 162 ]

(4) To a solution of 4- {2- [ (4' - { [ (2S) -1-ethoxy-2-methyl-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } biphenyl-4-yl) oxy ] ethyl } morpholine (93mg) obtained in example 19- (3) in THF (2.0mL) -methanol (2.0mL) was added an aqueous solution (2.0mL) of potassium hydroxide (0.11g), and the mixture was stirred at room temperature for 16 hours. The pH was adjusted to 6 with 10% aqueous citric acid solution, and the mixture was extracted with chloroform. The organic layer was separated by a phase separator (Phaseparator), and the solvent was distilled off under reduced pressure to give 4- {2- [ (4' - { [ (2S) -2-carboxy-1- (methylamino) -1-oxopropan-2-yl ] (methyl) carbamoyl } biphenyl-4-yl) oxy ] ethyl } morpholine (pale brown oil) (58mg, 65%).

MS(ESI/APCIDual)：470(M+H)⁺，492(M+Na)⁺

¹HNMR(200MHz，DMSO-d₆)ppm1.64(3H，s)，2.44-2.56(4H，m)，2.59-2.80(5H，m)，3.05(3H，s)，3.49-3.66(4H，m)，4.15(2H，t，J＝5.7Hz)，6.95-7.15(2H，m)，7.46-7.79(6H，m)

[ CHEM 163 ]

(5) To a solution of 4- {2- [ (4' - { [ (2S) -2-carboxy-1- (methylamino) -1-oxopropan-2-yl ] (methyl) carbamoyl } biphenyl-4-yl) oxy ] ethyl } morpholine (56mg) or HATU (68mg) in DMF (3.0mL) obtained in example 19- (4) were added DIPEA (84. mu.L) and O-benzylhydroxylamine hydrochloride (23mg) under ice-cooling, and the mixture was stirred at room temperature for 13 hours. Stirring was carried out at 80 ℃ for 3 hours. Water was added thereto, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, separated by a phase separator (Phaseseparator), and the solvent was distilled off under reduced pressure. The resulting residue was purified by NH silica gel chromatography (chloroform/methanol gradient 100/0 → 95/5) to give (2S) -N- (benzyloxy) -N ', 2-dimethyl-2- [ methyl ({ 4' - [2- (morpholin-4-yl) ethoxy ] biphenyl-4-yl } carbonyl) amino ] malonamide (light yellow solid) (35mg, 51%).

MS(ESI/APCIDual)：575(M+H)⁺，597(M+Na)⁺，573(M-H)^-

¹HNMR(600MHz，CHLOROFORM-d)ppm1.77(3H，s)，2.56-2.64(4H，m)，2.81-2.87(5H，m)，3.20(3H，s)，3.73-3.78(4H，m)，4.17(2H，t，J＝5.8Hz)，4.91-4.97(2H，m)，6.95-7.05(2H，m)，7.13-7.22(1H，m)，7.28-7.62(11H，m)，10.14(1H，s)

[ CHEM 164 ]

(6) To a solution of (2S) -N- (benzyloxy) -N ', 2-dimethyl-2- [ methyl ({ 4' - [2- (morpholin-4-yl) ethoxy ] biphenyl-4-yl } carbonyl) amino ] malonamide (27mg) obtained in example 19- (5) in methanol (3.0mL) was added 10% Pd-C (5.0mg), and the mixture was stirred at room temperature in a hydrogen atmosphere for 6 hours. The mixture was filtered through celite, and the solvent was distilled off under reduced pressure. The residue was purified by LC-separation to give (2S) -N-hydroxy-N ', 2-dimethyl-2- [ methyl ({ 4' - [2- (morpholin-4-yl) ethoxy ] biphenyl-4-yl } carbonyl) amino ] malonamide (compound 437, light yellow solid) (8.0mg, 35%).

MS(ESI/APCIDual)：485(M+H)⁺，483(M-H)^-

¹HNMR(600MHz，CD₃OD)ppm1.78(3H，s)，2.56-2.67(4H，m)，2.77-2.86(5H，m)，3.21(3H，s)，3.69-3.76(4H，m)，4.20(2H，t，J＝5.6Hz)，6.98-7.10(2H，m)，7.54-7.73(6H，m)

Compounds 399, 401, 402, 406, 408, 411 to 413, 415, 423, 426, 623, 624, 626 and 629 were synthesized by the same method as in example 19 using the corresponding starting materials.

Example 20

N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [3- (morpholin-4-yl) prop-1-yn-1-yl ] biphenyl-4-yl } carbonyl) amino ] malonamide (Compound 390)

[ CHEMICAL 165 ]

(1) 4' -iodobiphenyl-4-carboxylic acid (1.8g), N, obtained by the same method as the synthesis method described in the literature (Zhurnal organic heskoikuimi, 1981, Vol.17 (12), p.2598-2601)²O-trimethyl-3-oxoserinamide hydrochloride (intermediate 5-2, 1.1g) was synthesized in the same manner as in example 4- (4) to give 4-iodo-4' - { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl](methyl) carbamoyl } biphenyl (light yellow solid) (1.5g, 58%).

MS(ESI/APCIDual)：467(M+H)⁺，489(M+Na)⁺，465(M-H)^-

¹HNMR(200MHz，CHLOROFORM-d)ppm2.91(3H，d，J＝4.8Hz)，3.18(3H，br.s.)，3.85(3H，s)，5.49(1H，s)，7.20(1H，m)，7.31-7.35(2H，m)，7.56-7.63(4H，m)，7.76-7.82(2H，m)

[ CHEM 166 ]

(2) 4-iodo-4' - { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] obtained in example 20- (1)]To a chloroform (10mL) solution of (methyl) carbamoyl } biphenyl (0.52g) were added prop-2-yn-1-ol (0.19g) and PdCl₂(PPh₃)₂(39mg), CuI (21mg), and TEA (0.17g) were stirred at room temperature for 3 hours under a nitrogen atmosphere, and then the reaction mixture was concentrated. The residue obtained is purified by chromatography on silica gel type OH (hexane/ethyl acetate gradient 50/50 → 0/100) to give 4- (3-hydroxypropan-1-yn-1-yl) -4' - { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ](methyl) carbamoyl } biphenyl (white solid) (0.28g, 63%).

MS(ESI/APCIDual)：395(M+H)⁺，417(M+Na)⁺，393(M-H)^-

¹HNMR(200MHz，CHLOROFORM-d)ppm1.83(1H，t，J＝6.2Hz)，2.91(3H，d，J＝4.8Hz)，3.19(3H，s)，3.85(3H，s)，4.51(2H，d，J＝6.2Hz)，5.49(1H，s)，7.19-7.28(1H，m)，7.48-7.66(8H，m)

[ CHEM 167 ]

(3) Manganese dioxide (0.19g) was added to a chloroform (15mL) solution of 4- (3-hydroxyprop-1-yn-1-yl) -4' - { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } biphenyl (85mg) obtained in example 20- (2), and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere, and then the reaction solution was filtered, and the solvent was distilled off under reduced pressure. Morpholine (23mg) and acetic acid were added to a chloroform (5.0mL) solution of the obtained residue, and after stirring at room temperature for 30 minutes in a nitrogen atmosphere, sodium triacetoxyborohydride (73mg) was added, and stirring at room temperature for 4 hours in a nitrogen atmosphere was performed. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, and then the organic layer was washed with a saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the drying agent was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by OH silica gel chromatography (gradient elution of chloroform/methanol 100/0 → 90/10) to give 4- [3- (4' - { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } biphenyl-4-yl) prop-2-yn-1-yl ] morpholine as a pale yellow bubble (75mg, 75%).

MS(ESI/APCIDual)：464(M+H)⁺，486(M+Na)⁺，462(M-H)^-

¹HNMR(200MHz，CHLOROFORM-d)ppm2.63-2.70(4H，m)，2.91(3H，d，J＝4.8Hz)，3.18(3H，br.s.)，3.54(2H，s)，3.76-3.82(4H，m)，3.85(3H，s)，5.48(1H，s)，7.14-7.24(1H，m)，7.49-7.67(8H，m)

[ CHEM 168 ]

(4) The same procedures used in example 4- (5) were repeated except for using 4- [3- (4 ' - { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } biphenyl-4-yl) prop-2-yn-1-yl ] morpholine (75mg) obtained in example 20- (3) to give N-hydroxy-N ' -methyl-2- [ methyl ({4 ' - [3- (morpholin-4-yl) prop-1-yn-1-yl ] biphenyl-4-yl } carbonyl) amino ] malonamide (compound 390, white solid) (19mg, 25%).

MS(ESI/APCIDual)：465(M+H)⁺，487(M+Na)⁺，463(M-H)^-

¹HNMR(600MHz，CD₃OD)ppm2.65-2.72(4H，m)，2.83(3H，br.s.)，3.11(3H，s)，3.57(2H，s)，3.74-3.76(4H，m)，7.51-7.55(2H，m)，7.61-7.67(4H，m)，7.74-7.76(2H，m)

Compounds 389, 398, 400 and 405 were synthesized in the same manner as in example 20 using the corresponding starting materials.

Example 21

(2S) -2- { [ (4- { [4- (1-Aminocyclopropyl) phenyl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N-hydroxy-N', 2-dimethylmalonamide (Compound 404)

[ CHEM 169 ]

(1) Titanium (IV) isopropoxide (7.1mL) was added to a solution of 4-iodobenzonitrile (5.0g) in diethyl ether (0.14L), and a solution of 0.90 mol/L-ethylmagnesium bromide-THF (53mL) was added dropwise while maintaining the internal temperature at-60 ℃ or lower. After stirring at room temperature for 1 hour, boron trifluoride diethyl etherate (5.4mL) was added and the mixture was stirred at room temperature for 3 hours. After addition of 1.0mol/L hydrochloric acid (65mL), the aqueous layer was washed with diethyl ether. The washed aqueous layer was adjusted to pH9 by adding 1.0mol/L aqueous sodium hydroxide solution, the precipitate was filtered through celite, the filtrate was extracted with ethyl acetate, dried over magnesium sulfate, and then the drying agent was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH silica gel chromatography (hexane/ethyl acetate gradient 50/50 → 1/99) to give 1- (4-iodophenyl) cyclopropylamine (light yellow solid) (1.3g, 23%).

MS(ESI/APCIDual)：260(M+H)⁺

¹HNMR(200MHz，CHLOROFORM-d)ppm0.87-1.00(2H，m)，1.01-1.15(2H，m)，6.96-7.11(2H，m)，7.54-7.68(2H，m)

[ CHEM 170 ] to

(2) 1- (4-iodophenyl) cyclopropylamine (0.40g) obtained in example 21- (1), PdCl₂(PPh₃)₂To a suspension of (54mg) and CuI (29mg) in THF (10mL) was added TEA (0.64mL), and the mixture was stirred at room temperature for 3 hours. After the solvent was distilled off under reduced pressure, the obtained residue was purified by OH type silica gel chromatography (gradient elution of hexane/ethyl acetate ═ 70/30 → 30/70) to give 1- {4- [ (trimethylsilyl) ethynyl group]Phenyl } cyclopropylamine (brown oil) (0.39g, 100%).

MS(ESI/APCIDual)：230(M+H)⁺

¹HNMR(200MHz，CHLOROFORM-d)ppm0.24(9H，s)，0.90-1.04(2H，m)，1.05-1.18(2H，m)，7.13-7.29(2H，m)，7.32-7.49(2H，m)

[ CHEM 171 ]

(3) To a solution of 1- {4- [ (trimethylsilyl) ethynyl ] phenyl } cyclopropylamine (0.37g) obtained in example 21- (2) in methanol (10mL) was added potassium carbonate (0.33g), and the mixture was stirred at room temperature for 1 hour. After potassium carbonate was removed by filtration, the residue was washed with chloroform, and after the solvent was distilled off under reduced pressure, the obtained residue was purified by OH-type silica gel chromatography (gradient elution of hexane/AcOEt ═ 70/30 → 30/70) to give 1- (4-ethynylphenyl) cyclopropylamine (compound 404, yellow solid) (0.19g, 76%).

MS(ESI/APCIDual)：158(M+H)⁺

¹HNMR(200MHz，CHLOROFORM-d)ppm0.90-1.05(2H，m)，1.06-1.18(2H，m)，3.05(1H，s)，7.14-7.32(2H，m)，7.35-7.52(2H，m)

[ CHEM 172 ]

(4) In intermediate 15(0.10g), PdCl₂(PPh₃)₂To a suspension of (7.0mg) and CuI (4.0mg) in THF (3.0mL) was added a solution of TEA (84. mu.L) and 1- (4-ethynylphenyl) cyclopropylamine (32mg) obtained in example 21- (3) in THF (1.0mL), and the mixture was stirred at room temperature for 2.5 hours. After the solvent was distilled off under reduced pressure, the obtained residue was purified by OH type silica gel chromatography (gradient elution of chloroform/methanol ═ 100/0 → 95/5) to give (2S) -2- { [ (4- { [4- (1-aminocyclopropyl) phenyl ] 2 ]Ethynyl } phenyl) carbonyl](methyl) amino } -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (pale yellow solid) (54mg, 52%).

MS(ESI/APCIDual)：519(M+H)⁺，517(M-H)^-

¹HNMR(600MHz，CHLOROFORM-d)ppm0.94-1.07(2H，m)，1.08-1.18(2H，m)，[1.80]，1.82(3H，s)，1.41-2.21(6H，m)，2.77-2.91(3H，m)，[3.17]，3.19(3H，s)，3.50-3.70(1H，m)，3.81-4.08(1H，m)，4.93-5.02(1H，m)，6.96-7.71(9H，m)

[ CHEM 173 ]

(5) (2S) -2- { [ (4- { [4- (1-Aminocyclopropyl) phenyl ] obtained in example 21- (4)]Ethynyl } phenyl) carbonyl]To a solution of (methyl) amino } -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (34mg) in methanol (3.0mL) was added p-TsOH. H₂O (15mg), and the mixture was stirred at room temperature for 5.5 hours. After the solvent was distilled off under reduced pressure under water-cooling, the obtained residue was purified by LC separation to obtain (2S) -2- { [ (4- { [4- (1-aminocyclopropyl) phenyl ] phenyl]Ethynyl } phenyl) carbonyl](methyl) amino } -N-hydroxy-N', 2-dimethylmalonamide (compound 404, white solid) (1.8mg, 6.0%).

MS(ESI/APCIDual)：435(M+H)⁺，433(M-H)^-

¹HNMR(600MHz，CD₃OD)ppm1.00-1.05(2H，m)，1.07-1.13(2H，m)，1.77(3H，s)，2.79(3H，s)，3.17(3H，s)，7.32-7.39(2H，m)，7.43-7.63(6H，m)

Compound 394 was synthesized in the same manner as in example 21 using the corresponding starting materials.

Example 22

2- [ ({4- [ (1E) -4- {4- [ (cyclopropylamino) methyl ] phenyl } but-1-en-3-yn-1-yl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide (Compound 477)

[ CHEM 174 ]

(1) To a solution of 4-ethynylbenzaldehyde (1.0g) in THF (20mL) were added 1, 2-dichloroethylene (3.0mL), tetrakis (triphenylphosphine) palladium (0.44g), CuI (73mg), and piperidine (1.1mL), and the mixture was stirred at room temperature under nitrogen for 22.5 hours. IPE was added, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (hexane/ethyl acetate/chloroform-9/1/1) to give 4- ((E) -4-chlorobut-3-en-1-yn-1-yl) benzaldehyde (light brown solid) (0.87g, 59%).

¹HNMR(400MHz，CHLOROFORM-d)ppm6.18(1H，d，J＝13.7Hz)，6.71(1H，d，J＝13.7Hz)，7.58(2H，d，J＝8.3Hz)，7.60-7.80(2H，m)，10.01(1H，s)

[ CHEM 175 ]

(2) In factTo a solution of 4- ((E) -4-chlorobut-3-en-1-yn-1-yl) benzaldehyde (0.97g) obtained in example 22- (1) in toluene (5.0mL) and ethanol (2.5mL) was added 4-methoxycarbonylphenylboronic acid (1.0g), PdCl₂(PPh₃)₂(0.18g), triphenylphosphine (0.13g) and potassium carbonate (1.4g) were heated under reflux for 3 hours under a nitrogen atmosphere. After cooling to room temperature, ethyl acetate was added, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. Adding IPE to the obtained residue, filtering to remove solid, adding chloroform and OH-type silica gel (10g), filtering to remove insoluble substances, and concentrating the filtrate under reduced pressure to obtain 4- [ (1E) -4- (4-formylphenyl) but-1-en-3-yn-1-yl]Methyl benzoate (light brown solid) (1.2g, 78%).

¹HNMR(400MHz，CHLOROFORM-d)ppm3.93(3H，s)，6.51(1H，d，J＝16.2Hz)，7.13(1H，d，J＝16.2Hz)，7.50(2H，d，J＝8.3Hz)，7.63(2H，d，J＝8.3Hz)，7.83-7.90(2H，m)，8.00-8.06(2H，m)，10.02(1H，s)

[ CHEM 176 ]

(3) 4- [ (1E) -4- (4-formylphenyl) but-1-en-3-yn-1-yl group obtained in example 22- (2)]To a solution of methyl benzoate (1.2g) in methanol (40mL) and 1, 4-dioxane (40mL) was added a 20% aqueous solution of sodium hydroxide (3.0mL), and the mixture was stirred at room temperature for 3 hours. A20% aqueous sodium hydroxide solution (3.0mL) was added thereto, and the mixture was stirred at room temperature for 30 minutes, followed by addition of a 20% aqueous sodium hydroxide solution (3.0mL) and stirring at room temperature for 25 hours. Water was added thereto, the pH was adjusted to 3 with 12 mol/L-hydrochloric acid under ice-cooling, and the precipitate was filtered and washed with water and IPE to give a brown solid (1.0 g). To the resulting solid, DMF (10mL), HATU (2.8g) and DIPEA (2.5mL) were added and the mixture was stirred at room temperature for 1 hour. Adding N, N ²O-trimethyl-3-oxoserine amide hydrochloride (intermediate 5-2, 1.4g) was stirred at 80 ℃ for 1 hour. Cooling the reaction solution to room temperature, adding ethyl acetate and water, separating the organic layerThe extract was washed with water and saturated brine. The mixture was dried over anhydrous magnesium sulfate, filtered to remove the drying agent, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by OH silica gel column chromatography (gradient elution of chloroform/methanol 50/1 → 10/1) to obtain 1-formyl-4- [ (3E) -4- (4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl group](methyl) carbamoyl } phenyl) but-3-en-1-yn-1-yl]Benzene (yellow oil) (0.47g, 28%).

¹HNMR(400MHz，CHLOROFORM-d)ppm2.90(3H，d，J＝4.6Hz)，3.16(3H，s)，3.85(3H，s)，5.47(1H，s)，6.47(1H，d，J＝16.2Hz)，7.11(1H，d，J＝16.2Hz)，7.17-7.27(1H，m)，7.40-7.59(4H，m)，7.62(2H，d，J＝8.3Hz)，7.83-7.90(2H，m)，10.02(1H，s)

[ CHEM 177 ]

(4) To a suspension of 1-formyl-4- [ (3E) -4- (4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } phenyl) but-3-en-1-yn-1-yl ] benzene (0.20g) obtained in example 22- (3) in chloroform (4.0mL) were added cyclopropylamine (99. mu.L), acetic acid (27. mu.L) and sodium triacetoxyborohydride (0.10g), and the mixture was stirred at room temperature for 1 hour and 15 minutes. Sodium triacetoxyborohydride (0.10g) was added thereto, and the mixture was stirred at room temperature for 1.5 hours. Water and chloroform were added, and the organic layer was separated. The extract was dried over anhydrous sodium sulfate, then the drying agent was removed by filtration, and the solvent was distilled off under reduced pressure to give 1- [ (cyclopropylamino) methyl ] -4- [ (3E) -4- (4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } phenyl) but-3-en-1-yn-1-yl ] benzene (orange oil) (0.20g, 91%).

