JP5455913B2 - Novel hydroxamic acid derivatives having naphthyridine-N-oxide - Google Patents

Description

  The present invention relates to a novel hydroxamic acid derivative having naphthyridine-N-oxide or a salt thereof having inhibitory activity against uridyl diphospho (UDP) -3-O-acyl-N-acetylglucosamine deacetylase (LpxC), and salts thereof. It relates to an antibacterial drug contained as an active ingredient.

  Gram-negative bacteria have an outer membrane composed of a lipid bilayer that does not exist in Gram-positive bacteria, and therefore, drug resistance tends to be stronger than Gram-positive bacteria due to drug permeability problems. Moreover, it is known that Gram-negative bacteria have a plurality of drug efflux proteins, which are also known to be involved in drug resistance (Non-patent Document 1). Furthermore, lipopolysaccharide (LPS), one of the main components of the outer membrane, is greatly involved in toxicity as an endotoxin.

  Among gram-negative bacteria, Pseudomonas aeruginosa is known to have a strong tendency to exhibit natural resistance to various antibacterial drugs. Pseudomonas aeruginosa is an attenuated bacterium that is ubiquitous in the natural environment and living environment, but usually does not show pathogenicity in healthy individuals. However, for patients with serious underlying diseases, patients who are said to be so-called "complied hosts" that use immunosuppressants by transplantation, etc., patients who are performing medical procedures such as medical catheters, tracheal intubation, and surgery In the past, Pseudomonas aeruginosa is one of the important causative bacteria of opportunistic infections and nosocomial infections because it becomes a pathogen causing severe acute infections such as sepsis. In recent years, Pseudomonas aeruginosa that has acquired resistance to third-generation cephem drugs, carbapenem drugs, or aminoglycosides, which are originally expected to be effective against Pseudomonas aeruginosa, has often been clinically isolated. In addition, multidrug-resistant Pseudomonas aeruginosa that has acquired resistance to all the above three drugs has been isolated (Non-patent Document 3). Infection with multi-drug resistant Pseudomonas aeruginosa has little useful therapeutic agent, making it a global problem as an intractable infectious disease, and the development of a drug with a novel mechanism of action is eagerly desired. .

  UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is an enzyme responsible for the synthesis of lipid A (a hydrophobic anchor of LPS which is a constituent of the outer membrane). Lipid A biosynthesis consists of 10 steps of reaction, but LpxC catalyzes the second step of the biosynthesis reaction to release the acetyl group of UDP-3-O-acyl-N-acetylglucosamine (Non-Patent Document 4). ). Lipid A is an essential component for outer membrane formation, and as a result is essential for the survival of Gram-negative bacteria (Non-patent Document 5). LpxC is one of the important rate-limiting enzymes in the lipid A biosynthesis process, and is an essential enzyme for lipid A biosynthesis. Therefore, a drug that inhibits the activity of LpxC can be an effective antibacterial agent against Gram-negative bacteria including Pseudomonas aeruginosa, particularly against drug-resistant Pseudomonas aeruginosa, since it has a different mechanism of action from conventional drugs. Be expected.

  So far, Patent Documents 1 to 5 and Non-Patent Document 6 are known as LpxC inhibitors, but it is not known that the compound of the present invention has an LpxC inhibitory action.

International Publication No. 97/42179 Pamphlet WO04 / 007444 pamphlet International Publication No. 04/062601 Pamphlet International Publication No. 07/069020 Pamphlet International Publication No. 08/027466 Pamphlet

Antimicrobial Resistance (2002) Mar 1, 34, p. 634-640. J. et al. Antimicrob. Chemother. (2003) Jan 14, 51, p. 347-352. Jpn. J. et al. Antibiotics (2006), 59 (5), p. 355-363. J. et al. Biol. Chem. (1995) Dec 22, 270, p. 30384-30391. J. et al. Bacteriol. (1987), 169, p. 5408-5415. Org. Lett. (2003), 5, p. 539-541.

  An object of the present invention is to provide a novel compound useful as a pharmaceutical product by exhibiting strong antibacterial activity against Gram-negative bacteria such as Pseudomonas aeruginosa and resistant bacteria by inhibiting LpxC.

As a result of diligent research to find a compound having an LpxC inhibitory action, the present inventors have found that a compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof achieves this object. The headline, the present invention was completed.
The present invention will be described below.
The present invention relates to a general formula [1]

（式中、
Ｖ^２は、Ｃ−Ｒ^２又はＮ^＋−Ｏ⁻を示し、
Ｖ^３は、Ｃ−Ｒ^３又はＮ^＋−Ｏ⁻を示し、
Ｖ^４は、Ｃ−Ｒ^４又はＮ^＋−Ｏ⁻を示し、
Ｖ^５は、Ｃ−Ｒ^５又はＮ^＋−Ｏ⁻を示し、
但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻であり、
Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４及びＲ^５は、同一又は異なって、水素原子、ハロゲン原子、ヒドロキシ基、シアノ基、カルボキシ基、カルバモイル基、Ｃ_１−６アルキル基、Ｃ_３−８シクロアルキル基、Ｃ_２−６アルケニル基、Ｃ_２−６アルキニル基、Ｃ_１−６アルコキシ基、Ｃ_３−８シクロアルコキシ基、アリールオキシ基、Ｃ_１−６アルキルチオ基、Ｃ_１−６アルコキシカルボニル基、アリール基、ヘテロ環基（該Ｃ_１−６アルキル基、Ｃ_３−８シクロアルキル基、Ｃ_２−６アルケニル基、Ｃ_２−６アルキニル基、Ｃ_１−６アルコキシ基、Ｃ_３−８シクロアルコキシ基、アリールオキシ基、Ｃ_１−６アルキルチオ基、Ｃ_１−６アルコキシカルボニル基、アリール基及びヘテロ環基は、下記の置換基群Ｒ^ａより選ばれる同一又は異なる１から４個の置換基で置換されてもよい。）、−ＮＲ^６Ｒ^７又は−ＣＯＮＲ^６Ｒ^７を示し、
置換基群Ｒ^ａは、ハロゲン原子、ヒドロキシ基、カルボキシ基、アミノ基（該アミノ基は、１又は２個のＣ_１−６アルキル基で置換されてもよい。）、Ｃ_１−６アルキル基、Ｃ_３−８シクロアルキル基、Ｃ_１−６アルコキシ基、アリール基又はヘテロ環基を示し、
Ｒ^６及びＲ^７は、同一又は異なって、水素原子、Ｃ_１−６アルキル基、Ｃ_３−８シクロアルキル基、Ｃ_２−６アルカノイル基、Ｃ_１−６アルキルスルホニル基、アリール基又はヘテロ環基（該Ｃ_１−６アルキル基、Ｃ_３−８シクロアルキル基、Ｃ_２−６アルカノイル基、Ｃ_１−６アルキルスルホニル基、アリール基及びへテロ環基は、「ハロゲン原子、ヒドロキシ基、アミノ基、カルボキシ基及びＣ_１−６アルキル基」より選ばれる同一又は異なる１から４個の置換基で置換されてもよい。）を示し、
また、Ｒ^６及びＲ^７は、結合する窒素原子と共に一緒になって形成され、さらに窒素原子、酸素原子又は硫黄原子を１つ以上含んでもよい飽和又は不飽和の５又は６員環を形成してもよく、
Ａ^１は、２価のアリール基、２価の単環式複素環基（該２価のアリール基及び２価の単環式複素環基は、下記の置換基群Ｒ^ｂより選ばれる同一又は異なる１から４個の置換基で置換されてもよい。）又は−Ｃ≡Ｃ−を示し、
置換基群Ｒ^ｂは、ハロゲン原子、ヒドロキシ基、アミノ基（該アミノ基は、Ｃ_２−６アルカノイル基又は１もしくは２個のＣ_１−６アルキル基で置換されてもよい。）、カルボキシ基、カルバモイル基、Ｃ_１−６アルキル基、Ｃ_３−８シクロアルキル基、Ｃ_２−６アルケニル基又はＣ_１−６アルコキシ基（該Ｃ_１−６アルキル基、Ｃ_３−８シクロアルキル基、Ｃ_２−６アルケニル基及びＣ_１−６アルコキシ基は、「ハロゲン原子、ヒドロキシ基、アミノ基、カルボキシ基、Ｃ_１−６アルキルアミノカルボニル基及びＣ_１−６アルコキシカルボニル基」より選ばれる同一又は異なる１から４個の置換基で置換されてもよい。）を示し、
Ｌは、−Ｃ≡Ｃ−、−Ｃ≡Ｃ−Ｃ≡Ｃ−、−Ｏ−、−Ｓ−、−ＮＲ^８−、−ＣＯＮＲ^８−、−ＮＲ^８ＣＯ−、２価のヘテロ環基、−（ＣＨ_２）_ｍ−ＮＲ^８−、−（ＣＨ_２）_ｍ−Ｏ−、−ＮＲ^８−（ＣＨ_２）_ｍ−、−Ｏ−（ＣＨ_２）_ｍ−、−ＯＮ＝ＣＨ−、Ｃ_２−４アルキレン基又は結合手を示し、
Ｒ^８は、水素原子、Ｃ_１−６アルキル基、Ｃ_３−８シクロアルキル基又はアリール基を示し、
ｍは、１、２又は３を示し、
Ａ^２は、２価のアリール基、２価のヘテロ環基、２価の部分的に飽和された縮合多環式炭化水素環基、Ｃ_３−８シクロアルキレン基、Ｃ_１−４アルキレン基又はＣ_２−４アルケニレン基（該２価のアリール基、２価のヘテロ環基、２価の部分的に飽和された縮合多環式炭化水素環基、Ｃ_３−８シクロアルキレン基、Ｃ_１−４アルキレン基及びＣ_２−４アルケニレン基は、下記の置換基群Ｒ^ｃより選ばれる同一又は異なる１から４個の置換基で置換されてもよい。）を示し、
置換基群Ｒ^ｃは、ハロゲン原子、保護されてもよいヒドロキシ基、メルカプト基、シアノ基、ニトロ基、保護されてもよいアミノ基、保護されてもよいホルミル基、保護されてもよいカルボキシ基、カルバモイル基、スルホ基、ウレイド基、グアニジド基、Ｃ_１−６アルキル基、Ｃ_３−８シクロアルキル基、Ｃ_１−６ハロアルキル基、Ｃ_１−６ヒドロキシアルキル基、Ｃ_１−６アルコキシ基、Ｃ_１−６アルコキシカルボニル基、Ｃ_２−６アルカノイル基又はアリール基を示し、
Ｗは、Ｒ^９−Ｘ^１−、Ｒ^９−Ｘ^２−Ｙ^１−Ｘ^１−、Ｒ^９−Ｘ^４−Ｙ^１−Ｘ^２−Ｙ^３−Ｘ^３−、Ｑ−Ｘ^１−Ｙ^２−Ｘ^３−又はＱ−Ｘ^１−Ｙ^１−Ｘ^２−Ｙ^３−Ｘ^３−を示し、
Ｙ^２は、−Ｏ−、−ＮＲ^１０−、−ＣＯ−、−ＮＲ^１０ＣＯ−、−ＣＯＮＲ^１０−、−Ｓ（Ｏ）_ｎ−、−ＯＣＯ−、−ＣＯＯ−、−ＮＲ^１０ＳＯ_２−、−ＳＯ_２ＮＲ^１０−、−ＯＣＯＯ−、−ＯＣＯＮＲ^１０−、−ＮＲ^１０ＣＯＮＲ^１１−又は結合手を示し、
Ｙ^１及びＹ^３は、同一又は異なって、−Ｏ−、−ＮＲ^１０−、−ＣＯ−、−ＮＲ^１０ＣＯ−、−ＣＯＮＲ^１０−、−Ｓ（Ｏ）_ｎ−、−ＯＣＯ−、−ＣＯＯ−、−ＮＲ^１０ＳＯ_２−、−ＳＯ_２ＮＲ^１０−、−ＯＣＯＯ−、−ＯＣＯＮＲ^１０−又は−ＮＲ^１０ＣＯＮＲ^１１−を示し、
ｎは０、１又は２を示し、
Ｘ^１及びＸ^３は、同一又は異なって、Ｃ_１−１０アルキレン基、Ｃ_２−１０アルケニレン基、Ｃ_２−１０アルキニレン基（該Ｃ_１−１０アルキレン基、Ｃ_２−１０アルケニレン基及びＣ_２−１０アルキニレン基は、下記の置換基群Ｒ^ｄより選ばれる同一又は異なる１から４個の置換基で置換されてもよい。）又は結合手を示し、
Ｘ^２及びＸ^４は、同一又は異なって、Ｃ_１−１０アルキレン基、Ｃ_２−１０アルケニレン基又はＣ_２−１０アルキニレン基（該Ｃ_１−１０アルキレン基、Ｃ_２−１０アルケニレン基及びＣ_２−１０アルキニレン基は、下記の置換基群Ｒ^ｄより選ばれる同一又は異なる１から４個の置換基で置換されてもよい。）を示し、
Ｑは、Ｃ_３−８シクロアルキル基、アリール基又はヘテロ環基（該Ｃ_３−８シクロアルキル基、アリール基及びヘテロ環基は、下記の置換基群Ｒ^ｄより選ばれる同一又は異なる１から４個の置換基で置換されてもよい。）を示し、
Ｒ^９は、水素原子、ハロゲン原子、保護されてもよいヒドロキシ基、メルカプト基、シアノ基、ニトロ基、保護されてもよいアミノ基、保護されてもよいホルミル基、保護されてもよいカルボキシ基、カルバモイル基、スルホ基、ウレイド基、グアニジド基、Ｒ^１０−Ｏ−ＮＲ^１１−ＣＯ−、Ｒ^１１−ＯＮ＝ＣＲ^１２−、Ｒ^１１−ＯＮ＝ＣＲ^１２−ＮＨ−、Ｒ^１１−Ｏ−ＮＲ^１１−、Ｎ≡Ｃ−ＮＲ^１１−、リン酸基又は下記式［２］から選択される基を示し、

(Where
V ² is, ^{C-R 2} or ^N + -O ^- indicates,
V ³ is, ^{C-R 3} or ^N + -O ^- indicates,
V ⁴ represents C—R ⁴ or N ⁺ —O ⁻ .
V ⁵ represents C—R ⁵ or N ⁺ —O ⁻ .
Provided that any one of V ² , V ³ , V ⁴ and V ⁵ is N ⁺ -O ⁻ .
R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same or different and are a hydrogen atom, halogen atom, hydroxy group, cyano group, carboxy group, carbamoyl group, C _1-6 alkyl group, C _3-8. Cycloalkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 alkoxy group, C _3-8 cycloalkoxy group, aryloxy group, C _1-6 alkylthio group, C _1-6 alkoxycarbonyl Group, aryl group, heterocyclic group (the C _1-6 alkyl group, C _3-8 cycloalkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 alkoxy group, C _3-8 cycloalkoxy group, an aryloxy group, C _1-6 alkylthio group, C _1-6 alkoxycarbonyl group, aryl group and heterocyclic group are the same or selected from substituent group R ^a below May be substituted with 1 to 4 different substituents), -NR ⁶ R ⁷ or -CONR ⁶ R ⁷ ,
The substituent group R ^a is a halogen atom, a hydroxy group, a carboxy group, an amino group (the amino group may be substituted with 1 or 2 C _1-6 alkyl groups), a C _1-6 alkyl group. , C _3-8 cycloalkyl group, C _1-6 alkoxy group, aryl group or heterocyclic group,
R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkanoyl group, a C _1-6 alkylsulfonyl group, an aryl group or a heterocyclic ring. Group (the C _1-6 alkyl group, C _3-8 cycloalkyl group, C _2-6 alkanoyl group, C _1-6 alkylsulfonyl group, aryl group and heterocyclic group are “halogen atom, hydroxy group, amino group, And may be substituted with the same or different 1 to 4 substituents selected from “group, carboxy group and C _1-6 alkyl group”.
R ⁶ and R ⁷ are formed together with a nitrogen atom to be bonded, and form a saturated or unsaturated 5- or 6-membered ring that may further contain one or more nitrogen atoms, oxygen atoms, or sulfur atoms. You can,
A ¹ represents a divalent aryl group, a divalent monocyclic heterocyclic group (the divalent aryl group and divalent monocyclic heterocyclic group are the same or selected from the following substituent group R ^b , or May be substituted with 1 to 4 different substituents) or -C≡C-
The substituent group R ^b is a halogen atom, a hydroxy group, an amino group (the amino group may be substituted with a C _2-6 alkanoyl group or 1 or 2 C _1-6 alkyl groups), a carboxy group. , Carbamoyl group, C _1-6 alkyl group, C _3-8 cycloalkyl group, C _2-6 alkenyl group or C _1-6 alkoxy group (the C _1-6 alkyl group, C _3-8 cycloalkyl group, C _{The 2-6} alkenyl group and the C _1-6 alkoxy group are the same or different selected from “halogen atom, hydroxy group, amino group, carboxy group, C _1-6 alkylaminocarbonyl group and C _1-6 alkoxycarbonyl group”. And optionally substituted with 1 to 4 substituents)
L is —C≡C—, —C≡C—C≡C—, —O—, —S—, —NR ⁸ —, —CONR ⁸ —, —NR ⁸ CO—, a divalent heterocyclic group, _{^{- (CH 2) m -NR 8}} -, - (CH 2) m -O -, - NR 8 - (CH 2) m -, - O- (CH 2) m -, - ON = CH-, C 2 _{-4 represents an} alkylene group or a bond,
R ⁸ represents a hydrogen atom, a C _1-6 alkyl group, a C _3-8 cycloalkyl group or an aryl group,
m represents 1, 2 or 3,
A ² represents a divalent aryl group, a divalent heterocyclic group, a divalent partially saturated condensed polycyclic hydrocarbon ring group, a C _3-8 cycloalkylene group, a C _1-4 alkylene group or C _2-4 alkenylene group (the divalent aryl group, divalent heterocyclic group, divalent partially saturated condensed polycyclic hydrocarbon ring group, C _3-8 cycloalkylene group, C _{1- 4} alkylene group and C _2-4 alkenylene group may be substituted with the same or different 1 to 4 substituents selected from the following substituent group R ^c ):
The substituent group R ^c is a halogen atom, a hydroxy group that may be protected, a mercapto group, a cyano group, a nitro group, an amino group that may be protected, a formyl group that may be protected, or a carboxy group that may be protected. Carbamoyl group, sulfo group, ureido group, guanidide group, C _1-6 alkyl group, C _3-8 cycloalkyl group, C _1-6 haloalkyl group, C _1-6 hydroxyalkyl group, C _1-6 alkoxy group, A C _1-6 alkoxycarbonyl group, a C _2-6 alkanoyl group or an aryl group,
W represents R ⁹ -X ^1- , R ⁹ -X ² -Y ¹ -X ^1- , R ⁹ -X ⁴ -Y ¹ -X ² -Y ³ -X ^3- , Q-X ¹ -Y ^2-. X ³ - or ^{Q-X 1 -Y 1 -X 2} -Y 3 -X 3 - indicates,
Y ² represents —O—, —NR ¹⁰ —, —CO—, —NR ¹⁰ CO—, —CONR ¹⁰ —, —S (O) _n —, —OCO—, —COO—, —NR ¹⁰ SO ₂ —. ^{_{, -SO 2 NR 10 -, -}} OCOO -, - OCONR 10 -, - NR 10 CONR 11 - or denotes a valence bond,
Y ¹ and Y ³ are the same or different and are —O—, —NR ¹⁰ —, —CO—, —NR ¹⁰ CO—, —CONR ¹⁰ —, —S (O) _n —, —OCO—, —COO. _{^{-, - NR 10 SO 2 -}} , - SO 2 NR 10 -, - OCOO -, - OCONR 10 - or ^-NR 10 CONR ¹¹ - indicates,
n represents 0, 1 or 2,
X ¹ and X ³ are the same or different and each represents a C _1-10 alkylene group, a C _2-10 alkenylene group, a C _2-10 alkynylene group (the C _1-10 alkylene group, a C _2-10 alkenylene group and a C _{2). The -10} alkynylene group may be substituted with the same or different 1 to 4 substituents selected from the following substituent group R ^d ) or a bond;
X ² and X ⁴ are the same or different and each represents a C _1-10 alkylene group, a C _2-10 alkenylene group or a C _2-10 alkynylene group (the C _1-10 alkylene group, C _2-10 alkenylene group and C _{2 The -10} alkynylene group may be substituted with the same or different 1 to 4 substituents selected from the following substituent group R ^d );
Q is a C _3-8 cycloalkyl group, aryl group or heterocyclic group (the C _3-8 cycloalkyl group, aryl group and heterocyclic group are the same or different 1 selected from the following substituent group R ^d) Which may be substituted with four substituents),
R ⁹ is a hydrogen atom, a halogen atom, a hydroxy group that may be protected, a mercapto group, a cyano group, a nitro group, an amino group that may be protected, a formyl group that may be protected, or a carboxy group that may be protected , Carbamoyl group, sulfo group, ureido group, guanidide group, R ¹⁰ —O—NR ¹¹ —CO—, R ¹¹ —ON═CR ¹² —, R ¹¹ —ON═CR ¹² —NH—, R ¹¹ —O—NR ¹¹ −, N≡C—NR ¹¹ —, a phosphate group or a group selected from the following formula [2]:

式［２］中、
Ｒ^２１は、Ｃ_１−６アルキル基（該Ｃ_１−６アルキル基は、下記の置換基群Ｒ^ｐより選ばれる同一又は異なる１から２個の置換基で置換されてもよい。）を示し、
Ｒ^２２及びＲ^２３は、同一又は異なって、水素原子又はＣ_１−６アルキル基（該Ｃ_１−６アルキル基は、下記の置換基群Ｒ^ｐより選ばれる同一又は異なる１から２個の置換基で置換されてもよい。）を示し、
又は、Ｒ^２２及びＲ^２３は、結合する窒素原子と共に一緒になって４から７員の含窒素飽和へテロ環（該４から７員の含窒素飽和へテロ環は、下記の置換基群Ｒ^ｐより選ばれる同一又は異なる１から２個の置換基で置換されてもよい。）を形成してもよく、
Ｒ^ｐは、カルボキシ基、リン酸基、ホスホン酸基又は下記式［３］から示される基を示し、

In formula [2],
R ²¹ represents a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with the same or different 1 to 2 substituents selected from the following substituent group R ^p ). ,
R ²² and R ²³ are the same or different and are each a hydrogen atom or a C _1-6 alkyl group (the C _1-6 alkyl group is the same or different 1 to 2 substituents selected from the following substituent group R ^p ) Which may be substituted with a group)
Or R ²² and R ²³ together with the nitrogen atom to which they are bonded are a 4- to 7-membered nitrogen-containing saturated heterocyclic ring (the 4- to 7-membered nitrogen-containing saturated heterocyclic ring is represented by the following substituent group R may be substituted with the same or different 1 to 2 substituents selected from ^p .
R ^p represents a carboxy group, a phosphoric acid group, a phosphonic acid group or a group represented by the following formula [3],

式［３］中、
Ｒ^２４及びＲ^２５は、同一又は異なって、水素原子又はＣ_１−６アルキル基（該Ｃ_１−６アルキル基は、カルボキシ基、リン酸基又はホスホン酸基で置換されてもよい。）を示し、
又は、Ｒ^２４及びＲ^２５は、結合する窒素原子と共に一緒になって４から７員の含窒素飽和へテロ環を形成してもよく、
Ｒ^２６はＣ_１−６アルキル基（該Ｃ_１−６アルキル基は、カルボキシ基、リン酸基、ホスホン酸基又はこれらの陰イオンで置換されてもよい。）を示し、
Ｒ^２７及びＲ^２８は、同一又は異なって、Ｃ_１−６アルキル基を示し、
又は、Ｒ^２７及びＲ^２８は、結合する４級化された窒素原子と共に一緒になって４から７員の含窒素飽和へテロ環を形成してもよく、
Ｒ^１０及びＲ^１１は、同一又は異なって、水素原子、Ｃ_１−６アルキル基、Ｃ_３−８シクロアルキル基、アリール基又はヘテロ環基（該Ｃ_１−６アルキル基、Ｃ_３−８シクロアルキル基、アリール基及びヘテロ環基は、下記の置換基群Ｒ^ｄより選ばれる同一又は異なる１から４個の置換基で置換されてもよい。）を示し、
Ｒ^１２は、水素原子、Ｃ_１−６アルキル基、Ｃ_３−８シクロアルキル基、アミノ基又はＣ_１−６アルキルアミノ基を示し、
置換基群Ｒ^ｄは、ハロゲン原子、ヒドロキシ基、シアノ基、ニトロ基、アミノ基（該アミノ基は、Ｃ_２−６アルカノイル基又は１もしくは２個のＣ_１−６アルキル基で置換されてもよい。）、カルボキシ基、カルバモイル基、ウレイド基、グアニジド基、Ｃ_１−６アルキル基、Ｃ_１−６ヒドロキシアルキル基、Ｃ_１−６ハロアルキル基、Ｃ_３−８シクロアルキル基、Ｃ_１−６アルコキシ基、Ｃ_３−８シクロアルコキシ基、Ｃ_１−６アルコキシカルボニル基、Ｃ_１−６アルコキシカルボニルアミノ基、Ｃ_２−６アルカノイル基、Ｃ_１−６アルキルスルホニル基、Ｃ_１−６アルキルチオ基、アリール基又はヘテロ環基（該アリール基及びヘテロ環基は、「ハロゲン原子、ヒドロキシ基、シアノ基、ニトロ基、アミノ基及びカルボキシ基」より選ばれる同一又は異なる１から４個の置換基で置換されてもよい。）を示す。）
で表される化合物又はその薬学的に許容される塩である。

In formula [3],
R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with a carboxy group, a phosphate group, or a phosphonic acid group). Show
Or R ²⁴ and R ²⁵ together with the nitrogen atom to which they are attached may form a 4 to 7 membered nitrogen-containing saturated heterocycle;
R ²⁶ represents a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with a carboxy group, a phosphate group, a phosphonic acid group, or an anion thereof);
R ²⁷ and R ²⁸ are the same or different and each represents a C _1-6 alkyl group,
Or R ²⁷ and R ²⁸ together with the quaternized nitrogen atom to which they are attached may form a 4 to 7 membered nitrogen-containing saturated heterocycle;
R ¹⁰ and R ¹¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, an aryl group or a heterocyclic group (the C _1-6 alkyl group, C _3-8 cyclo group). An alkyl group, an aryl group and a heterocyclic group may be substituted with the same or different 1 to 4 substituents selected from the following substituent group R ^d ):
R ¹² represents a hydrogen atom, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, an amino group or a C _1-6 alkylamino group,
Substituent group R ^d is a halogen atom, hydroxy group, cyano group, nitro group, amino group (the amino group may be substituted with a C _2-6 alkanoyl group or 1 or 2 C _1-6 alkyl groups). Carboxy group, carbamoyl group, ureido group, guanidide group, C _1-6 alkyl group, C _1-6 hydroxyalkyl group, C _1-6 haloalkyl group, C _3-8 cycloalkyl group, C _1-6. An alkoxy group, a C _3-8 cycloalkoxy group, a C _1-6 alkoxycarbonyl group, a C _1-6 alkoxycarbonylamino group, a C _2-6 alkanoyl group, a C _1-6 alkylsulfonyl group, a C _1-6 alkylthio group, An aryl group or a heterocyclic group (the aryl group and heterocyclic group are “halogen atom, hydroxy group, cyano group, nitro group, amino group and carboxy group” More may be substituted the same or different 1 to 4 substituents selected.) Shows a. )
Or a pharmaceutically acceptable salt thereof.

  The compounds of the present invention and pharmaceutically acceptable salts thereof are useful as pharmaceutical compositions because they have a strong LpxC inhibitory action and a strong antibacterial activity against gram-negative bacteria such as Pseudomonas aeruginosa. It is useful as an antibacterial agent caused by bacteria.

Hereinafter, the present invention will be described in more detail.
First, terms used in this specification will be described.

  In the present invention, "n-" is normal, "i-" is iso, "s-" is secondary, "t-" is tertiary, "c-" is cyclo, and "o-" is Ortho, “m-” means meta, and “p-” means para.

  “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The “C _1-6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, or an n-butyl group. , N-pentyl, n-hexyl, i-propyl, i-butyl, t-butyl, s-butyl, i-pentyl, neopentyl, t-pentyl and 1,2-dimethylpropyl Groups.

The “C _1-6 hydroxyalkyl group” is an alkyl group in which one or more of the hydrogen atoms of the “C _1-6 alkyl group” are substituted with a hydroxy group, such as a hydroxymethyl group, 1- Hydroxyethyl group, 2-hydroxyethyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1-hydroxybutyl group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxybutyl group, 1-hydroxypentyl Group, 5-hydroxypentyl group, 1-hydroxyhexyl group, 6-hydroxyhexyl group, 2-hydroxymethyl-1-hydroxypropyl group, 2,2-dihydroxymethyl-1-hydroxypropyl group and 2-hydroxymethyl-1 -A hydroxypentyl group is mentioned.

The “C _1-6 haloalkyl group” is an alkyl group in which one or more of the hydrogen atoms of the “C _1-6 alkyl group” are substituted with a halogen atom, and examples thereof include a fluoromethyl group and a difluoromethyl group. , Trifluoromethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, pentafluoroethyl group, 3,3,3-trifluoropropyl group, perfluoropropyl group, 4- A fluorobutyl group, 4-chlorobutyl group, and 4-bromobutyl group are mentioned.

The “C _3-8 cycloalkyl group” is a cycloalkyl group having 3 to 8 carbon atoms, and examples thereof include a c-propyl group, a c-butyl group, a c-pentyl group, a c-hexyl group, a c— A heptyl group and c-octyl group are mentioned.

The “C _2-6 alkenyl group” means a linear or branched carbon atom having 2 to 6 carbon atoms having one or more double bonds at any position of the “C _1-6 alkyl group”. For example, vinyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 2-butenyl group, 1,3-butadienyl group, 2-pentenyl group, 3-pentenyl group and 2-hexenyl. Groups.

The “C _2-6 alkynyl group” means a linear or branched chain having one or more triple bonds at any position of the “C _1-6 alkyl group” and having 2 to 6 carbon atoms. Alkynyl groups such as ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 3-butynyl group, 1-pentynyl group, 4-pentynyl group, 1-hexynyl group and 5-hexynyl group Is mentioned.

The “C _1-6 alkoxy group” is a linear or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a 1-propoxy group, an isopropoxy group, Examples include 1-butoxy group, 1-methyl-1-propoxy group, t-butoxy group and 1-pentyloxy group.

The “C _3-8 cycloalkoxy group” is a cycloalkoxy group having 3 to 8 carbon atoms, such as a c-propyloxy group, a c-butyloxy group, a c-pentyloxy group, and a c-hexyloxy group. Is mentioned.

The “C _1-6 alkylthio group” is a linear or branched alkylthio group having 1 to 6 carbon atoms, such as a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, Examples include n-butylthio group, s-butylthio group, t-butylthio group, 1,1-dimethylpropylthio group, n-pentylthio group, isopentylthio group and n-hexylthio group.

The “C _1-6 alkylamino group” is a linear or branched alkylamino group having 1 to 6 carbon atoms, such as a methylamino group, an ethylamino group, or an n-propylamino group. , Isopropylamino group, n-butylamino group, s-butylamino group, t-butylamino group, 1,1-dimethylpropylamino group, n-pentylamino group, isopentylamino group and n-hexylamino group. It is done.

The “di (C _1-6 alkyl) amino group” is a dialkylamino group having two linear or branched alkyl groups having 1 to 6 carbon atoms, such as a dimethylamino group, Diethylamino group, di (n-propyl) amino group, diisopropylamino group, di (n-butyl) amino group, di (s-butyl) amino group, di (t-butyl) amino group, di (1,1-dimethyl) An ethyl) amino group, a di (n-pentyl) amino group, a diisopentylamino group and a di (n-hexyl) amino group.

The “C _2-6 alkanoyl group” is a linear or branched alkanoyl group having 2 to 6 carbon atoms, and examples thereof include an acetyl group, a propionyl group, a butyryl group, and a pivaloyl group.

The “C _1-6 alkoxycarbonyl group” is a carbonyl group having a linear or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, and i- A propoxycarbonyl group is mentioned.