MS(ESI)：460(M+H)⁺，458(M-H)^-

¹HNMR(400MHz，CHLOROFORM-d)ppm0.35-0.60(4H，m)，2.10-2.25(1H，m)，2.88(3H，d，J＝4.9Hz)，3.16(3H，s)，3.84(3H，s)，3.87(2H，br.s.)，5.49(1H，s)，6.45(1H，d，J＝16.2Hz)，7.03(1H，d，J＝16.2Hz)，7.24-7.59(9H，m)

[ CHEM 178 ]

(5) To a solution of 1- [ (cyclopropylamino) methyl ] -4- [ (3E) -4- (4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } phenyl) but-3-en-1-yn-1-yl ] benzene (0.20g) obtained in example 22- (4) in methanol (4.0mL) was added a 50% aqueous hydroxylamine solution (2.0mL) under ice-cooling, and after stirring for 30 minutes under ice-cooling, the mixture was stirred for 2 hours under water-cooling. To the reaction mixture were added ethyl acetate and water, the organic layer was separated, and the extract was washed with water and saturated brine in this order. Methanol and water were added to the precipitate to dissolve the precipitate, the organic layer was separated, chloroform, methanol and anhydrous sodium sulfate were added to the extract, the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by OH-type silica gel column chromatography (gradient elution of chloroform/methanol ═ 20/1 → 10/1) and by separation by silica gel thin layer chromatography (chloroform/methanol ═ 10/1) to obtain 2- [ ({4- [ (1E) -4- {4- [ (cyclopropylamino) methyl ] phenyl } but-1-en-3-yn-1-yl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide (compound 477, light yellow solid) (51mg, 25%).

MS(ESI)：461(M+H)⁺，459(M-H)^-

¹HNMR(400MHz，CD₃OD)ppm0.39-0.55(4H，m)，2.12-2.20(1H，m)，2.85(3H，s)，3.12(3H，s)，3.85(2H，s)，6.64(1H，d，J＝16.3Hz)，7.10(1H，d，J＝16.3Hz)，7.35-7.70(8H，m)

Example 23

2- [ ({4- [ (3E) -4- {4- [ (cyclopropylamino) methyl ] phenyl } but-3-en-1-yn-1-yl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide (Compound 481)

[ CHEM 179 ]

(1) To a solution of methyl 4- ((E) -4-chlorobut-3-en-1-yn-1-yl) benzoate (0.70g) obtained by the method described in patent (WO2008/154642) in toluene (3.5mL) and ethanol (1.8mL) were added 4-formylphenylboronic acid (0.49g) and PdCl₂(PPh₃)₂(0.11g), triphenylphosphine (78mg) and potassium carbonate (0.82g) were heated under reflux under nitrogen for 3 hours. After cooling to room temperature, ethyl acetate was added, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. To the resulting residue were added IPE and IPA, filtered to remove solid, added chloroform and OH-type silica gel (10g), filtered to remove insoluble matter, and the filtrate was concentrated under reduced pressure to give methyl 4- [ (E) -4- (4-formylphenyl) but-3-en-1-yn-1-yl) benzoate (orange solid) (0.59g, 69%).

¹HNMR(400MHz，CHLOROFORM-d)ppm3.93(3H，s)，6.55(1H，d，J＝16.2Hz)，7.12(1H，d，J＝16.2Hz)，7.51-7.62(2H，m)，7.59(2H，d，J＝8.3Hz)，7.87(2H，d，J＝8.3Hz)，7.98-8.06(2H，m)，10.01(1H，s)

[ CHEM 180 ]

(2) To a solution of methyl 4- [ (E) -4- (4-formylphenyl) but-3-en-1-yn-1-yl) benzoate (0.59g) obtained in example 23- (1) in methanol (20mL) and 1, 4-dioxane (20mL) was added a 20% aqueous solution of sodium hydroxide (1.5mL), and the mixture was stirred at room temperature for 3 hours. A20% aqueous solution of sodium hydroxide (1.5mL) was added thereto, and the mixture was stirred at room temperature for 30 minutes. Water was added thereto, the pH was adjusted to 3 with 12 mol/L-hydrochloric acid, and the precipitate was filtered to give 4- [ (E) -4- (4-formylphenyl) but-3-en-1-yn-1-yl) benzoic acid (orange solid) (0.55g, 98%).

¹HNMR(400MHz，DMSO-d₆)ppm6.91(1H，d，J＝16.3Hz)，7.26(1H，d，J＝16.3Hz)，7.52(2H，d，J＝8.3Hz)，7.82(2H，d，J＝8.3Hz)，7.88-7.95(4H，m)，10.00(1H，s)

[ CHEMICAL 181 ] to produce a pharmaceutical composition

(3) To a solution of 4- [ (E) -4- (4-formylphenyl) but-3-en-1-yn-1-yl) benzoic acid (0.54g) obtained in example 23- (2) in DMF (5.0mL) were added HATU (1.1g) and DIPEA (1.0mL), and the mixture was stirred at room temperature for 2 hours and 20 minutes. HATU (1.1g) was added thereto, and the mixture was stirred at room temperature for 40 minutes. Adding N, N²O-trimethyl-3-oxoserine amide hydrochloride (intermediate 5-2, 0.57g) was stirred at 80 ℃ for 20 minutes. The reaction solution was cooled to room temperature, ethyl acetate and water were added, the organic layer was separated, and the extract was washed with water and saturated brine in this order. The mixture was dried over anhydrous magnesium sulfate, filtered to remove the drying agent, and then the solvent was distilled off under reduced pressure. To the obtained residue were added chloroform, IPE and ethyl acetate, insoluble materials were removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by OH-type silica gel column chromatography (gradient elution of chloroform/methanol: 100/0 → 10/1) to obtain 1-formyl-4- [ (1E) -4- (4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl)](methyl) carbamoyl } phenyl) but-1-en-3-yn-1-yl]Benzene (orange oil) (0.61g, 74%).

¹HNMR(400MHz，CHLOROFORM-d)ppm2.90(3H，d，J＝4.9Hz)，3.14(3H，s)，3.85(3H，s)，5.47(1H，s)，6.54(1H，d，J＝16.2Hz)，7.10(1H，d，J＝16.2Hz)，7.19-7.31(1H，m)，7.46-7.62(6H，m)，7.87(2H，d，J＝8.3Hz)，10.01(1H，s)

[ CHEM 182 ]

(4) To a suspension of 1-formyl-4- [ (1E) -4- (4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } phenyl) but-1-en-3-yn-1-yl ] benzene (0.20g) obtained in example 23- (3) in chloroform (4.0mL) were added cyclopropylamine (99. mu.L), acetic acid (27. mu.L) and sodium triacetoxyborohydride (0.10g), and the mixture was stirred at room temperature for 1 hour and 10 minutes. Sodium triacetoxyborohydride (0.10g) was added thereto, and after stirring at room temperature for 1 hour and 15 minutes, sodium triacetoxyborohydride (0.10g) was further added thereto, and the mixture was stirred at room temperature for 1 hour and 15 minutes. Water and chloroform were added, the organic layer was separated, and the extract was washed with water and saturated brine in this order. The mixture was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was distilled off under reduced pressure. The obtained residue was purified by OH silica gel column chromatography (gradient elution of chloroform/methanol 50/1 → 10/1) to give 1- [ (cyclopropylamino) methyl ] -4- [ (1E) -4- (4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } phenyl) but-1-en-3-yn-1-yl ] benzene (orange oil) (0.18g, 83%).

¹HNMR(400MHz，CHLOROFORM-d)ppm0.42-0.61(4H，m)，2.10-2.25(1H，m)，2.89(3H，d，J＝4.9Hz)，3.15(3H，s)，3.85(3H，s)，3.89(2H，br.s.)，5.47(1H，s)，6.37(1H，d，J＝16.1Hz)，7.06(1H，d，J＝16.1Hz)，7.20-7.60(5H，m)，7.32(2H，d，J＝8.3Hz)，7.40(2H，d，J＝8.0Hz)

[ CHEM 183 ]

(5) To a solution of 1- [ (cyclopropylamino) methyl ] -4- [ (1E) -4- (4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } phenyl) but-1-en-3-yn-1-yl ] benzene (0.18g) obtained in example 23- (4) in methanol (4.0mL) was added a 50% aqueous hydroxylamine solution (2.0mL) under ice-cooling, and after stirring for 25 minutes under ice-cooling, the mixture was stirred for 1.5 hours under water-cooling. Ethyl acetate and water were added to the reaction solution, the organic layer was separated, and the extract was washed with water. After drying over anhydrous sodium sulfate, drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by OH type silica gel column chromatography (gradient elution of chloroform/methanol ═ 50/1 → 10/1), and further by silica gel thin layer chromatography (chloroform/methanol ═ 10/1) for separation to give 2- [ ({4- [ (3E) -4- {4- [ (cyclopropylamino) methyl ] phenyl } but-3-en-1-yn-1-yl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide (compound 481, pale yellow solid) (41mg, 23%).

MS(ESI)：461(M+H)⁺，459(M-H)^-

¹HNMR(400MHz，CD₃OD)ppm0.47-0.63(4H，m)，2.21-2.30(1H，m)，2.91(3H，s)，3.17(3H，s)，3.92(2H，s)，6.58(1H，d，J＝16.2Hz)，7.17(1H，d，J＝16.2Hz)，7.45(2H，d，J＝8.0Hz)，7.54-7.68(6H，m)

Example 24

(2S) -2- [ { [4- ({5- [ (cyclopropylamino) methyl ] furan-3-yl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide (Compound 585)

[ CHEM 184 ]

(1) In 4-bromofuran-2-carbaldehyde (2.0g), PdCl₂(PPh₃)₂(0.40g), CuI (0.22g), TEA (7.9mL), and AcOBu (20mL) in a mixture at 110-120 ℃ for 6 hours under nitrogenTriisopropylsilylacetylene (9.0mL) was added dropwise thereto, and the mixture was stirred for 2 hours. After cooling, ethyl acetate (50mL), OH-type silica gel (1.0g), Cellpure (1.2g) and activated carbon (20mg) were added to the mixture, and insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (gradient elution from hexane/ethyl acetate: 100/0 → 65/35) to obtain 4- [ (triisopropylsilyl) ethynyl group]Furan-2-carbaldehyde (black oil) (2.3g, 72%).

¹HNMR(400MHz，CHLOROFORM-d)ppm0.95-1.15(21H，m)，7.26(1H，br.s.)，7.83(1H，d，J＝0.7Hz)，9.63(1H，s)

[ CHEM 185 ]

(2) To a mixture of 4- [ (triisopropylsilyl) ethynyl ] furan-2-carbaldehyde (0.63g), THF (3.0mL) and acetic acid (0.20mL) obtained in example 24- (1) was added dropwise a 1mol/L-TBAF-THF solution (3.4mL) under ice-cooling over 1.5 hours. Diethyl ether and water were added to the reaction mixture, the pH was adjusted to 5 with a saturated aqueous ammonium chloride solution, and the organic layer was separated. The extract was washed with saturated brine, the solvent was distilled off under reduced pressure, and the obtained residue was purified by OH-type silica gel column chromatography (gradient elution from hexane/ethyl acetate: 100/0 → 80/20) to give 4-ethynylfuran-2-carbaldehyde (brown solid) (0.22g, 80%).

¹HNMR(400MHz，CHLOROFORM-d)ppm3.14(1H，s)，7.27(1H，s)，7.86(1H，s)，9.65(1H，s)

[ CHEM 186 ]

(3) From 4-ethynylfuran-2-carbaldehyde obtained in example 24- (2) (0.21g) and (2S) -2- [ (4-iodobenzoyl) (methyl) amino ] -N, 2-dimethyl-N '- (tetrahydro-2H-pyran-2-yloxy) malonamide (intermediate 15, 0.60g), in the same manner as in example 16- (1), there was obtained (2S) -2- [ {4- [ (5-formylfuran-3-yl) ethynyl ] benzoyl } (methyl) amino ] -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (brown solid) (0.46g, 78%).

MS(ESI)：505(M+Na)⁺，481(M-H)^-

¹HNMR(400MHz，CHLOROFORM-d)ppm1.40-1.92(9H，m)，2.82-2.92(3H，m)，3.13-3.25(3H，m)，3.45-4.20(2H，m)，4.93-5.05(1H，m)，6.95-7.85(5H，m)，7.33(1H，s)，7.92(1H，s)，9.68(1H，s)，[10.02]，10.70(1H，br.s.)

[ CHEM 187 ]

(4) From (2S) -2- [ {4- [ (5-formylfuran-3-yl) ethynyl ] benzoyl } (methyl) amino ] -N, 2-dimethyl-N '- (tetrahydro-2H-pyran-2-yloxy) malonamide (0.11g) obtained in example 24- (3) and cyclopropylamine (24. mu.L), according to the same manner as in example 16- (2), there was obtained (2S) -2- { [4- ({5- [ (cyclopropylamino) methyl ] furan-3-yl } ethynyl) benzoyl ] (methyl) amino } -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (yellow solid) (62mg, 52%).

MS(ESI)：523(M+H)⁺，521(M-H)^-

¹HNMR(400MHz，CHLOROFORM-d)ppm0.35-0.50(4H，m)，1.45-2.00(6H，m)，[1.81]，1.82(3H，s)，2.10-2.20(1H，m)，2.80-2.90(3H，m)，[3.16]，3.19(3H，s)，3.52-4.06(4H，m)，4.92-5.04(1H，m)，6.29-6.35(1H，m)，6.94-7.69(6H，m)，[10.12]，10.52(1H，br.s.)

[ CHEM 188 ]

(5) From (2S) -2- { [4- ({5- [ (cyclopropylamino) methyl ] furan-3-yl } ethynyl) benzoyl ] (methyl) amino } -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide ((62mg) obtained in example 24- (4), in the same manner as in example 16- (3), there was obtained (2S) -2- [ { [4- ({5- [ (cyclopropylamino) methyl ] furan-3-yl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide (compound 585, white solid) (18mg, 34%).

MS(ESI)：439(M+H)⁺，437(M-H)^-

¹HNMR(400MHz，CD₃OD)ppm-0.03-0.02(2H，m)，0.08-0.13(2H，m)，1.39(3H，s)，1.75-1.83(1H，m)，2.41(3H，s)，2.78(3H，s)，3.43(2H，s)，6.05(1H，s)，7.12-7.20(4H，m)，7.41(1H，s)

Compounds 583, 584 and 592 were synthesized in the same manner as in example 24 using the corresponding starting materials.

Example 25

(2S) -N-hydroxy-2- [ {4- [ (3E) -7-Methoxyhept-3-en-1-yn-1-yl ] benzoyl } (methyl) amino ] -N', 2-dimethylmalonamide (Compound 597)

[ CHEMICAL 189 ]

(1) A1.1M-LDA-THF/hexane solution (6.5mL) was added dropwise to a suspension of (3-trimethylsilyl-2-propynyl) triphenylphosphine bromide (2.7g) in THF (15mL) under ice-cooling, and the mixture was stirred for 40 minutes. After cooling to-70 ℃, a solution of 4-methoxybutyraldehyde (0.51g) obtained by the method described in the patent (WO2009/7814a1) in THF (5.0mL) was added dropwise, and the mixture was stirred for 30 minutes after warming to room temperature. To the reaction solution cooled to-60 ℃, a saturated aqueous ammonium chloride solution and diethyl ether were added, and the organic layer was separated. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered to remove the drying agent, the solvent was distilled off under reduced pressure, and the obtained residue was purified by OH-type silica gel column chromatography (gradient elution of hexane/diethyl ether ═ 96/4 → 94/6) to give ((E) -7-methoxyhept-3-en-1-yn-1-yl) trimethylsilane (yellow oil) (0.74g, 76%).

¹HNMR(400MHz，CHLOROFORM-d)ppm0.17(9H，s)，1.62-1.74(2H，m)，2.14-2.20(2H，m)，3.27-3.44(2H，m)，3.32(3H，s)，5.48-5.57(1H，m)，6.16-6.27(1H，m)

[ CHEM 190 ]

(2) To a methanol (3.7mL) solution of ((E) -7-methoxyhept-3-en-1-yn-1-yl) trimethylsilane (0.74g) obtained in example 25- (1) was added potassium carbonate (0.10g) under ice-cooling, and the mixture was stirred at room temperature for 45 minutes. Diethyl ether and aqueous ammonium chloride were added and the organic layer was separated. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered to remove the drying agent, and the solvent was distilled off under reduced pressure to give (E) -7-methoxyhept-3-en-1-yne (yellowish oil) (0.34g, 73%).

¹HNMR(400MHz，CHLOROFORM-d)ppm1.57-1.78(2H，m)，2.14-2.29(2H，m)，2.79(1H，s)，3.27-3.45(2H，m)，3.33(3H，s)，5.44-5.56(1H，m)，6.20-6.33(1H，m)

[ CHEMICAL 191 ]

(3) From (E) -7-methoxyhept-3-en-1-yne (0.11g) and (2S) -2- [ (4-iodobenzoyl) (methyl) amino ] -N, 2-dimethyl-N '- (tetrahydro-2H-pyran-2-yloxy) malonamide (intermediate 15, 0.15g) obtained in example 25- (2), in the same manner as in example 18- (4), there was obtained (2S) -2- [ {4- [ (3E) -7-methoxyhept-3-en-1-yn-1-yl ] benzoyl } (methyl) amino ] -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (brown foam) (0.15g, 100%).

¹HNMR(400MHz，CHLOROFORM-d)ppm1.41-1.90(11H，m)，2.20-2.32(2H，m)，2.77-2.88(3H，m)，[3.16]，3.18(3H，s)，3.28-3.45(2H，m)，3.35(3H，s)，3.50-3.70(1H，m)，3.80-4.07(1H，m)，4.90-5.00(1H，m)，5.67-5.76(1H，m)，6.23-6.34(1H，m)，[6.93-7.03]，7.57-7.70(1H，m)，7.35-7.52(4H，m)，[10.07]，10.49(1H，s)

[ CHEM 192 ]

(4) From (2S) -2- [ {4- [ (3E) -7-methoxyhept-3-en-1-yn-1-yl ] benzoyl } (methyl) amino ] -N, 2-dimethyl-N '- (tetrahydro-2H-pyran-2-yloxy) malonamide (0.15g) obtained in example 25- (3), according to the same manner as in example 18- (5), (2S) -N-hydroxy-2- [ {4- [ (3E) -7-methoxyhept-3-en-1-yn-1-yl ] benzoyl } (methyl) amino ] -N', 2-dimethylmalonamide (compound 597), pale yellow solid) (54mg, 45%).

MS(ESI)：401(M-H)^-

¹HNMR(400MHz，CD₃OD)ppm1.65-1.73(2H，m)，1.75(3H，s)，2.20-2.29(2H，m)，2.78(3H，s)，3.15(3H，s)，3.33(3H，s)，3.38-3.44(2H，m)，5.71-5.79(1H，m)，6.22-6.32(1H，m)，7.44-7.55(4H，m)

Compounds 590, 595, 596 and 606 were synthesized by the same methods as in example 25 using the corresponding starting materials.

Example 26

(2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { (E) -2- [4- (morpholin-4-ylmethyl) phenyl ] vinyl } phenyl) carbonyl ] amino } malonamide (Compound 434)

[ CHEM 193 ]

(1) To a DMF (1.2ml) solution of (2S) -2- [ (4-iodobenzoyl) (methyl) amino ] -N, 2-dimethyl-N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (intermediate 15, 90mg) and 4-vinylbenzaldehyde (98mg) obtained by the same method as described in the literature (journal of electrochemical chemistry, 2002, 529(1) volume, 43 to 50) were added palladium acetate (12mg), tris (4-methylphenyl) phosphine (24mg) and tris-N-butylamine (0.25ml), and the mixture was stirred at 80 ℃ overnight. The solvent was distilled off under reduced pressure, the obtained residue was purified by OH-type silica gel chromatography (gradient elution of chloroform/methanol: 100/0 → 94/6), and morpholine (30 μ l) and acetic acid (20 μ l) were added to a chloroform (1.0ml) solution of the obtained crude product, followed by stirring at room temperature for 2.5 hours. Sodium triacetoxyborohydride (62mg) was then added thereto, and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, extracted with chloroform, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by NH-type silica gel chromatography (gradient elution of chloroform/methanol ═ 100/0 → 94/6) to give (2S) -N, 2-dimethyl-2- { methyl [ (4- { (E) -2- [4- (morpholin-4-ylmethyl) phenyl ] vinyl } phenyl) carbonyl ] amino } -N' - (tetrahydro-2H-pyran-2-yloxy) malonamide (colorless oil) (32mg, 31%).

MS(ESI)：565(M+H)⁺，563(M-H)^-

¹HNMR(600MHz，CHLOROFORM-d)ppm1.61-1.69(3H，m)，1.73-1.91(6H，m)，2.41-2.50(4H，m)，2.81-2.89(3H，m)，[3.20]，3.23(3H，s)，3.51(2H，s)，3.54-3.76(5H，m)，3.83-4.06(1H，m)，4.95-5.03(1H，m)，7.01(1H，br.s.)，7.05-7.20(2H，m)，7.34(2H，d，J＝8.3Hz)，7.44-7.67(7H，m)

[ CHEM 194 ]

(2) The same procedures used in example 16-8- (2) were repeated except for using (2S) -N, 2-dimethyl-2- { methyl [ (4- { (E) -2- [4- (morpholin-4-ylmethyl) phenyl ] vinyl } phenyl) carbonyl ] amino } -N '- (tetrahydro-2H-pyran-2-yloxy) malonamide (32mg) obtained in example 26- (1) to obtain (2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { (E) -2- [4- (morpholin-4-ylmethyl) phenyl ] vinyl } phenyl) carbonyl ] amino } malonamide (compound 434), pale yellow solid) (16mg, 61%).