The “C _1-6 alkylaminocarbonyl group” is a linear or branched carbonyl group having 1 to 6 carbon atoms, such as methylaminocarbonyl group, ethylaminocarbonyl group. Group and i-propylaminocarbonyl group.

The “C _1-6 alkoxycarbonylamino group” is an amino group having a C _1-6 alkoxycarbonyl group, such as a methoxycarbonylamino group, an ethoxycarbonylamino group, an n-propoxycarbonylamino group, or an i-propoxycarbonyl group. An amino group and t-butoxycarbonylamino group are mentioned.

The “C _1-6 alkylsulfonyl group” is a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms, and examples thereof include a methylsulfonyl group, an ethylsulfonyl group, and a propylsulfonyl group. It is done.

  The “aryl group” is a monocyclic to tetracyclic aromatic carbocyclic group composed of 6 to 18 carbon atoms, such as a phenyl group, a naphthyl group, an anthryl group, a phenanthrenyl group, a tetracenyl group. And pyrenyl group.

  The “aryloxy group” is a group in which an oxy group is connected to the “aryl group”, and examples thereof include a phenoxy group and a naphthyloxy group.

  The “fused polycyclic hydrocarbon ring group” is a bicyclic to tetracyclic carbocyclic group composed of 6 to 18 carbon atoms, and includes a naphthyl group, an anthryl group, a phenanthrenyl group, a tetracenyl group, and In addition to a bicyclic to tetracyclic aryl group such as a pyrenyl group, a fluorenyl group, an indenyl group, an acenaphthylenyl, and the like can be given.

  The “partially saturated condensed polycyclic hydrocarbon ring group” is a condensed polycyclic hydrocarbon ring group partially hydrogenated, and examples thereof include an indanyl group and an acenaphthenyl group.

  “Heterocyclic group” means a “monocyclic heterocyclic group” or “fused cyclic heterocyclic ring” containing 1 to 5 atoms arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom as ring-constituting atoms. "Base". When the hetero atom is a sulfur atom, a dioxide form is also included in the present invention.

  The “monocyclic heterocyclic group” is a monocyclic heterocyclic group composed of 3 to 8 atoms in the ring among the above “heterocyclic groups”. “Heterocyclic group”, “monocyclic aromatic heterocyclic group” and “partially saturated monocyclic aromatic heterocyclic group” are included.

  The “fused cyclic heterocyclic group” is a condensed cyclic heterocyclic group having 7 to 14 atoms in the ring among the “heterocyclic groups”. “Heterocyclic group”, “fused cyclic aromatic heterocyclic group” and “fused cyclic heterocyclic group having a partially saturated monocycle” are included.

  The “monocyclic saturated heterocyclic group” is a monocyclic heterocyclic group in which a ring is constituted only by a saturated bond, and may be substituted with 1 to 2 oxo groups. For example, aziridinyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group (the sulfur atom on the ring may be oxidized), homopiperazinyl group, homomorpholinyl group, imidazolidinyl group, pyrazolidinyl group, oxazolidinyl group , Isoxazolidinyl group, 2,3-dioxopiperazinyl group, oxolanyl group, tetrahydropyranyl group, dithiolanyl group and thiolanyl group.

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

  The “partially saturated monocyclic aromatic heterocyclic group” is a monocyclic aromatic heterocyclic group in which a part of the bonds constituting the ring is saturated, and includes one or two oxo groups. Substituted ones are also included. Examples include 4,5-dihydro-1H-imidazolyl group, 1,2,3,6-tetrahydropyridyl group, 4H-1,3-oxazinyl group and 5,6-dihydro-4H-1,3-oxazinyl group. It is done.

  The “fused cyclic saturated heterocyclic group” is a condensed cyclic heterocyclic group in which a ring is constituted only by a saturated bond, and may be substituted with 1 to 3 oxo groups. Examples include octahydro-1H-isoindolyl group, decahydroquinolyl group and decahydroisoquinolyl group.

  Examples of the “fused aromatic heterocyclic group” include quinolyl group, isoquinolyl group, naphthyridinyl group (for example, 1,6-naphthyridinyl group, 1,7-naphthyridinyl group, 1,8-naphthyridinyl group), quinazolinyl group. , Benzofuranyl group, benzothienyl group, indolyl group, benzoxazolyl group, benzoisoxazolyl group (for example, benzo [c] isoxazolyl group, benzo [d] isoxazolyl group), indazolyl group, benzoimidazolyl group, benzooxadiazol group A ryl group (for example, benzo [1,2,5] oxadiazolyl group, benzo [1,2,3] oxadiazolyl group), a benzothiadiazolyl group (for example, [1,2,5] thiadiazolyl group, benzo [1, 2,3] thiadiazolyl group), indolizinyl group, benzofurazanyl group, thie Pyridyl group (for example, thieno [2,3-b] pyridyl group, [3,2-b] pyridyl group), pyrazolopyridyl group, imidazopyridyl group (for example, imidazo [1,5-a] pyridyl group, imidazo [1,2-a] pyridyl group, 3H-imidazo [4,5-b] pyridyl group), imidazopyrazinyl group (for example, imidazo [1,5-a] pyrazinyl group, imidazo [1,2-a ] Pyrazinyl group), pyrazolopyrimidinyl group (for example, pyrazolo [1,5-a] pyrimidinyl group, pyrazolo [1,5-c] pyrimidinyl group), triazolopyrimidinyl group (for example, [1,2,3] triazolo) [1,5-a] pyrimidinyl group, [1,2,3] triazolo [1,5-c] pyrimidinyl group, [1,2,4] triazolo [1,5-a] pyrimidinyl group, [1,2 , 4] G Azolo [1,5-c] pyrimidinyl group), thienothienyl group (for example, thieno [2,3-b] thienyl group, thieno [3,2-b] thienyl group) and imidazothiazolyl group (for example, imidazo [ 2,1-b] thiazolyl group, imidazo [5,1-b] thiazolyl group).

  The “fused cyclic heterocyclic group having a partially saturated monocyclic ring” is a condensed cyclic aromatic heterocyclic group having a monocyclic ring in which a part of the bonds constituting the ring is saturated. It may be substituted with 3 oxo groups. For example, 1,3-dihydrobenzimidazol-2-onyl group, 2-benzoxazolinonyl group, octahydroisoindolyl group, 2H-pyrido [3,2-b] -1,4-oxazine-3 (4H ) -Onyl group, [1,3] dioxolo [4,5-b] pyridyl group, 2,3-dihydrobenzofuranyl group, 2,3-dihydrobenzo [b] thienyl group, 1,3-benzodioxo Ryl group, 1,4-benzodioxanyl group, 3,4-dihydro-2H-benzo [b] [1,4] dioxepinyl group, indolinyl group, chromanyl group, chromonyl group, isoindolinyl group, isochromanyl group and 1, A 2,3,4-tetrahydroisoquinolyl group is mentioned.

  The “4- to 7-membered nitrogen-containing saturated heterocyclic ring” means that the “monocyclic saturated heterocyclic group” includes 4 to 7 atoms in the ring, and 1 or 2 in the ring. And a monocyclic saturated heterocyclic group containing a nitrogen atom. One or two oxygen atoms may be contained as ring constituent atoms and may be substituted with one or two oxo groups. For example, azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, homopiperazinyl group, homomorpholinyl group, imidazolidyl group, pyrazolidinyl group, oxazolidinyl group, isoxazolidinyl group and 2,3-dioxopiperazinyl group Can be mentioned.

The “C _1-4 alkylene group” is a linear or branched alkylene group having 1 to 4 carbon atoms, such as —CH ₂ —, — (CH ₂ ) ₂ —, — ( _{CH 2) 3 -, - CH} 2 -CH (CH 3) -, - C (CH 3) 2 -, - (CH 2) 4 -, - (CH 2) 2 -CH (CH 3) -, - CH _{2 -CH (CH 3) -CH 2} - and _{-CH (CH 3) - (CH} 2) 2 - and the like.

The “C _1-6 alkylene group” is a linear or branched alkylene group having 1 to 6 carbon atoms. For example, in addition to the specific examples of the “C _1-4 alkylene group”, , — (CH ₂ ) ₅ —, — (CH ₂ ) ₃ —CH (CH ₃ ) —, — (CH ₂ ) ₂ —CH (C ₂ H ₅ ) —, — (CH ₂ ) ₆ —, — (CH ₂ ) ₃ —CH (CH ₃ ) —CH ₂ — and —CH ₂ —CH (CH ₃ ) — (CH ₂ ) ₃ —.

The “C _1-10 alkylene group” is a linear or branched alkylene group having 1 to 10 carbon atoms. For example, in addition to the specific examples of the “C _1-6 alkylene group”, , — (CH ₂ ) ₇ —, — (CH ₂ ) ₅ —CH (CH ₃ ) —, — (CH ₂ ) ₄ —CH (C ₂ H ₅ ) —, — (CH ₂ ) ₈ —, — (CH ₂ ) _6- CH (CH ₃ ) —CH ₂ — and —CH ₂ —CH (CH ₃ ) — (CH ₂ ) ₇ —.

The “C _3-8 cycloalkylene group” is a divalent group formed by removing any two hydrogen atoms from a cycloalkane having 3 to 8 carbon atoms, such as a 1,2-c-pentylene group. 1,2-c-hexylene group, 1,3-c-hexylene group, 1,4-c-hexylene group and 1,3-c-heptylene group.

The “C _2-4 alkenylene group” is a linear or branched alkenylene group having 2 to 4 carbon atoms having 1 or 2 or more double bonds in the chain. _{CH = CH -, - CH =} CH-CH 2 -, - CH 2 -CH = CH -, - CH = C (CH 3) -, - (CH 2) 2 -CH = CH -, - CH (CH 3 _{) -CH = CH -, - CH} 2 -CH = CH-CH 2 - and -CH = CH-CH = CH- and the like.

The “C _2-6 alkenylene group” is a linear or branched alkenylene group having 2 to 6 carbon atoms having 1 or 2 or more double bonds in the chain. _In addition to the specific examples of “ _2-4 alkenylene group”, for example, — (CH ₂ ) ₃ —CH═CH—, — (CH ₂ ) ₂ —CH═C (CH ₃ ) —, — (CH ₂ ) ₄ — CH = CH- and _{- (CH 2) 2 -CH =} C (C 2 H 5) - and the like.

The “C _2-10 alkenylene group” is a linear or branched alkenylene group having 2 to 10 carbon atoms having one or more double bonds in the chain. _In addition to the specific examples of “ _2-6 alkenylene group”, for example, — (CH ₂ ) ₅ —CH═CH—, — (CH ₂ ) ₅ —CH═C (CH ₃ ) —, — (CH ₂ ) ₆ — CH = CH- and _{- (CH 2) 6 -CH =} C (C 2 H 5) - and the like.

The “C _2-6 alkynylene group” is a linear or branched alkynylene group having 2 to 6 carbon atoms having 1 or 2 or more triple bonds in the chain. And a divalent group having a triple bond formed by removing a hydrogen atom from the carbon atom of the double bond portion of the “C _2-6 alkenylene group”.

The “C _2-10 alkynylene group” is a linear or branched alkynylene group having 2 to 10 carbon atoms having one or more triple bonds in the chain. And a divalent group having a triple bond formed by removing a hydrogen atom from the carbon atom of the double bond portion of the “C _2-10 alkenylene group”.

  “Divalent aryl group” means any two hydrogen atoms removed from a monocyclic, bicyclic, tricyclic or tetracyclic aromatic carbocyclic ring composed of 6 to 18 carbon atoms. A divalent group formed by removing any two hydrogen atoms from benzene, naphthalene, azulene, fluorene, phenanthrene, anthracene and pyrene.

  The “divalent partially saturated condensed polycyclic hydrocarbon ring group” refers to any one hydrogen atom from the above “partially saturated condensed polycyclic hydrocarbon ring group”. Examples of the divalent group may be a divalent group formed by removing any one hydrogen atom from an indanyl group, an acenaphthenyl group, or the like.

  The “divalent heterocyclic group” is a divalent group formed by removing any one hydrogen atom from the above “heterocyclic group”, and includes “a divalent monocyclic heterocyclic group” and “ A divalent fused cyclic heterocyclic group ".

  The “divalent monocyclic heterocyclic group” is a divalent group formed by removing any one hydrogen atom from the above “monocyclic heterocyclic group”. “Saturated heterocyclic group”, “divalent monocyclic aromatic heterocyclic group” and “divalent partially saturated monocyclic aromatic heterocyclic group” are included.

  The “divalent fused cyclic heterocyclic group” is a divalent group formed by removing any one hydrogen atom from the above “fused cyclic heterocyclic group”. “Saturated heterocyclic group”, “divalent fused cyclic aromatic heterocyclic group” and “fused cyclic heterocyclic group having a divalent partially saturated monocycle” are included.

  The “divalent monocyclic saturated heterocyclic group” is a divalent group formed by removing any one hydrogen atom from the above “monocyclic saturated heterocyclic group”, and includes, for example, an aziridinyl group, Azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, imidazolidyl group, pyrazolidinyl group, oxazolidinyl group, isoxazolidinyl group, 2,3-dioxopiperazinyl group, oxolanyl group, tetrahydropyrani group And a divalent group formed by removing any one hydrogen atom from a ru group, a dithiolanyl group and a thiolanyl group.

  The “divalent monocyclic aromatic heterocyclic group” is a divalent group formed by removing any one hydrogen atom from the above “monocyclic aromatic heterocyclic group”. For example, pyridyl Group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, thienyl group, pyrrolyl group, thiazolyl group, isothiazolyl group, pyrazolyl group, imidazolyl group, furyl group, oxazolyl group, isoxazolyl group, oxadiazolyl group, thiadiazolyl group, 1,2,3- Examples thereof include a divalent group formed by removing any one hydrogen atom from a triazolyl group and a 1,2,4-triazolyl group.

  The “divalent partially saturated monocyclic aromatic heterocyclic group” means any one hydrogen atom further from the above “partially saturated monocyclic aromatic heterocyclic group”. Divalent groups formed by, for example, 4,5-dihydro-1H-imidazolyl group, 1,2,3,6-tetrahydropyridyl group, 4H-1,3-oxazinyl group and 5,6-dihydro-4H Examples thereof include a divalent group formed by removing any one hydrogen atom from a -1,3-oxazinyl group.

  The “divalent fused cyclic saturated heterocyclic group” is a divalent group formed by removing any one hydrogen atom from the above “fused cyclic saturated heterocyclic group”. For example, octahydro-1H -A divalent group formed by removing any one hydrogen atom from an isoindolyl group, a decahydroquinolyl group and a decahydroisoquinolyl group.

  The “divalent fused cyclic aromatic heterocyclic group” is a divalent group formed by removing any one hydrogen atom from the above “fused cyclic aromatic heterocyclic group”. For example, quinolyl Group, isoquinolyl group, naphthyridinyl group (for example, 1,6-naphthyridinyl group, 1,7-naphthyridinyl group, 1,8-naphthyridinyl group), quinazolinyl group, benzofuranyl group, benzothienyl group, indolyl group, benzoxazolyl group Benzoisoxazolyl group (for example, benzo [c] isoxazolyl group, benzo [d] isoxazolyl group), indazolyl group, benzoimidazolyl group, benzooxadiazolyl group (for example, benzo [1,2,5] oxadiazolyl group, Benzo [1,2,3] oxadiazolyl group), benzothiadiazolyl group (for example, [1,2,5] thiadiazo group) Group, benzo [1,2,3] thiadiazolyl group), indolizinyl group, benzofurazanyl group, thienopyridyl group (for example, thieno [2,3-b] pyridyl group, [3,2-b] pyridyl group), pyrazolo Pyridyl group, imidazopyridyl group (eg, imidazo [1,5-a] pyridyl group, imidazo [1,2-a] pyridyl group, 3H-imidazo [4,5-b] pyridyl group), imidazopyrazinyl group (For example, imidazo [1,5-a] pyrazinyl group, imidazo [1,2-a] pyrazinyl group), pyrazolopyrimidinyl group (for example, pyrazolo [1,5-a] pyrimidinyl group, pyrazolo [1,5- c) pyrimidinyl group), triazolopyrimidinyl group (for example, [1,2,3] triazolo [1,5-a] pyrimidinyl group, [1,2,3] triazolo [1,5- ] Pyrimidinyl group, [1,2,4] triazolo [1,5-a] pyrimidinyl group, [1,2,4] triazolo [1,5-c] pyrimidinyl group), thienothienyl group (for example, thieno [2, 3-b] thienyl group, thieno [3,2-b] thienyl group) and imidazothiazolyl group (for example, imidazo [2,1-b] thiazolyl group, imidazo [5,1-b] thiazolyl group) Examples thereof include divalent groups formed by removing any one hydrogen atom.

  “Fused cyclic heterocyclic group having a divalent partially saturated monocycle” means any one of the above “fused cyclic heterocyclic group having a partially saturated monocycle”. A divalent group formed by removing the hydrogen atom of, for example, 1,3-dihydrobenzimidazol-2-onyl group, 2-benzoxazolinonyl group, octahydroisoindolyl group, 2H-pyrido [3,2 -B] -1,4-oxazine-3 (4H) -onyl group, [1,3] dioxolo [4,5-b] pyridyl group, 2,3-dihydrobenzofuranyl group, 2,3-dihydrobenzo [B] Thienyl group, 1,3-benzodioxolyl group, 1,4-benzodioxanyl group, 3,4-dihydro-2H-benzo [b] [1,4] dioxepinyl group, indolinyl group, chromanyl Group, chromonyl group, isoindolinyl Include divalent groups obtained by removing arbitrary one hydrogen atom from isochromanyl group and 1,2,3,4 tetrahydroisoquinolyl group.

  “Saturated or unsaturated 5- or 6-membered ring which is formed together with the nitrogen atom to be bonded and may further contain one or more nitrogen atom, oxygen atom or sulfur atom” means, for example, pyrrolidinyl group, piperidinyl group , Piperazinyl group, morpholinyl group, thiomorpholinyl group and 1,2,3,6-tetrahydropyridyl group.

  “Hydroxy group which may be protected” means an unprotected or protected hydroxy group.

  The “protected hydroxy group” means a hydroxy group protected with a “protecting group for a hydroxy group”.

The term “hydroxy-protecting group” includes all groups that can be used as ordinary hydroxy-protecting groups. Green et al., Protective Groups in Organic Synthesis, 3rd edition, 1999, John Wiley & Sons, Inc. Etc. For example, C _1-6 alkoxy optionally substituted C _1-6 alkyl group with a group (a methyl group, methoxymethyl group and t- butoxymethyl groups), benzyloxymethyl group, tetrahydropyranyl group, tetrahydrofuranyl group, Benzyl group (benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, p-chlorobenzyl group, etc.) which may be substituted with a substituent selected from “halogen atom, C _1-6 alkoxy group and nitro group” , A C _1-6 alkoxycarbonyl group (methoxycarbonyl group, t-butoxycarbonyl group, 2,2,2-trichloroethoxy group) which may be substituted with 1 to 3 substituents selected from “halogen atom and aryl group” Carbonyl group, benzyloxycarbonyl group and 9-fluorenylmethoxycarbonyl group), benzo An yl group, a C _2-6 alkanoyl group (such as an acetyl group, a chloroacetyl group, a trichloroacetyl group, a trifluoroacetyl group and a pivaloyl group) optionally substituted with 1 to 3 halogen atoms, and “C _1-6 Examples thereof include silyl groups (trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, etc.) having three identical or different substituents selected from “alkyl group and aryl group”.

  The “amino group that may be protected” means an unprotected or protected amino group.

  The “protected amino group” means an amino group protected with an “amino protecting group”.

The “amino-protecting group” includes all groups that can be used as ordinary amino-protecting groups. Green et al., Protective Groups in Organic Synthesis, 3rd edition, 1999, John Wiley & Sons, Inc. Etc. For example, a benzyl group (benzyl group, p-methoxybenzyl group, p-nitrobenzyl group and p-chlorobenzyl group) which may be substituted with a substituent selected from “halogen atom, C _1-6 alkoxy group and nitro group” Etc.), a C _1-6 alkoxycarbonyl group (methoxycarbonyl group, t-butoxycarbonyl group, 2,2,2-) optionally substituted by 1 to 3 substituents selected from “halogen atom and aryl group” Trichloroethoxycarbonyl group, benzyloxycarbonyl group and 9-fluorenylmethoxycarbonyl group), allyl group, dialkylaminoalkylidene group (N, N-dimethylaminomethylene group and N, N-diethylaminomethylene group), formyl group , optionally substituted with one to three halogen atoms C _2-6 alkanoyl group Acetyl group, chloroacetyl group, trichloroacetyl group, trifluoroacetyl group and pivaloyl group), and benzoyl group.

  The “carboxy group that may be protected” means an unprotected or protected carboxy group.

  The “protected carboxy group” means a carboxy group protected with a “carboxy-protecting group”.

The “carboxy-protecting group” includes all groups that can be used as ordinary carboxy-protecting groups. Green et al., Protective Groups in Organic Synthesis, 3rd edition, 1999, John Wiley & Sons, Inc. Etc. For _{example, C 1-6} alkoxy optionally substituted _{C 1-6} alkyl group with a group (a methyl group, an ethyl group, t- butyl group, methoxymethyl group and t-butoxymethyl groups) and "halogen atom, _{C 1 Examples} include benzyl groups (benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, p-chlorobenzyl group and the like) which may be substituted with a substituent selected from “ _-6 alkoxy group and nitro group”.

  The “protected phosphate group” means a phosphate group protected with a “phosphate protecting group”.

The “phosphate protecting group” includes all groups that can be used as ordinary phosphate protecting groups. Green et al., Protective Groups in Organic Synthesis, 3rd edition, 1999, John Wiley & Sons, Inc. Etc. For example, a C _1-6 alkyl group (such as a methyl group, an ethyl group, a t-butyl group and a 2-cyanoethyl group) which may be substituted with a cyano group and a substituent selected from “halogen atom and nitro group”. Benzyl group (benzyl group, p-chlorobenzyl group, p-nitrobenzyl group and the like) which may be used.

  The “protected phosphonic acid group” means a phosphonic acid group protected by a “phosphonic acid group protecting group”.

The “protecting group for phosphonic acid group” includes all groups that can be used as ordinary phosphonic acid protecting groups. For example, a C _1-6 alkyl group (such as a methyl group, an ethyl group, a t-butyl group and a 2-cyanoethyl group) which may be substituted with a cyano group and a substituent selected from “halogen atom and nitro group”. Benzyl group (benzyl group, p-chlorobenzyl group, p-nitrobenzyl group and the like) which may be used.

  The “formyl group which may be protected” means an unprotected or protected formyl group.

  “Protected formyl group” includes a formyl group protected with all groups that can be used as conventional formyl protecting groups. Green et al., Protective Groups in Organic Synthesis, 3rd edition, 1999, John Wiley & Sons, Inc. Is mentioned. Examples include 1,1-dimethoxymethyl group, 1,1-diethoxymethyl group, 1,3-dioxanyl group, 1,3-dioxolanyl group, 1,3-dithianyl group, and 1,3-dithiolanyl group.

The “protecting group for the acetylene group” includes all groups that can be used as a protecting group for a normal acetylene group. Green et al., Protective Groups in Organic Synthesis, 3rd edition, 1999, John Wiley & Sons, Inc. Etc. For example, a silyl group (trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, etc.) having three identical or different substituents selected from “C _1-6 alkyl group and aryl group” ).

  Examples of the “leaving group” include a halogen atom, a methylsulfonyloxy group, a trifluoromethylsulfonyloxy group, and a p-toluenesulfonyloxy group.

  The term “antibacterial agent” means a substance that has the ability to act on bacteria such as gram positive bacteria and gram negative bacteria to suppress or sterilize their growth. It may be something that suppresses the growth of bacteria or kills some bacteria to reduce their number. Gram-positive bacteria include, for example, Staphylococcus (S. aureus, Staphylococcus epidermidis, etc.), Streptococcus (S. pyogenes, Group B Streptococcus, Streptococcus pneumoniae, etc.), Enterococcus (Enterococcus faecalis, Enterococcus Fesium etc.). Gram-negative bacteria include, for example, Pseudomonas genus (such as Pseudomonas aeruginosa), Escherichia genus (such as Escherichia coli), Klebsiella (such as Klebsiella pneumoniae, Klebsiella oxytoca), Haemophilus (such as Haemophilus influenzae and Parainfluenza), Bordetella genus (Such as Bordetella pertussis and Bacterial sepsis), Serratia (such as Serratia marcescens), Proteus (such as Proteus mirabilis), Enterobacter (such as Enterobacter cloaca), Campylobacter (such as Campylobacter jejuni), Citrobacter , Vibrio (Vibrio parahaemolyticus, Vibrio cholerae, etc.), Morganella (Morganella, Morgani, etc.), Salmonella (typhoid, Paratyphi, etc.), Shigella (Shigella, etc.), Acinetobacter (Acinetobacter baumani) Acinetobacter calcoaceticus), Legionella genus (Legionella pneumophila etc.), Bacteroides genus (Bacteroides fragilis etc.), Neisseria genus (gonococci, meningococcus etc.), Moraxella genus (Moraxella catarrhalis etc.), Chlamydia genus (Chlamydia) -Trachomatis, Chlamydia scitasty, etc.) and Helicobacter genus (Helicobacter pylori, etc.).

  Preferred forms of the compound of the present invention are as follows.

Preferred V ² is C—R ² .

Preferred ^{V 3} is ^N + -O ^- a.

Preferred V ⁴ is C—R ⁴ .

Preferred V ⁵ is C—R ⁵ .

Preferred R ¹ is a hydrogen atom, a halogen atom, an amino group, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _1-6 alkoxy group, a C _3-8 cycloalkoxy group, a C _1-6 alkylthio group or A C _1-6 alkylamino group, more preferably R ¹ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group, and even more preferably R ¹ is a hydrogen atom, a halogen atom, methyl; A most preferred R ¹ is a methoxy group.

Preferred R ² , R ³ , R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a halogen atom, a hydroxy group, an amino group, a C _1-6 alkyl group, a C _1-6 alkoxy group or a C _1-6 alkylamino. A group (the C _1-6 alkyl group, C _1-6 alkoxy group and C _1-6 alkylamino group are “halogen atom, hydroxy group and amino group (the amino group is 1 or 2 C _1-6 And may be substituted with the same or different 1 to 4 substituents selected from “), and more preferably R ² , R ³ , R ⁴ and R ⁵ are the same. Or differently, a hydrogen atom, a halogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group, and even more preferred R ² , R ³ , R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a halogen atom, Atom or A butoxy group, and most preferably R ² is hydrogen atom.

Preferred A ¹ is a phenylene group (the phenylene group may be substituted with the same or different 1 to 4 substituents selected from “halogen atom, hydroxy group, amino group and C _1-6 alkyl group”). And more preferable A ¹ is a phenylene group. Here, the phenylene group is preferably bonded as shown in the following formula [5].

式中、Ｒ^ｅはハロゲン原子、ヒドロキシ基、アミノ基又はＣ_１−６アルキル基であり、ｅは、０、１、２、３又は４である。

In the formula, R ^e is a halogen atom, a hydroxy group, an amino group, or a C _1-6 alkyl group, and e is 0, 1, 2, 3, or 4.

  Preferred L is —C≡C— or a bond.

Preferred A ² is a divalent aryl group (the divalent aryl group is substituted with 1 to 4 substituents which are the same or different and are selected from “halogen atom, hydroxy group, amino group and C _1-6 alkyl group”). A divalent monocyclic aromatic heterocyclic group, a divalent monocyclic saturated heterocyclic group, a divalent partially saturated monocyclic aromatic heterocyclic group (the 2 A divalent monocyclic aromatic heterocyclic group, a divalent monocyclic saturated heterocyclic group and a divalent partially saturated monocyclic aromatic heterocyclic group are composed of a nitrogen atom, an oxygen atom and a sulfur atom. 1 to 3 atoms arbitrarily selected as a ring member atom (more preferably, 4 to 6 members including 1 to 2 atoms arbitrarily selected from a nitrogen atom and an oxygen atom as a ring atom atom) monocyclic a heterocyclic group), "halogen atom, hydroxy group, an amino group and a C _1-6 alkyl group And may be substituted with the same or different 1 to 4 substituents selected from above.) A condensed ring having a divalent fused cyclic aromatic heterocyclic group or a divalent partially saturated monocycle Heterocyclic group (the divalent condensed cyclic aromatic heterocyclic group and the condensed cyclic heterocyclic group having a divalent partially saturated monocyclic ring are arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom. 9 to 12-membered bicyclic ring containing 1 to 4 atoms as ring-constituting atoms (more preferably 1 to 3 atoms arbitrarily selected from nitrogen atom and oxygen atom) A heterocyclic group), and at least one of the rings constituting the condensed ring is a benzene ring or a pyridine ring, and the same or different 1 selected from “halogen atom, hydroxy group, amino group and C _1-6 alkyl group” And may be substituted with four substituents). Ri preferably ^{A 2} is a phenylene group, pyridinediyl group, furandiyl group, quinolinediyl group, 1,4-benzodioxan-diyl group or 3,4-dihydro -2H- benzo [b] [1,4] Jiokisepiniru group (said phenylene Group, pyridinediyl group, furandiyl group, 1,4-benzodioxandiyl group and 3,4-dihydro-2H-benzo [b] [1,4] dioxepinyl group include “halogen atom, hydroxy group, amino group and A 1 to 4 substituents selected from the same or different substituents selected from “C _1-6 alkyl group” may be substituted, and A ² is more preferably phenylene group or pyridinediyl group (the phenylene group and pyridinediyl group). group is may be substituted by 1 to 4 halogen atoms.), and most preferably a ² is a phenylene group (the phenylene Group may be substituted with from 1 to 4 halogen atoms. ). Here, the phenylene group is preferably bonded as shown in the following formula [6].

式中、Ｒ^ｆはハロゲン原子、ヒドロキシ基、アミノ基又はＣ_１−６アルキル基であり、ｆは、０、１、２、３又は４である。

In the formula, R ^f is a halogen atom, a hydroxy group, an amino group, or a C _1-6 alkyl group, and f is 0, 1, 2, 3, or 4.

Preferred W is R ⁹ -X ^1- , R ⁹ -X ² -Y ¹ -X ^1- , R ⁹ -X ⁴ -Y ¹ -X ² -Y ³ -X ^3- , Q-X ¹ -Y ^2-. This is a case where each variable in X ³ -or QX ¹ -Y ¹ -X ² -Y ³ -X ^3- is as follows.

Preferred Y ² is —O—, —NR ¹⁰ —, —CO—, —NR ¹⁰ CO—, —CONR ¹⁰ —, —S (O) _n —, —OCO— or a bond, and more preferred Y ² is —O—, —NR ¹⁰ —, —OCO—, or a bond, and more preferable Y ² is —O—, —NR ¹⁰ —, or a bond.

Preferred Y ¹ and Y ³ are the same or different and are —O—, —NR ¹⁰ —, —CO—, —NR ¹⁰ CO—, —CONR ¹⁰ —, —S (O) _n — or —OCO—. More preferable Y ¹ and Y ³ are the same or different and are —O—, —NR ¹⁰ — or —OCO—, and still more preferable Y ¹ and Y ³ are the same or different, —O— or — NR ¹⁰ −.

Preferred ^{X 1} and ^{X 3} are the same or _{different, C 1-6} alkylene group (the _{C 1-6} alkylene group, substituent group ^R d ^{(R d} is preferably substituted more preferred substituent group ^{R d} or below It has the same meaning as the group R ^d .) May be substituted with the same or different 1 to 4 substituents selected from the group R).

Preferable X ² and X ⁴ are the same or different, and a C _1-6 alkylene group (the C _1-6 alkylene group is a substituent group R ^d (R ^d is the following preferable substituent group R ^d or more preferable substituent) It has the same meaning as the group R ^d .) And may be substituted with the same or different 1 to 4 substituents selected from.

When X ¹ and X ³ are directly bonded to form an alkylene group, the number of carbon atoms is preferably 1 to 10.

Preferred R ⁹ is a hydrogen atom, a halogen atom, a hydroxy group that may be protected, a cyano group, a nitro group, an amino group that may be protected, a carboxy group that may be protected, or R ¹⁰ —O—NR ¹¹ —CO—. R ⁹ is more preferably a hydrogen atom, a halogen atom, a hydroxy group or a cyano group.