MS(ESI/APCIDual)：MS(ESI)：481(M+H)⁺，479(M-H)^-

¹HNMR(600MHz，CD₃OD)ppm1.77(3H，s)，2.41-2.53(4H，m)，2.79(3H，s)，3.20(3H，s)，3.53(2H，s)，3.64-3.73(4H，m)，7.17-7.32(2H，m)，7.35(2H，d，J＝7.8Hz)，7.51-7.60(4H，m)，7.66(2H，d，J＝8.3Hz)

Compounds 621, 627 and 628 were synthesized in the same manner as in example 26 using the corresponding starting materials.

Test examples

The effects of the compounds of the present invention were confirmed by the following pharmacological tests.

Test example 1 evaluation test of inhibitory Activity of Pseudomonas aeruginosa LpxC enzyme

Pseudomonas aeruginosa LpxC enzyme Activity the amount of a reaction product thereof was determined quantitatively by reacting LpxC with UDP-3-O- (R-3-hydroxydecanoyl) -N-acetylglucosamine as a substrate thereof, by quantifying the amino group present in the product.

Specifically, 12.5ng of Pseudomonas aeruginosa LpxC enzyme (obtained by preparing chromosomal DNA from Pseudomonas aeruginosa, obtaining Pseudomonas aeruginosa LpxC gene by PCR method (polymerase chain reaction method) using LpxC specific primers, introducing it into a vector, and expressing it using Escherichia coli) was added with 80. mu. mol/L of UDP-3-O- (R-3-hydroxydecanoyl) -N-acetylglucosamine (Wako pure chemical industries, Ltd.), and incubated at room temperature for 40 minutes. The reaction was carried out in 40mmol/L-HEPES buffer (pH8.0) containing 0.02% Bridge35 and 80. mu. mol/L-dithiothreitol. 0.2 mol/L-borax was added to the reaction solution, and after completion of the reaction, 0.5 mg/mL-fluorescamine dissolved in anhydrous dioxane was added, and the amount of the reaction product was measured at an excitation wavelength/fluorescence wavelength of 390nm/495 nm. An inhibition curve was obtained by allowing test compounds at various concentrations to coexist in the above reaction. From the inhibition curve, the concentration of the compound to be measured (IC) at which the amount of the reaction product was 50% inhibited was determined ₅₀Value) as an index of the inhibitory activity of pseudomonas aeruginosa LpxC enzyme. The test results of the compounds are shown in tables 1 to 4. As shown in the table, the tested compounds show an inhibition rate of more than 25% on Pseudomonas aeruginosa LpxC enzyme at 1000 (nM).

Test example 2 evaluation test of inhibitory Activity of Enterobacter coli LpxC enzyme

Coliform LpxC enzymatic activity the amount of reaction product of LpxC is determined quantitatively by reacting it with UDP-3-O- (R-3-hydroxytetradecanoyl) -N-acetylglucosamine as its substrate, by quantifying the amino groups present in the product.

Specifically, 20. mu. mol/L of UDP-3-O- (R-3-hydroxytetradecanoyl) -N-acetylglucosamine (Wako pure chemical industries, Ltd.) was added to 12.5ng of Escherichia coli LpxC enzyme (obtained by preparing chromosomal DNA from Escherichia coli, obtaining Escherichia coli LpxC gene by PCR using LpxC-specific primers, introducing the gene into a vector, and expressing the gene using Escherichia coli), and the mixture was incubated at room temperature for 120 minutes. The reaction was carried out in 40 mmol/2-morpholinoethanesulfonic acid buffer (pH6.5) containing 0.02% Bridge35 and 80. mu. mol/L-dithiothreitol. 0.2 mol/L-borax is added into the reaction liquid, and 0.5 mg/mL-fluorescence dissolved in anhydrous dioxane is added after the reaction is finishedAmine, and the amount of the reaction product was measured at an excitation wavelength/fluorescence wavelength of 390nm/495 nm. An inhibition curve was obtained by allowing test compounds at various concentrations to coexist in the above reaction. From the inhibition curve, the concentration of the compound to be measured (IC) at which the amount of the reaction product was 50% inhibited was determined ₅₀Value) as an index of the inhibitory activity of coliform LpxC enzyme. The results of the tests for representative compounds are shown in table 4.

Test example 3 antibacterial Activity evaluation test

The Minimal Inhibitory Concentration (MIC) assay was performed according to CLSI (clinical and laboratory standards institute) standard method using the following microdilution method.

As the bacteria, Pseudomonas aeruginosa TS88 strain (clinical isolate), Escherichia coli ATCC25922 strain and Klebsiella pneumoniae ATCC13883 strain were used. The test cells obtained by culturing the cells in the heart infusion agar medium for 1 night were scraped off, suspended at a concentration corresponding to McFarland0.5, and diluted 10-fold to obtain an inoculum solution. 0.005mL of the inoculated cell suspension was inoculated into cation-adjusted Mueller-Hinton medium containing the test compound, and cultured at 35 ℃ for 18 hours. The minimum drug concentration at which bacterial development was not visually observed was taken as the MIC. The test results for representative compounds are shown in tables 1 and 4.

In tables 1 to 4, NT indicates that the test was not performed.

The symbols of the results of the test for inhibitory activity of Pseudomonas aeruginosa LpxC enzyme in tables 2 and 3 are as follows.

A：IC₅₀Values below 10nM

B：IC₅₀The value is more than 10nM and less than 100nM

C：IC₅₀The value is 100nM or more, and the inhibition rate at 1000nM is 25% or more

In Table 2, MS (ESI) represents a value ([ M + H ] +) which is partially detected by LC-MS and which indicates the retention time of LC-MS.

[ tables 1-1]

Table 1 structural formula, spectral data, Pseudomonas aeruginosa LpxC enzyme inhibitory activity and antibacterial activity of representative compounds

[ tables 1-2]

[ tables 1 to 3]

[ tables 1 to 4]

[ Table 2-1]

TABLE 2 structural formula of compound, spectral data, Pseudomonas aeruginosa LpxC enzyme inhibitory activity

[ tables 2-2]

[ tables 2 to 3]

[ tables 2 to 4]

[ tables 2 to 5]

[ tables 2 to 6]

[ tables 2 to 7]

[ tables 2 to 8]

[ tables 2 to 9]

[ tables 2 to 10]

[ tables 2 to 11]

[ tables 2 to 12]

[ tables 2 to 13]

[ tables 2 to 14]

[ tables 2 to 15]

[ tables 2 to 16]

[ tables 2 to 17]

[ tables 2 to 18]

[ tables 2 to 19]

[ tables 2 to 20]

[ tables 2 to 21]

[ tables 2 to 22]

[ tables 2 to 23]

[ tables 2 to 24]

[ tables 2 to 25]

[ tables 2 to 26]

[ tables 2 to 27]

[ tables 2 to 28]

[ tables 2 to 29]

[ tables 2 to 30]

[ tables 2 to 31]

[ tables 2 to 32]

[ tables 2 to 33]

[ tables 2 to 34]

[ tables 2 to 35]

[ tables 2 to 36]

[ tables 2 to 37]

[ tables 2 to 38]

[ tables 2 to 39]

[ tables 2 to 40]

[ tables 2 to 41]

[ tables 2 to 42]

[ tables 2 to 43]

[ tables 2 to 44]

[ tables 2 to 45]

[ Table 3-1]

TABLE 3 structural formula of compound, spectral data, Pseudomonas aeruginosa LpxC enzyme inhibitory Activity

[ tables 3-2]

[ tables 3 to 3]

[ tables 3 to 4]

[ tables 3 to 5]

[ tables 3 to 6]

[ tables 3 to 7]

[ tables 3 to 8]

[ tables 3 to 9]

[ tables 3 to 10]

[ tables 3 to 11]

[ tables 3 to 12]

[ tables 3 to 13]

[ tables 3 to 14]

[ tables 3 to 15]

[ tables 3 to 16]

[ tables 3 to 17]

[ tables 3 to 18]

[ tables 3 to 19]

[ tables 3 to 20]

[ tables 3 to 21]

[ tables 3 to 22]

[ tables 3 to 23]

[ tables 3 to 24]

[ tables 3 to 25]

[ tables 3 to 26]

[ tables 3 to 27]

[ tables 3 to 28]

[ tables 3 to 29]

[ tables 3 to 30]

[ tables 3 to 31]

[ tables 3 to 32]

[ tables 3 to 33]

[ tables 3 to 34]

[ tables 3 to 35]

[ tables 3 to 36]

[ tables 3 to 37]

[ tables 3 to 38]

[ tables 3 to 39]

[ tables 3 to 40]

[ tables 3 to 41]

[ tables 3 to 42]

[ tables 3 to 43]

[ tables 3 to 44]

[ tables 3 to 45]

[ tables 3 to 46]

[ tables 3 to 47]

[ tables 3 to 48]

[ tables 3 to 49]

[ tables 3 to 50]

[ tables 3 to 51]

[ tables 3 to 52]

[ tables 3 to 53]

[ tables 3 to 54]

[ tables 3 to 55]

[ tables 3 to 56]

[ tables 3 to 57]

[ Table 4]

Table 4 LpxC enzyme inhibitory activity (pseudomonas aeruginosa, coliform bacteria) and antibacterial activity (pseudomonas aeruginosa, coliform bacteria and pneumobacillus) of representative compounds among the compounds described in table 3

The compound names shown in table 1 are as follows.

The compound 12- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 2N-hydroxy-N '-methyl-2- (methyl { [ 4' - (methylamino) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 32- (biphenyl-4-ylmethoxy) -N-hydroxy-N' -methylmalonamide,

The compound 4N-hydroxy-2- [ { [4 '- (methoxymethyl) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

The compound 5N-hydroxy-N '-methyl-2- { methyl [ (4' -methylbiphenyl-4-yl) carbonyl ] amino } malonamide,

The compound 62- { [ (4 '-fluorobiphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 7N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [3- (morpholin-4-yl) propoxy ] biphenyl-4-yl } carbonyl) amino ] malonamide,

The compound 7 bN-hydroxy-N '-methyl-2- [ methyl ({ 4' - [3- (morpholin-4-yl) propoxy ] biphenyl-4-yl } carbonyl) amino ] malonamide tosylate, a,

The compound 82- { [4- (1, 3-benzodioxol-5-yl) benzoyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 40N-hydroxy-N' -methyl-2- { methyl [4- (1-methyl-2, 3-dihydro-1H-indol-5-yl) benzoyl ] amino } malonamide,

The compound 432- [ { [4 '- (dimethylamino) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 52N-hydroxy-N '-methyl-2- (methyl { [ 4' - (trifluoromethoxy) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 56N-hydroxy-N '-methyl-2- (methyl { [ 4' - (trifluoromethyl) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 58N-hydroxy-N '-methyl-2- { methyl [ (4' - { [5- (morpholin-4-yl) pentyl ] amino } biphenyl-4-yl) carbonyl ] amino } malonamide,

The compound 612- { [ (2-fluorobiphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 77N-hydroxy-2- (methyl { [4 '- (methylamino) biphenyl-4-yl ] carbonyl } amino) -N' - [ (5-methyl-1, 2-oxazol-3-yl) methyl ] malonamide,

The compound 94N-hydroxy-2- { [4- (2-methoxy-1, 3-benzodioxol-5-yl) benzoyl ] (methyl) amino } -N' -methylmalonamide,

The compound 153N-hydroxy-2- [ { [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

The compound 1722- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N-hydroxy-N' - [ (5-methyl-1, 2-oxazol-3-yl) methyl ] malonamide,

The compound 1882- { [4- (2, 3-dihydro-1-benzofuran-5-yl) benzoyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 218N-hydroxy-N' -methyl-2- { methyl [4- (phenylethynyl) benzoyl ] amino } malonamide,

The compound 2372- [ { [4 '- (fluoromethyl) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 2712- { [4- (2, 3-dihydro-1-benzofuran-6-yl) benzoyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide.

The compound names shown in table 2 are as follows.

The compound 9N- (cyclopropylmethyl) -N '-hydroxy-2- ({ [ 4' - (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 10N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - [2- (propan-2-yloxy) ethyl ] malonamide,

The compound 11N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - (1, 3-thiazol-5-ylmethyl) malonamide,

The compound 12N- (furan-2-ylmethyl) -N '-hydroxy-2- ({ [ 4' - (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 13N-hydroxy-2- { [ (4 '- {2- [2- (2-hydroxyethoxy) ethoxy ] ethoxy } biphenyl-4-yl) carbonyl ] amino } -N' -methylmalonamide,

The compound 14N-hydroxy-2- [ ({4 '- [2- (2-hydroxyethoxy) ethoxy ] biphenyl-4-yl } carbonyl) amino ] -N' -methylmalonamide,

The compound 15N-hydroxy-2- [ ({4 '- [2- (2-hydroxyethoxy) ethoxy ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N' -methylmalonamide,

The compound 16N-hydroxy-N' -methyl-2- { [4- (trifluoromethoxy) benzoyl ] amino } malonamide,

Compound 172- [ (biphenyl-4-ylcarbonyl) (methoxy) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 18N-hydroxy-N '-methyl-2- { methyl [ (2' -methylbiphenyl-4-yl) carbonyl ] amino } malonamide,

The compound 19N-hydroxy-N' -methyl-2- { methyl [4- (1-methyl-1H-indol-5-yl) benzoyl ] amino } malonamide,

The compound 20N-hydroxy-2- [ ({4 '- [ (4-hydroxybutyl) amino ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N' -methylmalonamide,

The compound 21N-hydroxy-N' -methyl-2- { methyl [ (3-methylbiphenyl-4-yl) carbonyl ] amino } malonamide,

The compound 22N-hydroxy-N' -methyl-2- { methyl [4- (trifluoromethoxy) benzoyl ] amino } malonamide,

The compound 232- { [ (2 ' -fluoro-4 ' -methylbiphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N ' -methylmalonamide,

The compound 24N-hydroxy-2- { [ (3-hydroxybiphenyl-4-yl) carbonyl ] (methyl) amino } -N' -methylmalonamide,

The compound 25N-hydroxy-N' -methyl-2- { methyl [4- (octyloxy) benzoyl ] amino } malonamide,

The compound 26N-hydroxy-2- [ {4- [1- (4-hydroxybutyl) -1H-indol-5-yl ] benzoyl } (methyl) amino ] -N' -methylmalonamide,

Compound 272- { [ (3-fluorobiphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 282- { [ (3 ' -fluoro-4 ' -methylbiphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N ' -methylmalonamide,

The compound 29N-hydroxy-N '-methyl-2- { methyl [ (3' -methylbiphenyl-4-yl) carbonyl ] amino } malonamide,

The compound 302- [ (4-cyclohexylbenzoyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 31N-hydroxy-2- [ {4- [1- (2-hydroxyethyl) -1H-indol-5-yl ] benzoyl } (methyl) amino ] -N' -methylmalonamide,

The compound 322- [ { [4 '- (ethylamino) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 33N-hydroxy-2- [ (4- {2- [ (methoxymethoxy) methyl ] -1-methyl-1H-indol-5-yl } benzoyl) (methyl) amino ] -N' -methylmalonamide,

Compound 34, [ (1R) -tert-butyl 1- (4' - { [1- (hydroxyamino) -3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } biphenyl-4-yl) ethyl ] carbamate,

The compound 352- [ (4-butoxybenzoyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 36N-hydroxy-N' -methyl-2- { methyl [4- (1-methyl-1H-indol-6-yl) benzoyl ] amino } malonamide,

The compound 372- [ (4-butylbenzoyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 382- [ { [3 ' -fluoro-4 ' - (methylamino) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N ' -methylmalonamide,

Compounds 392- { [4- (2, 3-dihydro-1H-indol-5-yl) benzoyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 41N-hydroxy-2- [ {4- [2- (hydroxymethyl) -1-methyl-1H-indol-5-yl ] benzoyl } (methyl) amino ] -N' -methylmalonamide,

The compound 42N-hydroxy-N '-methyl-2- (methyl { [ 4' - (methylthioalkyl) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 44 (tert-butyl 4' - { [1- (hydroxyamino) -3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } -3-methylbiphenyl-4-yl) methylcarbamate,

The compound 45N-hydroxy-N ' -methyl-2- (methyl { [3 ' -methyl-4 ' - (methylamino) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 46N-hydroxy-N' -methyl-2- (methyl {4- [ 1-methyl-2- (morpholin-4-ylmethyl) -1H-indol-5-yl ] benzoyl } amino) malonamide,

The compound 47N-hydroxy-N' -methyl-2- { methyl [4- (1, 1, 2, 2-tetrafluoroethoxy) benzoyl ] amino } malonamide,

The compound 48N-hydroxy-2- { [ (3 '-hydroxybiphenyl-4-yl) carbonyl ] (methyl) amino } -N' -methylmalonamide,

The compound 49N-hydroxy-2- { [ (4 '-hydroxybiphenyl-4-yl) carbonyl ] (methyl) amino } -N' -methylmalonamide,

The compound 50N-hydroxy-2- [ { [3 ' -methoxy-4 ' - (methylamino) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N ' -methylmalonamide,

The compound 512- [ { [4 '- (difluoromethoxy) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 53N-hydroxy-N '-methyl-2- (methyl { [ 4' - (morpholin-4-yl) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 542- [ { [4 ' - (dimethylamino) -3 ' -fluorobiphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N ' -methylmalonamide,

The compound 552- { [ (3 ', 4 ' -dimethoxybiphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N ' -methylmalonamide,

The compound 572- { [4- (1, 2-dimethyl-1H-indol-5-yl) benzoyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 592- { [ (2 '-fluorobiphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 60N-hydroxy-N '-methyl-2- (methyl { [ 4' - (2H-tetrazol-5-ylmethyl) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 62N-benzyl-2- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N' -hydroxy malonamide,

The compound 63N-hydroxy-N' -methyl-2- (methyl {4- [ (E) -2-phenylvinyl ] benzoyl } amino) malonamide,

The compound 64N-hydroxy-2- { [ (4 '- {3- [ (2-methoxyethyl) (methyl) amino ] propoxy } biphenyl-4-yl) carbonyl ] (methyl) amino } -N' -methylmalonamide,

The compound 65N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [ (pyridin-3-ylmethyl) amino ] biphenyl-4-yl } carbonyl) amino ] malonamide,

The compound 662- [ ({3 ' -fluoro-4 ' - [ (2-methoxyethyl) amino ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N-hydroxy-N ' -methylmalonamide,

The compound 672- [ { [2 ', 5' -difluoro-4 '- (methylamino) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 68N-hydroxy-N ' -methyl-2- (methyl { [4 ' - (methylamino) -3 ' - (trifluoromethyl) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 692- [ { [3 ', 5' -difluoro-4 '- (methylamino) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 702- { [ (4 '- {3- [ benzyl (methyl) amino ] propoxy } biphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 71N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [3- (2-oxo-1, 3-oxazolidin-3-yl) propoxy ] biphenyl-4-yl } carbonyl) amino ] malonamide,

The compound 72N-hydroxy-N '-methyl-2- (methyl { [ 2', 3 ', 5', 6 '-tetrafluoro-4' - (methylamino) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 732- { [ (2, 2 '-difluorobiphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 742- { [ (4 '- { [ (2, 2-dimethylpropyl) amino ] methyl } biphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 75N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [3- (phenylamino) propoxy ] biphenyl-4-yl } carbonyl) amino ] malonamide,

The compound 762- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N-hydroxy-N' - (2-phenylethyl) malonamide,

The compound 78N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [ (propylsulfonyl) amino ] biphenyl-4-yl } carbonyl) amino ] malonamide,

The compound 792- [ ({4 '- [ (cyclopropylmethyl) amino ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 802- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N' -hydroxy-N, N-dimethylmalonamide,

The compound 812- { [4- (2, 3-dihydro-1, 4-benzodioxin-6-yl) benzoyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 82N-hydroxy-N' -methyl-2- { methyl [4- (4-methyl-3-oxo-3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) benzoyl ] amino } malonamide,

The compound 83N-hydroxy-N '-methyl-2- (methyl { [ 4' - (1, 1, 2, 2-tetrafluoroethoxy) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 84N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [3- (4-phenylpiperazin-1-yl) propoxy ] biphenyl-4-yl } carbonyl) amino ] malonamide,