Desirable R ¹⁰ and R ¹¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a C _3-8 cycloalkyl group (the C _1-6 alkyl group and the C _3-8 cycloalkyl group are each a “halogen atom”). , hydroxy group, a cyano group, a nitro group, the same or different 1 selected from amino and C _1-6 alkylamino group "may be substituted with 4 substituents.), more preferably R ¹⁰ and R ¹¹ is the same or different and is a hydrogen atom, a C _1-6 alkyl group or a C _3-8 cycloalkyl group (the C _1-6 alkyl group and the C _3-8 cycloalkyl group are represented by “halogen atom, hydroxy group and It may be substituted with the same or different 1 to 4 substituents selected from the “cyano group”.

Preferred Q is a C _3-8 cycloalkyl group, aryl group or heterocyclic group (the C _3-8 cycloalkyl group, aryl group and heterocyclic group is a substituent group R ^d (R ^d is the following preferred substituent) have the same meaning as the group R ^d or more preferred substituent group R ^d.) than may be substituted the same or different 1 to 4 substituents selected.), more preferably Q is C _{3- From an 8} cycloalkyl group (the C _3-8 cycloalkyl group has a substituent group R ^d (R ^d has the same meaning as the following preferable substituent group R ^d or a more preferable substituent group R ^d )). Optionally substituted with the same or different 1 to 4 substituents selected), a tetrahydropyranyl group or the formula [4]

で表される４から７員の含窒素飽和へテロ環（Ｒ^ｄは、下記の好ましい置換基群Ｒ^ｄ又はより好ましい置換基群Ｒ^ｄと同様の意味を有し、ｑは、０、１、２、３又は４である。）であり、よりさらに好ましいＱはテトラヒドロピラニル基、アゼチジニル基、ピロリジニル基、ピペリジニル基（該テトラヒドロピラニル基、アゼチジニル基、ピロリジニル基及びピペリジニル基は、ヒドロキシ基で置換されてもよい。）又はモルホリニル基である。

4 to 7-membered nitrogen-containing saturated heterocyclic ring (R ^d has the same meaning as the following preferred substituent group R ^d or more preferable substituent group R ^d , Q is more preferably tetrahydropyranyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group (the tetrahydropyranyl group, azetidinyl group, pyrrolidinyl group and piperidinyl group are each a hydroxy group). Or a morpholinyl group.

Preferred substituent group R ^d is a halogen atom, a hydroxy group, a cyano group, an amino group (the amino group may be substituted with 1 or 2 C _1-6 alkyl groups), a C _1-6 alkyl group. , A C _1-6 hydroxyalkyl group, a C _1-6 haloalkyl group, a C _3-8 cycloalkyl group, a C _1-6 alkoxy group or a C _2-6 alkanoyl group, and a more preferred substituent group R ^d is a halogen atom , A hydroxy group, a cyano group, an amino group (the amino group may be substituted with 1 or 2 C _1-6 alkyl groups) or a C _1-6 hydroxyalkyl group.

  More preferable W is a group selected from the following formula [7]:

式中、
ｒは０、１、２、３、４、５又は６であり、
Ｘ^１、Ｘ^２、Ｘ^４、Ｒ^９、Ｒ^１０及びＱの定義並びに好ましい態様は、前記した通りである。

Where
r is 0, 1, 2, 3, 4, 5 or 6;
The definitions and preferred embodiments of X ¹ , X ² , X ⁴ , R ⁹ , R ¹⁰ and Q are as described above.

  Preferred forms of the compound of the present invention are as follows.

式中、Ｒ^１、Ｒ^２、Ｒ^４、Ｒ^５、Ｌ、（Ｒ^ｅ）_ｅ、（Ｒ^ｆ）_ｆ及びＷの定義並びに好ましい態様は、前記した通りである。

本発明の化合物には互変異性体、幾何異性体等の立体異性体及び光学異性体が存在しうるが、本発明はそれらも包含する。また、発明化合物及びその塩の各種水和物、溶媒和物及び結晶多形の物質をも包含する。

In the formula, the definitions and preferred embodiments of R ¹ , R ² , R ⁴ , R ⁵ , L, (R ^e ) _e , (R ^f ) _f and W are as described above.

The compound of the present invention may include stereoisomers such as tautomers and geometric isomers, and optical isomers, and the present invention includes these isomers. Also included are various hydrates, solvates and polymorphic substances of the inventive compounds and salts thereof.

  In the present invention, a pharmaceutically acceptable salt means a salt used in chemotherapy and prevention of bacterial infections. They are, for example, acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethyl succinic acid, lactobionic acid, gluconic acid, glucoheptonic acid, benzoic acid, methanesulfonic acid, Ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, lauryl sulfuric acid, malic acid, aspartic acid, glutamic acid, adipic acid, cysteine, N-acetylcysteine, hydrochloric acid, hydrobromic acid, phosphoric acid Salts with acids such as sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid, picric acid, thiocyanic acid, undecanoic acid, acrylic acid polymer and carboxyvinyl polymer, lithium salt, sodium salt, potassium salt and calcium salt Salts with inorganic bases, morpholine and piperi Organic amines such as down, and it can be exemplified salts with amino acids.

The compound of the present invention can be synthesized, for example, by the method shown below, but the production method of the compound of the present invention is not limited thereto.
(Scheme 1)

一般式（１ａ）（式中、Ｒ^１ａはカルボキシ基の保護基であり、Ｚ^２はＣ−Ｒ^２又はＮであり、Ｚ^３はＣ−Ｒ^３又はＮであり、Ｚ^４はＣ−Ｒ^４又はＮであり、Ｚ^５はＣ−Ｒ^５又はＮであり、その他の記号は前記と同義である。但し、Ｚ^２、Ｚ^３、Ｚ^４及びＺ^５のいずれか一つがＮである。）で表される化合物に、ｍ−クロロ過安息香酸等の酸化剤を塩基の存在下あるいは不存在下で作用させて、一般式（１ｂ）（式中の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物を得ることができる。さらに、ナトリウムメトキシド等の塩基存在下でヒドロキシルアミンと反応させることで、一般式［１］で表される化合物を得ることができる。
（スキーム２）

General formula (1a) (wherein R ^1a is a protecting group for a carboxy group, Z ² is C—R ² or N, Z ³ is C—R ³ or N, and Z ⁴ is C—R. ⁴ or N, Z ⁵ is C—R ⁵ or N, and other symbols are as defined above, provided that any one of Z ² , Z ³ , Z ⁴ and Z ⁵ is N. The compound represented by formula (1) is reacted with an oxidizing agent such as m-chloroperbenzoic acid in the presence or absence of a base, wherein the symbols in the formula are as defined above. , V ² , V ³ , V ^4, or V ⁵ is N ⁺ —O ⁻ ). Furthermore, the compound represented by the general formula [1] can be obtained by reacting with hydroxylamine in the presence of a base such as sodium methoxide.
(Scheme 2)

一般式（２ａ）（式中、Ｒ^２ａはカルボキシ基の保護基であり、その他の記号は前記と同義である。但し、Ｚ^２、Ｚ^３、Ｚ^４及びＺ^５のいずれか一つがＮである。）で表される化合物を、塩基性又は酸性条件下で加水分解反応を行い、次いで一般式（２ｂ）（式中、Ｒ^２ｂはヒドロキシ基の保護基又は水素原子である。）で表されるヒドロキシルアミン化合物を縮合剤の存在下で反応させることで、一般式（２ｃ）（式中の記号は前記と同義である。但し、Ｚ^２、Ｚ^３、Ｚ^４及びＺ^５のいずれか一つがＮである。）で表される化合物を得ることができる。さらに、ｍ−クロロ過安息香酸等の酸化剤を塩基の存在下あるいは不存在下で作用させて、一般式（２ｄ）（式中の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物を得ることができる。なお、反応の順序を入れ替えて、一般式（２ａ）で表される化合物に酸化剤を作用させ、その後に加水分解、次いでヒドロキシルアミン化合物を縮合させて、一般式（２ｄ）で表される化合物を得ることもできる。さらにＲ^２ｂがヒドロキシ基の保護基の場合、その種類に応じて適切な条件で脱保護反応を行うことで、一般式［１］で表される化合物を得ることができる。
（スキーム３）

General formula (2a) (wherein R ^2a is a protecting group for a carboxy group, and the other symbols are as defined above, provided that any one of Z ² , Z ³ , Z ⁴ and Z ⁵ is N. The compound represented by formula (1) is subjected to a hydrolysis reaction under basic or acidic conditions, and then represented by the general formula (2b) (wherein R ^2b is a protective group for a hydroxy group or a hydrogen atom). By reacting the hydroxylamine compound in the presence of a condensing agent, the general formula (2c) (wherein the symbols are as defined above, provided that any one of Z ² , Z ³ , Z ⁴ and Z ⁵ is used). One is N.) can be obtained. Further, an oxidant such as m-chloroperbenzoic acid is allowed to act in the presence or absence of a base to give a general formula (2d) (wherein the symbols are as defined above, provided that V ² , V ³ And any one of V ⁴ and V ⁵ is N ⁺ —O ⁻ ). The compound represented by the general formula (2d) is obtained by changing the order of the reaction, allowing the compound represented by the general formula (2a) to act on an oxidizing agent, followed by hydrolysis and then condensing the hydroxylamine compound. You can also get Furthermore, when R ^2b is a protecting group for a hydroxy group, a compound represented by the general formula [1] can be obtained by performing a deprotection reaction under conditions suitable for the type.
(Scheme 3)

一般式（３ａ）（式中、Ｘ^３ａは脱離基であり、Ｒ^３ａはカルボキシ基、保護されたカルボキシ基又は−ＣＯＮＨ−ＯＲ^３ｂ（式中、Ｒ^３ｂはヒドロキシ基の保護基であり、その他の記号は前記と同義である。）であり、その他の記号は前記と同義である。但し、Ｚ^２、Ｚ^３、Ｚ^４及びＺ^５のいずれか一つがＮである。）で表される化合物に、ｍ−クロロ過安息香酸等の酸化剤を塩基の存在下あるいは不存在下で作用させて、一般式（３ｂ）（式中の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物を得ることができる。一方、一般式（３ｃ）（式中、Ｘ^３ｂは脱離基であり、その他の記号は前記と同義である。）で表される化合物を、１，１’−ビス（ジフェニルホスフィノ）フェロセンジクロロパラジウム等の触媒の存在下、塩基の存在下又は不存在下、配位子の存在下又は不存在下、ビス（ピナコラト）ジボロン等のジボロン化合物と反応させることで、一般式（３ｄ）（式中の記号は前記と同義である。）で表される化合物を得ることができ、さらに一般式（３ｂ）で表される化合物と、テトラキス（トリフェニルホスフィン）パラジウム等の触媒の存在下、塩基の存在下又は不存在下、配位子の存在下又は不存在下、カップリング反応を行うことで、一般式（３ｅ）（式中の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物を得ることができる。一般式（３ｅ）で表される化合物から、スキーム１又は２の方法に従って一般式［１］で表される化合物を得ることができる。
（スキーム４）

General formula (3a) (wherein X ^3a is a leaving group, R ^3a is a carboxy group, a protected carboxy group or —CONH—OR ^3b (wherein R ^3b is a protecting group for a hydroxy group, Other symbols are as defined above, and other symbols are as defined above, provided that any one of Z ² , Z ³ , Z ⁴ and Z ⁵ is N). The compound is reacted with an oxidizing agent such as m-chloroperbenzoic acid in the presence or absence of a base to give a general formula (3b) (wherein the symbols are as defined above, provided that V ² , Any one of V ³ , V ^4, and V ⁵ is N ⁺ —O ⁻ ). On the other hand, a compound represented by the general formula (3c) (wherein X ^3b is a leaving group, and other symbols are as defined above) is converted to 1,1′-bis (diphenylphosphino) ferrocene. By reacting with a diboron compound such as bis (pinacolato) diboron in the presence or absence of a catalyst such as dichloropalladium, in the presence or absence of a base, or in the presence or absence of a ligand, general formula (3d) ( The symbols in the formula are as defined above.), And in the presence of a compound represented by the general formula (3b) and a catalyst such as tetrakis (triphenylphosphine) palladium, By performing the coupling reaction in the presence or absence of a base, in the presence or absence of a ligand, general formula (3e) (the symbols in the formula are as defined above, provided that V ² , one of V ^{3, V 4} and ^{V 5} One is N ⁺ -O ^- to obtain a compound represented by a is).. From the compound represented by the general formula (3e), the compound represented by the general formula [1] can be obtained according to the method of Scheme 1 or 2.
(Scheme 4)

一般式（４ａ）（式中、Ｘ^４ａは脱離基であり、Ｒ^４ａはカルボキシ基、保護されたカルボキシ基又は−ＣＯＮＨ−ＯＲ^４ｂ（式中、Ｒ^４ｂはヒドロキシ基の保護基である。）であり、その他の記号は前記と同義である。但し、Ｚ^２、Ｚ^３、Ｚ^４及びＺ^５のいずれか一つがＮである。）で表される化合物に、ｍ−クロロ過安息香酸等の酸化剤を塩基の存在下又は不存在下で作用させて、一般式（４ｂ）（式中の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物を得ることができる。さらに、一般式（４ｂ）及び（４ｃ）（式中、Ｘ^４ｂは脱離基であり、その他の記号は前記と同義である。）で表される化合物を用いて、スキーム３と同様の方法を用いて、一般式（４ｄ）（式中の記号は前記と同義である。）で表される化合物を経て、一般式（４ｅ）（式中の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物を得ることができる。一般式（４ｅ）で表される化合物から、スキーム１又は２の方法に従って、一般式［１］で表される化合物を得ることができる。
（スキーム５）

Formula (4a) (wherein X ^4a is a leaving group, R ^4a is a carboxy group, a protected carboxy group, or —CONH—OR ^4b (wherein R ^4b is a protecting group for a hydroxy group). And the other symbols are as defined above, provided that any one of Z ² , Z ³ , Z ⁴ and Z ⁵ is N.) m-chloroperbenzoic acid An oxidant such as the above is allowed to act in the presence or absence of a base, and the general formula (4b) (the symbols in the formula are as defined above, provided that any of V ² , V ³ , V ⁴ and V ⁵ one is N ⁺ -O or ^- can be obtained in a) represented by the compound.. Furthermore, the same method as in Scheme 3 using a compound represented by the general formulas (4b) and (4c) (wherein X ^4b is a leaving group, and other symbols are as defined above). Through a compound represented by the general formula (4d) (the symbols in the formula are as defined above), and then the general formula (4e) (the symbols in the formula are as defined above, provided that V ² , V ³ , V ^4, or V ⁵ is N ⁺ —O ⁻ ). From the compound represented by the general formula (4e), the compound represented by the general formula [1] can be obtained according to the method of Scheme 1 or 2.
(Scheme 5)

一般式（５ａ）（式中、Ｘ^５ａは脱離基であり、その他の記号は前記と同義である。）で表される化合物を、触媒の存在下、塩基の存在下又は不存在下、配位子の存在下又は不存在下、一般式（５ｂ）（式中、Ｒ^５ａはアセチレン基の保護基である。）で表される化合物と反応させた後、保護基Ｒ^５ａの種類に応じて適切な条件で脱保護を行うことで、一般式（５ｃ）（式中の記号は前記と同義である。）で表される化合物を得ることができる。さらに一般式（５ｃ）で表される化合物を、スキーム［４］の方法に従って得られた一般式（５ｄ）（式中、Ｘ^５ｂは脱離基であり、Ｒ^５ｂはカルボキシ基、保護されたカルボキシ基又は−ＣＯＮＨ−ＯＲ^５ｃ（式中、Ｒ^５ｃはヒドロキシ基の保護基である。）であり、その他の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮである。）で表される化合物と、ビス（トリフェニルホスフィン）ジクロロパラジウム及びヨウ化銅等の触媒の存在下、塩基の存在下又は不存在下、配位子の存在下又は不存在下、カップリング反応を行うことで、一般式（５ｅ）（式中の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物を得ることができる。なお、先に一般式（５ｄ）で表される化合物を一般式（５ｂ）で表される化合物と反応させ、脱保護を行ったのちに一般式（５ａ）で表される化合物と反応させても、同様に一般式（５ｅ）で表される化合物を得ることができる。さらにスキーム１又は２の方法に従って、一般式［１］で表される化合物を得ることができる。
（スキーム６）

A compound represented by the general formula (5a) (wherein X ^5a is a leaving group, and other symbols are as defined above), in the presence of a catalyst, in the presence or absence of a base, In the presence or absence of a ligand, after reacting with a compound represented by the general formula (5b) (wherein R ^5a is a protecting group for the acetylene group), the type of protecting group R ^5a is changed. Accordingly, by performing deprotection under appropriate conditions, a compound represented by the general formula (5c) (wherein the symbols are as defined above) can be obtained. Furthermore, the compound represented by the general formula (5c) was obtained by the general formula (5d) obtained according to the method of the scheme [4] (wherein X ^5b is a leaving group, R ^5b is a carboxy group, protected A carboxy group or —CONH—OR ^5c (wherein R ^5c is a protecting group for a hydroxy group), and other symbols are as defined above, provided that V ² , V ³ , V ⁴ and V ⁵ And the presence of a ligand in the presence or absence of a base, in the presence of a compound such as bis (triphenylphosphine) dichloropalladium and copper iodide. By performing the coupling reaction under or in the absence of general formula (5e) (wherein the symbols are as defined above, provided that any one of V ² , V ³ , V ⁴ and V ⁵ is N ⁺ -O ^-. a a) by obtaining a compound represented by It can be. The compound represented by general formula (5d) is first reacted with the compound represented by general formula (5b), and after deprotection, reacted with the compound represented by general formula (5a). In the same manner, a compound represented by the general formula (5e) can be obtained. Furthermore, according to the method of Scheme 1 or 2, a compound represented by the general formula [1] can be obtained.
(Scheme 6)

一般式（６ａ）（式中、Ｘ^６ａは脱離基であり、その他の記号は前記と同義である。）で表される化合物と、一般式（６ｂ）（式中、Ｒ^６ａは水素原子又はアミノ基の保護基であり、Ｒ^６ｂは水素原子又はカルボキシ基の保護基であり、その他の記号は前記と同義である。但し、Ｚ^２、Ｚ^３、Ｚ^４及びＺ^５のいずれか一つがＮである。）又は一般式（６ｃ）（式中、Ｒ^６ｃは水素原子又はアミノ基の保護基であり、その他の記号は前記と同義である。但し、Ｚ^２、Ｚ^３、Ｚ^４及びＺ^５のいずれか一つがＮである。）で表される化合物を、水酸化カリウム、水酸化ナトリウム又は水酸化リチウム等の塩基の存在下、メタノール、エタノール、１，４−ジオキサン及びテトラヒドロフラン等と水の混合溶媒中で、常温あるいは加熱条件下で反応を行うことで、一般式（６ｄ）（式中の記号は前記と同義である。但し、Ｚ^２、Ｚ^３、Ｚ^４及びＺ^５のいずれか一つがＮである。）で表される化合物を得ることができる。さらに、一般式（６ｄ）で表される化合物に対して、カルボキシ基の適切な保護基を施すか又は一般式Ｈ_２Ｎ−ＯＲ^６ｄ（式中、Ｒ^６ｄはヒドロキシ基の保護基である。）で表される化合物と縮合剤の存在下で反応させることによって、一般式（６ｅ）（Ｒ^６ｅは保護されたカルボキシ基又は−ＣＯＮＨ−ＯＲ^６ｄ（式中の記号は前記と同義である。）であり、その他の記号は前記と同義である。但し、Ｚ^２、Ｚ^３、Ｚ^４及びＺ^５のいずれか一つがＮである。）で表される化合物を得ることができる。さらにスキーム４又は５の方法に従って、一般式［１］で表される化合物を得ることができる。
なお、一般式（６ｂ）で表される化合物のうち、Ｚ^２が窒素原子である一般式（６ｆ）（式中の記号は前記と同義である。）で表される化合物は、

A compound represented by the general formula (6a) (wherein X ^6a is a leaving group, and other symbols are as defined above), and a general formula (6b) (wherein R ^6a is a hydrogen atom) Or a protective group for amino group, R ^6b is a protective group for hydrogen atom or carboxy group, and other symbols are as defined above, provided that any one of Z ² , Z ³ , Z ⁴ and Z ⁵ is used. One is N.) or General Formula (6c) (wherein R ^6c is a protecting group for a hydrogen atom or an amino group, and other symbols are as defined above, provided that Z ² , Z ³ , Z ^4). And Z ⁵ is N.) in the presence of a base such as potassium hydroxide, sodium hydroxide or lithium hydroxide, methanol, ethanol, 1,4-dioxane, tetrahydrofuran, etc. Room temperature or heating conditions in a mixed solvent of water and water By carrying out the reaction under the following formula, it is represented by the general formula (6d) (wherein the symbols are as defined above, but one of Z ² , Z ³ , Z ⁴ and Z ⁵ is N). Can be obtained. Furthermore, an appropriate protecting group for a carboxy group is applied to the compound represented by the general formula (6d) or the general formula H ₂ N—OR ^6d (wherein R ^6d is a protecting group for a hydroxy group). ) Is reacted with a compound represented by general formula (6e) (R ^6e is a protected carboxy group or —CONH—OR ^6d (wherein the symbols are as defined above). And the other symbols are as defined above, provided that any one of Z ² , Z ³ , Z ⁴ and Z ⁵ is N.). Furthermore, according to the method of Scheme 4 or 5, a compound represented by the general formula [1] can be obtained.
Of the compounds represented by the general formula (6b), the compound represented by the general formula (6f) (wherein the symbols are as defined above), wherein Z ² is a nitrogen atom,

一般式（６ｇ）（式中、Ｘ^６ｂは脱離基であり、その他の記号は前記と同義である。）で表される化合物にｎ−ブチルリチウム等の有機金属試薬を作用させた後、一般式（６ｈ）（式中、Ｒ^６ｆはカルボキシ基の保護基である。）で表される化合物を加えて反応させることで得ることができる。
（スキーム７）

After allowing an organometallic reagent such as n-butyllithium to act on the compound represented by the general formula (6g) (wherein X ^6b is a leaving group, and other symbols are as defined above), It can be obtained by adding and reacting a compound represented by the general formula (6h) (wherein R ^6f is a protecting group for a carboxy group).
(Scheme 7)

一般式（７ａ）（式中、Ｘ^７ａは脱離基であり、Ｒ^７ａはカルボキシ基、保護されたカルボキシ基又は−ＣＯＮＨ−ＯＲ^７ｂ（式中、Ｒ^７ｂはヒドロキシ基の保護基である。）であり、その他の記号は前記と同義である。但し、Ｚ^２、Ｚ^３、Ｚ^４及びＺ^５のいずれか一つがＮである。）で表される化合物を、１，１’−ビス（ジフェニルホスフィノ）フェロセンジクロロパラジウム等の触媒の存在下、塩基の存在下又は不存在下、配位子の存在下又は不存在下、ビス（ピナコラト）ジボロン等のジボロン化合物と反応させることで、一般式（７ｂ）（式中の記号は前記と同義である。但し、Ｚ^２、Ｚ^３、Ｚ^４及びＺ^５のいずれか一つがＮである。）で表される化合物を得ることができる。さらに一般式（７ｂ）で表される化合物を、一般式（７ｃ）（式中、Ｘ^７ｂは脱離基であり、その他の記号は前記と同義である。）で表される化合物と、テトラキス（トリフェニルホスフィン）パラジウム等の触媒の存在下、塩基の存在下又は不存在下、配位子の存在下又は不存在下、カップリング反応を行うことで、一般式（７ｄ）（式中の記号は前記と同義である。但し、Ｚ^２、Ｚ^３、Ｚ^４及びＺ^５のいずれか一つがＮである。）で表される化合物を得ることができる。さらにスキーム１又は２の方法に従って、一般式［１］で表される化合物を得ることができる。
（スキーム８）

General formula (7a) (wherein X ^7a is a leaving group, R ^7a is a carboxy group, a protected carboxy group or —CONH—OR ^7b (wherein R ^7b is a protecting group for a hydroxy group). The other symbols are as defined above, provided that any one of Z ² , Z ³ , Z ^4, and Z ⁵ is N.) The compound represented by 1,1′-bis In the presence of a catalyst such as (diphenylphosphino) ferrocene dichloropalladium, in the presence or absence of a base, in the presence or absence of a ligand, by reacting with a diboron compound such as bis (pinacolato) diboron, A compound represented by the general formula (7b) (the symbols in the formula are as defined above, provided that any one of Z ² , Z ³ , Z ⁴ and Z ⁵ is N) can be obtained. . Further, the compound represented by the general formula (7b) is converted into a compound represented by the general formula (7c) (wherein X ^7b is a leaving group, and other symbols are as defined above), tetrakis By performing the coupling reaction in the presence of a catalyst such as (triphenylphosphine) palladium, in the presence or absence of a base, or in the presence or absence of a ligand, The symbol is as defined above, provided that any one of Z ² , Z ³ , Z ⁴ and Z ⁵ is N.). Furthermore, according to the method of Scheme 1 or 2, a compound represented by the general formula [1] can be obtained.
(Scheme 8)

一般式（８ａ）（式中、Ｘ^８ａは脱離基であり、その他の記号は前記と同義である。）で表される化合物を、１，１’−ビス（ジフェニルホスフィノ）フェロセンジクロロパラジウム等の触媒の存在下、塩基の存在下又は不存在下、配位子の存在下又は不存在下、ビス（ピナコラト）ジボロン等のジボロン化合物と反応させることで、一般式（８ｂ）（式中の記号は前記と同義である。）で表される化合物を得ることができる。さらに一般式（８ｂ）で表される化合物を、一般式（８ｃ）（式中、Ｘ^８ｂは脱離基であり、その他の記号は前記と同義である。）で表される化合物と、テトラキス（トリフェニルホスフィン）パラジウム等の触媒の存在下、塩基の存在下又は不存在下、配位子の存在下又は不存在下、カップリング反応を行うことで、一般式（８ｄ）（式中の記号は前記と同義である。）で表される化合物を得ることができる。なお、反応の順序を入れ替えて、一般式（８ｃ）で表される化合物をボロン酸エステルに変換し、次いで一般式（８ａ）で表される化合物を反応させて一般式（８ｄ）で表される化合物を得ることもできる。さらにスキーム６の方法に従って、一般式［１］で表される化合物を得ることができる。
（スキーム９）

A compound represented by the general formula (8a) (wherein X ^8a is a leaving group, and other symbols are as defined above) is converted to 1,1′-bis (diphenylphosphino) ferrocenedichloropalladium. By reacting with a diboron compound such as bis (pinacolato) diboron in the presence or absence of a catalyst, etc., in the presence or absence of a base, or in the presence or absence of a ligand. Can be obtained in the same manner as described above. Further, the compound represented by the general formula (8b) is converted into a compound represented by the general formula (8c) (wherein X ^8b is a leaving group, and other symbols are as defined above), tetrakis By performing the coupling reaction in the presence of a catalyst such as (triphenylphosphine) palladium, in the presence or absence of a base, or in the presence or absence of a ligand, the compound represented by the general formula (8d) (in the formula: The symbol is as defined above.) Can be obtained. In addition, the order of the reaction is changed, the compound represented by the general formula (8c) is converted into a boronic ester, and then the compound represented by the general formula (8a) is reacted to represent the general formula (8d). Can also be obtained. Furthermore, according to the method of Scheme 6, a compound represented by the general formula [1] can be obtained.
(Scheme 9)

一般式（９ａ）（式中、Ｘ^９ａは脱離基であり、Ｒ^９ａは−ＣＮ又は−ＣＯＮＭｅ−ＯＭｅであり、その他の記号は前記と同義である。）で表される化合物に、一般式（９ｂ）（式中、Ｍ^９ａは−Ｌｉ又は−ＭｇＢｒ等の金属塩であり、その他の記号は前記と同義である。）で表される化合物を加えて反応させることで、一般式（９ｃ）（式中の記号は前記と同義である。）で表される化合物を得ることができる。さらにスキーム６又は８の方法に従って、一般式［１］で表される化合物を得ることができる。
（スキーム１０）

Examples of the compound represented by the general formula (9a) (wherein X ^9a is a leaving group, R ^9a is —CN or —CONMe-OMe, and other symbols are as defined above) By adding and reacting a compound represented by the formula (9b) (wherein M ^9a is a metal salt such as —Li or —MgBr, and other symbols are as defined above), the compound represented by the general formula ( 9c) (wherein the symbols are as defined above) can be obtained. Furthermore, according to the method of Scheme 6 or 8, the compound represented by the general formula [1] can be obtained.
(Scheme 10)

一般式（１０ａ）（式中、Ｘ^１０ａは脱離基であり、その他の記号は前記と同義である。）で表される化合物を、ｎ−ブチルリチウム等の有機金属試薬を用いて金属塩化させた後、一般式（１０ｂ）（式中、Ｒ^１０ａは−ＣＮ又は−ＣＯＮＭｅ−ＯＭｅであり、その他の記号は前記と同義である。）で表される化合物を加えて反応させることで、一般式（１０ｃ）（式中の記号は前記と同義である。）で表される化合物を得ることができる。さらにスキーム６又は８の方法に従って、一般式［１］で表される化合物を得ることができる。
（スキーム１１）

A compound represented by the general formula (10a) (wherein X ^10a is a leaving group, and other symbols are as defined above) is converted into a metal chloride using an organometallic reagent such as n-butyllithium. Then, a compound represented by the general formula (10b) (wherein R ^10a is —CN or —CONMe-OMe, and other symbols are as defined above) is added and reacted. A compound represented by the general formula (10c) (wherein the symbols are as defined above) can be obtained. Furthermore, according to the method of Scheme 6 or 8, the compound represented by the general formula [1] can be obtained.
(Scheme 11)

スキーム３、４、５又は６の方法に従って得られる一般式（１１ａ）（式中、Ｘ^１１ａは脱離基であり、Ｒ^１１ａはカルボキシ基、保護されたカルボキシ基又は−ＣＯＮＨ−ＯＲ^１１ｂ（式中、Ｒ^１１ｂはヒドロキシ基の保護基である。）であり、その他の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物と、一般式（１１ｂ）（式中、Ｒ^１１ｃは、Ｒ^９−Ｘ^２−、Ｒ^９−Ｘ^４−Ｙ^１−Ｘ^２−、Ｑ−Ｘ^１−又はＱ−Ｘ^１−Ｙ^１−Ｘ^２−であり、その他の記号は前記と同義である。）で表される化合物を、触媒の存在下又は不存在下、塩基の存在下又は不存在下、配位子の存在下又は不存在下、反応を行うことで、一般式（１１ｃ）（式中の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物を得ることができる。さらにスキーム１又は２の方法に従って、一般式［１］で表される化合物を得ることができる。
（スキーム１２）

General formula (11a) obtained according to the method of Scheme 3, 4, 5 or 6 wherein X ^11a is a leaving group and R ^11a is a carboxy group, a protected carboxy group or —CONH—OR ^11b (formula R ^11b is a protecting group for hydroxy group, and other symbols are as defined above, provided that any one of V ² , V ³ , V ⁴ and V ⁵ is N ⁺ -O ^−. in a compound represented by), the general formula (11b) ^{(wherein, R 11c is, R 9 -X 2 -.,} R 9 -X 4 -Y 1 -X 2 -, Q-X 1 - or Q—X ¹ —Y ¹ —X ² —, and the other symbols are as defined above.) In the presence or absence of a catalyst, in the presence or absence of a base, By carrying out the reaction in the presence or absence of a ligand, general formula (11c) (the symbol in the formula is Serial and is synonymous ^{However, V 2, V 3, V} 4 and any one of ^{V 5} is ^N + -O ^-. Can be obtained in a) and a compound represented by.. Furthermore, according to the method of Scheme 1 or 2, a compound represented by the general formula [1] can be obtained.
(Scheme 12)

一般式（１２ａ）（式中、Ｘ^１２ａ及びＸ^１２ｂは脱離基であり、その他の記号は前記と同義である。）で表される化合物と、一般式（１２ｂ）（式中、Ｒ^１２ａは、Ｒ^９−Ｘ^２−、Ｒ^９−Ｘ^４−Ｙ^１−Ｘ^２−、Ｑ−Ｘ^１−又はＱ−Ｘ^１−Ｙ^１−Ｘ^２−であり、その他の記号は前記と同義である。）で表される化合物を、触媒の存在下又は不存在下、塩基の存在下又は不存在下、配位子の存在下又は不存在下、反応を行うことで、一般式（１２ｃ）（式中の記号は前記と同義である。）で表される化合物を得ることができる。さらにスキーム４、５、６又は８の方法に従って、一般式［１］で表される化合物を得ることができる。
（スキーム１３）