Compound 852- [ ({4 '- [ (cyclopropylmethyl) (methyl) amino ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 86N-hydroxy-N '-methyl-2- { methyl [ (4' - { [3- (morpholin-4-yl) propyl ] amino } biphenyl-4-yl) carbonyl ] amino } malonamide,

The compound 87N-hydroxy-N '-methyl-2- { methyl [ (4' - { [3- (morpholin-4-ylmethyl) benzyl ] oxy } biphenyl-4-yl) carbonyl ] amino } malonamide,

The compound 882- [ ({4 '- [3- (2, 6-dimethylmorpholin-4-yl) propoxy ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 89N-hydroxy-N '-methyl-2- { methyl [ (4' - {2- [ methyl (phenyl) amino ] ethoxy } biphenyl-4-yl) carbonyl ] amino } malonamide,

The compound 90N-hydroxy-N '-methyl-2- { methyl [ (4' - { [4- (4-methylpiperazin-1-yl) benzyl ] oxy } biphenyl-4-yl) carbonyl ] amino } malonamide,

The compound 91N-hydroxy-N '-methyl-2- { methyl [ (4' - { [4- (morpholin-4-ylmethyl) benzyl ] oxy } biphenyl-4-yl) carbonyl ] amino } malonamide,

The compound 922- { [ (4 '- {3- [ (2, 6-difluorobenzyl) (methyl) amino ] propoxy } biphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 93N-hydroxy-N '-methyl-2- { methyl [ (4' - { [4- (1H-tetrazol-5-yl) benzyl ] oxy } biphenyl-4-yl) carbonyl ] amino } malonamide,

The compound 95N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [ (3-methyloxetan-3-yl) methoxy ] biphenyl-4-yl } carbonyl) amino ] malonamide,

The compound 96N-hydroxy-2- [ ({4 '- [3- (1H-imidazol-1-yl) propoxy ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N' -methylmalonamide,

The compound 972- [ { [4 '- ({3- [ benzyl (methyl) amino ] propyl } amino) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 984- { [ (4' - { [1- (hydroxyamino) -3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } biphenyl-4-yl) oxy ] methyl } benzoic acid,

The compound 99N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [ (2-methyl-1, 3-oxazol-4-yl) methoxy ] biphenyl-4-yl } carbonyl) amino ] malonamide,

The compound 100N-hydroxy-N '-methyl-2- { methyl [ (4' - { [3- (phenylamino) propyl ] amino } biphenyl-4-yl) carbonyl ] amino } malonamide,

The compound 1012- [ { [2, 4 '-bis (methylamino) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 102N-hydroxy-N '-methyl-2- { methyl [ (4' - { [1- (morpholin-4-ylmethyl) cyclopropyl ] methoxy } biphenyl-4-yl) carbonyl ] amino } malonamide,

The compound 103N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [ ({2- [ (phenylamino) methyl ] cyclopropyl } methyl) amino ] biphenyl-4-yl } carbonyl) amino ] malonamide,

The compound 104 (2- (phosphoryloxy) ethyl 2- (4' - { [1- (hydroxyamino) -3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } biphenyl-4-yl) methylcarbamate,

Compound 1052- { [4- (furan-3-yl) benzoyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 1062- [ { [4 ' - {3- [ benzyl (methyl) amino ] propoxy } -2 ' - (methylamino) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N ' -methylmalonamide,

The compound 1072- { [4- (3-fluoropyridin-2-yl) benzoyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 1082- { [4- (5-fluoropyridin-2-yl) benzoyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 1092- [ (biphenyl-4-ylcarbonyl) amino ] -N, N' -dihydroxymalonamide,

The compound 1102- [ (biphenyl-4-ylcarbonyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 1112- [ (biphenyl-4-ylcarbonyl) amino ] -N-hydroxy malonamide,

The compound 112N-hydroxy-N '-methyl-2- [ ({ 4' - [3- (1, 4-oxoazanan-4-yl) propoxy ] biphenyl-4-yl } carbonyl) amino ] malonamide,

The compound 113N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' -methylmalonamide,

The compound 114N-hydroxy-2- [ ({4 '- [ (2-hydroxyethyl) amino ] biphenyl-4-yl } carbonyl) amino ] -N' -methylmalonamide,

Compound 115N-hydroxy-2- { [4- ({4- [ (2-hydroxyethyl) amino ] phenyl } ethynyl) benzoyl ] amino } -N' -methylmalonamide,

Compound 116N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - (pyridin-3-yl) malonamide,

The compound 117N-hydroxy-N' -methyl-2- [ (4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } benzoyl) amino ] malonamide,

The compound 118N '-hydroxy-2- ({ [ 4' - (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N, N-dimethylmalonamide,

The compound 119N-tert-butyl-N '-hydroxy-2- ({ [ 4' - (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 120N-benzyl-N '-hydroxy-2- ({ [ 4' - (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 121N-cyclopropyl-N '-hydroxy-2- ({ [ 4' - (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) malonamide,

Compound 122N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - (2-hydroxyethyl) malonamide,

The compound 123N- [2- (dimethylamino) ethyl ] -N '-hydroxy-2- ({ [ 4' - (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 124N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - (pyridin-4-ylmethyl) malonamide,

The compound 125N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - (2-phenylethyl) malonamide,

Compound 126N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - (3-phenylpropyl) malonamide,

Compound 1272- [ (biphenyl-4-ylcarbonyl) (cyclopropyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 128N- (cyclobutylmethyl) -N '-hydroxy-2- ({ [ 4' - (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 129N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - (pyridin-3-ylmethyl) malonamide,

The compound 130N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - (pyridin-2-ylmethyl) malonamide,

The compound 131N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - (2-methoxyethyl) malonamide,

The compound 132N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - [2- (methylsulfanyl) ethyl ] malonamide,

The compound 133N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - [ (5-methyl-1, 2-oxazol-3-yl) methyl ] malonamide,

The compound 134N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - (tetrahydrofuran-2-ylmethyl) malonamide,

The compound 135N- [2- (acetylamino) ethyl ] -N '-hydroxy-2- ({ [ 4' - (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 136N- (2, 2-dimethylpropyl) -N '-hydroxy-2- ({ [ 4' - (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 137N- (2, 2-difluoroethyl) -N '-hydroxy-2- ({ [ 4' - (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 138N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - (2-phenoxyethyl) malonamide,

The compound 139N-ethyl-N '-hydroxy-2- ({ [ 4' - (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) malonamide,

Compound 140N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - [ (1-methyl-1H-pyrazol-3-yl) methyl ] malonamide,

The compound 141N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - [ 2-oxo-2- (pyrrolidin-1-yl) ethyl ] malonamide,

The compound 142N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' -propylmalonamide,

The compound 143N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - (propan-2-yl) malonamide,

The compound 144N- [2- (dimethylamino) -2-oxoethyl ] -N '-hydroxy-2- ({ [ 4' - (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 145N- {2- [ acetyl (methyl) amino ] ethyl } -N '-hydroxy-2- ({ [ 4' - (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 146N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - [ (1-methyl-1H-pyrazol-5-yl) methyl ] malonamide,

The compound 147N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - [ (1-methyl-1H-pyrazol-4-yl) methyl ] malonamide,

The compound 148N, N '-dihydroxy-2- ({ [ 4' - (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 149N- (2, 3-dihydro-1, 4-benzodioxin-2-ylmethyl) -N '-hydroxy-2- ({ [ 4' - (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 150N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - [ (6-methylpyridin-2-yl) methyl ] malonamide,

The compound 151N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - [2- (pyridin-2-yl) ethyl ] malonamide,

The compound 152N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - [ (3-oxo-3, 4-dihydro-2H-pyrido [3, 2-b ] [1, 4] oxazin-6-yl) methyl ] malonamide,

The compound 1542- (cyclopropyl { [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N-hydroxy-N' -methylmalonamide,

The compound 155N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] malonamide,

The compound 156N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - [ (1-methyl-1H-imidazol-2-yl) methyl ] malonamide,

The compound 157N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - (1, 3-oxazol-4-ylmethyl) malonamide,

The compound 158N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - [ (1-methyl-1H-imidazol-4-yl) methyl ] malonamide,

1592- [ (Biphenyl-4-ylcarbonyl) (ethyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 160N- [ (4-benzylmorpholin-2-yl) methyl ] -N '-hydroxy-2- ({ [ 4' - (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) malonamide,

Compound 1612- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N-hydroxy-N' - (pyridin-2-ylmethyl) malonamide,

Compound 162N-hydroxy-2- ({ [4 '- (2-hydroxyethoxy) biphenyl-4-yl ] carbonyl } amino) -N' - (morpholin-2-ylmethyl) malonamide,

Compound 1632- [ (biphenyl-4-ylcarbonyl) (cyclobutyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 1642- [ (biphenyl-4-ylcarbonyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 165N-hydroxy-2- [ { [4 '- (3-hydroxypropyl) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

The compound 1662- [ (biphenyl-4-ylcarbonyl) (2-methoxyethyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 167N-hydroxy-N' -methyl-2- [ methyl (4- { [4- (morpholin-4-ylmethyl) phenyl ] ethynyl } benzoyl) amino ] malonamide,

The compound 168N-hydroxy-N' -methyl-2- [ methyl (4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } benzoyl) amino ] malonamide,

The compound 169N-hydroxy-N' -methyl-2- { methyl [4- (pyridin-4-yl) benzoyl ] amino } malonamide,

The compound 1702- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N-hydroxy-N' - (pyrimidin-2-ylmethyl) malonamide,

Compound 1712- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N-hydroxy-N' -propylmalonamide,

The compound 1732- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N- [2- (dimethylamino) -2-oxoethyl ] -N' -hydroxymalonamide,

The compound 1742- [ (biphenyl-4-ylcarbonyl) (2, 2-difluoroethyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 1752- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N-cyclopropyl-N' -hydroxy malonamide,

Compound 176N-hydroxy-2- { [4- (2- {4- [ (2-hydroxyethyl) amino ] phenyl } ethyl) benzoyl ] (methyl) amino } -N' -methylmalonamide,

The compound 1772- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N-hydroxy-N' - (pyridin-3-ylmethyl) malonamide,

Compound 1782- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N-hydroxy-N' - (pyridin-4-ylmethyl) malonamide,

The compound 179N-hydroxy-2- [ ({4 '- [ (2-hydroxyethyl) amino ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N' -methylmalonamide,

The compound 180N-hydroxy-2- [ { [4 '- (4-hydroxybutoxy) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

The compound 1812- [ { [4 '- (3, 4-dihydroxybutoxy) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 182N-hydroxy-N '-methyl-2- { methyl [ (4' -propylbiphenyl-4-yl) carbonyl ] amino } malonamide,

Compound 183N-hydroxy-2- { [4- ({4- [ (2-hydroxyethyl) amino ] phenyl } ethynyl) benzoyl ] (methyl) amino } -N' -methylmalonamide,

Compound 1842- { [4- (1-benzofuran-5-yl) benzoyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 185N-hydroxy-2- [ { [ 3-hydroxy-4 '- (3-hydroxypropyl) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

The compound 1862- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N-hydroxy malonamide,

The compound 1872- [ { [4 '- (1, 3-dioxolan-2-yl) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 1892- { [4- (2, 1, 3-benzoxadiazol-5-yl) benzoyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 190N-hydroxy-N' -methyl-2- { methyl [ (6-phenylpyridin-3-yl) carbonyl ] amino } malonamide,

The compound 191N-hydroxy-2- [ { [4 '- (2-methoxyethoxy) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

The compound 192N-hydroxy-N' -methyl-2- { methyl [4- (quinolin-3-yl) benzoyl ] amino } malonamide,

The compound 1932- [ (biphenyl-4-ylcarbonyl) (2-fluoroethyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 1942- [ ({4 '- [ (dimethylamino) methyl ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 195N-hydroxy-2- [ ({4 '- [ (E) - (hydroxyimino) methyl ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N' -methylmalonamide,

The compound 196N-hydroxy-N' -methyl-2- { methyl [4- (1-methyl-1H-indazol-5-yl) benzoyl ] amino } malonamide,

The compound 197N-hydroxy-N' -methyl-2- { methyl [4- (2-methyl-2H-indazol-5-yl) benzoyl ] amino } malonamide,

The compound 1982- [ cyclopropyl ({4 '- [3- (morpholin-4-yl) propoxy ] biphenyl-4-yl } carbonyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 1992- { [4- (1, 3-benzothiazol-6-yl) benzoyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 200N-hydroxy-N' -methyl-2- { methyl [4- (quinolin-6-yl) benzoyl ] amino } malonamide,

The compound 201N-hydroxy-2- { [4- (1H-indol-5-yl) benzoyl ] (methyl) amino } -N' -methylmalonamide,

The compound 2022- { [4- ({4- [ (dimethylamino) methyl ] phenyl } ethynyl) benzoyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 203N-hydroxy-N' -methyl-2- { methyl [4- (2-methyl-1H-indol-5-yl) benzoyl ] amino } malonamide,

The compound 2042- { [ (4 '- { [ (2, 2-difluoroethyl) amino ] methyl } biphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 2052- [ ({4 '- [ (cyclopropylamino) methyl ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 206N-hydroxy-N' -methyl-2- { methyl [4- ({4- [2- (morpholin-4-yl) ethyl ] phenyl } ethynyl) benzoyl ] amino } malonamide,

Compound 207N-hydroxy-N' -methyl-2- { methyl [4- ({4- [2- (1, 4-oxoazanan-4-yl) ethyl ] phenyl } ethynyl) benzoyl ] amino } malonamide,

Compound 2082- [ ({3 ' -fluoro-4 ' - [3- (morpholin-4-yl) propoxy ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N-hydroxy-N ' -methylmalonamide,

The compound 209N-hydroxy-N' -methyl-2- { methyl [4- (2- {4- [2- (morpholin-4-yl) ethyl ] phenyl } ethyl) benzoyl ] amino } malonamide,

The compound 210N-hydroxy-N' -methyl-2- { methyl [4- (2- {4- [2- (1, 4-oxoazanan-4-yl) ethyl ] phenyl } ethyl) benzoyl ] amino } malonamide,

The compound 2112- { [ (4 '-ethoxybiphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

Compound 212N-hydroxy-N '-methyl-2- { methyl [ (4' -propoxybiphenyl-4-yl) carbonyl ] amino } malonamide,

The compound 213N-hydroxy-N '-methyl-2- (methyl { [ 4' - (propane-2-yloxy) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 214N-hydroxy-N '-methyl-2- (methyl { [ 4' - (2-methylpropyloxy) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 215N-hydroxy-2- [ { [4 '- (4-methoxybutoxy) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

The compound 2162- { [ (3 ' -fluoro-4 ' -methoxybiphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N ' -methylmalonamide,

The compound 2172- [ ({4 '- [3- (cyclopropylamino) propoxy ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 219N-hydroxy-2- [ {4- [ (6-methoxypyridin-3-yl) ethynyl ] benzoyl } (methyl) amino ] -N' -methylmalonamide,

The compound 220N-hydroxy-N '-methyl-2- { methyl [ (3', 4 ', 5' -trifluorobiphenyl-4-yl) carbonyl ] amino } malonamide,

The compound 221N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [4- (morpholin-4-yl) butyl ] biphenyl-4-yl } carbonyl) amino ] malonamide,

The compound 2222- { [ (3 ', 5 ' -dichlorobiphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N ' -methylmalonamide,

The compound 2232- { [ (3 ' -chloro-4 ' -fluorobiphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N ' -methylmalonamide,

The compound 2242- { [ (3 ', 4 ' -dichlorobiphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N ' -methylmalonamide,

The compound 2252- [ (2, 2-difluoroethyl) ({4 '- [3- (morpholin-4-yl) propoxy ] biphenyl-4-yl } carbonyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 2262- [ { [2 ' -fluoro-4 ' - (methylamino) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N ' -methylmalonamide,

The compound 2272- [ { [3 ' -chloro-4 ' - (methylamino) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N ' -methylmalonamide,

The compound 228N-hydroxy-2- [ ({4 '- [ (3-methoxypropyl) amino ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N' -methylmalonamide,

The compound 229N-hydroxy-2- [ { [4 '- (3-methoxyazetidin-1-yl) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

The compound 2302- [ { [4 ' - (ethylamino) -3 ' -fluorobiphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N ' -methylmalonamide,

The compound 2312- [ { [3 ' -fluoro-4 ' - (propylamino) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N ' -methylmalonamide,

The compound 232N-hydroxy-N '-methyl-2- (methyl { [ 4' - (morpholin-4-ylmethyl) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 2332- { [ (2 ', 6 ' -difluorobiphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N ' -methylmalonamide,

Compound 234N-hydroxy-N' -methyl-2- [ methyl (4- { [4- (piperidin-1-ylmethyl) phenyl ] ethynyl } benzoyl) amino ] malonamide,

The compound 2352- (ethyl { [4 '- (methylamino) biphenyl-4-yl ] carbonyl } amino) -N-hydroxy-N' -methylmalonamide,

Compound 236N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [2- (morpholin-4-yl) ethyl ] biphenyl-4-yl } carbonyl) amino ] malonamide,

The compound 2382- [ { [4 '- (2-fluoroethyl) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 2392- { [ (4 '- { [ acetyl (methyl) amino ] methyl } biphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 2402- { [ (4 '-tert-butylbiphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 2412- [ ({4 '- [ (acetylamino) methyl ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 2422- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N-ethyl-N' -hydroxymalonamide,

The compound 243N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [2- (morpholin-4-yl) ethoxy ] biphenyl-4-yl } carbonyl) amino ] malonamide,

The compound 244N-hydroxy-2- [ { [4 '- (3-hydroxyazetidin-1-yl) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

The compound 245N-hydroxy-N '-methyl-2- (methyl { [ 4' - (propylamino) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 246N-hydroxy-2- [ { [4 '- (2-methoxyethyl) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

The compound 247N-hydroxy-N '-methyl-2- (methyl { [ 4' - (2-oxo-1, 3-oxazolidin-3-yl) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 248N '-tert-butyl-N- [1- (hydroxyamino) -3- (methylamino) -1, 3-dioxopropan-2-yl ] -N-methylbiphenyl-4, 4' -dicarboxamide,

The compound 249N-hydroxy-N' -methyl-2- { methyl [4- (3-phenylazetidin-1-yl) benzoyl ] amino } malonamide,

Compounds 2502- { [4- (1, 3-dihydro-2H-isoindol-2-yl) benzoyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

Compound 2512- [ { [4 '- (1, 1-difluoropropyl) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 252N- [1- (hydroxyamino) -3- (methylamino) -1, 3-dioxopropan-2-yl ] -N, N ', N ' -trimethylbiphenyl-4, 4 ' -dicarboxamide,

The compound 2532- [ { [4 '- (1, 1-difluoroethyl) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 254N-hydroxy-N '-methyl-2- (methyl { [ 4' - (2-methyl-1, 3-dioxolan-2-yl) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 2552- [ { [4 '- (2-fluoroethoxy) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 256N-hydroxy-N '-methyl-2- (methyl { [ 4' - (pyrrolidin-1-yl) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 257N- [1- (hydroxyamino) -3- (methylamino) -1, 3-dioxopropan-2-yl ] -N-methyl-N '-propylbiphenyl-4, 4' -dicarboxamide,

The compound 2582- { [4- (2, 2-difluoro-1, 3-benzodioxol-5-yl) benzoyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 259N-hydroxy-2- { [ (4 '- { [ methoxy (methyl) amino ] methyl } biphenyl-4-yl) carbonyl ] (methyl) amino } -N' -methylmalonamide,

The compound 260N-hydroxy-2- [ ({4 '- [ (E) - (methoxyimino) methyl ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N' -methylmalonamide,

The compound 261N-hydroxy-2- [ { [4 '- (1-hydroxyethyl) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

The compound 262N-hydroxy-2- [ { [4 '- (2-hydroxypropan-2-yl) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

The compound 2632- [ ({4 '- [3- (3, 6-dihydropyridin-1 (2H) -yl) propoxy ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 2642- [ ({4 '- [3- (4, 4-difluoropiperidin-1-yl) propoxy ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 2652- [ ({4 '- [2- (dimethylamino) -2-oxoethyl ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 2662- [ ({4 '- [3- (dimethylamino) -3-oxopropyl ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 267N-hydroxy-N '-methyl-2- (methyl { [ 4' - (4-methylpiperazin-1-yl) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 2682- [ { [4 '- (cyclobutylamino) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 2692- { [4- (2, 2-dimethyl-1, 3-benzodioxol-5-yl) benzoyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

Compound 2702- { [4- (1-benzofuran-6-yl) benzoyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

Compound 272N-hydroxy-2- { [ (4 '- { [ (E) - (hydroxyamino) methylidene ] amino } biphenyl-4-yl) carbonyl ] (methyl) amino } -N' -methylmalonamide,