A compound represented by the general formula (12a) (wherein X ^12a and X ^12b are a leaving group, and other symbols are as defined above), and a general formula (12b) (wherein R ^{12a is, R 9 -X 2 -, R} 9 -X 4 -Y 1 -X 2 -, Q-X 1 - or ^{Q-X 1 -Y 1 -X 2} - and is, the other symbols having the same definition as above The compound represented by formula (12c) is reacted 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. (The symbols in the formula are as defined above.). Furthermore, according to the method of Scheme 4, 5, 6 or 8, a compound represented by the general formula [1] can be obtained.
(Scheme 13)

スキーム３、４又は５の方法に従って得られる一般式（１３ａ）（式中、Ｘ^１３ａは隣接するメチレン基と一緒になって−Ｘ^１−又は−Ｘ^２−Ｙ^３−Ｘ^３−を形成する基であり、Ｒ^１３ａはカルボキシ基、保護されたカルボキシ基又は−ＣＯＮＨ−ＯＲ^１３ｂ（式中、Ｒ^１３ｂはヒドロキシ基の保護基である。）であり、その他の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物と、一般式（１３ｂ）（式中、Ｘ^１３ｂは−Ｘ^２−又は−Ｘ^４−であり、その他の記号は前記と同義である。）で表される化合物を、水素化トリアセトキシホウ素ナトリウム、水素化シアノホウ素ナトリウム又は水素化ホウ素ナトリウム等の還元剤の存在下、塩化亜鉛等の金属塩の存在下又は不存在下で反応させることで、一般式（１３ｃ）（式中の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物を得ることができる。さらにスキーム１又は２の方法に従って、一般式［１］で表される化合物を得ることができる。
（スキーム１４）

General formula (13a) obtained according to the method of scheme 3, 4 or 5 wherein X ^13a together with the adjacent methylene group forms -X ¹ -or -X ² -Y ³ -X ^3-. R ^13a is a carboxy group, a protected carboxy group or —CONH—OR ^13b (wherein R ^13b is a protecting group for a hydroxy group), and other symbols are as defined above. However, any one of V ² , V ³ , V ⁴ and V ⁵ is N ⁺ —O ⁻ ) and a general formula (13b) (wherein X ^13b is —X ² — Or -X ^4- and other symbols are as defined above.) In the presence of a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride. , Gold such as zinc chloride Is reacted in the presence or absence of salt, the general formula (13c) (symbols in the formula are as defined above. However, V ^{2, V 3,} one of V ⁴ and V ⁵ is N ⁺ -O ^-. a it) can be obtained a compound represented by the. Furthermore, according to the method of Scheme 1 or 2, a compound represented by the general formula [1] can be obtained.
(Scheme 14)

スキーム３、４又は５の方法に従って得られる一般式（１４ａ）（式中、Ｘ^１４ａは隣接するメチレン基と一緒になって−Ｘ^１−又は−Ｘ^２−Ｙ^３−Ｘ^３−を形成する基であり、Ｒ^１４ａはカルボキシ基、保護されたカルボキシ基又は−ＣＯＮＨ−ＯＲ^１４ｂ（式中、Ｒ^１４ｂはヒドロキシ基の保護基である。）であり、その他の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物と、一般式（１４ｂ）（式中の記号は前記と同義である。）で表される化合物を、水素化トリアセトキシホウ素ナトリウム、水素化シアノホウ素ナトリウム又は水素化ホウ素ナトリウム等の還元剤の存在下、塩化亜鉛等の金属塩の存在下又は不存在下で反応させることで、一般式（１４ｃ）（式中の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物を得ることができる。さらにスキーム１又は２の方法に従って、一般式［１］で表される化合物を得ることができる。
（スキーム１５）

General formula (14a) obtained according to the method of Scheme 3, 4 or 5 wherein X ^14a is taken together with the adjacent methylene group to form —X ¹ — or —X ² —Y ³ —X ³ —. R ^14a is a carboxy group, a protected carboxy group or —CONH—OR ^14b (wherein R ^14b is a protecting group for a hydroxy group), and other symbols are as defined above. However, any one of V ² , V ³ , V ⁴ and V ⁵ is N ⁺ —O ⁻ ), and the general formula (14b) (the symbols in the formula are as defined above). .) Is reacted 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. That the general formula (14c) Obtaining a compound represented by the formula (the symbols in the formula are as defined above, provided that any one of V ² , V ³ , V ⁴ and V ⁵ is N ⁺ —O ⁻ ). Can do. Furthermore, according to the method of Scheme 1 or 2, a compound represented by the general formula [1] can be obtained.
(Scheme 15)

一般式（１５ａ）（式中、Ｘ^１５ａは隣接するメチレン基と一緒になって−Ｘ^１−又は−Ｘ^２−Ｙ^３−Ｘ^３−を形成する基であり、Ｘ^１５ｂは脱離基であり、その他の記号は前記と同義である。）で表される化合物と、一般式（１５ｂ）（式中、Ｘ^１５ｃは−Ｘ^２−又は−Ｘ^４−であり、その他の記号は前記と同義である。）で表される化合物を、水素化トリアセトキシホウ素ナトリウム、水素化シアノホウ素ナトリウム又は水素化ホウ素ナトリウム等の還元剤の存在下、塩化亜鉛等の金属塩の存在下又は不存在下で反応させることで、一般式（１５ｃ）（式中の記号は前記と同義である。）で表される化合物を得ることができる。さらにスキーム４又は５の方法に従って、一般式［１］で表される化合物を得ることができる。
（スキーム１６）

General formula (15a) (wherein X ^15a is a group which forms —X ¹ — or —X ² —Y ³ —X ³ — together with an adjacent methylene group, and X ^15b represents a leaving group; There, a compound represented by the other symbols are as defined above), the general formula (15b) ^{(wherein, X 15c} is -X ² -. or -X ⁴ - a and the other symbols are said In the presence of a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride, or in the presence or absence of a metal salt such as zinc chloride. The compound represented by the general formula (15c) (wherein the symbols are as defined above) can be obtained. Furthermore, according to the method of Scheme 4 or 5, a compound represented by the general formula [1] can be obtained.
(Scheme 16)

スキーム３、４、５又は６の方法に従って得られる一般式（１６ａ）（式中、Ｘ^１６ａは−Ｘ^１−又は−Ｘ^２−Ｙ^３−Ｘ^３−であり、Ｘ^１６ｂは脱離基であり、Ｒ^１６ａはカルボキシ基、保護されたカルボキシ基又は−ＣＯＮＨ−ＯＲ^１６ｂ（式中、Ｒ^１６ｂはヒドロキシ基の保護基である。）であり、その他の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物と、一般式（１６ｂ）（式中、Ｘ^１６ｃは−Ｘ^２−又は−Ｘ^４−であり、その他の記号は前記と同義である。）で表される化合物を、塩基の存在下又は不存在下で反応を行うことで、一般式（１６ｃ）（式中の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物を得ることができる。さらにスキーム１又は２の方法に従って、一般式［１］で表される化合物を得ることができる。
（スキーム１７）

General formula (16a) obtained according to the method of Scheme 3, 4, 5 or 6 wherein X ^16a is —X ¹ — or —X ² —Y ³ —X ³ —, and X ^16b is a leaving group. R ^16a is a carboxy group, a protected carboxy group or —CONH—OR ^16b (wherein R ^16b is a protecting group for a hydroxy group), and other symbols are as defined above. Any one of V ² , V ³ , V ⁴ and V ⁵ is N ⁺ —O ⁻ ), and a compound represented by the general formula (16b) (wherein X ^16c represents —X ² — or — X ^4- and the other symbols are as defined above.) By reacting in the presence or absence of a base, general formula (16c) (the symbols in the formula are As defined above, provided that any one of V ² , V ³ , V ⁴ and V ⁵ is N ⁺ -O ^-. A it) can be obtained a compound represented by the. Furthermore, according to the method of Scheme 1 or 2, a compound represented by the general formula [1] can be obtained.
(Scheme 17)

スキーム３、４、５又は６の方法に従って得られる一般式（１７ａ）（式中、Ｘ^１７ａは−Ｘ^１−Ｙ^２−Ｘ^３−又は−Ｘ^１−Ｙ^１−Ｘ^２−Ｙ^３−Ｘ^３−であり、Ｘ^１７ｂは脱離基であり、Ｒ^１７ａはカルボキシ基、保護されたカルボキシ基又は−ＣＯＮＨ−ＯＲ^１７ｂ（式中、Ｒ^１７ｂはヒドロキシ基の保護基である。）であり、その他の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物と、一般式（１７ｂ）（式中の記号は前記と同義である。）で表される化合物を、塩基の存在下又は不存在下で反応を行うことで、一般式（１７ｃ）（式中の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物を得ることができる。さらにスキーム１又は２の方法に従って、一般式［１］で表される化合物を得ることができる。
（スキーム１８）

General formula (17a) obtained according to the method of Scheme 3, 4, 5 or 6 (wherein X ^17a is -X ¹ -Y ² -X ³ -or -X ¹ -Y ¹ -X ² -Y ³ -X ^3- , X ^17b is a leaving group, R ^17a is a carboxy group, a protected carboxy group or —CONH—OR ^17b (wherein R ^17b is a protecting group for a hydroxy group), Other symbols are as defined above, provided that any one of V ² , V ³ , V ⁴ and V ⁵ is N ⁺ —O ⁻ ), and a compound represented by the general formula (17b) ( The symbol in the formula is as defined above.) The compound represented by formula (17c) is reacted in the presence or absence of a base (the symbols in the formula are as defined above). . ^However, one of V ^2, V 3, ^{V 4} and ^{V 5} is ^N + -O ^- a. ) Can be obtained. Furthermore, according to the method of Scheme 1 or 2, a compound represented by the general formula [1] can be obtained.
(Scheme 18)

スキーム３、４、５又は６の方法に従って得られる一般式（１８ａ）（式中、Ｒ^１８ａはカルボキシ基又は保護されたカルボキシ基であり、その他の記号は前記と同義である。）で表される化合物を、臭素又はＮ−ブロモコハク酸イミド等の臭素化試薬を用いて反応を行うことで、一般式（１８ｂ）（式中の記号は前記と同義である。）で表される化合物を得ることができる。さらに一般式（１８ｂ）で表される化合物を、触媒の存在下、塩基の存在下又は不存在下、配位子の存在下又は不存在下、塩基性条件下で反応を行うことで、一般式（１８ｃ）（式中の記号は前記と同義である。）で表される化合物を得ることができる。さらに、トリメチルシリルジアゾメタンなどを用いてメチル化することで、一般式（１８ｄ）（式中の記号は前記と同義である。）で表される化合物を得ることができる。一般式（１８ｂ）、（１８ｃ）及び（１８ｄ）で表される化合物を用いて、スキーム１又は２の方法に従って、一般式［１］で表される化合物を得ることができる。
（スキーム１９）

It is represented by the general formula (18a) obtained according to the method of Scheme 3, 4, 5 or 6 (wherein R ^18a is a carboxy group or a protected carboxy group, and other symbols are as defined above). Is reacted with a brominating reagent such as bromine or N-bromosuccinimide, to obtain a compound represented by the general formula (18b) (the symbols in the formula are as defined above). be able to. Further, by reacting the compound represented by the general formula (18b) under basic conditions in the presence of a catalyst, in the presence or absence of a base, in the presence or absence of a ligand, A compound represented by the formula (18c) (wherein the symbols are as defined above) can be obtained. Furthermore, the compound represented by general formula (18d) (the symbols in the formula are as defined above) can be obtained by methylation using trimethylsilyldiazomethane or the like. By using the compounds represented by the general formulas (18b), (18c) and (18d), the compound represented by the general formula [1] can be obtained according to the method of Scheme 1 or 2.
(Scheme 19)

スキーム４の方法などに従って得られる一般式（１９ａ）（式中、Ｇは−Ｘ^１−、−Ｘ^２−Ｙ^１−Ｘ^１−又は−Ｘ^４−Ｙ^１−Ｘ^２−Ｙ^３−Ｘ^３−であり、その他の記号は前記と同義である。）で表される化合物に対し、カルボジイミダゾール（以下、ＣＤＩと表す。）及び一般式（１９ｂ）で得られる化合物を順次反応させて、一般式（１９ｃ）（式中の記号は前記と同義である。）で表される化合物を得ることができる。さらにスキーム４の方法に従って、一般式［１］で表される化合物を得ることができる。
（スキーム２０）

General formula (19a) obtained according to the method of Scheme 4 and the like (wherein G is —X ¹ —, —X ² —Y ¹ —X ¹ — or —X ⁴ —Y ¹ —X ² —Y ³ —X ³ -And the other symbols are as defined above.) The compound represented by carbodiimidazole (hereinafter referred to as CDI) and the compound obtained by the general formula (19b) are sequentially reacted, A compound represented by the general formula (19c) (the symbols in the formula are as defined above) can be obtained. Furthermore, according to the method of Scheme 4, a compound represented by the general formula [1] can be obtained.
(Scheme 20)

スキーム２、４、５などの方法の従って得られる一般式（２０ａ）（式中、Ｒ^２０ａはヒドロキシ基の保護基であり、その他の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物と、一般的（２０ｂ）（式中、Ｇ^２０はＣ_１−６アルキレン基であり、Ｒ^２０ｂ及びＲ^２０ｃは同一又は異なってＣ_１−６アルキル基であり、その他の記号は前記と同義である。）で表される化合物を、縮合剤の存在下で反応を行うことで、一般式（２０ｃ）（式中の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表させる化合物を得ることができる。これをＲ^２０ａで表される保護基の種類に応じて適切な条件で脱保護反応を行うことで、一般式［１］で表される化合物のうち一般式（２０ｄ）（式中の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物を得ることができる。
一方、一般式（２０ｃ）で表される化合物に対して、一般式（２０ｅ）（式中、Ｘ^２０ａは脱離基であり、Ｒ^２０ｄはＣ_１−６アルキレン基であり、Ｒ^２０ｅは保護されたカルボキシ基、保護されたリン酸基、保護されたホスホン酸基又は水素原子である。）で表される化合物を作用させて一般式（２０ｆ）（式中の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物を得ることができ、さらにＲ^２０ａで表される保護基やＲ^２０ｅに含まれる保護基の種類に応じて適切な条件で脱保護反応を行うことで、一般式［１］で表される化合物のうち一般式（２０ｇ）（式中、Ｒ^２０ｆはカルボキシ基、リン酸基、ホスホン酸基、これらの陰イオン又は水素原子であり、その他の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物を得ることができる。
（スキーム２１）

General formula (20a) obtained by the method of Scheme 2, 4, 5 or the like (wherein R ^20a is a protecting group for a hydroxy group, and other symbols are as defined above, provided that V ² , V ³ And any one of V ⁴ and V ⁵ is N ⁺ —O ^— and a general formula (20b) (wherein G ²⁰ is a C _1-6 alkylene group, R ^20b And R ^20c are the same or different and each represents a C _1-6 alkyl group, and other symbols have the same ^{meanings as} described above.), By reacting a compound represented by the general formula ( 20c) (wherein the symbols are as defined above, provided that any one of V ² , V ³ , V ⁴ and V ⁵ is N ⁺ —O ⁻ ). . This is subjected to a deprotection reaction under an appropriate condition according to the type of the protecting group represented by R ^20a , so that among the compounds represented by the general formula [1], the general formula (20d) (the symbol in the formula is As defined above, provided that any one of V ² , V ³ , V ^4, and V ⁵ is N ⁺ —O ⁻ ).
On the other hand, for the compound represented by the general formula (20c), the general formula (20e) (wherein X ^20a is a leaving group, R ^20d is a C _1-6 alkylene group, and R ^20e is a protective group). A carboxy group, a protected phosphoric acid group, a protected phosphonic acid group or a hydrogen atom. Provided that any one of V ² , V ³ , V ⁴ and V ⁵ is N ⁺ —O ⁻ ), and a protective group represented by R ^20a and R By performing a deprotection reaction under an appropriate condition according to the type of the protecting group contained in ^20e , among the compounds represented by the general formula [1], the general formula (20g) (wherein R ^20f is a carboxy group, A phosphoric acid group, a phosphonic acid group, an anion or hydrogen atom thereof, Other symbols are as defined above, provided that any one of V ² , V ³ , V ^4, and V ⁵ is N ⁺ —O ⁻ ).
(Scheme 21)

国際公開番号ＷＯ２００８／１０５５１５に記載の方法で合成可能な一般式（２１ａ）（式中、Ｒ^２１ａはヒドロキシ基の保護基であり、その他の記号は前記と同義である。但し、Ｚ^２、Ｚ^３、Ｚ^４及びＺ^５のいずれか一つがＮである。）を、一般的（２１ｂ）（式中、Ｒ^２１ｂは「保護されたカルボキシ基、保護されたリン酸基又は保護されたホスホン酸基」から選ばれる同一又は異なる１から２個の置換基で置換されてもよいＣ_１−６アルキル基である。）で表される化合物と縮合剤の存在下で反応を行うことで、一般式（２１ｃ）（式中の記号は前記と同義である。但し、Ｚ^２、Ｚ^３、Ｚ^４及びＺ^５のいずれか一つがＮである。）で表させる化合物を得ることができる。これに対し、ｍ−クロロ過安息香酸等の酸化剤を塩基の存在下又は不存在下で作用させて、一般式（２１ｄ）（式中の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物を得ることができ、さらにＲ^２１ａで表される保護基やＲ^２１ｂに含まれる保護基の種類に応じて適切な条件で脱保護反応を行うことで、一般式［１］で表される化合物のうち一般式（２１ｅ）（式中、Ｒ^２１ｃは「カルボキシ基、リン酸基又はホスホン酸基」から選ばれる同一又は異なる１から２個の置換基で置換されてもよいＣ_１−６アルキル基であり、その他の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物を得ることができる。
（スキーム２２）

General formula (21a) that can be synthesized by the method described in International Publication No. WO2008 / 105515 (wherein R ^21a is a hydroxy-protecting group, and other symbols are as defined above, provided that Z ² , Z ³ , any one of Z ⁴ and Z ⁵ is N.) (21b) wherein R ^21b is a protected carboxy group, a protected phosphate group or a protected phosphonic acid. A C _1-6 alkyl group which may be substituted with the same or different 1 to 2 substituents selected from the group “)” in the presence of a condensing agent, A compound represented by the formula (21c) (the symbols in the formula are as defined above, provided that any one of Z ² , Z ³ , Z ⁴ and Z ⁵ is N) can be obtained. On the other hand, an oxidant such as m-chloroperbenzoic acid is allowed to act in the presence or absence of a base to give a general formula (21d) (the symbols in the formula are as defined above, provided that V ² , Any one of V ³ , V ⁴ and V ⁵ is N ⁺ —O ⁻ ), and a protective group represented by R ^21a and a protective group contained in R ^21b. In the compound represented by the general formula [1], the deprotection reaction is performed under an appropriate condition according to the type of the general formula (21e) (wherein R ^21c represents “carboxy group, phosphate group or phosphone”. C _1-6 alkyl group which may be substituted with the same or different 1 to 2 substituents selected from “acid group”, and other symbols are as defined above, provided that V ² , V ³ , V ⁴ or V ⁵ is N ⁺ —O ⁻ ). Can.
(Scheme 22)

国際公開番号ＷＯ２００８／１０５５１５に記載の方法で合成可能な一般式（２２ａ）（式中、Ｒ^２２ａはヒドロキシ基の保護基であり、その他の記号は前記と同義である。但し、Ｚ^２、Ｚ^３、Ｚ^４及びＺ^５のいずれか一つがＮである。）で表される化合物を、Ｎ，Ｎ−ジイソプロピルホスホルアミド酸ジ−ｔｅｒｔ−ブチルエステル等の一般式（２２ｂ）（式中、Ｒ^２２ｂ及びＲ^２２ｃは同一又は異なってリン酸基の保護基であり、Ｒ^２２ｄ及びＲ^２２ｅは同一又は異なってＣ_１−６アルキル基である。）で表される化合物と反応させ、さらにｍ−クロロ過安息香酸等の酸化剤を塩基の存在下又は不存在下で作用させることで、一般式（２２ｃ）（式中の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物を得ることができる。一般式（２２ｂ）で表される化合物の代わりに、リン酸ジエステル体や活性化されたリン酸誘導体を用いた一般的なリン酸エステル化反応によってリン酸エステル化を行ってもよい。リン酸ジエステルとしては例えばリン酸ジベンジルやリン酸ジブチルが、活性化されたリン酸誘導体としては例えばクロロリン酸ジエチルが、それぞれ挙げられる。一般式（２２ｃ）で表される化合物を、Ｒ^２２ａ、Ｒ^２２ｂ及びＲ^２２ｃで表される保護基の種類に応じて適切な条件で脱保護反応を行うことで一般式［１］で表される化合物のうち一般式（２２ｄ）（式中の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物を得ることができる。
（スキーム２３）

General formula (22a) which can be synthesized by the method described in International Publication No. WO2008 / 105515 (wherein R ^22a is a protecting group for a hydroxy group, and other symbols are as defined above, provided that Z ² , Z ³ , any one of Z ⁴ and Z ⁵ is N.) A compound represented by general formula (22b) (wherein N, N-diisopropylphosphoramidic acid di-tert-butyl ester) R ^22b and R ^22c are the same or different and are a protecting group for a phosphate group, and R ^22d and R ^22e are the same or different and are a C _1-6 alkyl group). -By allowing an oxidizing agent such as chloroperbenzoic acid to act in the presence or absence of a base, general formula (22c) (the symbols in the formula are as defined above, provided that V ² , V ³ , V any one of the ⁴ and ^{V 5} One is N ⁺ -O ^- to obtain a compound represented by a is).. Instead of the compound represented by the general formula (22b), phosphoric acid esterification may be performed by a general phosphoric acid esterification reaction using a phosphoric acid diester or an activated phosphoric acid derivative. Examples of the phosphoric acid diester include dibenzyl phosphate and dibutyl phosphate, and examples of the activated phosphoric acid derivative include diethyl chlorophosphate. The compound represented by the general formula (22c) is represented by the general formula [1] by performing a deprotection reaction under an appropriate condition according to the type of the protecting group represented by R ^22a , R ^22b and R ^22c. Table with ^- formula (22 d) (a is the symbol in the formula is as defined above provided ^that one of V ^2, V 3, ^{V 4} and ^{V 5} is ^N + -O..) of that compound Can be obtained.
(Scheme 23)

国際公開番号ＷＯ２００８／１０５５１５に記載の方法で合成可能な一般式（２３ａ）（式中、Ｒ^２３ａはヒドロキシ基の保護基であり、その他の記号は前記と同義である。但し、Ｚ^２、Ｚ^３、Ｚ^４及びＺ^５のいずれか一つがＮである。）を、塩基の存在下メシルクロライド（ＭｓＣｌ）を用いて一般式（２３ｂ）（式中の記号は前記と同義である。但し、Ｚ^２、Ｚ^３、Ｚ^４及びＺ^５のいずれか一つがＮである。）に変換した後、一般的（２３ｃ）（式中、Ｍ^２３ａはＣ_１−６アルキレン基である。）で表される化合物と塩基の存在下で反応を行うことで、一般式（２３ｄ）（式中の記号は前記と同義である。但し、Ｚ^２、Ｚ^３、Ｚ^４及びＺ^５のいずれか一つがＮである。）で表させる化合物を得ることができる。さらに、スキーム２２と同様の方法で、ヒドロキシ基のリン酸エステル化反応、Ｎオキシドへの酸化反応、脱保護反応を行うことで、一般式［１］で表される化合物のうち一般式（２３ｅ）（式中の記号は前記と同義である。但し、Ｖ^２、Ｖ^３、Ｖ^４及びＶ^５のいずれか一つがＮ^＋−Ｏ⁻である。）で表される化合物を得ることができる。

General formula (23a) that can be synthesized by the method described in International Publication No. WO2008 / 105515 (wherein R ^23a is a protecting group for a hydroxy group, and other symbols are as defined above, provided that Z ² , Z ³ , any one of Z ⁴ and Z ⁵ is N.) using mesyl chloride (MsCl) in the presence of a base, the general formula (23b) (the symbols in the formula are as defined above, provided that After conversion into Z ² , Z ³ , Z ⁴ and Z ⁵ is N.), it is represented by the general formula (23c) (wherein M ^23a is a C _1-6 alkylene group). By reacting with the compound to be represented by the formula (23d) (the symbols in the formula are as defined above, provided that any one of Z ² , Z ³ , Z ⁴ and Z ⁵ is N.) can be obtained. Further, by performing a phosphoric esterification reaction of a hydroxy group, an oxidation reaction to N oxide, and a deprotection reaction in the same manner as in Scheme 22, among the compounds represented by the general formula [1], the general formula (23e (The symbols in the formula are as defined above, provided that any one of V ² , V ³ , V ^4, and V ⁵ is N ⁺ —O ⁻ ). .

  In the synthesis method described above, the order of the reaction steps can be changed as necessary. For example, the compound represented by the general formula (6a) is reacted with (4d) described in Scheme 4 and then the reaction described in Scheme 6 and further an oxidizing agent such as m-chloroperbenzoic acid. To obtain a compound represented by the general formula (4e). Moreover, in the compound obtained by each reaction process, and those intermediates, when an amino group, a hydroxy group, a formyl group, and a carboxy group exist, it can react by changing suitably those protective groups.

  Unless otherwise specified, examples of the base when a base is used in the reaction include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate, potassium 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 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 and benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate.

  Examples of catalysts include palladium acetate, palladium chloride, bis (triphenylphosphine) dichloropalladium, tetrakis (triphenylphosphine) palladium, bis (acetonitrile) dichloropalladium, bis (benzonitrile) dichloropalladium, tris (dibenzylideneacetone) di Palladium, bis (dibenzylideneacetone) palladium, 1,1′-bis (diphenylphosphino) ferrocenedichloropalladium, bis (tricyclohexylphosphine) dichloropalladium, bis (tri-o-tolylphosphine) dichloropalladium, bis (tri- t-butylphosphine) dichloropalladium and copper iodide.

  Examples of the ligand include tri-t-butylphosphine, tricyclohexylphosphine, triphenylphosphine, tolylphosphine, tributylphosphite, tricyclohexylphosphite, triphenylphosphite, 1,1′-bis (diphenylphosphino ) Ferrocene, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2 ′, 4 ′, 6 Examples include '-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-chloroperbenzoic acid, urea hydrogen peroxide adduct / phthalic anhydride, t-butyl hydroperoxide, cumene hydroperoxide. Inorganic and organic peroxides such as selenium dioxide, lead (IV) acetate, t-butyl hypochlorite, sodium hypochlorite, and 1,1,1-triacetoxy-1,1-dihydro-1, 2-Benziodoxol-3 (1H) -one is mentioned.

  Examples of the reducing agent include lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, diisobutylaluminum hydride and the like, boranes, sodium and Sodium amalgam is mentioned.

  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 and is inert and does not interfere with the reaction, and a polar solvent (for example, an alcohol-based solvent such as water, methanol, ethanol, etc.), inert Solvents (for example, halogenated hydrocarbon solvents such as chloroform, methylene chloride, dichloroethane, carbon tetrachloride, ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, dimethylformamide, dimethyl sulfoxide, ethyl acetate , Aprotic solvents such as acetonitrile and propionitrile, aromatic hydrocarbons such as benzene and toluene, or hydrocarbons such as cyclohexane), or a mixed solvent thereof.

  In addition, the reaction can be carried out by selecting an appropriate temperature in the range of −78 ° C. to the boiling point of the solvent used for the reaction, under normal pressure or under pressure, under microwave irradiation, and the like.

  In order to use the compound of the present invention as a medicine, the compound of the present invention is added with usual excipients, extenders, pH adjusters, solubilizers, etc., and tablets, granules, pills, capsules are added by conventional formulation techniques. It can be prepared as an agent, powder, liquid, suspension, injection, drip, etc. and administered as an oral, injection or drip.

The compounds of the present invention also include compounds that function as prodrugs when administered. The compound that functions as a prodrug is preferably a group in which R ⁹ is selected from a phosphate group or formula [2]. More preferably, R ⁹ is a phosphate group or a group selected from the formula [2], and W is a group selected from the following formula [9]

である。式中のその他の記号は前記の通りである。プロドラッグとして機能する化合物群は、好ましくは以下のような特徴を有する。
（１）プロドラッグ化合物自体は、ＬｐｘＣ酵素阻害活性や抗菌活性を有していてもよいが、必須ではない。
（２）投与後、プロドラッグとして機能する官能基が体内の適当な酵素によって切断され、目的の薬理活性を示す化合物に変換される。この際、プロドラッグ自身に抗菌活性があれば、体内の酵素による切断を受けずにプロドラッグ体のままで薬効を示してもよい。また、プロドラッグ体及び体内の酵素により切断された化合物がともに混在していてもよい。
（３）プロドラッグ化する事により、水溶性の増大、薬効作用の増強や持続、副作用や毒性の軽減、安定性の向上などが期待される。特に好ましくは、水溶性の増大が期待される。例えば、注射剤あるいは点滴剤としてプロドラッグを使用する場合、投与液量の少量化等のような投与条件の改善が可能となり、有効成分量の増量化や、血中濃度の上昇による薬効の増強等が期待できる。

It is. Other symbols in the formula are as described above. The group of compounds that function as prodrugs preferably have the following characteristics.
(1) The prodrug compound itself may have LpxC enzyme inhibitory activity or antibacterial activity, but is not essential.
(2) After administration, the functional group functioning as a prodrug is cleaved by an appropriate enzyme in the body and converted into a compound exhibiting the desired pharmacological activity. At this time, if the prodrug itself has antibacterial activity, the prodrug may be effective as it is without being cleaved by enzymes in the body. Further, both a prodrug and a compound cleaved by an enzyme in the body may be present together.
(3) By forming a prodrug, it is expected to increase water solubility, enhance and sustain drug efficacy, reduce side effects and toxicity, and improve stability. Particularly preferably, an increase in water solubility is expected. For example, when prodrugs are used as injections or infusions, it is possible to improve administration conditions, such as reducing the amount of administration liquid, and increase the amount of active ingredients and enhance efficacy by increasing blood concentration Etc. can be expected.

  The compound of the present invention can be administered to an adult patient in an amount of 1 to 3000 mg per day divided into 1 to several times. This dose can be appropriately increased or decreased depending on the type of disease, patient age, weight, symptoms, and the like.

  Next, the present invention will be described in more detail with reference to examples and test examples. The compounds of the present invention are not limited to the compounds described in the following examples.

Unless otherwise specified, the carrier in silica gel chromatography is silica gel 60N manufactured by Kanto Chemical Co., Ltd., the carrier in NH type silica gel chromatography is Chromatrex NH-DM1020 manufactured by Fuji Silysia Chemical Co., Ltd., and the carrier in reverse phase silica gel chromatography is Co., Ltd. YMCI ODS-A-AA12S50 was used. For preparative silica gel thin layer chromatography, a PLC plate silica gel 60F ₂₅₄ manufactured by Merck & Co., Inc. was used. The NMR spectrum showed proton NMR, and δ value was expressed in ppm using tetramethylsilane as an internal standard.

Moreover, the symbol in an Example is shown below.
Ac: Acetyl Bn: Benzyl Boc: t-Butoxycarbonyl Bu: Butyl DEAD: Diethyl azodicarboxylate DHP: 3,4-Dihydro-2H-pyran DIPEA: N, N-diisopropylethylamine DME: 1,2-dimethoxyethane DMF: N, N-dimethylformamide DMSO: dimethyl sulfoxide dppf: 1,1′-bis (diphenylphosphino) ferrocene Et: ethyl HOBt · H ₂ O: 1-hydroxybenzotriazole monohydrate IPA: 2-propanol IPE: diisopropyl ether iPr: isopropyl mCPBA: metachloroperbenzoic acid Me: methyl Ms: methanesulfonyl MsCl: methanesulfonyl chloride PdCl ₂ (dppf): 1,1'-bis (diphenylphosphino) ferrocene para di Beam (II) dichloride-dichloromethane complex (1: 1)
PdCl ₂ (PPh ₃ ) ₂ : Bis (triphenylphosphine) palladium (II) dichloride Pd (PPh ₃ ) ₄ : Tetrakis (triphenylphosphine) palladium Pd ₂ (dba) ₃ : Tris (dibenzylideneacetone) dipalladium Ph: Phenyl Piv: 2,2-dimethylpropanoyl PTS · H ₂ O: p-toluenesulfonic acid monohydrate TFA: trifluoroacetic acid THF: tetrahydrofuran THP: tetrahydropyranyl TMS: trimethylsilyl WSC · HCl: 1- (3- Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride s: singlet br. s. : Broad singlet (wide singlet)
d: Doublet dd: Double doublet t: Triplet q: Quartet m: Multiplet Example 1
2- (biphenyl-4-yl) -N-hydroxy-3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride (Compound 1)

（１）４−アミノピリジン（２４ｇ）のクロロホルム（４２０ｍｌ）溶液に、０℃でトリエチルアミン（５３ｍｌ）を加えた後、２，２−ジメチルプロパノイルクロリド（３５ｍｌ）のクロロホルム（２０ｍｌ）溶液を滴下して加え、０℃で１時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて、クロロホルムで抽出した。抽出物を無水硫酸マグネシウムで乾燥し乾燥剤を濾別した後、溶媒を減圧下留去した。残留物にクロロホルム／ヘキサン＝１／４の混合溶媒を加え、析出した固体を濾別して、２，２−ジメチル−Ｎ−（ピリジン−４−イル）プロパンアミド（白色固体）を得た（３８ｇ，８４％）。
ＭＳ（ＥＳＩ）：１７７（Ｍ−Ｈ）^−
1H NMR (600 MHz, CHLOROFORM-d)δppm 1.31 (9 H, s), 7.45 - 7.54 (3 H, m), 8.47 (2 H, d, J=6.4 Hz)

(1) To a solution of 4-aminopyridine (24 g) in chloroform (420 ml) was added triethylamine (53 ml) at 0 ° C., and then a solution of 2,2-dimethylpropanoyl chloride (35 ml) in chloroform (20 ml) was added dropwise. And stirred at 0 ° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. A mixed solvent of chloroform / hexane = 1/4 was added to the residue, and the precipitated solid was separated by filtration to obtain 2,2-dimethyl-N- (pyridin-4-yl) propanamide (white solid) (38 g, 84%).
MS (ESI): 177 (M−H) ^−
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.31 (9 H, s), 7.45-7.54 (3 H, m), 8.47 (2 H, d, J = 6.4 Hz)

（２）実施例１−（１）で得た２，２−ジメチル−Ｎ−（ピリジン−４−イル）プロパンアミド（２０ｇ）のＴＨＦ（４５０ｍｌ）溶液に、−７０℃で２．６ｍｏｌ／ｌ−ｎ−ブチルリチウム−ヘキサン溶液（１００ｍｌ）を滴下し、０℃で３時間攪拌した。その後−７０℃でシュウ酸ジエチル（４１ｇ）のＴＨＦ（５０ｍｌ）溶液を加え、室温まで昇温し、１時間攪拌した。反応液を１ｍｏｌ／ｌ−塩酸水溶液に注ぎジエチルエーテルで抽出した。抽出物を無水硫酸マグネシウムで乾燥し、乾燥剤を濾別した後、溶媒を減圧下留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチルの勾配溶離＝６０／４０→３０／７０→クロロホルム／メタノールの勾配溶離＝９８／２→８５／１５）で精製して、（４−（（２，２−ジメチルプロパノイル）アミノ）ピリジン−３−イル）（オキソ）酢酸エチル（褐色油状物）を得た（２３ｇ，７５％）。
ＭＳ（ＥＳＩ）： ２７７（Ｍ−Ｈ）^−
1H NMR (600 MHz, CHLOROFORM-d)δppm 1.36 (9 H, s), 1.45 (3 H, t, J=7.2 Hz), 4.51 (2 H, q, J=7.2 Hz), 8.66 (1 H, d, J=6.4 Hz), 8.74 (1 H, d, J=6.4 Hz), 8.93 (1 H, s), 11.49 (1 H, s)

(2) To a solution of 2,2-dimethyl-N- (pyridin-4-yl) propanamide (20 g) obtained in Example 1- (1) in THF (450 ml) at −70 ° C., 2.6 mol / l. A n-butyllithium-hexane solution (100 ml) was added dropwise, and the mixture was stirred at 0 ° C. for 3 hours. Thereafter, a solution of diethyl oxalate (41 g) in THF (50 ml) was added at −70 ° C., and the mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was poured into a 1 mol / l-hydrochloric acid aqueous solution and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate gradient elution = 60/40 → 30/70 → chloroform / methanol gradient elution = 98/2 → 85/15) to give (4-((2 , 2-Dimethylpropanoyl) amino) pyridin-3-yl) (oxo) ethyl acetate (brown oil) was obtained (23 g, 75%).
MS (ESI): 277 (MH) ^−
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.36 (9 H, s), 1.45 (3 H, t, J = 7.2 Hz), 4.51 (2 H, q, J = 7.2 Hz), 8.66 (1 H , d, J = 6.4 Hz), 8.74 (1 H, d, J = 6.4 Hz), 8.93 (1 H, s), 11.49 (1 H, s)

（３）１，４−ジヨードベンゼン（４２ｇ）をＴＨＦ（４２０ｍｌ）に溶解し−７８℃に冷却し２．６ｍｏｌ／ｌ−ｎ−ブチルリチウム−ヘキサン溶液（４９ｍｌ）を滴下した。−７８℃で１時間攪拌後、メトキシアセトニトリル（１８ｇ）のＴＨＦ（４０ｍｌ）溶液を−７８℃で滴下し、２時間攪拌した。−７８℃で４ｍｏｌ／ｌ−ＨＣｌ−酢酸エチル溶液を加えて１時間攪拌後、０℃に昇温し水を加えた後に分液し、抽出物を水酸化ナトリウム水溶液、飽和食塩水で洗浄した。水層を酢酸エチルで抽出し、抽出物を無水硫酸ナトリウムで乾燥し乾燥剤を濾別した後、溶媒を減圧下留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチルの勾配溶離＝９０／１０→７０／３０）で精製して、１−（４−ヨードフェニル）−２−メトキシエタノン（黄色固体）を得た（１７ｇ，５０％）。
ＭＳ（ＥＳＩ）：２７７（Ｍ＋Ｈ）^＋
1H NMR (600 MHz, CHLOROFORM-d)δppm 3.50 (3 H, s), 4.64 (2 H, s), 7.66 (2 H, d, J=8.7 Hz), 7.84 (2 H, d, J=8.7 Hz)

(3) 1,4-Diiodobenzene (42 g) was dissolved in THF (420 ml), cooled to −78 ° C., and a 2.6 mol / l-n-butyllithium-hexane solution (49 ml) was added dropwise. After stirring at −78 ° C. for 1 hour, a solution of methoxyacetonitrile (18 g) in THF (40 ml) was added dropwise at −78 ° C. and stirred for 2 hours. 4 mol / l-HCl-ethyl acetate solution was added at −78 ° C., and the mixture was stirred for 1 hour. The temperature was raised to 0 ° C., water was added, and the mixture was separated. . The aqueous layer was extracted with ethyl acetate, the extract was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (gradient elution of hexane / ethyl acetate = 90/10 → 70/30) to give 1- (4-iodophenyl) -2-methoxyethanone (yellow solid ) Was obtained (17 g, 50%).
MS (ESI): 277 (M + H) ^+
1 H NMR (600 MHz, CHLOROFORM-d) δppm 3.50 (3 H, s), 4.64 (2 H, s), 7.66 (2 H, d, J = 8.7 Hz), 7.84 (2 H, d, J = (8.7 Hz)

（４）実施例１−（２）で得た（４−（（２，２−ジメチルプロパノイル）アミノ）ピリジン−３−イル）（オキソ）酢酸エチル（１８ｇ）にエタノール（４０ｍｌ）、水（９０ｍｌ）、水酸化カリウム（１８ｇ）を加え、１００℃で３０分間攪拌した。実施例１−（３）で得た１−（４−ヨードフェニル）−２−メトキシエタノン（１７ｇ）及びエタノール（５０ｍｌ）を加えて１００℃で１２時間攪拌した。反応液を放冷後、酢酸を加えｐＨ４に調整し反応液を濃縮した。残留物に酢酸エチルを加えて析出した固体を濾別により取り除き母液を濃縮した。この操作を３度繰り返して得られた残留物にヘキサン／酢酸エチル＝１／１の混合溶媒を加え析出した固体を濾別した。母液を濃縮し、水を加え析出した固体を濾別、乾燥し、２−（４−ヨードフェニル）−３−メトキシ−１，６−ナフチリジン−４−カルボン酸（薄黄土色固体）を得た（１７ｇ，６５％）。
ＭＳ（ＥＳＩ）：４０７（Ｍ＋Ｈ）^＋，４０５（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆) δppm 3.67 (3 H, s), 7.81 (2 H, d, J=8.7 Hz), 7.96 (2 H, d, J=8.7 Hz), 7.98 (1 H, d, J=6.0 Hz), 8.76 (1 H, d, J=6.0 Hz), 9.24 (1 H, s)

(4) Ethyl (40 ml), (4-((2,2-dimethylpropanoyl) amino) pyridin-3-yl) (oxo) acetate (18 g) obtained in Example 1- (2), 90 ml) and potassium hydroxide (18 g) were added and stirred at 100 ° C. for 30 minutes. 1- (4-Iodophenyl) -2-methoxyethanone (17 g) and ethanol (50 ml) obtained in Example 1- (3) were added and stirred at 100 ° C. for 12 hours. After allowing the reaction solution to cool, acetic acid was added to adjust to pH 4 and the reaction solution was concentrated. Ethyl acetate was added to the residue, the precipitated solid was removed by filtration, and the mother liquor was concentrated. A mixed solvent of hexane / ethyl acetate = 1/1 was added to the residue obtained by repeating this operation three times, and the precipitated solid was separated by filtration. The mother liquor was concentrated, water was added and the precipitated solid was separated by filtration and dried to obtain 2- (4-iodophenyl) -3-methoxy-1,6-naphthyridine-4-carboxylic acid (light ocher solid). (17 g, 65%).
MS (ESI): 407 (M + H) ⁺ , 405 (M−H) ^−
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 3.67 (3 H, s), 7.81 (2 H, d, J = 8.7 Hz), 7.96 (2 H, d, J = 8.7 Hz), 7.98 (1 H, d, J = 6.0 Hz), 8.76 (1 H, d, J = 6.0 Hz), 9.24 (1 H, s)

（５）実施例１−（４）で得た２−（４−ヨードフェニル）−３−メトキシ−１，６−ナフチリジン−４−カルボン酸（１５ｇ）のＤＭＦ（１５０ｍｌ）懸濁液に、Ｏ−（テトラヒドロ−２Ｈ−ピラン−２−イル）ヒドロキシルアミン（５．０ｇ）、ＷＳＣ・ＨＣｌ（８．５ｇ）、ＨＯＢｔ・Ｈ_２Ｏ（６．０ｇ）を加え、室温で２日間攪拌した。反応液に飽和食塩水を入れ、酢酸エチル／トルエン＝５／１の混合溶媒で抽出し飽和食塩水で３回洗浄した。水層を酢酸エチル／トルエン＝５／１の混合溶媒で２回抽出し、得られた抽出物を無水硫酸マグネシウムで乾燥し乾燥剤を濾別した後、溶媒を減圧下留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノールの勾配溶離＝９９／１→９５／５）で２回精製して、２−（４−ヨードフェニル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド（淡黄色固体）を得た（９．１ｇ，４９％）。
ＭＳ（ＥＳＩ）：５０６（Ｍ＋Ｈ）^＋，５０４（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆) δppm 1.54 - 1.66 (3 H, m), 1.73 - 1.84 (3 H, m), 3.59 - 3.64 (1 H, m), 3.72 (3 H, s), 4.05 - 4.11 (1 H, m), 5.22 - 5.25 (1 H, m), 7.80 (2 H, d, J=8.7 Hz), 7.96 (2 H, d, J=8.7 Hz), 7.97 - 7.98 (1 H, m), 8.75 (1 H, d, J=5.5 Hz), 9.22 (1 H, s), 11.98 (1 H, s)

(5) To a suspension of 2- (4-iodophenyl) -3-methoxy-1,6-naphthyridine-4-carboxylic acid (15 g) obtained in Example 1- (4) in DMF (150 ml), O -(Tetrahydro-2H-pyran-2-yl) hydroxylamine (5.0 g), WSC · HCl (8.5 g) and HOBt · H ₂ O (6.0 g) were added, and the mixture was stirred at room temperature for 2 days. Saturated brine was added to the reaction solution, and the mixture was extracted with a mixed solvent of ethyl acetate / toluene = 5/1 and washed 3 times with saturated brine. The aqueous layer was extracted twice with a mixed solvent of ethyl acetate / toluene = 5/1, the obtained extract was dried over anhydrous magnesium sulfate and the desiccant was filtered off, and then the solvent was distilled off under reduced pressure. The obtained crude product was purified twice by silica gel column chromatography (gradient elution of chloroform / methanol = 99/1 → 95/5) to give 2- (4-iodophenyl) -3-methoxy-N- ( Tetrahydro-2H-pyran-2-yloxy) -1,6-naphthyridine-4-carboxamide (pale yellow solid) was obtained (9.1 g, 49%).
MS (ESI): 506 (M + H) ⁺ , 504 (M−H) ^−
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 1.54-1.66 (3 H, m), 1.73-1.84 (3 H, m), 3.59-3.64 (1 H, m), 3.72 (3 H, s) , 4.05-4.11 (1 H, m), 5.22-5.25 (1 H, m), 7.80 (2 H, d, J = 8.7 Hz), 7.96 (2 H, d, J = 8.7 Hz), 7.97-7.98 (1 H, m), 8.75 (1 H, d, J = 5.5 Hz), 9.22 (1 H, s), 11.98 (1 H, s)

（６）実施例１−（５）で得た２−（４−ヨードフェニル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド（１．０ｇ）のクロロホルム（２０ｍｌ）溶液に、炭酸水素ナトリウム（０．５１ｇ）、ｍＣＰＢＡ（＞６５％）（０．７０ｇ）を順次加え、室温で３０分間攪拌した。反応液をシリカゲルカラムクロマトグラフィー（酢酸エチル→クロロホルム／メタノール＝９０／１０）で精製し酢酸エチルで再結晶した。析出した固体を濾別し酢酸エチルで洗浄し乾燥して、２−（４−ヨードフェニル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（淡黄色固体）を得た（０．３７ｇ，３５％）。
ＭＳ（ＥＳＩ）：５２２（Ｍ＋Ｈ）^＋，５２０（Ｍ−Ｈ）^−
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.61 - 2.02 (5 H, m), 2.05 - 2.11 (1 H, m), 3.78 - 3.83 (1 H, m), 3.85 (3 H, s), 4.15 - 4.22 (1 H, m), 5.45 - 5.48 (1 H, m), 7.53 (1 H, d, J=7.3 Hz), 7.60 - 7.65 (1 H, m), 7.79 - 7.83 (2 H, m), 7.88 - 7.93 (2 H, m), 8.82 (1 H, d, J=1.4 Hz), 11.53 (1 H, br. s.)

(6) 2- (4-Iodophenyl) -3-methoxy-N- (tetrahydro-2H-pyran-2-yloxy) -1,6-naphthyridine-4-carboxamide obtained in Example 1- (5) To a solution of 1.0 g) in chloroform (20 ml), sodium hydrogen carbonate (0.51 g) and mCPBA (> 65%) (0.70 g) were sequentially added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was purified by silica gel column chromatography (ethyl acetate → chloroform / methanol = 90/10) and recrystallized from ethyl acetate. The precipitated solid was filtered off, washed with ethyl acetate and dried to give 2- (4-iodophenyl) -3-methoxy-N- (tetrahydro-2H-pyran-2-yloxy) -1,6-naphthyridine-4. Carboxamide 6-oxide (pale yellow solid) was obtained (0.37 g, 35%).
MS (ESI): 522 (M + H) ⁺ , 520 (M−H) ^−
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.61-2.02 (5 H, m), 2.05-2.11 (1 H, m), 3.78-3.83 (1 H, m), 3.85 (3 H, s), 4.15-4.22 (1 H, m), 5.45-5.48 (1 H, m), 7.53 (1 H, d, J = 7.3 Hz), 7.60-7.65 (1 H, m), 7.79-7.83 (2 H, m), 7.88-7.93 (2 H, m), 8.82 (1 H, d, J = 1.4 Hz), 11.53 (1 H, br.s.)

（７）実施例１−（６）で得た２−（４−ヨードフェニル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（２．１ｇ）のＤＭＥ（３２ｍｌ）懸濁液に、フェニルボロン酸（０．７４ｇ）、Ｐｄ（ＰＰｈ_３）_４（０．２４ｇ）、２ｍｏｌ／ｌ−炭酸ナトリウム水溶液（８ｍｌ）を順次加え、８０℃の油浴中で１．５時間攪拌した。放冷後、反応液に３ｍｏｌ／ｌ−塩化アンモニウム水溶液を加えクロロホルムで２回抽出した。得られた抽出物を無水硫酸マグネシウムで乾燥し乾燥剤を濾別した後、溶媒を減圧下留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル→クロロホルム／メタノール＝９０／１０）で精製した。得られた固体にエタノールを加え析出した固体を濾別しエタノールで洗浄し乾燥して、２−（ビフェニル−４−イル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（淡黄色固体）を得た（１．４ｇ，７４％）。
ＭＳ（ＥＳＩ）：４７２（Ｍ＋Ｈ）^＋，４７０（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆) δppm 1.51 - 1.86 (6 H, m), 3.59 - 3.65 (1 H, m), 3.77 (3 H, s), 4.07 - 4.14 (1 H, m), 5.21 (1 H, br. s.), 7.40 - 7.46 (1 H, m), 7.50 - 7.55 (2 H, m), 7.76 - 7.81 (2 H, m), 7.84 - 7.92 (2 H, m), 8.02 - 8.12 (3 H, m), 8.38 (1 H, dd, J=7.3, 1.8 Hz), 8.54 (1 H, d, J=1.8 Hz), 12.00 (1 H, br. s.)

(7) 2- (4-Iodophenyl) -3-methoxy-N- (tetrahydro-2H-pyran-2-yloxy) -1,6-naphthyridine-4-carboxamide obtained in Example 1- (6) -To a suspension of oxide (2.1 g) in DME (32 ml), phenylboronic acid (0.74 g), Pd (PPh ₃ ) ₄ (0.24 g), 2 mol / l-sodium carbonate aqueous solution (8 ml) were sequentially added. In addition, the mixture was stirred in an oil bath at 80 ° C. for 1.5 hours. After allowing to cool, a 3 mol / l-ammonium chloride aqueous solution was added to the reaction solution, and the mixture was extracted twice with chloroform. The obtained extract was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate → chloroform / methanol = 90/10). Ethanol was added to the resulting solid, the precipitated solid was filtered off, washed with ethanol and dried to give 2- (biphenyl-4-yl) -3-methoxy-N- (tetrahydro-2H-pyran-2-yloxy). -1,6-Naphthyridine-4-carboxamide 6-oxide (light yellow solid) was obtained (1.4 g, 74%).
MS (ESI): 472 (M + H) ⁺ , 470 (M−H) ^−
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 1.51-1.86 (6 H, m), 3.59-3.65 (1 H, m), 3.77 (3 H, s), 4.07-4.14 (1 H, m) , 5.21 (1 H, br. S.), 7.40-7.46 (1 H, m), 7.50-7.55 (2 H, m), 7.76-7.81 (2 H, m), 7.84-7.92 (2 H, m ), 8.02-8.12 (3 H, m), 8.38 (1 H, dd, J = 7.3, 1.8 Hz), 8.54 (1 H, d, J = 1.8 Hz), 12.00 (1 H, br.s.)

（８）実施例１−（７）で得た２−（ビフェニル−４−イル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（１．３ｇ）のメタノール（３０ｍｌ）懸濁液に、４ｍｏｌ／ｌ−ＨＣｌ−１，４−ジオキサン溶液（３０ｍｌ）を加え室温で２時間攪拌した。ジエチルエーテル（３００ｍｌ）を加え１５分間攪拌した後、析出した固体を濾別した。これをジエチルエーテルで洗浄し乾燥して、２−（ビフェニル−４−イル）−Ｎ−ヒドロキシ−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩（淡黄色固体）を得た（１．１ｇ，９４％）。
ＭＳ（ＥＳＩ）：３８８（Ｍ＋Ｈ）^＋，３８６（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆) δppm 3.73 (3 H, s), 7.37 - 7.42 (1 H, m), 7.46 - 7.51 (2 H, m), 7.74 - 7.77 (2 H, m), 7.82 - 7.86 (2 H, m), 7.99 - 8.07 (3 H, m), 8.34 (1 H, dd, J=7.3, 1.8 Hz), 8.50 (1 H, d, J=1.8 Hz), 11.39 (1 H, br. s.)
実施例２
２−（４’−（３，４−ジヒドロキシブトキシ）ビフェニル−４−イル）−Ｎ−ヒドロキシ−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩（化合物５）

(8) 2- (biphenyl-4-yl) -3-methoxy-N- (tetrahydro-2H-pyran-2-yloxy) -1,6-naphthyridine-4-carboxamide obtained in Example 1- (7) To a suspension of 6-oxide (1.3 g) in methanol (30 ml), 4 mol / l-HCl-1,4-dioxane solution (30 ml) was added and stirred at room temperature for 2 hours. Diethyl ether (300 ml) was added and stirred for 15 minutes, and then the precipitated solid was separated by filtration. This was washed with diethyl ether and dried to give 2- (biphenyl-4-yl) -N-hydroxy-3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride (pale yellow solid). (1.1 g, 94%).
MS (ESI): 388 (M + H) ⁺ , 386 (M−H) ^−
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 3.73 (3 H, s), 7.37-7.42 (1 H, m), 7.46-7.51 (2 H, m), 7.74-7.77 (2 H, m) , 7.82-7.86 (2 H, m), 7.99-8.07 (3 H, m), 8.34 (1 H, dd, J = 7.3, 1.8 Hz), 8.50 (1 H, d, J = 1.8 Hz), 11.39 (1 H, br. S.)
Example 2
2- (4 ′-(3,4-dihydroxybutoxy) biphenyl-4-yl) -N-hydroxy-3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride (Compound 5)

（１）４−ヨードフェノール（５．５ｇ）のＤＭＦ（５０ｍｌ）溶液に、５５％水素化ナトリウム（１．３ｇ）を加え、室温で２０分間攪拌した。これに、２−（２，２−ジメチル−１，３−ジオキソラン−４−イル）エチル ４−メチルベンゼンスルホナート（７．５１ｇ）のＴＨＦ（５０ｍｌ）溶液を加え、８０℃の油浴中で３時間攪拌した。放冷後、反応液に水を加え酢酸エチルで抽出、１ｍｏｌ／ｌ−水酸化ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し乾燥剤を濾別した後、溶媒を減圧下留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝８０／２０）で精製して、４−（２−（４−ヨードフェノキシ）エチル）−２，２−ジメチル−１，３−ジオキソラン（無色油状物）を得た（７．９ｇ，９１％）。
ＭＳ（ＥＳＩ）：３４９（Ｍ＋Ｈ）^＋
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.36 (3 H, s), 1.42 (3 H, s), 1.99 - 2.08 (2 H, m), 3.61 - 3.66 (1 H, m), 4.00 - 4.14 (3 H, m), 4.25 - 4.31 (1 H, m), 6.64 - 6.70 (2 H, m), 7.51 - 7.58 (2 H, m)

(1) To a solution of 4-iodophenol (5.5 g) in DMF (50 ml) was added 55% sodium hydride (1.3 g), and the mixture was stirred at room temperature for 20 minutes. To this was added a solution of 2- (2,2-dimethyl-1,3-dioxolan-4-yl) ethyl 4-methylbenzenesulfonate (7.51 g) in THF (50 ml) and placed in an oil bath at 80 ° C. Stir for 3 hours. After allowing to cool, water was added to the reaction solution, extracted with ethyl acetate, washed successively with 1 mol / l-sodium hydroxide aqueous solution and saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was filtered off. Distilled off. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 80/20) to give 4- (2- (4-iodophenoxy) ethyl) -2,2-dimethyl-1,3-dioxolane (colorless oil) Product) (7.9 g, 91%).
MS (ESI): 349 (M + H) ^+
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.36 (3 H, s), 1.42 (3 H, s), 1.99-2.08 (2 H, m), 3.61-3.66 (1 H, m), 4.00- 4.14 (3 H, m), 4.25-4.31 (1 H, m), 6.64-6.70 (2 H, m), 7.51-7.58 (2 H, m)

（２）実施例２−（１）で得た４−（２−（４−ヨードフェノキシ）エチル）−２，２−ジメチル−１，３−ジオキソラン（７．０ｇ）のＤＭＳＯ（４０ｍｌ）溶液に、酢酸カリウム（５．９ｇ）、ビス（ピナコラト）ジボロン（７．６ｇ）、ＰｄＣｌ_２（ｄｐｐｆ）（０．８２ｇ）を順次加え、１００℃の油浴中で３時間攪拌した。放冷後、反応液を酢酸エチルで希釈し、不溶物をセライト濾過により濾別した。濾液に水を加え分液し、飽和食塩水で洗浄した。抽出物を無水硫酸マグネシウムで乾燥し、乾燥剤を濾別した後、溶媒を減圧下留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチルの勾配溶離＝９０／１０→８０／２０）にて精製して、２−（４−（２−（２，２−ジメチル−１，３−ジオキソラン−４−イル）エトキシ）フェニル）−４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン（無色油状物）を得た（７．２ｇ，１００％）。
ＭＳ（ＥＳＩ）：３７１（Ｍ＋Ｎａ）^＋
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.26 (6 H, s), 1.33 (6 H, s), 1.36 (3 H, s), 1.42 (3 H, s), 2.01 - 2.10 (2 H, m), 3.62 - 3.67 (1 H, m), 4.06 - 4.17 (3 H, m), 4.25 - 4.33 (1 H, m), 6.85 - 6.91 (2 H, m), 7.71 - 7.77 (2 H, m)

(2) To a solution of 4- (2- (4-iodophenoxy) ethyl) -2,2-dimethyl-1,3-dioxolane (7.0 g) obtained in Example 2- (1) in DMSO (40 ml) , Potassium acetate (5.9 g), bis (pinacolato) diboron (7.6 g), and PdCl ₂ (dppf) (0.82 g) were sequentially added, and the mixture was stirred in an oil bath at 100 ° C. for 3 hours. After allowing to cool, the reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. Water was added to the filtrate for liquid separation, and the filtrate was washed with saturated brine. The extract was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution of hexane / ethyl acetate = 90/10 → 80/20) to give 2- (4- (2- (2,2-dimethyl-1,3-dioxolane). -4-yl) ethoxy) phenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (colorless oil) was obtained (7.2 g, 100%).
MS (ESI): 371 (M + Na) ^+
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.26 (6 H, s), 1.33 (6 H, s), 1.36 (3 H, s), 1.42 (3 H, s), 2.01-2.10 (2 H , m), 3.62-3.67 (1 H, m), 4.06-4.17 (3 H, m), 4.25-4.33 (1 H, m), 6.85-6.91 (2 H, m), 7.71-7.77 (2 H , m)

（３）実施例２−（２）で得た２−（４−（２−（２，２−ジメチル−１，３−ジオキソラン−４−イル）エトキシ）フェニル）−４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン（０．５２ｇ）を用い、実施例１−（７）と同様の方法で、２−（４’−（２−（２，２−ジメチル−１，３−ジオキソラン−４−イル）エトキシ）ビフェニル−４−イル）−３−メトキシ−４−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシカルバモイル）−１，６−ナフチリジン ６−オキシド（黄色固体）を得た（０．３０ｇ，４９％）。
ＭＳ（ＥＳＩ）：６１６（Ｍ＋Ｈ）^＋，６１４（Ｍ−Ｈ）^−
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.39 (3 H, s), 1.45 (3 H, s), 1.67 - 1.74 (2 H, m), 1.74 - 1.82 (1 H, m), 1.87 - 2.00 (2 H, m), 2.07 - 2.13 (3 H, m), 3.69 (1 H, dd, J=8.0, 7.1 Hz), 3.81 - 3.86 (1 H, m), 3.88 (3 H, s), 4.13 - 4.24 (4 H, m), 4.31 - 4.37 (1 H, m), 5.48 - 5.51 (1 H, m), 7.01 - 7.04 (2 H, m), 7.53 - 7.56 (1 H, m), 7.61 - 7.65 (3 H, m), 7.72 - 7.76 (2 H, m), 8.12 - 8.15 (2 H, m), 8.80 (1 H, d, J=1.8 Hz), 11.65 (1 H, br. s.)

(3) 2- (4- (2- (2,2-Dimethyl-1,3-dioxolan-4-yl) ethoxy) phenyl) -4,4,5,5 obtained in Example 2- (2) -Using tetramethyl-1,3,2-dioxaborolane (0.52 g) and in the same manner as in Example 1- (7), 2- (4 ′-(2- (2,2-dimethyl-1, 3-dioxolan-4-yl) ethoxy) biphenyl-4-yl) -3-methoxy-4- (tetrahydro-2H-pyran-2-yloxycarbamoyl) -1,6-naphthyridine 6-oxide (yellow solid) Obtained (0.30 g, 49%).
MS (ESI): 616 (M + H) ⁺ , 614 (M−H) ^−
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.39 (3 H, s), 1.45 (3 H, s), 1.67-1.74 (2 H, m), 1.74-1.82 (1 H, m), 1.87- 2.00 (2 H, m), 2.07-2.13 (3 H, m), 3.69 (1 H, dd, J = 8.0, 7.1 Hz), 3.81-3.86 (1 H, m), 3.88 (3 H, s) , 4.13-4.24 (4 H, m), 4.31-4.37 (1 H, m), 5.48-5.51 (1 H, m), 7.01-7.04 (2 H, m), 7.53-7.56 (1 H, m) , 7.61-7.65 (3 H, m), 7.72-7.76 (2 H, m), 8.12-8.15 (2 H, m), 8.80 (1 H, d, J = 1.8 Hz), 11.65 (1 H, br .s.)