The compound 2732- [ { [4- (4-chlorophenyl) cyclohexyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 2742- [ ({4 '- [3- (dimethylamino) propoxy ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 2752- [ ({4 '- [ (E) - (dimethylhydrazono) methyl ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 276N-hydroxy-2- [ ({4 '- [3- (3-methoxyazetidin-1-yl) propoxy ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N' -methylmalonamide,

The compound 277N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [3- (1, 4-oxoazanan-4-yl) propoxy ] biphenyl-4-yl } carbonyl) amino ] malonamide,

Compound 278N-hydroxy-N '-methyl-2- (methyl { [ 3' - (methylamino) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 279N-hydroxy-2- { [ (3 '-methoxybiphenyl-4-yl) carbonyl ] (methyl) amino } -N' -methylmalonamide,

The compound 280N-hydroxy-2- [ { [4 '- (2-hydroxy-2-methylpropyloxy) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

The compound 281N-hydroxy-N' -methyl-2- { methyl [4- (1-methyl-1H-benzimidazol-5-yl) benzoyl ] amino } malonamide,

The compound 282N-hydroxy-N' -methyl-2- { methyl [4- (1-methyl-1H-benzimidazol-6-yl) benzoyl ] amino } malonamide,

The compound 2832- [ ({4 '- [ 2-fluoro-3- (morpholin-4-yl) propoxy ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 2842- { [ (4 '-aminobiphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 2852- [ { [4 '- (ethoxymethyl) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 286N-hydroxy-N '-methyl-2- { methyl [ (4' - { [3- (morpholin-4-yl) propyl ] sulfanyl } biphenyl-4-yl) carbonyl ] amino } malonamide,

The compound 287N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [3- (morpholin-4-ylmethyl) pyrrolidin-1-yl ] biphenyl-4-yl } carbonyl) amino ] malonamide,

Compound 288N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [3- (thiomorpholin-4-yl) propoxy ] biphenyl-4-yl } carbonyl) amino ] malonamide,

The compound 2892- [ ({4 '- [3- (1, 1-thiomorpholin-4-yl) propoxy ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 2902- [ { [4- (1, 3-dihydro-2-benzofuran-5-yl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 291N-hydroxy-2- [ ({4 '- [ (2-methoxyethyl) sulfanyl ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N' -methylmalonamide,

Compound 292N-hydroxy-N' -methyl-2- (methyl { [4- (thien-3-yl) phenyl ] carbonyl } amino) malonamide,

The compound 2932- [ { [4 '- ({3- [ (2-fluorophenyl) amino ] propyl } amino) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 294N-hydroxy-N '-methyl-2- (methyl { [ 4' - ({3- [3- (methylamino) phenoxy ] propyl } amino) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 295N-hydroxy-N' -methyl-2- (methyl { [4- (6-methylpyridin-2-yl) phenyl ] carbonyl } amino) malonamide,

The compound 296N-hydroxy-2- [ { [4- (6-methoxypyridin-2-yl) phenyl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

Compound 297N-hydroxy-N' -methyl-2- [ methyl ({4- [5- (trifluoromethyl) pyridin-2-yl ] phenyl } carbonyl) amino ] malonamide,

The compound 298N-hydroxy-2- [ { [4- (imidazo [1, 2-a ] pyridin-7-yl) phenyl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

The compound 299N-hydroxy-N' -methyl-2- { methyl [ (5-phenylpyrazin-2-yl) carbonyl ] amino } malonamide.

The compound names shown in Table 3 are as follows.

The compound 3002- [ ({4- [ (4- { [ (2-fluoroethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 3012- [ { [4- ({4- [ (cyclopropylamino) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 3022- [ ({4- [ (4- { [ (2, 2-difluoroethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 303N-hydroxy-N' -methyl-2- { methyl [ (4- { [4- (8-oxa-3-azabicyclo [3.2.1] octa-3-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

The compound 304N-hydroxy-N' -methyl-2- (methyl { [4- ({4- [ (4-methylpiperazin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } amino) malonamide,

The compound 3052- [ { [4- ({4- [ (1, 1-thiomorpholin-4-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 306N-hydroxy-2- { [ (4- { [4- (hydroxymethyl) phenyl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N' -methylmalonamide,

The compound 307N-hydroxy-N' -methyl-2- (methyl { [4- (1H-pyrrol-1-yl) phenyl ] carbonyl } amino) malonamide,

The compound 308N-hydroxy-N' -methyl-2- (methyl { [4- (thien-2-yl) phenyl ] carbonyl } amino) malonamide,

Compound 309N-hydroxy-N' -methyl-2- (methyl { [4- (pyrazin-2-yl) phenyl ] carbonyl } amino) malonamide,

Compound 310N-hydroxy-N' -methyl-2- (methyl { [4- (1, 3-oxazol-5-yl) phenyl ] carbonyl } amino) malonamide,

The compound 311N-hydroxy-N' -methyl-2- (methyl { [4- (pyrimidin-2-yl) phenyl ] carbonyl } amino) malonamide,

The compound 3122- [ { [4- (1-benzofuran-2-yl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 3132- [ { [4- ({4- [ (3-fluoroazetidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 314N-hydroxy-N' -methyl-2- [ methyl ({4- [ (4- { [ (tetrahydro-2H-pyran-4-ylmethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) amino ] malonamide, or,

The compound 3152- [ ({4- [ (4- { [ bis (2-hydroxyethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 3162- [ { [4- ({4- [ (cyclobutylamino) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 3172- [ { [4- ({4- [ (cyclopentylamino) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 3182- [ { [4- ({4- [ (cyclohexylamino) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 319N-hydroxy-2- [ ({4- [ (4-methoxybenzyl) oxy ] phenyl } carbonyl) (methyl) amino ] -N' -methylmalonamide,

The compound 3202- { [ (4- { [4- (2, 3-dihydroxypropoxy) phenyl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 321N-hydroxy-2- [ { [4- ({4- [ (3-hydroxy-3-methylazetidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

Compound 322N-hydroxy-N' -methyl-2- { methyl [ (4- { [4- (2-oxa-6-azaspiro [3.3] hept-6-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

The compound 323N-hydroxy-2- [ ({4- [ (4- { [ (3-hydroxy-3-methylbutyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N' -methylmalonamide,

The compound 3242- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

Compound 325N-hydroxy-N' -methyl-2- { methyl [ (4- { [4- ({ [3- (2-oxopyrrolidin-1-yl) propyl ] amino } methyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

Compound 326N-hydroxy-N '-methyl-2- { methyl [ (4- { [4- ({ [2- (pyrrolidin-1-yl) ethyl ] amino } methyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide, N-hydroxy-N' -methyl-2- { methyl { [4- ({ [2- (pyrrolidin-1-yl) ethyl ] amino } methyl) phenyl ] ethynyl } phenyl),

The compound 3272- [ ({4- [ (4- { [ cyclohexyl (methyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 3282- [ { [4- ({4- [ (tert-butylamino) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 3292- [ ({4- [ (4- { [ (2, 2-dimethylpropyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 3302- [ { [4- ({4- [ (benzylamino) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 331N-hydroxy-N' -methyl-2- { methyl [ (4- { [4- ({ [2- (morpholin-4-yl) ethyl ] amino } methyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

Compound 332N-hydroxy-N' -methyl-2- (methyl { [4- ({4- [ (2-methyl-1-oxo-2, 8-diazaspiro [4.5] decan-8-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } amino) malonamide,

Compound 333N-hydroxy-2- [ { [4- ({4- [ (3-hydroxypyrrolidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

Compound 334N-hydroxy-2- [ { [4- ({4- [ (4-hydroxypiperidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

The compound 3352- [ { [4- ({4- [ (1, 3-dihydroxypropan-2-yl) oxy ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 3362- { ethyl [ (4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } -N-hydroxy-N' -methylmalonamide,

Compounds 337N-hydroxy-N' -methyl-2- (methyl { [4- ({4- [ (oxetan-3-ylamino) methyl ] phenyl } ethynyl) phenyl ] carbonyl } amino) malonamide,

Compound 338N-hydroxy-N' -methyl-2- (methyl { [4- (4-phenylpiperazin-1-yl) phenyl ] carbonyl } amino) malonamide,

The compound 3391- { [1- (hydroxyamino) -3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } -4- [ (4- { [ 1-methoxy-3- (methylamino) -1, 3-dioxopropan-2-yl ] (methyl) carbamoyl } phenyl) ethynyl ] benzene, a,

The compound 3402, 2' - { acetylene-1, 2-diylbis [ benzene-4, 1-diylcarbonyl (methylimino) ] } bis (N1-hydroxy-N3-methylmalonamide),

The compound 341(2S) -2- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 3422- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -2-ethyl-N-hydroxy-N' -methylmalonamide,

The compound 343(2R) -2- [ (biphenyl-4-ylcarbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 3442- [ { [4- (1, 3-benzothiazol-2-yl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 345N-hydroxy-N', 2-dimethyl-2- (methyl { [4- (phenylethynyl) phenyl ] carbonyl } amino) malonamide,

Compound 346N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

The compound 3472- [ { [4- (1, 3-benzoxazol-2-yl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 348N-hydroxy-2- { [ (4 '-methoxybiphenyl-4-yl) carbonyl ] (methyl) amino } -N', 2-dimethylmalonamide,

The compound 349N-hydroxy-N ', 2-dimethyl-2- { methyl [ (4' -methylbiphenyl-4-yl) carbonyl ] amino } malonamide,

The compound 350N-hydroxy-N ', 2-dimethyl-2- [ methyl ({ 4' - [3- (morpholin-4-yl) propoxy ] biphenyl-4-yl } carbonyl) amino ] malonamide,

The compound 3512- [ ({4 '- [2- (benzyloxy) ethoxy ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 352N-hydroxy-N '-methyl-2- (methyl { [ 4' - (methylsulfonyl) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 3532- [ { [4- ({4- [ (3, 3-difluoroazetidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 354N-hydroxy-N' -methyl-2- [ methyl ({4- [ (4- { [ (3-phenylpropyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

Compound 3552- [ ({4- [ (4- { [ ethyl (2-methoxyethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 356N-hydroxy-N' -methyl-2- { methyl [ (4- { [4- ({ [ (1-methyl-1H-imidazol-2-yl) methyl ] amino } methyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

Compound 3572- [ { [4- ({4- [1- (cyclopropylamino) ethyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 3582- { [ (4- { [4- (1-aminoethyl) phenyl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

Compound 359N-hydroxy-N' -methyl-2- { methyl [ (4- { [4- ({ [ (5-methylpyrazin-2-yl) methyl ] amino } methyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

The compound 360N-hydroxy-N' -methyl-2- [ methyl ({4- [ (4- { [ (pyrimidin-2-ylmethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

Compound 3612- [ ({4- [ (4- { [ (cycloheptylmethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 3622- [ ({4- [ (4- { [ (cyclohexylmethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 363N-hydroxy-N' -methyl-2- [ methyl ({4- [ (4- { [ (pyridin-2-ylmethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

The compound 364N-hydroxy-2- [ { [4 '- (4-hydroxybutoxy) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N', 2-dimethylmalonamide,

Compound 3652- [ { [4- ({4- [ (3, 3-difluoropyrrolidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 3662- [ ({4- [ (4- { [ bis (2-methoxyethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 367N-hydroxy-N' -methyl-2- (methyl { [4- ({4- [1- (morpholin-4-yl) ethyl ] phenyl } ethynyl) phenyl ] carbonyl } amino) malonamide,

The compound 368N-hydroxy-N' -methyl-2- [ methyl ({4- [ (4- { [ methyl (2-phenylethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

Compound 369N-hydroxy-N' -methyl-2- { methyl [ (4- { [4- ({ [2- (pyridin-4-yl) ethyl ] amino } methyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

The compound 3702- [ ({4- [ (4- { [ (1, 1-tetrahydrothien-3-yl) (methyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 371N-hydroxy-N' -methyl-2- (methyl { [4- ({4- [ (tetrahydro-2H-thiopyran-4-ylamino) methyl ] phenyl } ethynyl) phenyl ] carbonyl } amino) malonamide,

The compound 372N-hydroxy-N' -methyl-2- [ methyl ({4- [ (4- { [ (tetrahydrofuran-2-ylmethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

Compound 3732- [ { [4- ({4- [ (4-acetylpiperazin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 374N-hydroxy-N' -methyl-2- [ methyl ({4- [ (4- { [ (pyridin-3-ylmethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

Compound 375N-hydroxy-N' -methyl-2- { methyl [ (4- { [3- (morpholin-4-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

Compound 376(2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

The compound 377(2R) -N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

Compound 378N-hydroxy-N' -methyl-2- { methyl [ (4- { [4- ({ [2- (methylsulfonyl) ethyl ] amino } methyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide, or,

Compound 3792- [ { [4- ({3- [ (cyclopropylamino) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 380N-hydroxy-N', 2-dimethyl-2- { [ (4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

The compound 381N-hydroxy-N' -methyl-2- (methyl { [4- ({4- [2- (1, 4-oxoazanan-4-yl) ethoxy ] phenyl } ethynyl) phenyl ] carbonyl } amino) malonamide,

Compound 382N-hydroxy-N' -methyl-2- (methyl { [4- ({4- [2- (morpholin-4-yl) ethoxy ] phenyl } ethynyl) phenyl ] carbonyl } amino) malonamide,

The compound 383N-hydroxy-2- [ { [4- ({4- [ (4-methoxypiperidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

Compound 3842- [ ({4- [ (4- { [ (2R, 6S) -2, 6-dimethylmorpholin-4-yl ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 3852- [ ({4- [ (2-cyclopropyl-2, 3-dihydro-1H-isoindol-5-yl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 386N-hydroxy-N' -methyl-2- [ methyl ({4- [ (4- { [4- (trifluoromethyl) piperidin-1-yl ] methyl } phenyl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

The compound 387N-hydroxy-N' -methyl-2- [ methyl ({4- [ (4- { [3- (trifluoromethyl) piperidin-1-yl ] methyl } phenyl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

Compound 3882- [ ({4- [ (4- { [ cyclopropyl (2-methoxyethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 389N-hydroxy-2- [ { [4 '- (3-hydroxyprop-1-yn-1-yl) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

The compound 390N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [3- (morpholin-4-yl) prop-1-yn-1-yl ] biphenyl-4-yl } carbonyl) amino ] malonamide,

The compound 391N-hydroxy-N' -methyl-2- (methyl { [4- ({4- [ (3-oxopiperazin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } amino) malonamide,

The compound 3922- { [ (4- { [4- (1, 4-dioxa-8-azaspiro [4.5] decan-8-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

Compound 393N-hydroxy-2- [ { [4- ({4- [ (3-methoxypyrrolidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

the compound 3942- { [ (4- { [4- (1-aminocyclopropyl) phenyl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 395N-hydroxy-2- [ ({4- [ (4- { [3- (hydroxycarbamoyl) azetidin-1-yl ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N' -methylmalonamide,

The compound 396(2S) -N-hydroxy-N', 2-dimethyl-2- (methyl { [4- ({4- [ (oxetan-3-ylamino) methyl ] phenyl } ethynyl) phenyl ] carbonyl } amino) malonamide,

The compound 397(2S) -N-hydroxy-N', 2-dimethyl-2- [ methyl ({4- [ (4- { [ methyl (oxetan-3-yl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

Compound 3982- [ { [4 '- (cyclopropylethynyl) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 399(2S) -2- { [ (4 '-ethoxybiphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N', 2-dimethylmalonamide,

The compound 400N-hydroxy-N '-methyl-2- { methyl [ (4' - {3- [2- (morpholin-4-yl) ethoxy ] prop-1-yn-1-yl } biphenyl-4-yl) carbonyl ] amino } malonamide,

The compound 401(2S) -N-hydroxy-N', 2-dimethyl-2- (methyl { [4- (1-methyl-2, 3-dihydro-1H-indol-5-yl) phenyl ] carbonyl } amino) malonamide,

The compound 402(2S) -N-hydroxy-N', 2-dimethyl-2- (methyl { [4- (1-methyl-1H-indol-5-yl) phenyl ] carbonyl } amino) malonamide,

Compound 403(2S) -N-hydroxy-2- { [ (4- { [4- (methoxymethyl) phenyl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N', 2-dimethylmalonamide,

Compound 404(2S) -2- { [ (4- { [4- (1-aminocyclopropyl) phenyl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N-hydroxy-N', 2-dimethylmalonamide,

The compound 405N-hydroxy-2- [ { [4 '- (3-methoxyprop-1-yn-1-yl) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

The compound 406(2S) -N-hydroxy-N ', 2-dimethyl-2- (methyl { [ 4' - (methylsulfanyl) biphenyl-4-yl ] carbonyl } amino) malonamide,

Compound 407N-hydroxy-N' -methyl-2- { methyl [ (4- { [5- (propylamino) pyridin-2-yl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

The compound 408(2S) -N-hydroxy-2- [ ({4 '- [ (E) - (methoxyimino) methyl ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N', 2-dimethylmalonamide,

Compound 409(2S) -2- [ { [4- ({4- [ (4-fluoropiperidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 410(2S) -N-hydroxy-N', 2-dimethyl-2- (methyl { [4- ({4- [2- (morpholin-4-yl) ethyl ] phenyl } ethynyl) phenyl ] carbonyl } amino) malonamide,

The compound 411(2S) -2- [ { [4- (1, 3-benzodioxol-5-yl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 412(2S) -N-hydroxy-2- { [ (4 '-methoxybiphenyl-4-yl) carbonyl ] (methyl) amino } -N', 2-dimethylmalonamide,

The compound 413(2S) -2- [ { [4- (2, 3-dihydro-1, 4-benzodioxin-6-yl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 414(2S) -N-hydroxy-N', 2-dimethyl-2- (methyl { [4- ({4- [ (methylamino) methyl ] phenyl } ethynyl) phenyl ] carbonyl } amino) malonamide,

Compound 415(2S) -2- { [ (4 '-fluorobiphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N', 2-dimethylmalonamide,

The compound 416(2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { [4- (2-oxa-6-azaspiro [3.3] hept-6-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

The compound 417(2S) -2- [ ({4- [ (4- { [ (furan-2-ylmethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 418N-hydroxy-N' -methyl-2- [ methyl ({4- [ (1-methyl-1H-pyrazol-3-yl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

The compound 419(2S) -N-hydroxy-N', 2-dimethyl-2- [ methyl ({4- [ (4- { [ (pyridin-3-ylmethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

The compound 420N-hydroxy-N' -methyl-2- { methyl [ (4- { [4- (trifluoromethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

The compound 421(2S) -N-hydroxy-N', 2-dimethyl-2- [ methyl ({4- [ (4- { [ (pyridin-2-ylmethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

The compound 422(2S) -N-hydroxy-N', 2-dimethyl-2- (methyl { [4- ({4- [ (methylsulfonyl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } amino) malonamide,

Compound 423(2S) -2- { [ (4 '-ethylbiphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N', 2-dimethylmalonamide,

Compound 424N-hydroxy-N' -methyl-2- [ methyl ({4- [ (1-methyl-1H-pyrrol-3-yl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

The compound 425(2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- {2- [4- (morpholin-4-ylmethyl) phenyl ] ethyl } phenyl) carbonyl ] amino } malonamide,

The compound 426(2S) -N-hydroxy-2- [ { [4 '- (3-hydroxypropyl) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N', 2-dimethylmalonamide,

The compound 427(2S) -2- [ ({4- [ (4- { [ (2-cyanoethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 428N-hydroxy-2- [ ({4- [ (4-methoxyphenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N' -methylmalonamide,

The compound 429(2S) -2- [ ({4- [ (4- { [ (2, 2-difluoroethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 430(2S) -2- { [4- ({4- [ (3-fluoropyrrolidin-1-yl) methyl ] phenyl } ethynyl) benzoyl ] (methyl) amino } -N-hydroxy-N', 2-dimethylmalonamide,

The compound 431(2S) -N-hydroxy-N', 2-dimethyl-2- (methyl { [4- ({4- [ (tetrahydro-2H-pyran-4-ylamino) methyl ] phenyl } ethynyl) phenyl ] carbonyl } amino) malonamide,

The compound 432(2S) -N-hydroxy-N', 2-dimethyl-2- [ methyl ({4- [ (4- { [ (tetrahydro-2H-pyran-4-ylmethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

The compound 433(2S) -N-hydroxy-N', 2-dimethyl-2- [ methyl ({4- [ (1-methyl-1H-pyrazol-4-yl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

Compound 434(2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { (E) -2- [4- (morpholin-4-ylmethyl) phenyl ] vinyl } phenyl) carbonyl ] amino } malonamide,

The compound 435(2S) -N-hydroxy-N', 2-dimethyl-2- (methyl { [4- ({4- [1- (methylamino) cyclopropyl ] phenyl } ethynyl) phenyl ] carbonyl } amino) malonamide,

Compound 436N-hydroxy-2- [ (4- { [5- (methoxymethyl) thiophen-3-yl ] ethynyl } benzoyl) (methyl) amino ] -N' -methylmalonamide,

The compound 437(2S) -N-hydroxy-N ', 2-dimethyl-2- [ methyl ({ 4' - [2- (morpholin-4-yl) ethoxy ] biphenyl-4-yl } carbonyl) amino ] malonamide,

The compound 438(2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [4- ({4- [2- (1, 4-oxoazanan-4-yl) ethyl ] phenyl } ethynyl) benzoyl ] amino } malonamide,

The compound 439(2S) -2- [ {4- [ (4- { [ (cyanomethyl) amino ] methyl } phenyl) ethynyl ] benzoyl } (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 440(2S) -2- [ (4- { [4- (1, 4-dioxa-8-azaspiro [4.5] dec-8-ylmethyl) phenyl ] ethynyl } benzoyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 441(2S) -N-hydroxy-2- [ {4- [ (4- { [ (3-methoxypropyl) amino ] methyl } phenyl) ethynyl ] benzoyl } (methyl) amino ] -N', 2-dimethylmalonamide,

The compound 442N-hydroxy-N' -methyl-2- { methyl [ (5-phenylthiophen-2-yl) carbonyl ] amino } malonamide,

Compound 443N-hydroxy-N' -methyl-2- { methyl [ (4-phenoxyphenyl) carbonyl ] amino } malonamide,

The compound 4442- [ { [4- (cyclohex-2-en-1-yloxy) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 4452- { [ (4-phenylmethylphenyl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 446N-hydroxy-N' -methyl-2- [ methyl ({4- [5- (trifluoromethyl) pyridin-3-yl ] phenyl } carbonyl) amino ] malonamide,

Compound 447N-hydroxy-2- [ { [4- (5-methoxypyridin-3-yl) phenyl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

The compound 4482- [ { [4- (3-fluoropyridin-4-yl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 449N-hydroxy-2- [ { [4- (6-methoxypyridin-3-yl) phenyl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

The compound 450N-hydroxy-N' -methyl-2- (methyl { [4- (6-methylpyridin-3-yl) phenyl ] carbonyl } amino) malonamide,

The compound 451N-hydroxy-N' -methyl-2- (methyl { [4- (2-methylpyridin-4-yl) phenyl ] carbonyl } amino) malonamide,

The compound 452N-hydroxy-N' -methyl-2- (methyl { [4- (4-methylpyridin-2-yl) phenyl ] carbonyl } amino) malonamide,

The compound 453N-hydroxy-N' -methyl-2- [ methyl ({4- [ (3-phenylprop-2-yn-1-yl) oxy ] phenyl } carbonyl) amino ] malonamide,

The compound 4542- [ { [4- (benzyloxy) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 455N-hydroxy-N' -methyl-2- (methyl { [5- (phenylethynyl) pyridin-2-yl ] carbonyl } amino) malonamide,

The compound 456N-hydroxy-N' -methyl-2- (methyl { [4- (5-methylfuran-2-yl) phenyl ] carbonyl } amino) malonamide,

The compound 4572- [ { [ 5-fluoro-6- (4-methoxyphenyl) pyridin-3-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 4582- [ { [6- (1, 3-benzodioxol-5-yl) -5-fluoropyridin-3-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 459N-hydroxy-N ' -methyl-2- { methyl [ (2, 2 ', 4 ' -trifluorobiphenyl-4-yl) carbonyl ] amino } malonamide,

The compound 4602- { [ (2, 2 ' -difluoro-4 ' -methylbiphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N ' -methylmalonamide,

Compound 4612- [ { [4- (furan-3-ylethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 4622- [ { [4- (6-fluoropyridin-3-yl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 4632- [ { [4- (5-ethyl-6-methoxypyridin-3-yl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 464N-hydroxy-N' -methyl-2- [ methyl ({4- [ (2-methylpyridin-4-yl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

Compound 465N-hydroxy-N' -methyl-2- (methyl { [4- ({4- [3- (morpholin-4-yl) propoxy ] phenyl } ethynyl) phenyl ] carbonyl } amino) malonamide,

The compound 466N-hydroxy-N' -methyl-2- [ methyl ({6- [ (E) -2-phenylvinyl ] pyridin-3-yl } carbonyl) amino ] malonamide,

The compound 467N-hydroxy-N' -methyl-2- (methyl { [4- (6-propoxypyridin-3-yl) phenyl ] carbonyl } amino) malonamide,

Compound 4682- [ ({4- [6- (benzyloxy) pyridin-3-yl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 469N-hydroxy-N' -methyl-2- [ methyl ({4- [6- (methylsulfanyl) pyridin-3-yl ] phenyl } carbonyl) amino ] malonamide,

The compound 4702- { [ (2, 2 ' -difluoro-4 ' -methoxybiphenyl-4-yl) carbonyl ] (methyl) amino } -N-hydroxy-N ' -methylmalonamide,

The compound 471N-hydroxy-N' -methyl-2- (methyl { [4- (quinolin-6-ylethynyl) phenyl ] carbonyl } amino) malonamide,

Compound 472N-hydroxy-2- [ { [4- (isoquinolin-6-ylethynyl) phenyl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

Compound 473N-hydroxy-N' -methyl-2- { methyl [ (4- { [4- (4-methylpiperazin-1-yl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

The compound 4742- [ { [4- (6-butylpyridin-3-yl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 475N-hydroxy-N' -methyl-2- [ methyl ({4- [6- (pentylamino) pyridin-3-yl ] phenyl } carbonyl) amino ] malonamide,

The compound 4762- [ { [4- (4- {4- [ (cyclopropylamino) methyl ] phenyl } but-1, 3-diyn-1-yl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 4772- [ ({4- [ (1E) -4- {4- [ (cyclopropylamino) methyl ] phenyl } but-1-en-3-yn-1-yl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 478N-hydroxy-2- [ ({4- [ (3E) -4- (6-methoxypyridin-3-yl) but-3-en-1-yn-1-yl ] phenyl } carbonyl) (methyl) amino ] -N' -methylmalonamide,

The compound 479N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [5- (morpholin-4-ylmethyl) furan-2-yl ] biphenyl-4-yl } carbonyl) amino ] malonamide,

The compound 480N-hydroxy-N' -methyl-2- [ methyl ({4- [6- (pentyloxy) pyridin-3-yl ] phenyl } carbonyl) amino ] malonamide,

The compound 4812- [ ({4- [ (3E) -4- {4- [ (cyclopropylamino) methyl ] phenyl } but-3-en-1-yn-1-yl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 482N-hydroxy-N' -methyl-2- { methyl [ (4- { [4- ({ [ (5-methyl-1, 2-oxazol-3-yl) methyl ] amino } methyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

Compound 483N-hydroxy-N' -methyl-2- { methyl [ (4- { [5- (morpholin-4-ylmethyl) furan-3-yl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

The compound 4842- [ ({4- [4- (furan-3-yl) but-1, 3-diyn-1-yl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 485N-hydroxy-N' -methyl-2- [ methyl ({4- [ (4- { [ (1, 3-oxazol-2-ylmethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

The compound 4862- [ ({4- [ (4- { [ (4-fluorophenylmethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 4872- { [ (4- { [4- ({ [2- (4-fluorophenyl) ethyl ] amino } methyl) phenyl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 488N-hydroxy-N' -methyl-2- [ methyl ({4- [ (5- { [ (2, 2, 2-trifluoroethyl) amino ] methyl } furan-3-yl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

The compound 4892- { [ (4- { [4- (1, 3-dihydro-2H-isoindol-2-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 4902- { [ (4- { [4- (3, 4-dihydroisoquinolin-2 (1H) -ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 491N-hydroxy-N' -methyl-2- [ methyl ({4- [ (5-methyl-1, 2-oxazol-4-yl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

The compound 492N-hydroxy-N' -methyl-2- (methyl { [4- (4- {4- [ (4-methylpiperazin-1-yl) methyl ] phenyl } but-1, 3-diyn-1-yl) phenyl ] carbonyl } amino) malonamide,

The compound 4932- [ ({4- [4- (4- { [ (2, 2-dimethylpropyl) amino ] methyl } phenyl) but-1, 3-diyn-1-yl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 4942- [ { [4- ({4- [ (2, 3-dihydro-1H-inden-1-ylamino) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 4952- [ ({4- [ (4- { [ benzyl (methyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 496N-hydroxy-N' -methyl-2- (methyl { [4- ({4- [4- (morpholin-4-yl) piperidin-1-yl ] phenyl } ethynyl) phenyl ] carbonyl } amino) malonamide,

The compound 4972- [ ({4- [ (4- { [ (furan-2-ylmethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 4982- [ { [4- ({4- [2- (1, 3-dihydro-2H-isoindol-2-yl) ethyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 499N-hydroxy-2- [ ({4 '- [5- (hydroxymethyl) furan-2-yl ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N' -methylmalonamide,

The compound 5002- [ { [4- (4- {4- [ (cyclobutylamino) methyl ] phenyl } but-1, 3-diyn-1-yl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 5012- [ { [4- ({5- [ (E) - (ethoxyimino) methyl ] furan-2-yl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

the compound 502N-hydroxy-N '-methyl-2- [ methyl ({ 4' - [3- (1, 4-oxoazanan-4-yl) propyl ] biphenyl-4-yl } carbonyl) amino ] malonamide,

Compound 5032- [ { [4- (cyclopropylethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 504N-hydroxy-N' -methyl-2- [ methyl ({4- [ (1-methyl-1H-pyrazol-4-yl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

The compound 505N-hydroxy-2- [ { [4- ({4- [ (3-methoxyazetidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

the compound 5062- [ { [4- ({5- [ (E) - (ethoxyimino) methyl ] furan-3-yl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 5072- [ { [4- (4-cyclopropylbut-1, 3-diyn-1-yl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 5082- [ { [4- ({4- [ (2-amino-2-methylpropoxy) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 509N-hydroxy-N' -methyl-2- [ methyl ({4- [4- (pyridin-4-yl) but-1, 3-diyn-1-yl ] phenyl } carbonyl) amino ] malonamide,

Compound 5102- [ ({4- [ (4- { [ (2, 2-dimethylpentyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 511N-hydroxy-N' -methyl-2- [ methyl ({4- [4- (1-methyl-1H-pyrazol-4-yl) but-1, 3-diyn-1-yl ] phenyl } carbonyl) amino ] malonamide,

The compound 512N-hydroxy-N' -methyl-2- (methyl { [4- ({4- [ (2-methylpyrrolidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } amino) malonamide,

The compound 5132- [ { [4- ({4- [ (3, 3-dimethylpiperidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 514N-hydroxy-2- { [ (4- { [5- (methoxymethyl) furan-3-yl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N' -methylmalonamide,

The compound 5152- { [ (4- { [4- (3-azabicyclo [3.1.0] hex-3-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 5162- { [ (4- { [ (1R) -2-ethyl-1-methyl-2, 3-dihydro-1H-isoindol-5-yl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 5172- [ ({4- [ (1-ethyl-1H-pyrazol-4-yl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 518N-hydroxy-2- { [ (4- { [1- (2-methoxyethyl) -1H-pyrazol-4-yl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N' -methylmalonamide,

The compound 519N-hydroxy-2- [ ({4 '- [3- (hydroxymethyl) -1, 2-oxazol-5-yl ] biphenyl-4-yl } carbonyl) (methyl) amino ] -N' -methylmalonamide,

The compound 520N-hydroxy-2- { methyl [ (4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } -N' - (pyridin-2-ylmethyl) malonamide,

The compound 521N-hydroxy-2-methyl-2- { methyl [ (4- { [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } -N' - (pyridin-2-ylmethyl) malonamide,

The compound 5222- [ { [4- ({4- [ (4-fluoropiperidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 5232- [ { [4- (cyclohex-1-en-1-ylethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 5242- { [ (4- { [4- (2-azaspiro [3.3] hept-2-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 5252- [ { [4- ({4- [ (3, 3-dimethylazetidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 526N-hydroxy-2- { [ (4 '-methoxybiphenyl-4-yl) carbonyl ] (methyl) amino } -N' - (pyridin-2-ylmethyl) malonamide,

The compound 5272- { [ (4- { [4- (7-azabicyclo [2.2.1] hept-7-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

Compound 528N-hydroxy-2- { [ (4- { [5- (methoxymethyl) furan-3-yl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N', 2-dimethylmalonamide,

Compound 529N-hydroxy-N', 2-dimethyl-2- [ methyl ({4- [4- (1-methyl-1H-pyrazol-4-yl) but-1, 3-diyn-1-yl ] phenyl } carbonyl) amino ] malonamide,

The compound 530N-hydroxy-2- [ ({4- [ (4- { [3- (2-methoxyethylene) azetidin-1-yl ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N' -methylmalonamide,

The compound 5312- [ { [4- ({4- [ (3-ethoxyazetidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

Compound 532N-hydroxy-N' -methyl-2- { methyl [ (4- { [4- (7-oxa-2-azaspiro [3.5] non-2-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

The compound 533N-hydroxy-2- [ { [4- ({4- [ (3-methoxy-3-methylazetidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N' -methylmalonamide,

The compound 534N-hydroxy-N', 2-dimethyl-2- [ methyl ({4- [ (4- { [3- (propan-2-yloxy) azetidin-1-yl ] methyl } phenyl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

The compound 5352- [ { [4- ({4- [ (3-ethoxyazetidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 5362- { [ (4- { [ 3-fluoro-4- (morpholin-4-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 5372- [ { [4- ({4- [ (3-ethoxy-3-methylazetidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 5382- [ { [4- ({4- [ (3-ethyl-3-methoxyazetidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 5392- [ ({4- [ (4- { [3- (2-fluoroethoxy) azetidin-1-yl ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 5402- [ ({4- [ (4- { [ cyclopropyl (methyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 5412- [ ({4- [ (4- { [ cyclopropyl (methyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 5422- [ ({4- [ (4- { [3- (cyclobutyloxy) azetidin-1-yl ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compounds 543N-hydroxy-N' -methyl-2- (methyl { [4- ({4- [ (3-propylazetidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } amino) malonamide,

Compound 544N-hydroxy-N' -methyl-2- { methyl [ (4- { [ 3-methyl-4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

The compound 5452- { [ (4- { [ 3-fluoro-4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 5462- [ ({4- [ (4- { [ (2-fluoroethyl) (methyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 5472- { [ (4- { [ 2-fluoro-4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N-hydroxy-N' -methylmalonamide,

The compound 5482- [ ({4- [ (4- { [ (2-fluoroethyl) (methyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 5492- [ { [4- ({4- [ (cyclopropylamino) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 550(2S) -N-hydroxy-2- { [ (4- { [5- (methoxymethyl) furan-3-yl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N', 2-dimethylmalonamide,

The compound 5512- [ ({4- [ (4- { [ cyclobutyl (methyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 5522- [ ({4- [ (4- { [ (2, 2-dimethylpropyl) (methyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 553(2S) -2- [ { [4- ({4- [ (cyclopropylamino) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 554(2S) -2- [ ({4- [ (4- { [ (2-fluoroethyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 555(2S) -2- [ { [4- ({4- [ (cyclobutylamino) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide, methyl, ethyl, propyl, butyl,

The compound 556(2S) -2- [ ({4- [ (4- { [ (2, 2-dimethylpropyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 557(2S) -2- [ { [4- ({4- [ (3-ethoxyazetidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 558(2S) -N-hydroxy-2- [ { [4- ({4- [ (3-methoxy-3-methylazetidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N', 2-dimethylmalonamide,

The compound 559(2S) -2- [ ({4- [ (4- { [3- (2-fluoroethoxy) azetidin-1-yl ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 560(2S) -N-hydroxy-N', 2-dimethyl-2- (methyl { [4- ({4- [ (2-methylmorpholin-4-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } amino) malonamide,

The compound 561(2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { [4- (morpholin-4-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

The compound 5622- [ { [4- ({4- [ (3-ethoxyazetidin-1-yl) methyl ] -3-methylphenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 5632- [ { [4- ({4- [ (3-ethoxyazetidin-1-yl) methyl ] -3-fluorophenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 5642- [ { [4- ({4- [ (3-ethoxyazetidin-1-yl) methyl ] -2-fluorophenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 565(2S) -N-hydroxy-2- [ { [4- ({4- [ (4-methoxypiperidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N', 2-dimethylmalonamide,

The compound 566(2S) -2- [ { [4- ({4- [ (4-ethoxypiperidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 567(2S) -N-hydroxy-2- [ { [4- ({4- [ (3-methoxyazetidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N', 2-dimethylmalonamide,

The compound 5682- [ { [4- ({4- [ (3-ethoxyazetidin-1-yl) methyl ] -2-methylphenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 569(2S) -N-hydroxy-N', 2-dimethyl-2- (methyl { [4- ({4- [ (3-propoxyazetidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } amino) malonamide,

The compound 570(2S) -2- [ ({4- [ (4- { [3- (cyclopropylmethoxy) azetidin-1-yl ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 571(2S) -N-hydroxy-N', 2-dimethyl-2- [ methyl ({4- [ (4- { [ (2-methylpropyl) amino ] methyl } phenyl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

The compound 5722- [ { [4- ({4- [ (3-ethoxyazetidin-1-yl) methyl ] -3-methoxyphenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

Compound 5732- [ { [4- ({4- [ (3-ethoxyazetidin-1-yl) methyl ] -3- (trifluoromethyl) phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 5742- [ { [4- ({4- [ (3-ethoxyazetidin-1-yl) methyl ] -2- (trifluoromethyl) phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 575(2S) -N-hydroxy-N', 2-dimethyl-2- [ methyl ({4- [ (2-methyl-1, 3-oxazol-4-yl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

The compound 576(2S) -N-hydroxy-N', 2-dimethyl-2- [ methyl ({4- [ (5-methyl-1, 2-oxazol-3-yl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

The compound 577(2S) -N-hydroxy-2- [ ({4- [ (4- { [3- (2-methoxyethoxy) azetidin-1-yl ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N', 2-dimethylmalonamide,

Compound 578(2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { [4- ({ [ (3-methyloxetan-3-yl) methyl ] amino } methyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

The compound 5792- [ { [4- ({ 3-chloro-4- [ (3-ethoxyazetidin-1-yl) methyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 5802- [ { [4- ({4- [ (3-ethoxyazetidin-1-yl) methyl ] -2, 3-difluorophenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 5812- [ { [4- ({4- [ (3-ethoxyazetidin-1-yl) methyl ] phenyl } ethynyl) -3-fluorophenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 5822- [ { [4- ({4- [ (3-ethoxyazetidin-1-yl) methyl ] phenyl } ethynyl) -3-methylphenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N' -methylmalonamide,

The compound 583(2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { [5- (1, 4-oxoazepan-4-ylmethyl) furan-3-yl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

The compound 584(2S) -2- [ { [4- ({5- [ (3-ethoxyazetidin-1-yl) methyl ] furan-3-yl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 585(2S) -2- [ { [4- ({5- [ (cyclopropylamino) methyl ] furan-3-yl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

Compound 586(2S) -N-hydroxy-N', 2-dimethyl-2- [ methyl ({4- [ (2-methyl-1, 3-thiazol-4-yl) ethynyl ] phenyl } carbonyl) amino ] malonamide,

The compound 587(2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { [4- ({ [ (1-methylcyclopentyl) methyl ] amino } methyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

The compound 588(2S) -2- [ { [4- (1, 3-benzodioxol-5-ylethynyl) phenyl ] carbonyl } (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 589(2S) -2- { [ (4- { [4- (difluoromethoxy) phenyl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N-hydroxy-N', 2-dimethylmalonamide,

The compound 590(2S) -N-hydroxy-N', 2-dimethyl-2- (methyl {4- [ (3E) -4- (tetrahydro-2H-pyran-4-yl) but-3-en-1-yn-1-yl ] benzoyl } amino) malonamide,

The compound 591(2S) -N-hydroxy-N', 2-dimethyl-2- [ methyl (4- { [4- ({ [ (2-methylcyclopropyl) methyl ] amino } methyl) phenyl ] ethynyl } benzoyl) amino ] malonamide,

the compound 592(2S) -N-hydroxy-N', 2-dimethyl-2- [ methyl (4- { [5- (morpholin-4-ylmethyl) furan-3-yl ] ethynyl } benzoyl) amino ] malonamide,

The compound 593(2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [4- ({4- [2- (2-methylmorpholin-4-yl) ethyl ] phenyl } ethynyl) benzoyl ] amino } malonamide,