（４）実施例２−（３）で得た２−（４’−（２−（２，２−ジメチル−１，３−ジオキソラン−４−イル）エトキシ）ビフェニル−４−イル）−３−メトキシ−４−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシカルバモイル）−１，６−ナフチリジン ６−オキシド（７４ｍｇ）を用い、実施例１−（８）と同様の方法で、２−（４’−（３，４−ジヒドロキシブトキシ）ビフェニル−４−イル）−４−（ヒドロキシカルバモイル）−３−メトキシ−１，６−ナフチリジン ６−オキシド塩酸塩（黄色固体）を得た（６２ｍｇ，９８％）。
ＭＳ（ＥＳＩ）：４９２（Ｍ＋Ｈ）^＋，４９０（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆) δppm 1.64 - 1.71 (1 H, m), 1.93 - 2.00 (1 H, m), 3.29 - 3.34 (1 H, m), 3.35 - 3.40 (1 H, m), 3.64 - 3.69 (1 H, m), 3.76 (3 H, s), 4.12 - 4.17 (2 H, m), 7.05 - 7.09 (2 H, m), 7.71 - 7.75 (2 H, m), 7.81 - 7.84 (2 H, m), 8.01 - 8.07 (3 H, m), 8.37 (1 H, dd, J=7.1, 2.1 Hz), 8.52 (1 H, d, J=2.1 Hz), 11.41 (1 H, br. s.)
実施例３
Ｎ−ヒドロキシ−２−（４’−（（４−ヒドロキシブチル）アミノ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩（化合物１２）

(4) 2- (4 ′-(2- (2,2-dimethyl-1,3-dioxolan-4-yl) ethoxy) biphenyl-4-yl) -3- obtained in Example 2- (3) Using methoxy-4- (tetrahydro-2H-pyran-2-yloxycarbamoyl) -1,6-naphthyridine 6-oxide (74 mg) in the same manner as in Example 1- (8), 2- (4 ′ -(3,4-Dihydroxybutoxy) biphenyl-4-yl) -4- (hydroxycarbamoyl) -3-methoxy-1,6-naphthyridine 6-oxide hydrochloride (yellow solid) was obtained (62 mg, 98%) .
MS (ESI): 492 (M + H) ⁺ , 490 (M−H) ^−
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 1.64-1.71 (1 H, m), 1.93-2.00 (1 H, m), 3.29-3.34 (1 H, m), 3.35-3.40 (1 H, m), 3.64-3.69 (1 H, m), 3.76 (3 H, s), 4.12-4.17 (2 H, m), 7.05-7.09 (2 H, m), 7.71-7.75 (2 H, m) , 7.81-7.84 (2 H, m), 8.01-8.07 (3 H, m), 8.37 (1 H, dd, J = 7.1, 2.1 Hz), 8.52 (1 H, d, J = 2.1 Hz), 11.41 (1 H, br. S.)
Example 3
N-hydroxy-2- (4 ′-((4-hydroxybutyl) amino) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride (Compound 12)

（１）１，４−ジヨードベンゼン（５．４ｇ）、４−アミノブタン−１−オール（１．４ｍｌ）、エチレングリコール（１．８ｍｌ）、ヨウ化銅（Ｉ）（１５５ｍｇ）、リン酸カリウム（１．４ｇ）をＩＰＡ（１５ｍｌ）に懸濁し、８０℃で１９時間攪拌した。反応液にクロロホルムを加え不溶物を濾別後、溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝２０／１→１０／１）で精製して、褐色油状物（２．２ｇ）を得た。この褐色油状物（２．２ｇ）、ＰｄＣｌ_２（ｄｐｐｆ）（０．２２ｇ）、酢酸カリウム（２．２ｇ）及びビス（ピナコラト）ジボロン（２．４ｇ）のＤＭＳＯ（２２ｍｌ）懸濁液を、窒素雰囲気下８５℃で４時間攪拌した。反応液を放冷後、水を加えトルエンで２回抽出し、飽和食塩水洗浄、無水硫酸マグネシウムで乾燥し乾燥剤を濾別後、溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／１）で精製して、４−（（４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェニル）アミノ）ブタン−１−オール（褐色油状物）を得た（１．７ｇ、２工程収率３６％）。
ＭＳ（ＥＳＩ）：２９２（Ｍ＋Ｈ）^＋
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.32 (12 H, s), 1.65 - 1.75 (4 H, m), 3.17 - 3.20 (2 H, m), 3.67 - 3.71 (2 H, m), 6.58 (2 H, d, J=8.7 Hz), 7.63 (2 H, d, J=8.7 Hz)

(1) 1,4-diiodobenzene (5.4 g), 4-aminobutan-1-ol (1.4 ml), ethylene glycol (1.8 ml), copper (I) iodide (155 mg), potassium phosphate (1.4 g) was suspended in IPA (15 ml) and stirred at 80 ° C. for 19 hours. Chloroform was added to the reaction solution, the insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol = 20/1 → 10/1) to give a brown oil (2.2 g). A suspension of this brown oil (2.2 g), PdCl ₂ (dppf) (0.22 g), potassium acetate (2.2 g) and bis (pinacolato) diboron (2.4 g) in DMSO (22 ml) The mixture was stirred at 85 ° C. for 4 hours under an atmosphere. The reaction solution was allowed to cool, water was added, the mixture was extracted twice with toluene, washed with saturated brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 4-((4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane). -2-yl) phenyl) amino) butan-1-ol (brown oil) was obtained (1.7 g, 2-step yield 36%).
MS (ESI): 292 (M + H) ^+
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.32 (12 H, s), 1.65-1.75 (4 H, m), 3.17-3.20 (2 H, m), 3.67-3.71 (2 H, m), 6.58 (2 H, d, J = 8.7 Hz), 7.63 (2 H, d, J = 8.7 Hz)

（２）実施例３−（１）で得た４−（（４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェニル）アミノ）ブタン−１−オール（０．３７ｇ）、実施例１−（６）で得た２−（４−ヨードフェニル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（０．３７ｇ）及びＰｄ（ＰＰｈ_３）_４（８１ｍｇ）に２ｍｏｌ／ｌ−炭酸ナトリウム水溶液（１ｍｌ）、水（４ｍｌ）及びＤＭＥ（１２ｍｌ）を加えた懸濁液を、窒素雰囲気下９０℃で２．５時間攪拌した。反応液を放冷後、飽和塩化アンモニウム水溶液を加えクロロホルムで２回抽出した。抽出物を無水硫酸マグネシウムで乾燥し乾燥剤を濾別後、溶媒を減圧下留去した。得られた残留物を分取用シリカゲル薄層クロマトグラフィー（クロロホルム／メタノール＝３０／１）で精製して、２−（４’−（（４−ヒドロキシブチル）アミノ）ビフェニル−４−イル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（黄色油状物）を得た（０．１９ｇ、４８％）。
ＭＳ（ＥＳＩ）：５５９（Ｍ＋Ｈ）^＋，５５７（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆) δppm 1.50 - 1.82 (10 H, m), 3.04 - 3.10 (2 H, m), 3.41 - 3.47 (2 H, m), 3.58 - 3.64 (1 H, m), 3.76 (3 H, s), 4.06 - 4.14 (1 H, m), 4.43 (1 H, t, J=5.0 Hz), 5.19 (1 H, br. s.), 5.90 (1 H, t, J=5.5 Hz), 6.67 (2 H, d, J=8.7 Hz), 7.55 (2 H, d, J=8.7 Hz), 7.75 (2 H, d, J=8.3 Hz), 7.99 - 8.05 (3 H, m), 8.33 - 8.37 (1 H, m), 8.53 (1 H, s), 11.96 (1 H, br. s.)

(2) 4-((4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) amino) butane-1 obtained in Example 3- (1) -Ol (0.37 g), 2- (4-iodophenyl) -3-methoxy-N- (tetrahydro-2H-pyran-2-yloxy) -1,6-naphthyridine obtained in Example 1- (6) A suspension of -4-carboxamide 6-oxide (0.37 g) and Pd (PPh ₃ ) ₄ (81 mg) with 2 mol / l-sodium carbonate aqueous solution (1 ml), water (4 ml) and DME (12 ml) added. The mixture was stirred at 90 ° C. for 2.5 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool, saturated aqueous ammonium chloride solution was added, and the mixture was extracted twice with chloroform. The extract was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative silica gel thin layer chromatography (chloroform / methanol = 30/1) to give 2- (4 ′-((4-hydroxybutyl) amino) biphenyl-4-yl)- 3-Methoxy-N- (tetrahydro-2H-pyran-2-yloxy) -1,6-naphthyridine-4-carboxamide 6-oxide (yellow oil) was obtained (0.19 g, 48%).
MS (ESI): 559 (M + H) ⁺ , 557 (M−H) ^−
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 1.50-1.82 (10 H, m), 3.04-3.10 (2 H, m), 3.41-3.47 (2 H, m), 3.58-3.64 (1 H, m), 3.76 (3 H, s), 4.06-4.14 (1 H, m), 4.43 (1 H, t, J = 5.0 Hz), 5.19 (1 H, br.s.), 5.90 (1 H, t, J = 5.5 Hz), 6.67 (2 H, d, J = 8.7 Hz), 7.55 (2 H, d, J = 8.7 Hz), 7.75 (2 H, d, J = 8.3 Hz), 7.99-8.05 (3 H, m), 8.33-8.37 (1 H, m), 8.53 (1 H, s), 11.96 (1 H, br.s.)

（３）実施例３−（２）で得た２−（４’−（（４−ヒドロキシブチル）アミノ）ビフェニル−４−イル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（０．１９ｇ）にメタノール（３ｍｌ）、１，４−ジオキサン（３ｍｌ）及び４ｍｏｌ／ｌ−ＨＣｌ−１，４−ジオキサン溶液（６ｍｌ）を加え、室温で１時間攪拌した。ジエチルエーテルを加え上澄を除去、固体にメタノールを加えて溶媒を減圧下留去、１，４−ジオキサンで洗浄して、Ｎ−ヒドロキシ−２−（４’−（（４−ヒドロキシブチル）アミノ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩（黄色固体）を得た（０．１８ｇ，９８％）。
ＭＳ（ＥＳＩ）：４７５（Ｍ＋Ｈ）^＋，４７３（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆) δppm 1.49 - 1.55 (2 H, m), 1.65 - 1.72 (2 H, m), 3.21 - 3.28 (2 H, m), 3.44 (2 H, t, J=6.2 Hz), 3.76 (3 H, s), 7.17 - 7.44 (2 H, m), 7.76 - 7.83 (2 H, m), 7.85 (2 H, d, J=8.7 Hz), 8.03 (1 H, d, J=7.3 Hz), 8.07 (2 H, d, J=8.7 Hz), 8.38 (1 H, dd, J=7.3, 2.1 Hz), 8.53 (1 H, d, J=2.1 Hz), 11.43 (1 H, br. s.)
実施例４
Ｎ−ヒドロキシ−２−（４’−（３−ヒドロキシプロピル）ビフェニル−４−イル）−３，８−ジメトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩（化合物１６）

(3) 2- (4 ′-((4-hydroxybutyl) amino) biphenyl-4-yl) -3-methoxy-N- (tetrahydro-2H-pyran-2-2) obtained in Example 3- (2) Yloxy) -1,6-naphthyridine-4-carboxamide 6-oxide (0.19 g) in methanol (3 ml), 1,4-dioxane (3 ml) and 4 mol / l-HCl-1,4-dioxane solution (6 ml) And stirred at room temperature for 1 hour. Diethyl ether was added and the supernatant was removed. Methanol was added to the solid, the solvent was distilled off under reduced pressure, washed with 1,4-dioxane, and N-hydroxy-2- (4 ′-((4-hydroxybutyl) amino. ) Biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride (yellow solid) was obtained (0.18 g, 98%).
MS (ESI): 475 (M + H) ⁺ , 473 (M−H) ^−
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 1.49-1.55 (2 H, m), 1.65-1.72 (2 H, m), 3.21-3.28 (2 H, m), 3.44 (2 H, t, J = 6.2 Hz), 3.76 (3 H, s), 7.17-7.44 (2 H, m), 7.76-7.83 (2 H, m), 7.85 (2 H, d, J = 8.7 Hz), 8.03 (1 H, d, J = 7.3 Hz), 8.07 (2 H, d, J = 8.7 Hz), 8.38 (1 H, dd, J = 7.3, 2.1 Hz), 8.53 (1 H, d, J = 2.1 Hz) , 11.43 (1 H, br. S.)
Example 4
N-hydroxy-2- (4 ′-(3-hydroxypropyl) biphenyl-4-yl) -3,8-dimethoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride (Compound 16)

（１）実施例１−（４）で得た２−（４−ヨードフェニル）−３−メトキシ−１，６−ナフチリジン−４−カルボン酸（１０ｇ）のメタノール（４４ｍｌ）及びトルエン（６６ｍｌ）懸濁液に、氷冷下２ｍｏｌ／ｌ−トリメチルシリルジアゾメタン−へキサン溶液（２５ｍｌ）を滴下し、室温で３．５時間攪拌した。水冷下酢酸を加え、窒素雰囲気下室温で４０分間攪拌した。減圧下溶媒を留去し、得られた残留物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノールの勾配溶離＝１００／０→９６／４）で精製して、２−（４−ヨードフェニル）−３−メトキシ−１，６−ナフチリジン−４−カルボン酸メチル（淡黄色固体）を得た（５．３ｇ，５２％）。
ＭＳ（ＥＳＩ）：４２１（Ｍ＋Ｈ）^＋
1H NMR (600 MHz, CHLOROFORM-d) δppm 3.66 (3 H, s), 4.14 (3 H, s), 7.83 (2 H, d, J=8.7 Hz), 7.88 - 7.90 (2 H, m), 7.94 (1 H, d, J=6.0 Hz), 8.76 (1 H, d, J=6.0 Hz), 9.23 (1 H, s)

(1) 2- (4-Iodophenyl) -3-methoxy-1,6-naphthyridine-4-carboxylic acid (10 g) obtained in Example 1- (4) in methanol (44 ml) and toluene (66 ml) To the suspension, 2 mol / l-trimethylsilyldiazomethane-hexane solution (25 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 3.5 hours. Acetic acid was added under water cooling, and the mixture was stirred at room temperature for 40 minutes under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (gradient elution of chloroform / methanol = 100/0 → 96/4) to give 2- (4-iodophenyl) -3- Methyl methoxy-1,6-naphthyridine-4-carboxylate (pale yellow solid) was obtained (5.3 g, 52%).
MS (ESI): 421 (M + H) ^+
1 H NMR (600 MHz, CHLOROFORM-d) δppm 3.66 (3 H, s), 4.14 (3 H, s), 7.83 (2 H, d, J = 8.7 Hz), 7.88-7.90 (2 H, m) , 7.94 (1 H, d, J = 6.0 Hz), 8.76 (1 H, d, J = 6.0 Hz), 9.23 (1 H, s)

（２）実施例４−（１）で得た２−（４−ヨードフェニル）−３−メトキシ−１，６−ナフチリジン−４−カルボン酸メチル（５．３ｇ）の酢酸（４０ｍｌ）溶液に臭素（１．３ｍｌ）を滴下し、窒素雰囲気下、９０℃で４時間攪拌した。反応液を放冷後、１０％水酸化ナトリウム水溶液及び飽和炭酸水素ナトリウム水溶液を加えｐＨ７に調整し、酢酸エチルで抽出した。溶媒を減圧下留去し、得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチルの勾配溶離＝７５／２０→４０／６０）で精製して、８−ブロモ−２−（４−ヨードフェニル）−３−メトキシ−１，６−ナフチリジン−４−カルボン酸メチル（黄色固体）を得た（３．５ｇ，５５％）。
ＭＳ（ＥＳＩ）：４９９，５０１（Ｍ＋Ｈ）^＋
1H NMR (600 MHz, CHLOROFORM-d) δppm 3.70 (3 H, s), 4.14 (3 H, s), 7.90 (2 H, d, J=8.7 Hz), 7.96 - 7.98 (2 H, m), 8.97 (1 H, s), 9.10 (1 H, s)

(2) Bromine was added to a solution of methyl 2- (4-iodophenyl) -3-methoxy-1,6-naphthyridine-4-carboxylate (5.3 g) obtained in Example 4- (1) in acetic acid (40 ml). (1.3 ml) was added dropwise, and the mixture was stirred at 90 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool, 10% aqueous sodium hydroxide solution and saturated aqueous sodium hydrogen carbonate solution were added to adjust to pH 7, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (gradient elution of hexane / ethyl acetate = 75/20 → 40/60) to obtain 8-bromo-2- (4-iodo Methyl phenyl) -3-methoxy-1,6-naphthyridine-4-carboxylate (yellow solid) was obtained (3.5 g, 55%).
MS (ESI): 499, 501 (M + H) ^+
1 H NMR (600 MHz, CHLOROFORM-d) δppm 3.70 (3 H, s), 4.14 (3 H, s), 7.90 (2 H, d, J = 8.7 Hz), 7.96-7.98 (2 H, m) , 8.97 (1 H, s), 9.10 (1 H, s)

（３）実施例４−（２）で得た８−ブロモ−２−（４−ヨードフェニル）−３−メトキシ−１，６−ナフチリジン−４−カルボン酸メチル（１．９ｇ）、（４−（３−ヒドロキシプロピル）フェニル）ボロン酸（０．７４ｇ）、Ｐｄ（ＰＰｈ_３）_４（０．４３ｇ）、２ｍｏｌ／ｌ−炭酸ナトリウム水溶液（５．６ｍｌ）、水（２０ｍｌ）及びＤＭＦ（９．３ｍｌ）のＤＭＥ（６０ｍｌ）懸濁液を、窒素雰囲気下８５℃で３時間攪拌した。反応液を放冷後、飽和食塩水を加えクロロホルムで３回抽出した。溶媒を減圧下留去し、得られた残留物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノールの勾配溶離＝１００／０→９５／５）で精製して、８−ブロモ−２−（４’−（３−ヒドロキシプロピル）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボン酸メチル（黄褐色固体）を得た（１．７ｇ，９１％）。
ＭＳ（ＥＳＩ）：５０７，５０９（Ｍ＋Ｈ）^＋
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.93 - 1.98 (2 H, m), 2.77 - 2.82 (2 H, m), 3.71 - 3.73 (2 H, m), 3.74 (3 H, s), 4.15 (3 H, s), 7.33 (2 H, d, J=8.3 Hz), 7.62 (2 H, d, J=8.3 Hz), 7.77 (2 H, d, J=8.3 Hz), 8.32 (2 H, d, J=8.3 Hz), 8.97 (1 H, s), 9.10 (1 H, s)

(3) Methyl 8-bromo-2- (4-iodophenyl) -3-methoxy-1,6-naphthyridine-4-carboxylate (1.9 g) obtained in Example 4- (2), (4- (3-Hydroxypropyl) phenyl) boronic acid (0.74 g), Pd (PPh ₃ ) ₄ (0.43 g), 2 mol / l-sodium carbonate aqueous solution (5.6 ml), water (20 ml) and DMF (9. 3 ml) of DME (60 ml) was stirred at 85 ° C. for 3 hours under nitrogen atmosphere. The reaction mixture was allowed to cool, saturated brine was added, and the mixture was extracted 3 times with chloroform. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (gradient elution of chloroform / methanol = 100/0 → 95/5) to obtain 8-bromo-2- (4 ′-( Methyl 3-hydroxypropyl) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxylate (tan solid) was obtained (1.7 g, 91%).
MS (ESI): 507,509 (M + H) ^+
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.93-1.98 (2 H, m), 2.77-2.82 (2 H, m), 3.71-3.73 (2 H, m), 3.74 (3 H, s), 4.15 (3 H, s), 7.33 (2 H, d, J = 8.3 Hz), 7.62 (2 H, d, J = 8.3 Hz), 7.77 (2 H, d, J = 8.3 Hz), 8.32 (2 H, d, J = 8.3 Hz), 8.97 (1 H, s), 9.10 (1 H, s)

（４）実施例４−（３）で得た８−ブロモ−２−（４’−（３−ヒドロキシプロピル）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボン酸メチル（１．７ｇ）の１，４−ジオキサン（８．５ｍｌ）及び水（８．５ｍｌ）溶液に、水酸化カリウム（０．８５ｇ）、Ｐｄ_２（ｄｂａ）_３（０．１４ｇ）及び２−ジ−ｔ−ブチルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル（０．２５ｇ）を加え、窒素雰囲気下１００℃で１４時間攪拌した。反応液を室温まで放冷後、酢酸を加え中和して減圧下濃縮した。得られた残留物に水を加えて析出した固体を濾別、水及び酢酸エチルで洗浄、乾燥して、黄色固体（０．５２ｇ）を得た。この黄色固体（０．５９ｇ）のメタノール（２．３ｍｌ）−トルエン（３．４ｍｌ）懸濁液に、窒素雰囲気下、氷冷下２ｍｏｌ／ｌ−トリメチルシリルジアゾメタン−へキサン溶液（１．８ｍｌ）を滴下し、氷冷下４０分間、室温にて１．５時間攪拌した。水冷下酢酸を加え、室温にて３０分間攪拌した後に、減圧下溶媒を留去し、得られた残留物をＮＨ型シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチルの勾配溶離＝４２／５８→０／１００）で精製して、２−（４’−（３−ヒドロキシプロピル）ビフェニル−４−イル）−３，８−ジメトキシ−１，６−ナフチリジン−４−カルボン酸メチル（黄色油状物）を得た（０．１５ｇ，１３％）。
ＭＳ（ＥＳＩ）：４５９（Ｍ＋Ｈ）^＋
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.92 - 1.99 (2 H, m), 2.76 - 2.81 (2 H, m), 3.69 (3 H, s), 3.70 - 3.76 (2 H, m), 4.14 (3 H, s), 4.16 (3 H, s), 7.32 (2 H, d, J=8.3 Hz), 7.61 (2 H, d, J=8.3 Hz), 7.74 (2 H, d, J=8.3 Hz), 8.16 (2 H, d, J=8.3 Hz), 8.33 (1 H, s), 8.83 (1 H, s)

(4) 8-Bromo-2- (4 ′-(3-hydroxypropyl) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxylic acid obtained in Example 4- (3) To a solution of methyl (1.7 g) in 1,4-dioxane (8.5 ml) and water (8.5 ml) was added potassium hydroxide (0.85 g), Pd ₂ (dba) ₃ (0.14 g) and 2- Di-t-butylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (0.25 g) was added, and the mixture was stirred at 100 ° C. for 14 hours in a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, neutralized with acetic acid, and concentrated under reduced pressure. Water was added to the obtained residue, and the precipitated solid was separated by filtration, washed with water and ethyl acetate, and dried to give a yellow solid (0.52 g). To a suspension of this yellow solid (0.59 g) in methanol (2.3 ml) -toluene (3.4 ml) was added 2 mol / l-trimethylsilyldiazomethane-hexane solution (1.8 ml) under a nitrogen atmosphere under ice cooling. The solution was added dropwise, and stirred for 40 minutes under ice-cooling and 1.5 hours at room temperature. Acetic acid was added under water cooling, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (hexane / ethyl acetate gradient elution = 42/58 → 0 / 100) to give methyl 2- (4 ′-(3-hydroxypropyl) biphenyl-4-yl) -3,8-dimethoxy-1,6-naphthyridine-4-carboxylate (yellow oil). (0.15 g, 13%).
MS (ESI): 459 (M + H) ^+
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.92-1.99 (2 H, m), 2.76-2.81 (2 H, m), 3.69 (3 H, s), 3.70-3.76 (2 H, m), 4.14 (3 H, s), 4.16 (3 H, s), 7.32 (2 H, d, J = 8.3 Hz), 7.61 (2 H, d, J = 8.3 Hz), 7.74 (2 H, d, J = 8.3 Hz), 8.16 (2 H, d, J = 8.3 Hz), 8.33 (1 H, s), 8.83 (1 H, s)

（５）実施例４−（４）で得た２−（４’−（３−ヒドロキシプロピル）ビフェニル−４−イル）−３，８−ジメトキシ−１，６−ナフチリジン−４−カルボン酸メチル（０．１６ｇ）にエタノール（１．０ｍｌ）、水（１．０ｍｌ）、ＴＨＦ（１．６ｍｌ）及び１０％水酸化ナトリウム水溶液（０．８０ｍｌ）を加え、６０℃で１．５時間攪拌した。反応液を放冷後、酢酸を加え中和して減圧下濃縮した。得られた残留物に水を加えて析出した固体を濾別、水及び酢酸エチルで洗浄、乾燥して、黄色固体（０．１１ｇ）を得た。この黄色固体（０．１１ｇ）のＤＭＦ（２．０ｍｌ）溶液に、ＤＩＰＥＡ（７０μｌ）、Ｏ−（テトラヒドロ−２Ｈ−ピラン−２−イル）ヒドロキシルアミン（４７ｍｇ）、ＷＳＣ・ＨＣｌ（６９ｍｇ）及びＨＯＢｔ・Ｈ_２Ｏ（５１ｍｇ）を加え、室温で１３時間攪拌した。反応液に氷冷下、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。溶媒を減圧下留去し、得られた残留物を分取用シリカゲル薄層クロマトグラフィー（クロロホルム／メタノール＝２０／１）で精製して、２−（４’−（３−ヒドロキシプロピル）ビフェニル−４−イル）−３，８−ジメトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド（淡黄色固体）を得た（０．１３ｇ、６５％）。
ＭＳ（ＥＳＩ）：５４４（Ｍ＋Ｈ）^＋，５４２（Ｍ−Ｈ）^−
1H NMR (600 MHz, CHLOROFORM-d) δppm1.53 - 1.76 (3 H, m), 1.90 - 1.99 (4 H, m), 2.00 - 2.04 (1 H, m), 2.76 - 2.82 (2 H, m), 3.68 - 3.78 (6 H, m), 4.02 - 4.10 (1 H, m), 4.13 (3 H, s), 5.29 (1 H, br. s.), 7.33 (2 H, d, J=8.3 Hz), 7.61 (2 H, d, J=8.3 Hz), 7.73 (2 H, d, J=8.3 Hz), 8.14 (2 H, d, J=8.3 Hz), 8.28 (1 H, s), 9.09 (1 H, s)

(5) Methyl 2- (4 ′-(3-hydroxypropyl) biphenyl-4-yl) -3,8-dimethoxy-1,6-naphthyridine-4-carboxylate obtained in Example 4- (4) 0.16 g) was added ethanol (1.0 ml), water (1.0 ml), THF (1.6 ml) and 10% aqueous sodium hydroxide solution (0.80 ml), and the mixture was stirred at 60 ° C. for 1.5 hours. The reaction solution was allowed to cool, neutralized with acetic acid, and concentrated under reduced pressure. Water was added to the obtained residue, and the precipitated solid was separated by filtration, washed with water and ethyl acetate, and dried to give a yellow solid (0.11 g). To a solution of this yellow solid (0.11 g) in DMF (2.0 ml) was added DIPEA (70 μl), O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (47 mg), WSC · HCl (69 mg) and HOBt. · _H 2 O a (51 mg) was added, followed by stirring at room temperature for 13 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative silica gel thin layer chromatography (chloroform / methanol = 20/1) to give 2- (4 ′-(3-hydroxypropyl) biphenyl- 4-yl) -3,8-dimethoxy-N- (tetrahydro-2H-pyran-2-yloxy) -1,6-naphthyridine-4-carboxamide (pale yellow solid) was obtained (0.13 g, 65%). .
MS (ESI): 544 (M + H) ⁺ , 542 (M−H) ^−
1 H NMR (600 MHz, CHLOROFORM-d) δppm1.53-1.76 (3 H, m), 1.90-1.99 (4 H, m), 2.00-2.04 (1 H, m), 2.76-2.82 (2 H, m), 3.68-3.78 (6 H, m), 4.02-4.10 (1 H, m), 4.13 (3 H, s), 5.29 (1 H, br.s.), 7.33 (2 H, d, J = 8.3 Hz), 7.61 (2 H, d, J = 8.3 Hz), 7.73 (2 H, d, J = 8.3 Hz), 8.14 (2 H, d, J = 8.3 Hz), 8.28 (1 H, s ), 9.09 (1 H, s)

（６）実施例４−（５）で得た２−（４’−（３−ヒドロキシプロピル）ビフェニル−４−イル）−３，８−ジメトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド（０．１１ｇ）のクロロホルム（２．０ｍｌ）溶液に、ｍＣＰＢＡ（＞６５％）（０．１０ｇ）、炭酸水素ナトリウム（５２ｍｇ）を加え、室温で２時間攪拌した。反応液に飽和食塩水を加えてクロロホルムで抽出した。溶媒を減圧下留去した。得られた残留物を分取用シリカゲル薄層クロマトグラフィー（クロロホルム／メタノール＝８／１）で精製して、２−（４’−（３−ヒドロキシプロピル）ビフェニル−４−イル）−３，８−ジメトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（黄色固体）を得た（４５ｍｇ、４１％）。
ＭＳ（ＥＳＩ）：５６０（Ｍ＋Ｈ）^＋，５５８（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆) δppm1.56 - 1.64 (3 H, m), 1.72 - 1.82 (5 H, m), 2.65 - 2.70 (2 H, m), 3.41 - 3.47 (2 H, m), 3.59 - 3.64 (1 H, m), 3.75 (3 H, s), 4.04 (3 H, s), 4.07 - 4.13 (1 H, m), 4.50 (1 H, t, J=5.3 Hz), 5.19 (1 H, s), 7.34 (2 H, d, J=8.3 Hz), 7.70 (2 H, d, J=8.3 Hz), 7.85 (2 H, d, J=8.7 Hz), 8.06 (2 H, d, J=8.7 Hz), 8.16 (1 H, d, J=1.8 Hz), 8.21 (1 H, d, J=1.8 Hz), 11.96 (1 H, s)

(6) 2- (4 ′-(3-hydroxypropyl) biphenyl-4-yl) -3,8-dimethoxy-N- (tetrahydro-2H-pyran-2-yloxy) obtained in Example 4- (5) ) -1,6-naphthyridine-4-carboxamide (0.11 g) in chloroform (2.0 ml) was added mCPBA (> 65%) (0.10 g) and sodium hydrogen carbonate (52 mg), and 2 at room temperature. Stir for hours. Saturated saline was added to the reaction solution, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure. The obtained residue was purified by preparative silica gel thin layer chromatography (chloroform / methanol = 8/1) to give 2- (4 ′-(3-hydroxypropyl) biphenyl-4-yl) -3,8. -Dimethoxy-N- (tetrahydro-2H-pyran-2-yloxy) -1,6-naphthyridine-4-carboxamide 6-oxide (yellow solid) was obtained (45 mg, 41%).
MS (ESI): 560 (M + H) ⁺ , 558 (M−H) ^−
1 H NMR (600 MHz, DMSO-d ₆ ) δppm1.56-1.64 (3 H, m), 1.72-1.82 (5 H, m), 2.65-2.70 (2 H, m), 3.41-3.47 (2 H , m), 3.59-3.64 (1 H, m), 3.75 (3 H, s), 4.04 (3 H, s), 4.07-4.13 (1 H, m), 4.50 (1 H, t, J = 5.3 Hz), 5.19 (1 H, s), 7.34 (2 H, d, J = 8.3 Hz), 7.70 (2 H, d, J = 8.3 Hz), 7.85 (2 H, d, J = 8.7 Hz), 8.06 (2 H, d, J = 8.7 Hz), 8.16 (1 H, d, J = 1.8 Hz), 8.21 (1 H, d, J = 1.8 Hz), 11.96 (1 H, s)

（７）実施例４−（６）で得た２−（４’−（３−ヒドロキシプロピル）ビフェニル−４−イル）−３，８−ジメトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（３６ｍｇ）のメタノール（０．５０ｍｌ）及び１，４−ジオキサン（１．０ｍｌ）溶液に、４ｍｏｌ／ｌ−ＨＣｌ−１，４−ジオキサン溶液（０．５０ｍｌ）を加え、室温で３０分間攪拌した。反応液を濃縮し、クロロホルムを加え析出した固体を濾別、乾燥し、Ｎ−ヒドロキシ−２−（４’−（３−ヒドロキシプロピル）ビフェニル−４−イル）−３，８−ジメトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩（黄色固体）を得た（３２ｍｇ，９７％）。
ＭＳ（ＥＳＩ）：４７６（Ｍ＋Ｈ）^＋，４７４（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆) δppm 1.73 - 1.79 (2 H, m), 2.65 - 2.70 (2 H, m), 3.45 (2 H, t, J=6.4 Hz), 3.74 (3 H, s), 4.04 (3 H, s), 7.34 (2 H, d, J=8.3 Hz), 7.69 (2 H, d, J=8.3 Hz), 7.85 (2 H, d, J=8.3 Hz), 8.05 (2 H, d, J=8.3 Hz), 8.14 (1 H, d, J=1.8 Hz), 8.19 (1 H, d, J=1.8 Hz), 11.37 (1 H, s)
実施例５
８−ブロモ−Ｎ−ヒドロキシ−２−（４’−（２−ヒドロキシエトキシ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩（化合物１７）

(7) 2- (4 ′-(3-hydroxypropyl) biphenyl-4-yl) -3,8-dimethoxy-N- (tetrahydro-2H-pyran-2-yloxy) obtained in Example 4- (6) ) -1,6-naphthyridine-4-carboxamide 6-oxide (36 mg) in methanol (0.50 ml) and 1,4-dioxane (1.0 ml) in a 4 mol / l-HCl-1,4-dioxane solution (0.50 ml) was added and stirred at room temperature for 30 minutes. The reaction mixture was concentrated, chloroform was added and the precipitated solid was filtered off and dried, and N-hydroxy-2- (4 ′-(3-hydroxypropyl) biphenyl-4-yl) -3,8-dimethoxy-1, 6-naphthyridine-4-carboxamide 6-oxide hydrochloride (yellow solid) was obtained (32 mg, 97%).
MS (ESI): 476 (M + H) ⁺ , 474 (M−H) ^−
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 1.73-1.79 (2 H, m), 2.65-2.70 (2 H, m), 3.45 (2 H, t, J = 6.4 Hz), 3.74 (3 H , s), 4.04 (3 H, s), 7.34 (2 H, d, J = 8.3 Hz), 7.69 (2 H, d, J = 8.3 Hz), 7.85 (2 H, d, J = 8.3 Hz) , 8.05 (2 H, d, J = 8.3 Hz), 8.14 (1 H, d, J = 1.8 Hz), 8.19 (1 H, d, J = 1.8 Hz), 11.37 (1 H, s)
Example 5
8-Bromo-N-hydroxy-2- (4 ′-(2-hydroxyethoxy) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride (Compound 17)

（１）２−（４−ブロモフェノキシ）エタノール（６．５ｇ）のジエチルエーテル（２００ｍｌ）溶液に、ｐ−トルエンスルホン酸１水和物（１．９ｇ）、ＤＨＰ（８．２ｍｌ）を加え、室温で４時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えてジエチルエーテルで抽出した。無水硫酸マグネシウムで乾燥し、乾燥剤を濾別した後、溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（クロロホルム）で精製して無色油状物（８．１ｇ）を得た。この無色油状物（２．０ｇ）、ＰｄＣｌ_２（ｄｐｐｆ）（０．２７ｇ）、酢酸カリウム（２．０ｇ）及びビス（ピナコラト）ジボロン（２．２ｇ）のＤＭＳＯ（２０ｍｌ）懸濁液を、窒素雰囲気下１００℃で２時間攪拌した。放冷後、反応液にクロロホルムを加え不溶物をセライトにて濾別し濾液を飽和炭酸水素ナトリウム水溶液で洗浄した。抽出物を無水硫酸ナトリウムで乾燥し乾燥剤を濾別した後、溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチルの勾配溶離＝９５／５→８０／２０）で２回精製して、２−（２−（４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェノキシ）エトキシ）テトラヒドロ−２Ｈ−ピラン（黄色油状物）を得た（１．２ｇ，５３％）。
¹H NMR (600 MHz, CHLOROFORM-d) δppm 1.33 (12 H, s), 1.49 - 1.67 (4 H, m), 1.70 - 1.77 (1 H, m), 1.80 - 1.89 (1 H, m), 3.50 - 3.56 (1 H, m), 3.80 - 3.85 (1 H, m), 3.87 - 3.92 (1 H, m), 4.03 - 4.08 (1 H, m), 4.16 - 4.20 (2 H, m), 4.69 - 4.72 (1 H, m), 6.92 (2 H, d, J=8.7 Hz), 7.74 (2 H, d, J=8.7 Hz)

(1) To a solution of 2- (4-bromophenoxy) ethanol (6.5 g) in diethyl ether (200 ml), p-toluenesulfonic acid monohydrate (1.9 g) and DHP (8.2 ml) were added, Stir at room temperature for 4 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. After drying over anhydrous magnesium sulfate and filtering off the desiccant, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform) to obtain a colorless oil (8.1 g). A suspension of this colorless oil (2.0 g), PdCl ₂ (dppf) (0.27 g), potassium acetate (2.0 g) and bis (pinacolato) diboron (2.2 g) in DMSO (20 ml) The mixture was stirred at 100 ° C. for 2 hours under an atmosphere. After allowing to cool, chloroform was added to the reaction solution, the insoluble material was filtered off through celite, and the filtrate was washed with a saturated aqueous sodium hydrogen carbonate solution. The extract was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified twice by silica gel column chromatography (hexane / ethyl acetate gradient elution = 95/5 → 80/20) to give 2- (2- (4- (4,4,5,5). -Tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) ethoxy) tetrahydro-2H-pyran (yellow oil) was obtained (1.2 g, 53%).
¹ H NMR (600 MHz, CHLOROFORM-d) δppm 1.33 (12 H, s), 1.49-1.67 (4 H, m), 1.70-1.77 (1 H, m), 1.80-1.89 (1 H, m), 3.50-3.56 (1 H, m), 3.80-3.85 (1 H, m), 3.87-3.92 (1 H, m), 4.03-4.08 (1 H, m), 4.16-4.20 (2 H, m), 4.69-4.72 (1 H, m), 6.92 (2 H, d, J = 8.7 Hz), 7.74 (2 H, d, J = 8.7 Hz)

（２）実施例４−（２）で得た８−ブロモ−２−（４−ヨードフェニル）−３−メトキシ−１，６−ナフチリジン−４−カルボン酸メチル（０．２９ｇ）、実施例５−（６）で得た２−（２−（４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェノキシ）エトキシ）テトラヒドロ−２Ｈ−ピラン（０．２２ｇ）及びＰｄ（ＰＰｈ_３）_４（６６ｍｇ）に、２ｍｏｌ／ｌ−炭酸ナトリウム水溶液（０．８６ｍｌ）、水（５．０ｍｌ）、ＤＭＦ（１．５ｍｌ）及びＤＭＥ（５．０ｍｌ）を加えた懸濁液を、窒素雰囲気下８５℃で３時間攪拌した。反応液を放冷後、飽和食塩水を加えクロロホルムで3回抽出した。溶媒を減圧下留去し、得られた残留物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノールの勾配溶離＝１００／０→９５／５）で精製して、８−ブロモ−３−メトキシ−２−（４’−（２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エトキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボン酸メチル（淡黄色固体）を得た（０．１３ｇ，３９％）。
¹H NMR (600 MHz, CHLOROFORM-d) δppm 1.51 - 1.69 (4 H, m), 1.72 - 1.80 (1 H, m), 1.82 - 1.90 (1 H, m), 3.53 - 3.58 (1 H, m), 3.73 (3 H, s), 3.84 - 3.89 (1 H, m), 3.89 - 3.95 (1 H, m), 4.07 - 4.13 (1 H, m), 4.15 (3 H, s), 4.19 - 4.28 (2 H, m), 4.71 - 4.76 (1 H, m), 7.05 (2 H, d, J=8.7 Hz), 7.62 (2 H, d, J=8.7 Hz), 7.74 (2 H, d, J=8.7 Hz), 8.31 (2 H, d, J=8.7 Hz), 8.97 (1 H, s), 9.09 (1 H, s)

(2) Methyl 8-bromo-2- (4-iodophenyl) -3-methoxy-1,6-naphthyridine-4-carboxylate (0.29 g) obtained in Example 4- (2), Example 5 2- (2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) ethoxy) tetrahydro-2H-pyran (0) obtained in (6) .22 g) and Pd (PPh ₃ ) ₄ (66 mg) were added 2 mol / l-sodium carbonate aqueous solution (0.86 ml), water (5.0 ml), DMF (1.5 ml) and DME (5.0 ml). The suspension was stirred at 85 ° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool, saturated brine was added, and the mixture was extracted 3 times with chloroform. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (gradient elution of chloroform / methanol = 100/0 → 95/5) to give 8-bromo-3-methoxy-2- ( 4 ′-(2- (Tetrahydro-2H-pyran-2-yloxy) ethoxy) biphenyl-4-yl) -1,6-naphthyridine-4-carboxylate (pale yellow solid) was obtained (0.13 g, 39%).
¹ H NMR (600 MHz, CHLOROFORM-d) δppm 1.51-1.69 (4 H, m), 1.72-1.80 (1 H, m), 1.82-1.90 (1 H, m), 3.53-3.58 (1 H, m ), 3.73 (3 H, s), 3.84-3.89 (1 H, m), 3.89-3.95 (1 H, m), 4.07-4.13 (1 H, m), 4.15 (3 H, s), 4.19- 4.28 (2 H, m), 4.71-4.76 (1 H, m), 7.05 (2 H, d, J = 8.7 Hz), 7.62 (2 H, d, J = 8.7 Hz), 7.74 (2 H, d , J = 8.7 Hz), 8.31 (2 H, d, J = 8.7 Hz), 8.97 (1 H, s), 9.09 (1 H, s)

（３）実施例５−（２）で得た８−ブロモ−３−メトキシ−２−（４’−（２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エトキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボン酸メチル（０．１３ｇ）にエタノール（０．７０ｍｌ）、水（０．７０ｍｌ）、ＴＨＦ（１．３ｍｌ）及び１０％水酸化ナトリウム水溶液（０．３６ｍｌ）を加え、５０℃で２時間攪拌した。反応液を放冷後、酢酸を加え中和して減圧下濃縮した。得られた残留物に水を加えて析出した固体を濾別、水及び酢酸エチルで洗浄、乾燥して、黄色固体（８７ｍｇ）を得た。この黄色固体（８７ｍｇ）のＤＭＦ（１．４ｍｌ）溶液に、ＤＩＰＥＡ（４５μｌ）、Ｏ−（テトラヒドロ−２Ｈ−ピラン−２−イル）ヒドロキシルアミン（３４ｍｇ）、ＷＳＣ・ＨＣｌ（４５ｍｇ）及びＨＯＢｔ・Ｈ_２Ｏ（３２ｍｇ）を加え、室温で１５時間攪拌した。反応液に氷冷下、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。溶媒を減圧下留去し、得られた残留物を分取用シリカゲル薄層クロマトグラフィー（クロロホルム／メタノール＝２０／１）で精製して、８−ブロモ−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−２−（４’−（２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エトキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド（淡黄色油状物）を得た（８３ｍｇ，６２％）
ＭＳ（ＥＳＩ）：６７８，６８０（Ｍ＋Ｈ）^＋，６７６，６７８（Ｍ−Ｈ）^−
1H NMR (600 MHz, CHLOROFORM-d) δppm1.51 - 1.96 (11 H, m), 1.99 - 2.04 (1 H, m), 3.53 - 3.58 (1 H, m), 3.72 - 3.76 (1 H, m), 3.81 (3 H, s), 3.84 - 3.89 (1 H, m), 3.90 - 3.95 (1 H, m), 4.06 - 4.12 (2 H, m), 4.21 - 4.26 (2 H, m), 4.73 - 4.76 (1 H, m), 5.29 (1 H, br. s.), 7.06 (2 H, d, J=8.3 Hz), 7.63 (2 H, d, J=8.7 Hz), 7.74 (2 H, d, J=8.3 Hz), 8.01 (1 H, s), 8.30 (2 H, d, J=8.7 Hz), 8.93 (1 H, s), 9.39 (1 H, s)

(3) 8-Bromo-3-methoxy-2- (4 ′-(2- (tetrahydro-2H-pyran-2-yloxy) ethoxy) biphenyl-4-yl)-obtained in Example 5- (2) Ethanol (0.70 ml), water (0.70 ml), THF (1.3 ml) and 10% aqueous sodium hydroxide (0.36 ml) were added to methyl 1,6-naphthyridine-4-carboxylate (0.13 g). The mixture was further stirred at 50 ° C. for 2 hours. The reaction solution was allowed to cool, neutralized with acetic acid, and concentrated under reduced pressure. Water was added to the obtained residue, and the precipitated solid was separated by filtration, washed with water and ethyl acetate, and dried to give a yellow solid (87 mg). To a solution of this yellow solid (87 mg) in DMF (1.4 ml) was added DIPEA (45 μl), O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (34 mg), WSC · HCl (45 mg) and HOBt · H. ₂ O (32 mg) was added and stirred at room temperature for 15 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative silica gel thin layer chromatography (chloroform / methanol = 20/1) to give 8-bromo-3-methoxy-N- (tetrahydro-2H). -Pyran-2-yloxy) -2- (4 '-(2- (tetrahydro-2H-pyran-2-yloxy) ethoxy) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide (light yellow oil Product) (83 mg, 62%)
MS (ESI): 678, 680 (M + H) ⁺ , 676, 678 (M−H) ^−
1 H NMR (600 MHz, CHLOROFORM-d) δppm1.51-1.96 (11 H, m), 1.99-2.04 (1 H, m), 3.53-3.58 (1 H, m), 3.72-3.76 (1 H, m), 3.81 (3 H, s), 3.84-3.89 (1 H, m), 3.90-3.95 (1 H, m), 4.06-4.12 (2 H, m), 4.21-4.26 (2 H, m) , 4.73-4.76 (1 H, m), 5.29 (1 H, br.s.), 7.06 (2 H, d, J = 8.3 Hz), 7.63 (2 H, d, J = 8.7 Hz), 7.74 ( 2 H, d, J = 8.3 Hz), 8.01 (1 H, s), 8.30 (2 H, d, J = 8.7 Hz), 8.93 (1 H, s), 9.39 (1 H, s)

（４）実施例５−（３）で得た８−ブロモ−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−２−（４’−（２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エトキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド（６６ｍｇ）のクロロホルム（１．３ｍｌ）溶液に、ｍＣＰＢＡ（＞６５％）（５２ｍｇ）、炭酸水素ナトリウム（２７ｍｇ）を加え、室温で４時間攪拌した。反応液に飽和食塩水を加えてクロロホルムで抽出した。溶媒を減圧下留去した。得られた残留物を分取用シリカゲル薄層クロマトグラフィー（クロロホルム／メタノール＝２０／１）で精製して、８−ブロモ−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−２−（４’−（２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エトキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（黄色固体）を得た（２６ｍｇ，３８％）
¹H NMR (600 MHz, DMSO-d₆) δppm 1.41 - 1.82 (12 H, m), 3.43 - 3.49 (1 H, m), 3.58 - 3.64 (2 H, m), 3.73 - 3.79 (1 H, m), 3.81 (3 H, s), 3.93 - 3.98 (1 H, m), 4.06 - 4.13 (1 H, m), 4.18 - 4.23 (2 H, m), 4.68 (1 H, t, J=3.7 Hz), 5.20 (1 H, br. s.), 7.10 (2 H, d, J=8.7 Hz), 7.75 (2 H, d, J=8.7 Hz), 7.86 (2 H, d, J=8.7 Hz), 8.15 (2 H, d, J=8.7 Hz), 8.52 (1 H, s), 8.89 (1 H, s), 11.99 (1 H, br. s.)

(4) 8-Bromo-3-methoxy-N- (tetrahydro-2H-pyran-2-yloxy) -2- (4 ′-(2- (tetrahydro-2H-pyran) obtained in Example 5- (3) 2-yloxy) ethoxy) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide (66 mg) in chloroform (1.3 ml) was added mCPBA (> 65%) (52 mg), sodium bicarbonate ( 27 mg) was added and stirred at room temperature for 4 hours. Saturated saline was added to the reaction solution, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure. The obtained residue was purified by preparative silica gel thin layer chromatography (chloroform / methanol = 20/1) to give 8-bromo-3-methoxy-N- (tetrahydro-2H-pyran-2-yloxy)- 2- (4 ′-(2- (tetrahydro-2H-pyran-2-yloxy) ethoxy) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide (yellow solid) was obtained (26 mg , 38%)
¹ H NMR (600 MHz, DMSO-d ₆ ) δppm 1.41-1.82 (12 H, m), 3.43-3.49 (1 H, m), 3.58-3.64 (2 H, m), 3.73-3.79 (1 H, m), 3.81 (3 H, s), 3.93-3.98 (1 H, m), 4.06-4.13 (1 H, m), 4.18-4.23 (2 H, m), 4.68 (1 H, t, J = 3.7 Hz), 5.20 (1 H, br.s.), 7.10 (2 H, d, J = 8.7 Hz), 7.75 (2 H, d, J = 8.7 Hz), 7.86 (2 H, d, J = 8.7 Hz), 8.15 (2 H, d, J = 8.7 Hz), 8.52 (1 H, s), 8.89 (1 H, s), 11.99 (1 H, br.s.)

（５）実施例５−（４）で得た８−ブロモ−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−２−（４’−（２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エトキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（１４ｍｇ）のメタノール（０．２０ｍｌ）及び１，４−ジオキサン（０．４０ｍｌ）溶液に、４ｍｏｌ／ｌ−ＨＣｌ−１，４−ジオキサン溶液（０．２０ｍｌ）を加え、室温で３０分間攪拌した。反応液を濃縮し、クロロホルムを加え析出した固体を濾別、乾燥し、８−ブロモ−Ｎ−ヒドロキシ−２−（４’−（２−ヒドロキシエトキシ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩（淡黄色固体）を得た（１４ｍｇ，８７％）
ＭＳ（ＥＳＩ）：５２６，５２８（Ｍ＋Ｈ）^＋
1H NMR (600 MHz, DMSO-d₆) δppm 3.75 (2 H, t, J=5.0 Hz), 3.80 (3 H, s), 4.06 (2 H, t, J=5.0 Hz), 7.08 (2 H, d, J=8.7 Hz), 7.74 (2 H, d, J=8.7 Hz), 7.85 (2 H, d, J=8.7 Hz), 8.14 (2 H, d, J=8.7 Hz), 8.49 (1 H, d, J=1.8 Hz), 8.89 (1 H, d, J=1.8 Hz), 11.41 (1 H, s)
実施例６
３−クロロ−Ｎ−ヒドロキシ−２−（４’−（２−ヒドロキシエトキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩（化合物１８）

(5) 8-Bromo-3-methoxy-N- (tetrahydro-2H-pyran-2-yloxy) -2- (4 ′-(2- (tetrahydro-2H-pyran) obtained in Example 5- (4) 2-yloxy) ethoxy) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide (14 mg) in methanol (0.20 ml) and 1,4-dioxane (0.40 ml) 4 mol / l-HCl-1,4-dioxane solution (0.20 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, chloroform was added and the precipitated solid was filtered off and dried, and 8-bromo-N-hydroxy-2- (4 ′-(2-hydroxyethoxy) biphenyl-4-yl) -3-methoxy- 1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride (pale yellow solid) was obtained (14 mg, 87%)
MS (ESI): 526, 528 (M + H) ^+
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 3.75 (2 H, t, J = 5.0 Hz), 3.80 (3 H, s), 4.06 (2 H, t, J = 5.0 Hz), 7.08 (2 H, d, J = 8.7 Hz), 7.74 (2 H, d, J = 8.7 Hz), 7.85 (2 H, d, J = 8.7 Hz), 8.14 (2 H, d, J = 8.7 Hz), 8.49 (1 H, d, J = 1.8 Hz), 8.89 (1 H, d, J = 1.8 Hz), 11.41 (1 H, s)
Example 6
3-Chloro-N-hydroxy-2- (4 ′-(2-hydroxyethoxy) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride (Compound 18)

（１）文献（ジャーナル オブ ヘテロサイクリック ケミストリー、１９９７年、３４巻、４４１−４４４頁）記載の（４−（ｔ−ブトキシカルボニルアミノ）ピリジン−３−イル）グリオキシル酸エチル（３．０ｇ）のエタノール（４５ｍｌ）及び水（４５ｍｌ）溶液に、水酸化カリウム（６．９ｇ）を加え、１時間加熱還流した。１−（４−ブロモフェニル）−２−ヒドロキシエタノン（２．２ｇ）を添加して１時間加熱還流後、１−（４−ブロモフェニル）−２−ヒドロキシエタノン（２．２ｇ）を追加して１時間加熱還流し、さらに１−（４−ブロモフェニル）−２−ヒドロキシエタノン（２．２ｇ）を添加して１時間加熱還流した。室温に冷却し、不溶物を濾別した後、濾液を減圧下で濃縮し、水を加え、酢酸でｐＨ４．５に調整した。析出した固体を濾別し、水及びＩＰＥで洗浄することにより、２−（４−ブロモフェニル）−３−ヒドロキシ−１，６−ナフチリジン−４−カルボン酸（黄色固体）を得た（２．７ｇ，７７％）。
¹H NMR (400 MHz, DMSO-d₆) δppm 7.74 (2 H, d, J=8.8 Hz), 8.20 (1 H, d, J=6.4 Hz), 8.34 (2 H, d, J=8.8 Hz), 8.52 (1 H, d, J=6.4 Hz), 10.61 (1 H, s)

(1) (4- (t-Butoxycarbonylamino) pyridin-3-yl) glyoxylate ethyl (3.0 g) described in the literature (Journal of Heterocyclic Chemistry, 1997, 34, 441-444) To a solution of ethanol (45 ml) and water (45 ml) was added potassium hydroxide (6.9 g), and the mixture was heated to reflux for 1 hour. 1- (4-Bromophenyl) -2-hydroxyethanone (2.2 g) was added and heated under reflux for 1 hour, and then 1- (4-bromophenyl) -2-hydroxyethanone (2.2 g) was added. The mixture was heated to reflux for 1 hour, 1- (4-bromophenyl) -2-hydroxyethanone (2.2 g) was added, and the mixture was heated to reflux for 1 hour. After cooling to room temperature and filtering insolubles, the filtrate was concentrated under reduced pressure, water was added, and the pH was adjusted to 4.5 with acetic acid. The precipitated solid was separated by filtration and washed with water and IPE to obtain 2- (4-bromophenyl) -3-hydroxy-1,6-naphthyridine-4-carboxylic acid (yellow solid) (2. 7g, 77%).
¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 7.74 (2 H, d, J = 8.8 Hz), 8.20 (1 H, d, J = 6.4 Hz), 8.34 (2 H, d, J = 8.8 Hz ), 8.52 (1 H, d, J = 6.4 Hz), 10.61 (1 H, s)

（２）実施例６−（１）で得た２−（４−ブロモフェニル）−３−ヒドロキシ−１，６−ナフチリジン−４−カルボン酸（２．０ｇ）のオキシ塩化リン（４０ｍｌ）懸濁液を６時間加熱還流した。放冷後、減圧下で濃縮し、メタノール（２０ｍｌ）を加え、３０〜４０℃で３０分間攪拌した。減圧下で溶媒を留去し、ＩＰＥを加え、飽和炭酸水素ナトリウム水溶液及び２０％水酸化ナトリウム水溶液でｐＨ９に調整した。濾別した固形物にクロロホルムを加え、不溶物を濾別し、濾液をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチルの勾配溶離＝６０／４０→３０／７０）で精製して、２−（４−ブロモフェニル）−３−クロロ−１，６−ナフチリジン−４−カルボン酸メチル（紫色固体）を得た（１．３ｇ）。
¹H NMR (400 MHz, CHLOROFORM-d) δppm 4.17 (3 H, s), 7.64 - 7.74 (4 H, m), 7.96 (1 H, dd, J=6.0, 0.9 Hz), 8.85 (1 H, d, J=6.0 Hz), 9.20 (1 H, d, J=0.9 Hz)

(2) A suspension of 2- (4-bromophenyl) -3-hydroxy-1,6-naphthyridine-4-carboxylic acid (2.0 g) obtained in Example 6- (1) in phosphorus oxychloride (40 ml) The solution was heated to reflux for 6 hours. After allowing to cool, the mixture was concentrated under reduced pressure, methanol (20 ml) was added, and the mixture was stirred at 30 to 40 ° C. for 30 min. The solvent was distilled off under reduced pressure, IPE was added, and the pH was adjusted to 9 with a saturated aqueous sodium hydrogen carbonate solution and a 20% aqueous sodium hydroxide solution. Chloroform was added to the filtered solid, the insoluble material was filtered off, and the filtrate was purified by silica gel column chromatography (hexane / ethyl acetate gradient elution = 60/40 → 30/70) to give 2- (4- Bromophenyl) -3-chloro-1,6-naphthyridine-4-carboxylate methyl ester (purple solid) was obtained (1.3 g).
¹ H NMR (400 MHz, CHLOROFORM-d) δppm 4.17 (3 H, s), 7.64-7.74 (4 H, m), 7.96 (1 H, dd, J = 6.0, 0.9 Hz), 8.85 (1 H, d, J = 6.0 Hz), 9.20 (1 H, d, J = 0.9 Hz)

（３）実施例６−（２）で得た２−（４−ブロモフェニル）−３−クロロ−１，６−ナフチリジン−４−カルボン酸メチル（０．５３ｇ）、実施例５−（１）で得た２−（２−（４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェノキシ）エトキシ）テトラヒドロ−２Ｈ−ピラン（０．５６ｇ）、Ｐｄ（ＰＰｈ_３）_４（０．１６ｇ）、炭酸セシウム（１．４ｇ）のＤＭＦ（６．０ｍｌ）懸濁液を窒素雰囲気下８０℃で６時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて酢酸エチルで抽出した。無水硫酸マグネシウムで乾燥し、乾燥剤を濾別した後、溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチルの勾配溶離＝６５／３５→４５／５５）で精製して、３−クロロ−２−（４’−（２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エトキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボン酸メチル（淡黄色固体）を得た（０．２６ｇ，３６％）。
ＭＳ（ＥＳＩ）：５１９（Ｍ＋Ｈ）^＋
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.50 - 1.58 (2 H, m), 1.59 - 1.69 (2 H, m), 1.73 - 1.80 (1 H, m), 1.82 - 1.90 (1 H, m), 3.52 - 3.58 (1 H, m), 3.84 - 3.89 (1 H, m), 3.90 - 3.95 (1 H, m), 4.06 - 4.15 (1 H, m), 4.17 (3 H, s), 4.20 - 4.25 (2 H, m), 4.69 - 4.77 (1 H, m), 7.05 (2 H, d, J=8.7 Hz), 7.60 (2 H, d, J=8.7 Hz), 7.72 (2 H, d, J=8.7 Hz), 7.86 (2 H, d, J=8.7 Hz), 7.99 (1 H, d, J=6.0 Hz), 8.84 (1 H, d, J=6.0 Hz), 9.20 (1 H, s)

(3) Methyl 2- (4-bromophenyl) -3-chloro-1,6-naphthyridine-4-carboxylate (0.53 g) obtained in Example 6- (2), Example 5- (1) 2- (2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) ethoxy) tetrahydro-2H-pyran (0.56 g) obtained in A suspension of Pd (PPh ₃ ) ₄ (0.16 g) and cesium carbonate (1.4 g) in DMF (6.0 ml) was stirred at 80 ° C. for 6 hours under a nitrogen atmosphere. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate and filtering off the desiccant, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate gradient elution = 65/35 → 45/55) to give 3-chloro-2- (4 ′-(2- (tetrahydro-2H— Pyran-2-yloxy) ethoxy) biphenyl-4-yl) -1,6-naphthyridine-4-carboxylate (pale yellow solid) was obtained (0.26 g, 36%).
MS (ESI): 519 (M + H) ^+
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.50-1.58 (2 H, m), 1.59-1.69 (2 H, m), 1.73-1.80 (1 H, m), 1.82-1.90 (1 H, m ), 3.52-3.58 (1 H, m), 3.84-3.89 (1 H, m), 3.90-3.95 (1 H, m), 4.06-4.15 (1 H, m), 4.17 (3 H, s), 4.20-4.25 (2 H, m), 4.69-4.77 (1 H, m), 7.05 (2 H, d, J = 8.7 Hz), 7.60 (2 H, d, J = 8.7 Hz), 7.72 (2 H , d, J = 8.7 Hz), 7.86 (2 H, d, J = 8.7 Hz), 7.99 (1 H, d, J = 6.0 Hz), 8.84 (1 H, d, J = 6.0 Hz), 9.20 ( 1 H, s)

（４）実施例６−（３）で得た３−クロロ−２−（４’−（２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エトキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボン酸メチル（０．１３ｇ）にエタノール（０．７０ｍｌ）、水（０．７０ｍｌ）、ＴＨＦ（１．３ｍｌ）及び１０％水酸化ナトリウム水溶液（０．４０ｍｌ）を加え、６０℃で２時間攪拌した。反応液を放冷後、酢酸を加え中和して減圧下濃縮した。得られた残留物に水を加えて析出した固体を濾別、水及び酢酸エチルで洗浄、乾燥して、黄色固体（０．１１ｇ）を得た。この黄色固体（０．１１ｇ）のＤＭＦ（２．０ｍｌ）溶液に、ＤＩＰＥＡ（６５μｌ）、Ｏ−（テトラヒドロ−２Ｈ−ピラン−２−イル）ヒドロキシルアミン（４５ｍｇ）、ＷＳＣ・ＨＣｌ（６０ｍｇ）及びＨＯＢｔ・Ｈ_２Ｏ（４３ｍｇ）を加え、室温で２１時間攪拌した。反応液に氷冷下、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。溶媒を減圧下留去し、得られた残留物を分取用シリカゲル薄層クロマトグラフィー（クロロホルム／メタノール＝２０／１）で精製して、３−クロロ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−２−（４’−（２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エトキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド（淡黄色固体）を得た（５３ｍｇ，３６％）。
ＭＳ（ＥＳＩ）：６０４（Ｍ＋Ｈ）^＋
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.62 - 2.08 (12 H, m), 3.56 (1 H, br. s.), 3.74 (1 H, br. s.), 3.84 - 3.96 (2 H, m), 4.07 - 4.15 (2 H, m), 4.19 - 4.27 (2 H, m), 4.72 - 4.77 (1 H, m), 5.40 (1 H, br. s.), 7.06 (2 H, d, J=8.7 Hz), 7.61 (2 H, d, J=8.7 Hz), 7.74 (2 H, d, J=8.3 Hz), 7.92 (2 H, d, J=8.3 Hz), 8.02 (1 H, s), 8.15 (1 H, d, J=6.0 Hz), 8.70 (1 H, d, J=6.0 Hz), 9.52 (1 H, br. s.)

(4) 3-Chloro-2- (4 ′-(2- (tetrahydro-2H-pyran-2-yloxy) ethoxy) biphenyl-4-yl) -1,6- obtained in Example 6- (3) Ethanol (0.70 ml), water (0.70 ml), THF (1.3 ml) and 10% aqueous sodium hydroxide solution (0.40 ml) were added to methyl naphthyridine-4-carboxylate (0.13 g) at 60 ° C. For 2 hours. The reaction solution was allowed to cool, neutralized with acetic acid, and concentrated under reduced pressure. Water was added to the obtained residue, and the precipitated solid was separated by filtration, washed with water and ethyl acetate, and dried to give a yellow solid (0.11 g). To a solution of this yellow solid (0.11 g) in DMF (2.0 ml) was added DIPEA (65 μl), O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (45 mg), WSC · HCl (60 mg) and HOBt. · _H 2 O a (43 mg) was added, followed by stirring at room temperature for 21 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative silica gel thin layer chromatography (chloroform / methanol = 20/1) to give 3-chloro-N- (tetrahydro-2H-pyran-2. -Yloxy) -2- (4 '-(2- (tetrahydro-2H-pyran-2-yloxy) ethoxy) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide (pale yellow solid) was obtained. (53 mg, 36%).
MS (ESI): 604 (M + H) ^+
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.62-2.08 (12 H, m), 3.56 (1 H, br. S.), 3.74 (1 H, br. S.), 3.84-3.96 (2 H , m), 4.07-4.15 (2 H, m), 4.19-4.27 (2 H, m), 4.72-4.77 (1 H, m), 5.40 (1 H, br.s.), 7.06 (2 H, d, J = 8.7 Hz), 7.61 (2 H, d, J = 8.7 Hz), 7.74 (2 H, d, J = 8.3 Hz), 7.92 (2 H, d, J = 8.3 Hz), 8.02 (1 H, s), 8.15 (1 H, d, J = 6.0 Hz), 8.70 (1 H, d, J = 6.0 Hz), 9.52 (1 H, br.s.)

（５）実施例６−（４）で得た３−クロロ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−２−（４’−（２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エトキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド（４０ｍｇ）のクロロホルム（１．０ｍｌ）溶液に、ｍＣＰＢＡ（＞６５％）（５４ｍｇ）、炭酸水素ナトリウム（３０ｍｇ）を加え、室温で２４時間攪拌した。反応液に飽和食塩水を加えてクロロホルムで抽出した。溶媒を減圧下留去し、得られた残留物を分取用シリカゲル薄層クロマトグラフィー（クロロホルム／メタノール＝２０／１）で精製して、３−クロロ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−２−（４’−（２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エトキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（黄色固体）を得た（７．３ｍｇ，１８％）。
¹H NMR (600 MHz, CHLOROFORM-d) δppm 1.66 - 2.08 (12 H, m), 3.55 (1 H, ddd, J=10.9, 5.4, 5.3 Hz), 3.75 - 3.96 (3 H, m), 4.07 - 4.16 (2 H, m), 4.20 - 4.27 (2 H, m), 4.72 - 4.76 (1 H, m), 5.40 (1 H, br. s.), 7.05 (2 H, d, J=8.7 Hz), 7.61 (2 H, d, J=8.7 Hz), 7.73 (2 H, d, J=8.3 Hz), 7.82 (1 H, d, J=6.9 Hz), 7.87 (2 H, d, J=8.3 Hz), 8.04 - 8.09 (1 H, m), 8.87 (1 H, br. s.)