The compound 594(2S) -N-hydroxy-N', 2-dimethyl-2- (methyl {4- [ (4- { [ (2-methylcyclopropyl) amino ] methyl } phenyl) ethynyl ] benzoyl } amino) malonamide,

A mixture of the compounds 595(2S) -N-hydroxy-N ', 2-dimethyl-2- (methyl {4- [ (3E) -4- (5-methyl-1, 2-oxazol-3-yl) but-3-en-1-yn-1-yl ] benzoyl } amino) malonamide and (2S) -N-hydroxy-N', 2-dimethyl-2- (methyl {4- [ (3Z) -4- (5-methyl-1, 2-oxazol-3-yl) but-3-en-1-yn-1-yl ] benzoyl } amino) malonamide, and,

The compound 596(2S) -N-hydroxy-2- [ (4- { (3E) -4- [2- (methoxymethyl) cyclopropyl ] but-3-en-1-yn-1-yl } benzoyl) (methyl) amino ] -N', 2-dimethylmalonamide,

The compound 597(2S) -N-hydroxy-2- [ {4- [ (3E) -7-methoxyhept-3-en-1-yn-1-yl ] benzoyl } (methyl) amino ] -N', 2-dimethylmalonamide,

The compound 598(2S) -2- [ {4- [ (4- { [3- (benzyloxy) azetidin-1-yl ] methyl } phenyl) ethynyl ] benzoyl } (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 599(2S) -N-hydroxy-2- { [4- ({4- [2- (3-methoxyazetidin-1-yl) ethyl ] phenyl } ethynyl) benzoyl ] (methyl) amino } -N', 2-dimethylmalonamide,

The compound 600(2S) -2- [ (4- { [4- ({ [1- (2-fluoroethyl) azetidin-3-yl ] oxy } methyl) phenyl ] ethynyl } benzoyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 601(2S) -N-hydroxy-2- { [4- (5-methoxypent-1-yn-1-yl) benzoyl ] (methyl) amino } -N', 2-dimethylmalonamide,

The compound 602(2S) -N-hydroxy-2- { [4- ({4- [2- (4-methoxypiperidin-1-yl) ethyl ] phenyl } ethynyl) benzoyl ] (methyl) amino } -N', 2-dimethylmalonamide,

The compound 603(2S) -N-hydroxy-2- { [4- ({5- [ (2-methoxyethoxy) methyl ] furan-3-yl } ethynyl) benzoyl ] (methyl) amino } -N', 2-dimethylmalonamide,

Compound 604(2S) -2- [ {4- [ (4- { [1- (2-fluoroethyl) azetidin-3-yl ] oxy } phenyl) ethynyl ] benzoyl } (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 605(2S) -N-hydroxy-2- [ (4- { [5- (2-methoxyethyl) furan-3-yl ] ethynyl } benzoyl) (methyl) amino ] -N', 2-dimethylmalonamide,

The compound 606(2S) -2- [ ({4- [ (3E) -4- (1-phenylmethylazetidin-3-yl) but-3-en-1-yn-1-yl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

Compound 607(2S) -2- [ ({4- [ (4- { [3- (furan-2-ylmethoxy) azetidin-1-yl ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 608(2S) -N-hydroxy-2- [ { [4- ({4- [3- (3-methoxyazetidin-1-yl) propyl ] phenyl } ethynyl) phenyl ] carbonyl } (methyl) amino ] -N', 2-dimethylmalonamide, c,

The compound 609(2S) -N-hydroxy-2- { [ (4- { [5- (1-methoxyethyl) furan-3-yl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N', 2-dimethylmalonamide,

The compound 610(2S) -2- [ ({4- [ (4-acetylphenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 611(2S) -N-hydroxy-N', 2-dimethyl-2- (methyl {4- [ (4- { [ (tetrahydrofuran-2-ylmethyl) amino ] methyl } phenyl) ethynyl ] benzoyl } amino) malonamide,

The compound 612(2S) -2- [ (4- { [5- (ethoxymethyl) furan-3-yl ] ethynyl } benzoyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 613(2S) -N-hydroxy-N', 2-dimethyl-2- (methyl {4- [ (4- { [3- (propan-2-yloxy) azetidin-1-yl ] methyl } phenyl) ethynyl ] benzoyl } amino) malonamide,

The compound 614(2S) -N-hydroxy-2- [ {4- [ (4- { [ (2-methoxyethyl) amino ] methyl } phenyl) ethynyl ] benzoyl } (methyl) amino ] -N', 2-dimethylmalonamide,

The compound 615(2S) -N-hydroxy-N', 2-dimethyl-2- (methyl {4- [ (4- { [ (4, 4, 4-trifluorobutyl) amino ] methyl } phenyl) ethynyl ] benzoyl } amino) malonamide,

The compound 616(2S) -N-hydroxy-2- [ (4- { [5- (hydroxymethyl) furan-3-yl ] ethynyl } benzoyl) (methyl) amino ] -N', 2-dimethylmalonamide,

Compound 617(2S) -N-hydroxy-N', 2-dimethyl-2- [ methyl (4- { [4- (1-oxa-6-azaspiro [3.3] hept-6-ylmethyl) phenyl ] ethynyl } benzoyl) amino ] malonamide,

The compound 618(2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [4- ({4- [ (tetrahydrofuran-3-ylamino) methyl ] phenyl } ethynyl) benzoyl ] amino } malonamide,

The compound 619(2S) -2- { [4- ({4- [ (3-fluoroazetidin-1-yl) methyl ] phenyl } ethynyl) benzoyl ] (methyl) amino } -N-hydroxy-N', 2-dimethylmalonamide,

The compound 620(2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { [4- ({ [ (5-methylfuran-2-yl) methyl ] amino } methyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide,

The compound 621(2S) -2- [ ({4- [ (E) -2- {4- [ (cyclopropylamino) methyl ] phenyl } vinyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide

The compound 622(2S) -N-hydroxy-2- { [ (4- { [6- (methoxymethyl) pyridin-3-yl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N', 2-dimethylmalonamide

The compound 623(2S) -N-hydroxy-N ', 2-dimethyl-2- [ methyl ({ 4' - [ (3-methyloxetan-3-yl) methoxy ] biphenyl-4-yl } carbonyl) amino ] malonamide,

The compound 624(2S) -N-hydroxy-N ', 2-dimethyl-2- [ methyl ({ 4' - [4- (morpholin-4-yl) butoxy ] biphenyl-4-yl } carbonyl) amino ] malonamide,

The compound 625(2S) -2- [ ({4- [ (4- { [3- (cyclopropyloxy) azetidin-1-yl ] methyl } phenyl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

The compound 626(2S) -N-hydroxy-N ', 2-dimethyl-2- (methyl { [ 4' - (tetrahydro-2H-pyran-4-ylmethoxy) biphenyl-4-yl ] carbonyl } amino) malonamide,

The compound 627(2S) -N-hydroxy-N', 2-dimethyl-2- [ methyl ({4- [ (E) -2- {4- [ (oxetan-3-ylamino) methyl ] phenyl } vinyl ] phenyl } carbonyl) amino ] malonamide,

The compound 628(2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { (E) -2- [4- (1, 4-oxoazepan-4-ylmethyl) phenyl ] vinyl } phenyl) carbonyl ] amino } malonamide,

The compound 629(2S) -2- [ { [2 ' -chloro-4 ' - (methylamino) biphenyl-4-yl ] carbonyl } (methyl) amino ] -N-hydroxy-N ', 2-dimethylmalonamide,

The compound 630(2S) -N-hydroxy-2- { [ (4- { [5- (methoxymethyl) furan-2-yl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N', 2-dimethylmalonamide,

The compound 631(2S) -N-hydroxy-N', 2-dimethyl-2- [ methyl ({4- [5- (3-methyloxetan-3-yl) pent-1-yn-1-yl ] phenyl } carbonyl) amino ] malonamide,

Compound 632(2S) -N-hydroxy-2- { [ (4- { [4- (hydroxymethyl) phenyl ] ethynyl } phenyl) carbonyl ] (methyl) amino } -N', 2-dimethylmalonamide,

Compound 633(2S) -2- [ ({4- [ (1, 5-dimethyl-1H-pyrazol-4-yl) ethynyl ] phenyl } carbonyl) (methyl) amino ] -N-hydroxy-N', 2-dimethylmalonamide,

Compound 634(2S) -N-hydroxy-N', 2-dimethyl-2- { methyl [ (4- { [4- (6-oxa-1-azaspiro [3.3] hept-1-ylmethyl) phenyl ] ethynyl } phenyl) carbonyl ] amino } malonamide.

Claims

1. A compound represented by the general formula [1] or a pharmaceutically acceptable salt thereof,

in the formula (I), the compound is shown in the specification,

R¹is represented by C_1-6Alkyl radical, C_1-6The alkyl groups may be substituted by 1 to 3 identical or different halogen atoms,

R²represents a hydrogen atom, C_1-6Alkyl radical, C_3-8Cycloalkyl radicalsOr C_1-6Alkoxy radical, C_1-6Alkyl radical, C_1-6Alkoxy and C_3-8Cycloalkyl radicals may be chosen from "halogen atoms, hydroxy groups, C_3-8Cycloalkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkoxy, amino, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, -N (R)¹¹）COR¹²、-N（R¹¹）SO₂R¹²Cyano, carboxy, carbamoyl, -CON (R)¹³）（R¹⁴）、-SO₂N（R¹³）（R¹⁴）、C_1-6Alkylthio and C_1-6Alkylsulfonyl "is substituted with 1 to 3 substituents which may be the same or different,

R³represents a hydrogen atom, and is represented by,

R⁴is represented by C_1-6Alkyl radical, C_1-6The alkyl group may be substituted with a phenyl group, isoxazolyl group, furyl group, pyrazolyl group, imidazolyl group, oxazolyl group, thiazolyl group, thiadiazolyl group, pyridyl group or pyrimidinyl group, and the phenyl group, isoxazolyl group, furyl group, pyrazolyl group, imidazolyl group, oxazolyl group, thiazolyl group, thiadiazolyl group, pyridyl group and pyrimidinyl group may be substituted with a substituent selected from the group consisting of "halogen atom, C _1-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_2-8Alkoxyalkyl, hydroxy, C_1-6Alkoxy radical, C_3-8Cycloalkoxy, amino, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, -N (R)⁴⁵）COR⁴⁶、-CON（R⁴⁷）（R⁴⁸) "is substituted with 1 to 3 substituents which may be the same or different,

R⁴⁵、R⁴⁶、R⁴⁷and R⁴⁸Same or different and represents a hydrogen atom or C_1-6An alkyl group, a carboxyl group,

A¹represents phenylene, pyridyldiyl, pyrazinediyl, thiophenediyl or C_3-8Cycloalkylene radical, the phenylene, pyridinediyl, pyrazindiyl, thiophenediyl and C_3-8The cycloalkylene group may be selected from the following substituent group R^aIs substituted with 1 to 4 substituents which may be the same or different,

substituent group R^aRepresents a halogen atom, a hydroxyl group, an amino group, a carboxyl group, a carbamoyl group, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_2-6Alkenyl and C_1-6Alkoxy, the amino group possibly being substituted by C_2-6Alkanoyl or 1 or 2C_1-6Alkyl substitution of the C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_2-6Alkenyl and C_1-6Alkoxy groups may be selected from "halogen atoms, hydroxy groups, amino groups, carboxyl groups, C_1-6Alkylaminocarbonyl and C_1-6Alkoxycarbonyl "is substituted by 1 to 4 substituents which may be the same or different,

L represents-C.ident.C-, -C.ident.C- (CH)₂）_m-O-、-CH＝CH-、-CH＝CH-C≡C-、-C≡C-CH＝CH-、-O-、-S-、-NR⁵-、-CONR⁵-、-NR⁵CO-, azetidinediyl, piperazinediyl, - (CH)₂）_m-NR⁵-、-（CH₂）_m-O-、-NR⁵-（CH₂）_m-、-O-（CH₂）_m-、-ON＝CH-、C_1-4An alkylene group or a chemical bond,

R⁵represents a hydrogen atom, C_1-6Alkyl or C_3-8A cycloalkyl group,

m represents 1, 2 or 3,

A²represents phenylene, pyridyldiyl, pyrimidyldiyl, furandiyl, pyrazolediyl, pyrrolediyl, pyrazinediyl, furandiyl, thiophenediyl, oxazolediyl, isoxazolediyl, thiazolediyl, indolediyl or 1H-indazoleDiyl, 2H-indazoldiyl, benzofurandiyl, benzimidazolediyl, benzothiazolediyl, benzoxazolediyl, benzisoxazolediyl, imidazopyridinediyl, quinolinediyl, isoquinolinediyl, 2H-isoindolindindiyl, indolinediyl, benzodioxolyl, dihydroisobenzofurandiyl, dihydrobenzofurandiyl, 2H-benzo [ b ] benzo][1，4]Oxazin-3 (4H) -one-diyl, tetrahydropyran-diyl, azetidinediyl, C3-8 cycloalkylene, C_3-8Cycloalkenylene group, C_1-4Alkylene or C_2-4Alkenylene radical, phenylene, pyridyldiyl, pyrimidyldiyl, furandiyl, pyrazolediyl, pyrrolediyl, pyrazinediyl, furandiyl, thiophenediyl, oxazolediyl, isoxazolediyl, thiazolediyl, indolediyl, 1H-indazolediyl, 2H-indazolediyl, benzofurandiyl, benzimidazolediyl, benzothiazolediyl, benzoxazolediyl, benzisoxazolediyl, imidazopyridinediyl, quinolinediyl, isoquinolinediyl, 2H-isoindolindinediyl, indolinediyl, benzodioxolyl, dihydroisobenzofurandiyl, dihydrobenzofurandiyl, 2H-benzo [ b ] b ][1，4]Oxazin-3 (4H) -one-diyl, tetrahydropyran-diyl, azetidinediyl, C_3-8Cycloalkenylene group, C_3-8Cycloalkylene radical, C_1-4Alkylene and C_2-4The alkenylene group may be substituted by a substituent group R selected from the group consisting of^bIs substituted with 1 to 4 substituents which may be the same or different,

substituent group R^bRepresents a halogen atom, an optionally protected hydroxyl group, a mercapto group, a cyano group, a nitro group, an optionally protected amino group, an optionally protected formyl group, an optionally protected carboxyl group, a carbamoyl group, a sulfo group, a ureido group, a guanidino group, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, C_1-6Alkoxycarbonyl and C_2-6An alkanoyl group, a carbonyl group,

w represents R⁶-Ｘ¹-、R⁶-Ｘ²-Ｙ¹-Ｘ¹-、R⁶-Ｘ⁴-Ｙ¹-Ｘ²-Ｙ³-Ｘ³-、Ｑ-Ｘ¹-Ｙ²-Ｘ³-or Q-X¹-Ｙ¹-Ｘ²-Ｙ³-Ｘ³-，

Ｙ²represents-O-, -NR⁷-、-CO-、-NR⁷CO-、-CONR⁷-、-S（O）_n-、-OCO-、-COO-、-NR⁷SO₂-、-SO₂NR⁷-、-OCOO-、-OCONR⁷-、-NR⁷CONR⁸-or a chemical bond,

Ｙ¹and Y³The same or different, represent-O-, -NR⁷-、-CO-、-NR⁷CO-、-CONR⁷-、-S（O）_n-、-OCO-、-COO-、-NR⁷SO₂-、-SO₂NR⁷-、-OCOO-、-OCONR⁷-or-NR⁷CONR⁸-，

n represents 0, 1 or 2,

Ｘ¹and X³Same or different, represent C_1-10Alkylene radical, C_2-10Alkenylene radical, C_2-10Alkynylene, C_3-8Cycloalkylene, -C_1-6alkylene-C_3-8cycloalkylene-C_1-6Alkylene-or chemical bonds, of this type C_1-10Alkylene radical, C_2-10Alkenylene radical, C_2-10Alkynylene, C_3-8Cycloalkylene and-C_1-6alkylene-C_3-8cycloalkylene-C_1-6Alkylene-may be substituted by a substituent group R^cIs substituted with 1 to 4 substituents which may be the same or different,

Ｘ²And X⁴Same or different, represent C_1-10Alkylene radical, C_2-10Alkenylene radical, C_2-10Alkynylene or-C_1-6alkylene-C_3-8cycloalkylene-C_1-6Alkylene-of the C_1-10Alkylene radical, C_2-10Alkenylene radical, C_2-10Alkynylene and-C_1-6alkylene-C_3-8cycloalkylene-C_1-6Alkylene-may be substituted by a substituent group R^cIs substituted with 1 to 4 substituents which may be the same or different,

q represents C_3-8Cycloalkyl, phenyl, tetrazolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl, pyridyl, pyrazinyl, piperidinyl, morpholinyl, homomorpholinyl, 2-oxa-6-azaspiro [3.3]Heptyl, 1-oxa-6-azaspiro [3.3]Heptyl, 6-oxa-1-azaspiro [3.3]Heptyl, 1, 4-dioxa-8-azaspiro [4.5 ]]Decyl, 7-oxa-2-azaspiro [3.5 ]]Nonyl, 1-oxa-2, 8-diazaspiro [4.5 ]]Decyl, piperazinyl, 3-oxopiperazinyl, piperidinyl, 1,2,3, 6-tetrahydropyridinyl, pyrrolidinyl, azetidinyl, 2H-isoindolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 2-azaspiro [3.3]Heptyl, 3-azabicyclo [3.1.0]Hex-3-yl, 2-oxo-1, 3-oxazolidin-3-yl, 2-oxopyrrolidinyl, thiomorpholinyl, 1-dioxo-thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetan-2-yl, oxetan-3-yl, 1, 3-dioxolanyl or tetrahydro-2H-thiopyranyl, C _3-8Cycloalkyl, phenyl, tetrazolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl, pyridyl, pyrazinyl, piperidinyl, morpholinyl, homomorpholinyl, 2-oxa-6-azaspiro [3.3]Heptyl, 1-oxa-6-azaspiro [3.3]Heptyl, 6-oxa-1-azaspiro [3.3]Heptyl, 1, 4-dioxa-8-azaspiro [4.5 ]]Decyl, 7-oxa-2-azaspiro [3.5 ]]Nonyl, 1-oxa-2, 8-diazaspiro [4.5 ]]Decyl, piperazinyl, 3-oxopiperazinyl, piperidinyl, 1,2,3, 6-tetrahydropyridinyl, pyrrolidinyl, azetidinyl, 2H-isoindolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 2-azaspiro [3.3]Heptyl, 3-azabicyclo [3.1.0]Hex-3-yl, 2-oxo-1, 3-oxazolidin-3-yl, 2-oxopyrrolidinyl, thiomorpholinyl, 1-dioxo-thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetan-2-yl, oxetan-3-yl, 1, 3-dioxolanyl and tetrahydro-2H-thiopyranyl may be selected from the following group of substituents R^cIs substituted by 1 to 4 substituents which may be the same or different, such as tetrazolyl, imidazolyl, oxazolyl, isoxazolyl, furyl, pyridyl, pyrazinyl, piperidyl, morpholinyl, homomorpholinyl, 2-oxa-6-azaspiro [3.3 ] ]Heptyl, 1-oxa-6-azaspiro [3.3]Heptyl, 6-oxa-1-azaspiro [3.3]Heptyl, 1, 4-dioxa-8-azaspiro [4.5 ]]Decyl, 7-oxa-2-azaspiro [3.5]Nonyl, 1-oxa-2, 8-diazaspiro [4.5 ]]Decyl, piperazinyl, 3-oxopiperazinyl, piperidinyl, 1,2,3, 6-tetrahydropyridinyl, pyrrolidinyl, azetidinyl, 2H-isoindolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 2-azaspiro [3.3]Heptyl, 3-azabicyclo [3.1.0]Hex-3-yl, 2-oxo-1, 3-oxazolidin-3-yl, 2-oxopyrrolidinyl, thiomorpholinyl, 1-dioxo-thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetan-2-yl, oxetan-3-yl, 1, 3-dioxolanyl and tetrahydro-2H-thiopyranyl rings, which may be interrupted by C_1-6Alkylene or-C_1-6alkylene-O-C_1-6An alkylene-bridge is present between the two,

R⁶represents a hydrogen atom, a halogen atom, a hydroxyl group which may be protected, a mercapto group, a cyano group, a nitro group, an amino group which may be protected, a formyl group which may be protected, a carboxyl group which may be protected, a carbamoyl group, a sulfo group, a phosphoric acid group which may be protected, a ureido group, a guanidino group, R⁷-O-NR⁸-CO-、R⁸-ON＝CR⁹-、R⁸-ON＝CR⁹-NH-、R⁷-O-NR⁸-CH＝N-、（R⁷）（R⁸）N-N＝CH-、R⁸-O-NR⁸-、N≡C-NR⁸-or C_1-6Alkoxy radical, C_1-6The alkoxy group may be substituted with 1 to 3 hydroxyl groups,

R⁷And R⁸The same or different represent a hydrogen atom, C_1-6Alkyl or C_3-8Cycloalkyl radical, C_1-6Alkyl and C_3-8The cycloalkyl group may be selected from the following substituent groups R^cIs substituted with 1 to 4 substituents which may be the same or different,

substituent group R^cRepresents a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, a carboxyl group, a carbamoyl group, a ureido group, a guanidino group, C_1-6Alkyl radical, C_1-6Hydroxyalkyl radical, C_1-6Haloalkyl, C_3-8Cycloalkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkoxy, C_1-6Alkoxycarbonyl group, C_1-6Alkoxycarbonylamino group, C_2-6Alkanoyl radical, C_1-6Alkylsulfonyl radical, C_1-6Alkylthio, phenyl, piperazinyl, morpholinyl, tetrazolyl, C_1-6Alkylene group, C_3-8Cycloalkylene and hydroxyaminocarbonyl; the amino group may be substituted by C_2-6Alkanoyl or 1 or 2C_1-6Alkyl substitution; the C is_1-6Alkyl may be substituted with morpholinyl; the C is_1-6The alkoxy group may be selected from the group consisting of a hydroxyl group, a halogen atom, C_3-8Cycloalkyl radical, C_1-6Alkoxy, phenyl and furanyl, which are identical or different, are substituted by 1 to 3 substituents; the phenyl group, piperazinyl group, morpholinyl group and tetrazolyl group may be selected from the group consisting of "halogen atom, hydroxy group, cyano group, nitro group, amino group, carboxyl group and C_1-6Alkyl "is substituted with 1 to 4 substituents which may be the same or different; the C is _1-6The alkylene group may be substituted by C_1-6Alkoxy substitution.