(5) 3-Chloro-N- (tetrahydro-2H-pyran-2-yloxy) -2- (4 ′-(2- (tetrahydro-2H-pyran-2-yloxy) obtained in Example 6- (4) MCPBA (> 65%) (54 mg) and sodium bicarbonate (30 mg) were added to a solution of) ethoxy) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide (40 mg) in chloroform (1.0 ml). And stirred for 24 hours at room temperature. Saturated saline was added to the reaction solution, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative silica gel thin layer chromatography (chloroform / methanol = 20/1) to give 3-chloro-N- (tetrahydro-2H-pyran-2. -Yloxy) -2- (4 '-(2- (tetrahydro-2H-pyran-2-yloxy) ethoxy) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide (yellow solid) Obtained (7.3 mg, 18%).
¹ H NMR (600 MHz, CHLOROFORM-d) δppm 1.66-2.08 (12 H, m), 3.55 (1 H, ddd, J = 10.9, 5.4, 5.3 Hz), 3.75-3.96 (3 H, m), 4.07 -4.16 (2 H, m), 4.20-4.27 (2 H, m), 4.72-4.76 (1 H, m), 5.40 (1 H, br.s.), 7.05 (2 H, d, J = 8.7 Hz), 7.61 (2 H, d, J = 8.7 Hz), 7.73 (2 H, d, J = 8.3 Hz), 7.82 (1 H, d, J = 6.9 Hz), 7.87 (2 H, d, J = 8.3 Hz), 8.04-8.09 (1 H, m), 8.87 (1 H, br.s.)

（６）実施例６−（５）で得た３−クロロ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−２−（４’−（２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エトキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（７．３ｍｇ）のメタノール（０．２０ｍｌ）、１，４−ジオキサン（０．３０ｍｌ）の溶液に、４ｍｏｌ／ｌ−ＨＣｌ−１，４−ジオキサン溶液（０．２０ｍｌ）を加え、室温で３０分間攪拌した。反応液を濃縮し、クロロホルムを加え析出した固体を濾別、乾燥し、３−クロロ−Ｎ−ヒドロキシ−２−（４’−（２−ヒドロキシエトキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩（褐色油状物）を得た（４．３ｍｇ，９８％）。
ＭＳ（ＥＳＩ）：４５２（Ｍ＋Ｈ）^＋
1H NMR (600 MHz, DMSO-d₆) δppm 3.72 - 3.77 (2 H, m), 4.06 (2 H, t, J=5.0 Hz), 7.08 (2 H, d, J=8.7 Hz), 7.72 (2 H, d, J=8.7 Hz), 7.82 (4 H, m), 8.10 (1 H, d, J=6.9 Hz), 8.47 (1 H, dd, J=6.9, 1.8 Hz), 8.54 (1 H, d, J=1.8 Hz), 11.48 (1 H, s)
実施例７
Ｎ−ヒドロキシ−３−メトキシ−２−（４’−（メトキシアセチル）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩（化合物２６）

(6) 3-chloro-N- (tetrahydro-2H-pyran-2-yloxy) -2- (4 ′-(2- (tetrahydro-2H-pyran-2-yloxy) obtained in Example 6- (5) 4) To a solution of ethoxy) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide (7.3 mg) in methanol (0.20 ml), 1,4-dioxane (0.30 ml) / L-HCl-1,4-dioxane solution (0.20 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, chloroform was added, and the precipitated solid was filtered off and dried, then 3-chloro-N-hydroxy-2- (4 ′-(2-hydroxyethoxy) biphenyl-4-yl) -1,6- Naphthyridine-4-carboxamide 6-oxide hydrochloride (brown oil) was obtained (4.3 mg, 98%).
MS (ESI): 452 (M + H) ^+
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 3.72-3.77 (2 H, m), 4.06 (2 H, t, J = 5.0 Hz), 7.08 (2 H, d, J = 8.7 Hz), 7.72 (2 H, d, J = 8.7 Hz), 7.82 (4 H, m), 8.10 (1 H, d, J = 6.9 Hz), 8.47 (1 H, dd, J = 6.9, 1.8 Hz), 8.54 ( 1 H, d, J = 1.8 Hz), 11.48 (1 H, s)
Example 7
N-hydroxy-3-methoxy-2- (4 ′-(methoxyacetyl) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride (Compound 26)

（１）実施例１−（３）で得た１−（４−ヨードフェニル）−２−メトキシエタノン（１０ｇ）のＤＭＳＯ（１００ｍｌ）溶液に、ビス（ピナコラト）ジボロン（１３ｇ）、ＰｄＣｌ_２（ｄｐｐｆ）（１．５ｇ）、酢酸カリウム（１１ｇ）を加え、１００℃で５時間攪拌した。放冷後、反応液を飽和食塩水に注ぎ酢酸エチル／トルエン＝４：１混合溶媒で３回抽出、抽出物をあわせて無水硫酸ナトリウムで乾燥し、乾燥剤を濾別した後、溶媒を減圧下留去した。残留物をシリカゲルカラムクロマトグラフィーで２回（１回目：ヘキサン／酢酸エチルの勾配溶離＝９０／１０→５０／５０、２回目：ヘキサン／酢酸エチルの勾配溶離＝９０／１０→６０／４０）精製して、２−メトキシ−１−（４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェニル）エタノン（褐色油状物）を得た（６．９ｇ，６９％）。
ＭＳ（ＥＳＩ）：２７７（Ｍ＋Ｈ）^＋
1H NMR (600 MHz, CHLOROFORM-d)δppm 1.35 (12 H, s) 3.50 (3 H, s) 4.71 (2 H, s) 7.66 - 7.92 (4 H, m)

(1) To a solution of 1- (4-iodophenyl) -2-methoxyethanone (10 g) obtained in Example 1- (3) in DMSO (100 ml), bis (pinacolato) diboron (13 g), PdCl ₂ ( dppf) (1.5 g) and potassium acetate (11 g) were added, and the mixture was stirred at 100 ° C. for 5 hours. After allowing to cool, the reaction mixture was poured into saturated brine, extracted three times with a mixed solvent of ethyl acetate / toluene = 4: 1, the extracts were combined, dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was reduced in pressure. The bottom distilled off. The residue was purified by silica gel column chromatography twice (first: hexane / ethyl acetate gradient elution = 90/10 → 50/50, second: hexane / ethyl acetate gradient elution = 90/10 → 60/40) To 2-methoxy-1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) ethanone (brown oil) (6. 9g, 69%).
MS (ESI): 277 (M + H) ^+
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.35 (12 H, s) 3.50 (3 H, s) 4.71 (2 H, s) 7.66-7.92 (4 H, m)

（２）実施例１−（６）で得た２−（４−ヨードフェニル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（０．１０ｇ）、実施例７−（１）で得た２−メトキシ−１−（４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェニル）エタノン（７９ｍｇ）、Ｐｄ（ＰＰｈ_３）_４（１１ｍｇ）、２ｍｏｌ／ｌ−炭酸ナトリウム水溶液（０．５ｍｌ）のＤＭＥ（２ｍｌ）懸濁液を窒素雰囲気下８０℃で３時間攪拌した。反応液に水を加えてクロロホルムで抽出した。無水硫酸マグネシウムで乾燥し、乾燥剤を濾別した後、溶媒を減圧下留去した。残留物を分取用シリカゲル薄層クロマトグラフィーで２回（１回目：クロロホルム／メタノール＝１０／１、２回目：酢酸エチル）精製して、２−（４’−（メトキシアセチル）ビフェニル−４−イル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（黄色固体）を得た（１２ｍｇ，１１％）。
ＭＳ（ＥＳＩ）：５４４（Ｍ＋Ｈ）^＋
1H NMR (600 MHz, DMSO-d₆) δppm 1.45 - 1.83 (6 H, m) 3.36 (3 H, s) 3.52 - 3.63 (1 H, m) 3.75 (3 H, s) 3.96 - 4.16 (1 H, m) 4.82 (2 H, s) 5.12 - 5.21 (1 H, m) 7.85 - 7.98 (4 H, m) 8.02 (2 H, d, J=8.3 Hz) 8.04 - 8.13 (3 H, m) 8.34 (2 H, d, J=6.0 Hz) 8.52 (1 H, s) 11.97 (1 H, br. s.)

(2) 2- (4-Iodophenyl) -3-methoxy-N- (tetrahydro-2H-pyran-2-yloxy) -1,6-naphthyridine-4-carboxamide obtained in Example 1- (6) 6 -Oxide (0.10 g), 2-methoxy-1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) obtained in Example 7- (1) ) Phenyl) ethanone (79 mg), Pd (PPh ₃ ) ₄ (11 mg), a 2 mol / l-sodium carbonate aqueous solution (0.5 ml) in DME (2 ml) was stirred at 80 ° C. for 3 hours under a nitrogen atmosphere. Water was added to the reaction solution and extracted with chloroform. After drying over anhydrous magnesium sulfate and filtering off the desiccant, the solvent was distilled off under reduced pressure. The residue was purified twice by preparative silica gel thin layer chromatography (first time: chloroform / methanol = 10/1, second time: ethyl acetate) to give 2- (4 ′-(methoxyacetyl) biphenyl-4- Yl) -N- (tetrahydro-2H-pyran-2-yloxy) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide (yellow solid) was obtained (12 mg, 11%).
MS (ESI): 544 (M + H) ^+
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 1.45-1.83 (6 H, m) 3.36 (3 H, s) 3.52-3.63 (1 H, m) 3.75 (3 H, s) 3.96-4.16 (1 H, m) 4.82 (2 H, s) 5.12-5.21 (1 H, m) 7.85-7.98 (4 H, m) 8.02 (2 H, d, J = 8.3 Hz) 8.04-8.13 (3 H, m) 8.34 (2 H, d, J = 6.0 Hz) 8.52 (1 H, s) 11.97 (1 H, br.s.)

（３）実施例７−（２）で得た２−（４’−（メトキシアセチル）ビフェニル−４−イル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（１１ｍｇ）に４ｍｏｌ／ｌ−ＨＣｌ−１，４−ジオキサン溶液（０．２５ｍｌ）及び１，４−ジオキサン（０．７５ｍｌ）を加え、室温で１時間攪拌した。反応液にジエチルエーテルを加え、析出した固体を濾別し、ジエチルエーテルで洗浄して、Ｎ−ヒドロキシ−３−メトキシ−２−（４’−（メトキシアセチル）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩（淡褐色固体）を得た（２．６ｍｇ，２６％）。
ＭＳ（ＥＳＩ）：４５８（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆) δppm 3.53 (3 H, s) 3.73 (3 H, s) 4.82 (2 H, s) 7.86 - 7.98 (4 H, m) 7.95 - 8.15 (5 H, m) 8.34 (1 H, dd, J=7.1, 1.8 Hz) 8.49 (1 H, d, J=1.8 Hz) 9.52 (1 H, br. s.) 11.38 (1 H, br. s)
実施例８
Ｎ−ヒドロキシ−２−（４’−（（４−ヒドロキシブチル）アミノ）ビフェニル−４−イル）−１，７−ナフチリジン−４−カルボキサミド ７−オキシド２塩酸塩（化合物３１）

(3) 2- (4 ′-(methoxyacetyl) biphenyl-4-yl) -N- (tetrahydro-2H-pyran-2-yloxy) -3-methoxy-1, obtained in Example 7- (2) 6-Naphthyridine-4-carboxamide 6-oxide (11 mg) was added with 4 mol / l-HCl-1,4-dioxane solution (0.25 ml) and 1,4-dioxane (0.75 ml) and stirred at room temperature for 1 hour. did. Diethyl ether was added to the reaction solution, and the precipitated solid was filtered off and washed with diethyl ether to give N-hydroxy-3-methoxy-2- (4 ′-(methoxyacetyl) biphenyl-4-yl) -1, 6-naphthyridine-4-carboxamide 6-oxide hydrochloride (light brown solid) was obtained (2.6 mg, 26%).
MS (ESI): 458 (M-H) ^−
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 3.53 (3 H, s) 3.73 (3 H, s) 4.82 (2 H, s) 7.86-7.98 (4 H, m) 7.95-8.15 (5 H, m) 8.34 (1 H, dd, J = 7.1, 1.8 Hz) 8.49 (1 H, d, J = 1.8 Hz) 9.52 (1 H, br. s.) 11.38 (1 H, br. s)
Example 8
N-hydroxy-2- (4 ′-((4-hydroxybutyl) amino) biphenyl-4-yl) -1,7-naphthyridine-4-carboxamide 7-oxide dihydrochloride (Compound 31)

（１）３−アミノピリジン（４．７ｇ）のクロロホルム（７５ｍｌ）溶液に、０℃でトリエチルアミン（８．７ｍｌ）を加えた後、２，２−ジメチルプロパノイルクロリド（７．１ｍｌ）のクロロホルム（１０ｍｌ）溶液を滴下して加え、０℃で１時間、室温で１４時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。抽出物を無水硫酸マグネシウムで乾燥し、乾燥剤を濾別した後、溶媒を減圧下留去した。残留物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノールの勾配溶離＝９６／４→８８／１２）で精製し、２，２−ジメチル−Ｎ−（ピリジン−３−イル）プロパンアミド（淡灰色固体）を得た（８．７ｇ，９８％）。
ＭＳ（ＥＳＩ）： １７７（Ｍ−Ｈ）^−
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.34 (9 H, s), 7.27 (1 H, dd, J=8.3, 5.0 Hz), 7.50 (1 H, s), 8.14 - 8.21 (1 H, m), 8.34 (1 H, d, J=5.0 Hz), 8.56 (1 H, d, J=2.3 Hz)

(1) Triethylamine (8.7 ml) was added to a solution of 3-aminopyridine (4.7 g) in chloroform (75 ml) at 0 ° C., and then 2,2-dimethylpropanoyl chloride (7.1 ml) in chloroform (7.1 ml) was added. 10 ml) solution was added dropwise and stirred for 1 hour at 0 ° C. and 14 hours at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution of chloroform / methanol = 96/4 → 88/12) to obtain 2,2-dimethyl-N- (pyridin-3-yl) propanamide (light gray solid). Obtained (8.7 g, 98%).
MS (ESI): 177 (M−H) ^−
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.34 (9 H, s), 7.27 (1 H, dd, J = 8.3, 5.0 Hz), 7.50 (1 H, s), 8.14-8.21 (1 H, m), 8.34 (1 H, d, J = 5.0 Hz), 8.56 (1 H, d, J = 2.3 Hz)

（２）実施例８−（１）で得た２，２−ジメチル−Ｎ−（ピリジン−３−イル）プロパンアミド（５．０ｇ）のＴＨＦ（７０ｍｌ）溶液に、−７０℃で２．６ｍｏｌ／ｌ−ｎ−ブチルリチウム−ヘキサン溶液（２７ｍｌ）を滴下し、０℃で３時間攪拌した。その後−７０℃でシュウ酸ジエチル（１０ｇ）のＴＨＦ（１０ｍｌ）溶液を滴下して加え、室温まで昇温し、１．５時間攪拌した。１ｍｏｌ／ｌ−塩酸水溶液に反応液を加えジエチルエーテルで抽出した。抽出物を無水硫酸マグネシウムで乾燥し、乾燥剤を濾別した後、溶媒を減圧下留去した。残留物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノールの勾配溶離＝９８／２→９４／６）で精製して、（３−（（２，２−ジメチルプロパノイル）アミノ）ピリジン−４−イル）（オキソ）酢酸エチル（褐色油状物）を得た（２．６ｇ，３３％）。
ＭＳ（ＥＳＩ）： ２７７（Ｍ−Ｈ）^−
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.38 (9 H, s), 1.45 (3 H, t, J=7.3 Hz), 4.50 (2 H, q, J=7.3 Hz), 7.57 (1 H, d, J=5.0 Hz), 8.52 (1 H, d, J=5.0 Hz), 10.16 (1 H, s), 10.84 (1 H, s)

(2) 2.6 mol of 2,2-dimethyl-N- (pyridin-3-yl) propanamide (5.0 g) obtained in Example 8- (1) in a THF (70 ml) solution at −70 ° C. A / l-n-butyllithium-hexane solution (27 ml) was added dropwise, and the mixture was stirred at 0 ° C. for 3 hours. Thereafter, a solution of diethyl oxalate (10 g) in THF (10 ml) was added dropwise at −70 ° C., and the mixture was warmed to room temperature and stirred for 1.5 hours. The reaction solution was added to a 1 mol / l-hydrochloric acid aqueous solution and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution of chloroform / methanol = 98/2 → 94/6) to give (3-((2,2-dimethylpropanoyl) amino) pyridin-4-yl) ( Oxo) ethyl acetate (brown oil) was obtained (2.6 g, 33%).
MS (ESI): 277 (MH) ^−
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.38 (9 H, s), 1.45 (3 H, t, J = 7.3 Hz), 4.50 (2 H, q, J = 7.3 Hz), 7.57 (1 H , d, J = 5.0 Hz), 8.52 (1 H, d, J = 5.0 Hz), 10.16 (1 H, s), 10.84 (1 H, s)

（３）実施例８−（２）で得た（３−（（２，２−ジメチルプロパノイル）アミノ）ピリジン−４−イル）（オキソ）酢酸エチル（２．８ｇ）の５０％エタノール水溶液（３０ｍｌ）に水酸化カリウム（２．７ｇ）を加え、９５℃で１時間攪拌後、４−ブロモアセトフェノン（２．１ｇ）を加え、８時間加熱還流した。室温まで放冷後、酢酸を加えて析出した固体を濾別した。得られた固体をクロロホルムに懸濁し、固体を濾別して、２−（４−ブロモフェニル）−１，７−ナフチリジン−４−カルボン酸（淡褐色固体）を得た（１．５ｇ，４５％）。
ＭＳ（ＥＳＩ）： ３２７（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆) δppm 7.77 (2 H, d, J=8.7 Hz), 8.26 (2 H, d, J=8.7 Hz), 8.55 (1 H, d, J=6.0 Hz), 8.62 - 8.68 (2 H, m), 9.47 (1 H, s)

(3) 50% aqueous ethanol solution of (3-((2,2-dimethylpropanoyl) amino) pyridin-4-yl) (oxo) acetate (2.8 g) obtained in Example 8- (2) ( 30 ml) was added potassium hydroxide (2.7 g), stirred at 95 ° C. for 1 hour, 4-bromoacetophenone (2.1 g) was added, and the mixture was heated to reflux for 8 hours. After cooling to room temperature, acetic acid was added and the precipitated solid was filtered off. The obtained solid was suspended in chloroform, and the solid was filtered off to obtain 2- (4-bromophenyl) -1,7-naphthyridine-4-carboxylic acid (light brown solid) (1.5 g, 45%). .
MS (ESI): 327 (M−H) ^−
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 7.77 (2 H, d, J = 8.7 Hz), 8.26 (2 H, d, J = 8.7 Hz), 8.55 (1 H, d, J = 6.0 Hz ), 8.62-8.68 (2 H, m), 9.47 (1 H, s)

（４）実施例８−（３）で得た２−（４−ブロモフェニル）−１，７−ナフチリジン−４−カルボン酸（１．４ｇ）のＤＭＦ（１３ｍｌ）溶液に、Ｏ−（テトラヒドロ−２Ｈ−ピラン−２−イル）ヒドロキシルアミン（０．５９ｇ）、ＷＳＣ・ＨＣｌ（０．９３ｇ）、ＨＯＢｔ・Ｈ_２Ｏ（０．６６ｇ）、ＤＩＰＥＡ（０．７８ｇ）を加え、室温で４１時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて酢酸エチルで抽出した。抽出物を無水硫酸マグネシウムで乾燥し、乾燥剤を濾別した後、溶媒を減圧下留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチルの勾配溶離＝３９／６１→１８／８２）で精製し、２−（４−ブロモフェニル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，７−ナフチリジン−４−カルボキサミド（淡黄色泡状物）を得た（１．５ｇ，８８％）。
ＭＳ（ＥＳＩ）：４２６（Ｍ−Ｈ）^−
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.54 - 2.04 (6 H, m), 3.68 - 3.75 (1 H, m), 4.00 - 4.08 (1 H, m), 5.24 - 5.31 (1 H, m), 7.69 (2 H, d, J=8.7 Hz), 8.03 - 8.15 (4 H, m), 8.62 (1 H, d, J=6.0 Hz), 9.04 (1 H, s), 9.54 (1 H, s)

(4) To a solution of 2- (4-bromophenyl) -1,7-naphthyridine-4-carboxylic acid (1.4 g) obtained in Example 8- (3) in DMF (13 ml), O- (tetrahydro- 2H-pyran-2-yl) hydroxylamine (0.59 g), WSC · HCl (0.93 g), HOBt · H ₂ O (0.66 g), DIPEA (0.78 g) were added, and the mixture was stirred at room temperature for 41 hours. did. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution of hexane / ethyl acetate = 39/61 → 18/82), 2- (4-bromophenyl) -N- (tetrahydro-2H-pyran-2-yloxy) -1,7-naphthyridine-4-carboxamide (pale yellow foam) was obtained (1.5 g, 88%).
MS (ESI): 426 (M−H) ^−
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.54-2.04 (6 H, m), 3.68-3.75 (1 H, m), 4.00-4.08 (1 H, m), 5.24-5.31 (1 H, m ), 7.69 (2 H, d, J = 8.7 Hz), 8.03-8.15 (4 H, m), 8.62 (1 H, d, J = 6.0 Hz), 9.04 (1 H, s), 9.54 (1 H , s)

（５）実施例８−（４）で得た２−（４−ブロモフェニル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，７−ナフチリジン−４−カルボキサミド（５０ｍｇ）のクロロホルム（１．０ｍｌ）溶液に、ｍＣＰＢＡ（＞６５％）（４６ｍｇ）、炭酸水素ナトリウム（２８ｍｇ）を加え、室温で３０分間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えてクロロホルムで抽出、無水硫酸マグネシウムで乾燥し、乾燥剤を濾別した後、溶媒を減圧下留去した。得られた残留物を分取用シリカゲル薄層クロマトグラフィー（クロロホルム／メタノール＝２０／１）で精製して、２−（４−ブロモフェニル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，７−ナフチリジン−４−カルボキサミド ７−オキシド（黄色固体）を得た（３９ｍｇ，７５％）。
ＭＳ（ＥＳＩ）：４４４，４４６（Ｍ＋Ｈ）^＋，４４２，４４４（Ｍ−Ｈ）^−
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.67 - 2.13 (6 H, m), 3.83 (1 H, br. s.), 4.22 (1 H, br. s.), 5.40 (1 H, br. s.), 7.68 - 7.73 (1 H, m), 7.73 - 7.78 (3 H, m), 8.00 (1 H, s), 8.08 (2 H, d, J=8.7 Hz), 8.63 (1 H, br. s.), 11.17 (1 H, br. s.)

(5) 2- (4-Bromophenyl) -N- (tetrahydro-2H-pyran-2-yloxy) -1,7-naphthyridine-4-carboxamide (50 mg) chloroform obtained in Example 8- (4) To the (1.0 ml) solution, mCPBA (> 65%) (46 mg) and sodium bicarbonate (28 mg) were added and stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with chloroform, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative silica gel thin layer chromatography (chloroform / methanol = 20/1) to give 2- (4-bromophenyl) -N- (tetrahydro-2H-pyran-2-yloxy). -1,7-naphthyridine-4-carboxamide 7-oxide (yellow solid) was obtained (39 mg, 75%).
MS (ESI): 444, 446 (M + H) ⁺ , 442, 444 (M−H) ^−
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.67-2.13 (6 H, m), 3.83 (1 H, br. S.), 4.22 (1 H, br. S.), 5.40 (1 H, br s.), 7.68-7.73 (1 H, m), 7.73-7.78 (3 H, m), 8.00 (1 H, s), 8.08 (2 H, d, J = 8.7 Hz), 8.63 (1 H , br. s.), 11.17 (1 H, br. s.)

（６）実施例８−（５）で得た２−（４−ブロモフェニル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，７−ナフチリジン−４−カルボキサミド ７−オキシド（３９ｍｇ）、実施例３−（１）で得た４−（４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェニルアミノ）ブタン−１−オール（３９ｍｇ）、Ｐｄ（ＰＰｈ_３）_４（１０ｍｇ）、２ｍｏｌ／ｌ−炭酸ナトリウム水溶液（０．１５ｍｌ）及び水（０．３０ｍｌ）のＤＭＥ（１．６ｍｌ）懸濁液を、窒素雰囲気下８５℃で２．５時間攪拌した。反応液を放冷後、飽和食塩水を加えクロロホルムで３回抽出した。溶媒を減圧下留去し、残留物を分取用シリカゲル薄層クロマトグラフィー（クロロホルム／メタノール＝１５／１）で精製して、２−（４’−（（４−ヒドロキシブチル）アミノ）ビフェニル−４−イル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，７−ナフチリジン−４−カルボキサミド ７−オキシド（黄色固体）を得た（３３ｍｇ，７２％）。
ＭＳ（ＥＳＩ）：５２９（Ｍ＋Ｈ）^＋，５２７（Ｍ−Ｈ）^−
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.67 - 1.84 (7 H, m), 1.89 - 2.03 (2 H, m), 2.07 - 2.15 (1 H, m), 3.25 (2 H, t, J=6.6 Hz), 3.74 (2 H, t, J=6.2 Hz), 3.81 - 3.90 (1 H, m), 4.23 - 4.31 (1 H, m), 5.44 (1 H, br. s.), 6.73 (2 H, d, J=8.7 Hz), 7.57 (2 H, d, J=8.7 Hz), 7.64 (1 H, d, J=6.0 Hz), 7.70 (1 H, d, J=6.0 Hz), 7.77 (2 H, d, J=8.3 Hz), 8.07 (1 H, s), 8.23 (2 H, d, J=8.3 Hz), 8.62 (1 H, br. s.), 11.61 (1 H, br. s.)

(6) 2- (4-Bromophenyl) -N- (tetrahydro-2H-pyran-2-yloxy) -1,7-naphthyridine-4-carboxamide 7-oxide (39 mg) obtained in Example 8- (5) ), 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenylamino) butan-1-ol obtained in Example 3- (1) ( 39 mg), Pd (PPh ₃ ) ₄ (10 mg), 2 mol / l-sodium carbonate aqueous solution (0.15 ml) and water (0.30 ml) in DME (1.6 ml) suspension at 85 ° C. under nitrogen atmosphere. Stir for 2.5 hours. The reaction mixture was allowed to cool, saturated brine was added, and the mixture was extracted 3 times with chloroform. The solvent was distilled off under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (chloroform / methanol = 15/1) to give 2- (4 ′-((4-hydroxybutyl) amino) biphenyl- 4-yl) -N- (tetrahydro-2H-pyran-2-yloxy) -1,7-naphthyridine-4-carboxamide 7-oxide (yellow solid) was obtained (33 mg, 72%).
MS (ESI): 529 (M + H) ⁺ , 527 (M−H) ^−
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.67-1.84 (7 H, m), 1.89-2.03 (2 H, m), 2.07-2.15 (1 H, m), 3.25 (2 H, t, J = 6.6 Hz), 3.74 (2 H, t, J = 6.2 Hz), 3.81-3.90 (1 H, m), 4.23-4.31 (1 H, m), 5.44 (1 H, br.s.), 6.73 (2 H, d, J = 8.7 Hz), 7.57 (2 H, d, J = 8.7 Hz), 7.64 (1 H, d, J = 6.0 Hz), 7.70 (1 H, d, J = 6.0 Hz) , 7.77 (2 H, d, J = 8.3 Hz), 8.07 (1 H, s), 8.23 (2 H, d, J = 8.3 Hz), 8.62 (1 H, br.s.), 11.61 (1 H , br. s.)

（７）実施例８−（６）で得た２−（４’−（（４−ヒドロキシブチル）アミノ）ビフェニル−４−イル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，７−ナフチリジン−４−カルボキサミド ７−オキシド（２４ｍｇ）のメタノール（０．３０ｍｌ）及び１，４−ジオキサン（０．３０ｍｌ）溶液に、４ｍｏｌ／ｌ−ＨＣｌ−１，４−ジオキサン溶液（０．３０ｍｌ）を加え、室温で３０分間攪拌した。反応液を濃縮し、クロロホルムを加え析出した固体を濾別、乾燥し、Ｎ−ヒドロキシ−２−（４’−（（４−ヒドロキシブチル）アミノ）ビフェニル−４−イル）−１，７−ナフチリジン−４−カルボキサミド ７−オキシド２塩酸塩（淡黄色固体）を得た（１７ｍｇ，７２％）。
ＭＳ（ＥＳＩ）：４４５（Ｍ＋Ｈ）^＋，４４３（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆) δppm 1.48 - 1.57 (2 H, m), 1.60 - 1.70 (2 H, m), 3.17 (2 H, br. s.), 3.44 (2 H, t, J=6.4 Hz), 7.07 (2 H, br. s.), 7.71 (2 H, br. s.), 7.85 (2 H, d, J=8.7 Hz), 8.19 (1 H, d, J=7.3 Hz), 8.25 (1 H, s), 8.31 (1 H, dd, J=7.3, 1.8 Hz), 8.36 (2 H, d, J=8.7 Hz), 8.98 (1 H, br. s.), 11.65 (1 H, br. s.)
実施例９
Ｎ−ヒドロキシ−２−（４’−（４−ヒドロキシブトキシ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩（化合物３２）

(7) 2- (4 ′-((4-hydroxybutyl) amino) biphenyl-4-yl) -N- (tetrahydro-2H-pyran-2-yloxy) -1 obtained in Example 8- (6) , 7-naphthyridine-4-carboxamide 7-oxide (24 mg) in a solution of methanol (0.30 ml) and 1,4-dioxane (0.30 ml) in a 4 mol / l-HCl-1,4-dioxane solution (0. 30 ml) was added and stirred at room temperature for 30 minutes. The reaction mixture was concentrated, chloroform was added, and the precipitated solid was filtered off and dried, and N-hydroxy-2- (4 ′-((4-hydroxybutyl) amino) biphenyl-4-yl) -1,7-naphthyridine. -4-carboxamide 7-oxide dihydrochloride (pale yellow solid) was obtained (17 mg, 72%).
MS (ESI): 445 (M + H) ⁺ , 443 (M−H) ^−
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 1.48-1.57 (2 H, m), 1.60-1.70 (2 H, m), 3.17 (2 H, br.s.), 3.44 (2 H, t , J = 6.4 Hz), 7.07 (2 H, br.s.), 7.71 (2 H, br.s.), 7.85 (2 H, d, J = 8.7 Hz), 8.19 (1 H, d, J = 7.3 Hz), 8.25 (1 H, s), 8.31 (1 H, dd, J = 7.3, 1.8 Hz), 8.36 (2 H, d, J = 8.7 Hz), 8.98 (1 H, br. S. ), 11.65 (1 H, br.s.)
Example 9
N-hydroxy-2- (4 ′-(4-hydroxybutoxy) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride (Compound 32)

（１）４−ヨードフェノール（２．０ｇ）、４−（ベンジルオキシ）ブタン−１−オール（１．６ｇ）、トリフェニルホスフィン（３．６ｇ）のトルエン（２０ｍｌ）溶液を氷冷下攪拌し、２．２ｍｏｌ／ｌ−ＤＥＡＤ−トルエン溶液（６．２ｍｌ）を加え１時間攪拌、その後室温で２時間攪拌した。反応液に水を加え酢酸エチルで２回抽出し、無水硫酸マグネシウムで乾燥し乾燥剤を濾別後、溶媒を減圧下留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝５／１）で精製して、１−（４−（ベンジルオキシ）ブトキシ）−４−ヨードベンゼン（無色油状物）を得た（１．７ｇ，４８％）。
ＭＳ（ＥＳＩ）：３８３（Ｍ＋Ｈ）^＋
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.75 - 1.81 (2 H, m), 1.84 - 1.91 (2 H, m), 3.54 (2 H, t, J=6.4 Hz), 3.94 (2 H, t, J=6.4 Hz), 4.51 (2 H, s), 6.65 (2 H, d, J=8.7 Hz), 7.27 - 7.37 (5 H, m), 7.53 (2 H, d, J=8.7 Hz)

(1) A solution of 4-iodophenol (2.0 g), 4- (benzyloxy) butan-1-ol (1.6 g) and triphenylphosphine (3.6 g) in toluene (20 ml) was stirred under ice-cooling. 2.2 mol / l-DEAD-toluene solution (6.2 ml) was added and stirred for 1 hour, and then stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to give 1- (4- (benzyloxy) butoxy) -4-iodobenzene (colorless oil) (1.7 g). 48%).
MS (ESI): 383 (M