2. The compound according to claim 1, which is represented by the general formula [1],

in the formula (I), the compound is shown in the specification,

R²represents a hydrogen atom, C_1-6Alkyl radical, C_3-8Cycloalkyl or C_1-6Alkoxy radical, C_1-6Alkyl radical, C_1-6Alkoxy and C_3-8Cycloalkyl radicals may be chosen from "halogen atoms, hydroxy groups, C_3-8Cycloalkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkoxy, amino, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, -N (R)¹¹）COR¹²、-N（R¹¹）SO₂R¹²Cyano, carboxy, carbamoyl, -CON (R)¹³）（R¹⁴）、-SO₂N（R¹³）（R¹⁴）、C_1-6Alkylthio and C_1-6Alkylsulfonyl "is substituted with 1 to 3 substituents which may be the same or different,

R³represents a hydrogen atom, and is represented by,

R⁴is represented by C_1-6Alkyl radical, C_1-6The alkyl group may be substituted by a phenyl group, isoxazolyl group, furyl group, pyrazolyl group, imidazolyl group, oxazolyl group, thiazolyl group, thiadiazolyl group, pyridyl group or pyrimidinyl group, and the phenyl group, isoxazolyl group, furyl group, pyrazolyl group, imidazolyl group, oxazolyl group, thiazolyl group, thiadiazolyl group, pyridyl group or pyrimidinyl group may be substituted by a substituent selected from the group consisting of "halogen atom, C _1-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_2-8Alkoxyalkyl, hydroxy, C_1-6Alkoxy radical, C_3-8Cycloalkoxy, amino, C_1-6Alkylamino radical, di (C)_1-6Alkyl) amino, -N (R)⁴⁵）COR⁴⁶、-CON（R⁴⁷）（R⁴⁸) "is substituted with 1 to 3 substituents which may be the same or different,

L represents-C.ident.C-, -C.ident.C-, -O-, -S-, -NR-, -⁵-、-CONR⁵-、-NR⁵CO-, azetidinediyl, piperazinediyl, - (CH)₂）_m-NR⁵-、-（CH₂）_m-O-、-NR⁵-（CH₂）_m-、-O-（CH₂）_m-、-ON＝CH-、C_1-4An alkylene group or a chemical bond,

R⁵represents a hydrogen atom, C_1-6Alkyl or C_3-8A cycloalkyl group,

m represents 1, 2 or 3,

A²represents phenylene, pyridyldiyl, pyrimidyldiyl, furandiyl, pyrazolediyl, pyrrolediyl, pyrazinediyl, furandiyl, thiophenediyl, oxazolediyl, isoxazolediyl, thiazolediyl, indolediyl, 1H-indazolediyl, 2H-indazolediyl, benzofurandiyl, benzimidazolediyl, benzothiazolediyl, benzoxazolediyl, benzisoxazolediyl, imidazopyridinediyl, quinolinediyl, isoquinolinediyl, 2H-isoindolindinediyl, indolinediyl, benzodioxodiyl, dihydroisobenzofurandiyl, dihydrobenzofurandiyl, 2H-benzo [ b ] b][1，4]Oxazin-3 (4H) -one-diyl, tetrahydropyran-diyl, azetidinediyl, C_3-8Cycloalkylene radical, C_1-4Alkylene or C_2-4Alkenylene radical, phenylene, pyridyldiyl, pyrimidyldiyl, furandiyl, pyrazolediyl, pyrrolediylPyrazinediyl, furandiyl, thiophenediyl, oxazolediyl, isoxazolediyl, thiazolediyl, indonediyl, 1H-indazolediyl, 2H-indazolediyl, benzofurandiyl, benzimidazolediyl, benzothiazediyl, benzoxazodiyl, benzisoxazodiyl, imidazopyridinediyl, quinolinediyl, isoquinolinediyl, 2H-isoindolinodiyl, indolinediyl, benzodioxonediyl, dihydroisobenzofurandiyl, dihydrobenzofurandiyl, 2H-benzo [ b ] b ][1，4]Oxazin-3 (4H) -one-diyl, tetrahydropyran-diyl, azetidinediyl, C_3-8Cycloalkylene radical, C_1-4Alkylene and C_2-4The alkenylene group may be substituted by a substituent group R selected from the group consisting of^bIs substituted with 1 to 4 substituents which may be the same or different,

n represents 0, 1 or 2,

Ｘ¹and X³Same or different, represent C_1-10Alkylene radical, C_2-10Alkenylene radical, C_2-10Alkynylene or a chemical bond, C_1-10Alkylene radical, C_2-10Alkenylene and C_2-10The alkynylene group may be selected from the following substituent group R^cIs substituted with 1 to 4 substituents which may be the same or different,

Ｘ²and X⁴Same or different, represent C_1-10Alkylene radical, C_2-10Alkenylene radical, C_2-10Alkynylene or-C_1-6alkylene-C_3-8cycloalkylene-C_1-6Alkylene-of the C_1-10Alkylene radical, C _2-10Alkenylene radical, C_2-10Alkynylene and-C_1-6alkylene-C_3-8cycloalkylene-C_1-6Alkylene-may be substituted by a substituent group R^cIs substituted with 1 to 4 substituents which may be the same or different,

q represents C_3-8Cycloalkyl, phenyl, tetrazolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl, pyridyl, pyrazinyl, piperidinyl, morpholinyl, homomorpholinyl, 2-oxa-6-azaspiro [3.3]Heptyl, 1-oxa-6-azaspiro [3.3]Heptyl, 6-oxa-1-azaspiro [3.3]Heptyl, 1, 4-dioxa-8-azaspiro [4.5 ]]Decyl, 7-oxa-2-azaspiro [3.5 ]]Nonyl, 1-oxa-2, 8-diazaspiro [4.5 ]]Decyl, piperazinyl, 3-oxopiperazinyl, piperidinyl, 1,2,3, 6-tetrahydropyridinyl, pyrrolidinyl, azetidinyl, 2H-isoindolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 2-azaspiro [3.3]Heptyl, 3-azabicyclo [3.1.0]Hex-3-yl, 2-oxo-1, 3-oxazolidin-3-yl, 2-oxopyrrolidinyl, thiomorpholinyl, 1-dioxo-thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetan-2-yl, oxetan-3-yl, 1, 3-dioxolanyl or tetrahydro-2H-thiopyranyl, C_3-8Cycloalkyl radicalsPhenyl, tetrazolyl, imidazolyl, oxazolyl, isoxazolyl, furyl, pyridyl, pyrazinyl, piperidyl, morpholinyl, homomorpholinyl, 2-oxa-6-azaspiro [3.3 ] ]Heptyl, 1-oxa-6-azaspiro [3.3]Heptyl, 6-oxa-1-azaspiro [3.3]Heptyl, 1, 4-dioxa-8-azaspiro [4.5 ]]Decyl, 7-oxa-2-azaspiro [3.5 ]]Nonyl, 1-oxa-2, 8-diazaspiro [4.5 ]]Decyl, piperazinyl, 3-oxopiperazinyl, piperidinyl, 1,2,3, 6-tetrahydropyridinyl, pyrrolidinyl, azetidinyl, 2H-isoindolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 2-azaspiro [3.3]Heptyl, 3-azabicyclo [3.1.0]Hex-3-yl, 2-oxo-1, 3-oxazolidin-3-yl, 2-oxopyrrolidinyl, thiomorpholinyl, 1-dioxo-thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetan-2-yl, oxetan-3-yl, 1, 3-dioxolanyl, tetrahydro-2H-thiopyranyl may be selected from the following group of substituents R^cIs substituted with 1 to 4 substituents which may be the same or different,

R⁶represents a hydrogen atom, a halogen atom, a hydroxyl group which may be protected, a mercapto group, a cyano group, a nitro group, an amino group which may be protected, a formyl group which may be protected, a carboxyl group which may be protected, a carbamoyl group, a sulfo group, a phosphoric acid group which may be protected, a ureido group, a guanidino group, R⁷-O-NR⁸-CO-、R⁸-ON＝CR⁹-、R⁸-ON＝CR⁹-NH-、R⁷-O-NR⁸-CH＝N-、（R⁷）（R⁸）N-N＝CH-、R⁸-O-NR⁸-or N ≡ C-NR⁸-，

R⁷And R⁸The same or different represent a hydrogen atom, C _1-6Alkyl or C_3-8Cycloalkyl radical, C_1-6Alkyl and C_3-8The cycloalkyl group may be selected from the following substituent groups R^cIs substituted with 1 to 4 substituents which may be the same or different,

substituent group R^cRepresents a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, a carboxyl group, a carbamoyl group, or a urea groupBase, guanidino, C_1-6Alkyl radical, C_1-6Hydroxyalkyl radical, C_1-6Haloalkyl, C_3-8Cycloalkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkoxy, C_1-6Alkoxycarbonyl group, C_1-6Alkoxycarbonylamino group, C_2-6Alkanoyl radical, C_1-6Alkylsulfonyl radical, C_1-6Alkylthio, phenyl, piperazinyl, morpholinyl, and tetrazolyl; the amino group may be substituted by C_2-6Alkanoyl or 1 or 2C_1-6Alkyl substitution; the C is_1-6Alkyl may be substituted with morpholinyl; the C is_1-6Alkoxy groups may be substituted with 1 to 3 hydroxy groups; the phenyl group, piperazinyl group, morpholinyl group and tetrazolyl group may be selected from the group consisting of "halogen atom, hydroxy group, cyano group, nitro group, amino group, carboxyl group and C_1-6Alkyl "is substituted with 1 to 4 substituents, which may be the same or different.

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, R¹Is methyl.

4. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, R²Is a hydrogen atom.

5. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, R²Is methyl.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, R³Is a hydrogen atom, R⁴Is methyl.

7. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, a¹Is a phenylene group which may be selected from the group consisting of "a halogen atom, a hydroxyl group, an amino group and C_1-6Alkyl "is substituted with 1 to 4 substituents, which may be the same or different.

8. A compound or compound of claim 7Pharmaceutically acceptable salts thereof, A¹Is phenylene.

9. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, L is-C ≡ C-, -CH ≡ CH-C ≡ C-, -C ≡ C-CH ≡ CH-, ethylene, or a chemical bond.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, L is a bond or-C ≡ C-.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, L is a bond.

12. The compound of claim 10, or a pharmaceutically acceptable salt thereof, L is-C ≡ C-.

13. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, a²Is phenylene, pyridyldiyl, pyrimidyldiyl, furandiyl, pyrazolediyl, pyrrolediyl, pyrazinediyl, furandiyl, thiophenediyl, oxazolediyl, isoxazolediyl, thiazolediyl, indolediyl, 1H-indazolediyl, 2H-indazolediyl, benzofurandiyl, benzimidazolediyl, benzothiazolediyl, benzoxazolediyl, benzisoxazolediyl, imidazopyridinediyl, quinolinediyl, isoquinolinediyl, 2H-isoindolindiediyl, indolidinyl, benzodioxolyl, dihydroisobenzofurandiyl, dihydrobenzofurandiyl or 2H-benzo [ b ][1，4]Oxazin-3 (4H) -one-diyl; the phenylene group may be selected from the group consisting of "halogen atom, hydroxyl group, amino group and C_1-6Alkyl "is substituted with 1 to 4 substituents which may be the same or different; the pyridyldiyl, pyrimidyldiyl, furandiyl, pyrazolediyl, pyrrolediyl, pyrazinediyl, furandiyl, thiophenediyl, oxazolediyl, isoxazolediyl and thiazolediyl groups may be selected from "halogen atom, hydroxyl group, amino group and C_1-6Alkyl "is substituted with 1 to 4 substituents which may be the same or different; the indole isDiyl, 1H-indazoldiyl, 2H-indazoldiyl, benzofurandiyl, benzimidazolediyl, benzothiazolediyl, benzoxazolediyl, benzisoxazolediyl, imidazopyridinediyl, quinolinediyl, isoquinolinediyl, 2H-isoindolindindiyl, indolinediyl, benzodioxolyl, dihydroisobenzofurandiyl, dihydrobenzofurandiyl and 2H-benzo [ b][1，4]Oxazin-3 (4H) -one-diyl may be substituted by a substituent selected from the group consisting of "halogen atom, hydroxy, amino and C_1-6Alkyl "is substituted with 1 to 4 substituents, which may be the same or different.

14. A compound according to claim 13, or a pharmaceutically acceptable salt thereof, a²Is phenylene or of the formula [2]The 2-valent radical of the formula (I),

In the formula, Z¹And Z²Same or different is-CH₂-、-O-、-NH-、-N（CH₃) -or-S-, wherein Z¹And Z²Are all-CH₂Except for the case of-a.

15. A compound according to claim 13, or a pharmaceutically acceptable salt thereof, a²Is phenylene, pyridyldiyl, pyrimidinediyl, furandiyl, pyrazolediyl, pyrrolediyl, indoldiyl, 1H-indazolediyl, 2H-indazolediyl, benzofurandiyl, benzimidazolediyl, benzothiazolediyl, benzoxazolediyl, benzisoxazolediyl, imidazopyridinediyl, 2H-isoindolindindiyl, indolindiyl, benzodioxolyl, dihydroisobenzofurandiyl or dihydrobenzofurandiyl, the phenylene, pyridyldiyl, pyrimidinediyl, furandiyl, pyrazolediyl, pyrrolediyl, indoldiyl, 1H-indazolediyl, 2H-indazolediyl, benzofurandiyl, benzimidazolediyl, benzothiazolediyl, benzoxazolediyl, benzisoxazolediyl, imidazopyridinediyl, 2H-isoindolindindiyl, indazolediyl, 2H-indazolediyl, benzimidazolediyl, benzothiazolediyl, benzoxazolediyl, benzisoxazolediyl, imidazopyridinediyl, 2H-isoindolindindiyl, pyrazolediyl, dihydroindolyl diyl, pyrazolediyl, benz-diyl, indolinediyl and benzodioxoleThe diyl, dihydroisobenzofurandiyl and dihydrobenzofurandiyl group may be selected from the group consisting of "halogen atom, hydroxyl group, amino group and C_1-6Alkyl "is substituted with 1 to 4 substituents, which may be the same or different.

16. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof,

w is R⁶-Ｘ¹-，

Ｘ¹Is a methylene group or a chemical bond,

R⁸Is a hydrogen atom or C_1-6Alkyl radical, C_1-6The alkyl group may be substituted by a substituent group R^cIs substituted with 1 to 4 substituents which may be the same or different,

substituent group R^cHalogen atom and hydroxyl group.

17. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof,

w is R⁶-Ｘ²-Ｙ¹-Ｘ¹-，

Ｙ¹is-O-or-NR⁷-，

Ｘ¹Is methylene, ethylene, C_3-8Cycloalkylene or a bond, the methylene and ethylene groups being substituted by 1 to 2 methyl groups,

Ｘ²is C_1-4Alkylene radical of the formula C_1-4The alkylene group may be selected from the following substituent groups R^cIs substituted with 1 to 4 substituents which may be the same or different,

R⁷is a hydrogen atom, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-6Alkyl radical, C_3-8The cycloalkyl group may be selected from the following substituent groups R^cIs substituted with 1 to 4 substituents which may be the same or different,

18. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof,

w is Q-X ¹-Ｙ²-Ｘ³-，

Ｙ²is-O-, -NR⁷-or a chemical bond,

Ｘ¹is C_1-4Alkylene or chemical bond, C_1-4The alkylene group may be selected from the following substituent groups R^cIs substituted with 1 to 4 substituents which may be the same or different,

Ｘ³is methylene, ethylene, C_3-8Cycloalkylene or a bond, the methylene and ethylene groups being substituted by 1 to 2 methyl groups,

q is C_3-8Cycloalkyl, phenyl, tetrazolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl, pyridyl, pyrazinyl, piperidinyl, morpholinyl, homomorpholinyl, 2-oxa-6-azaspiro [3.3]Heptyl, 1-oxa-6-azaspiro [3.3]Heptyl, 6-oxa-1-azaspiro [3.3]Heptyl, 1, 4-dioxa-8-azaspiro [4.5 ]]Decyl, 7-oxa-2-azaspiro [3.5 ]]Nonyl, 1-oxa-2, 8-diazaspiro [4.5 ]]Decyl, piperazinyl, 3-oxopiperazinyl, piperidinyl, 1,2,3, 6-tetrahydropyridinyl, pyrrolidinyl, azetidinyl, 2H-isoindolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 2-azaspiro [3.3]Heptyl, 3-azabicyclo [3.1.0]Hex-3-yl, 2-oxo-1, 3-oxazolidin-3-yl, 2-oxopyrrolidinyl, thiomorpholinyl, 1-dioxo-thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetan-2-yl, oxetan-3-yl, 1, 3-dioxolanyl or tetrahydro-2H-thiopyranyl, C _3-8Cycloalkyl, phenyl, tetrazolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl, pyridyl, pyrazinyl, piperidinyl, morpholinyl, homomorpholinyl, 2-oxa-6-azaspiro [3.3]Heptyl, 1-oxa-6-azaspiro [ 2 ]3.3]Heptyl, 6-oxa-1-azaspiro [3.3]Heptyl, 1, 4-dioxa-8-azaspiro [4.5 ]]Decyl, 7-oxa-2-azaspiro [3.5 ]]Nonyl, 1-oxa-2, 8-diazaspiro [4.5 ]]Decyl, piperazinyl, 3-oxopiperazinyl, piperidinyl, 1,2,3, 6-tetrahydropyridinyl, pyrrolidinyl, azetidinyl, 2H-isoindolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 2-azaspiro [3.3]Heptyl, 3-azabicyclo [3.1.0]Hex-3-yl, 2-oxo-1, 3-oxazolidin-3-yl, 2-oxopyrrolidinyl, thiomorpholinyl, 1-dioxo-thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetan-2-yl, oxetan-3-yl, 1, 3-dioxolanyl and tetrahydro-2H-thiopyranyl may be selected from the following group of substituents R^cIs substituted with 1 to 4 substituents which may be the same or different,

Substituent group R^cIs a halogen atom, a hydroxyl group, C_1-6Alkyl radical, C_1-6Hydroxyalkyl radical, C_1-6Haloalkyl, C_3-8Cycloalkyl, C which may be substituted by 1 to 3 hydroxy or halogen atoms_1-6Alkoxy radical, C_3-8Cycloalkoxy, C_2-6Alkanoyl radical may be substituted by C_1-6Alkoxy-substituted C_1-6Alkylidene and hydroxyaminocarbonyl.

19. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof,

w is a hydrogen atom, a halogen atom, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, the C_1-6Alkyl radical, C_1-6Alkoxy and C_1-6The alkylamino group may be selected from "halogen atom, hydroxy group, C_1-6Alkoxy and morpholino "are substituted with 1 to 3 substituents which may be the same or different.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof.

An LpxC inhibitor comprising a compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof.

22. An antibacterial agent comprising a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof.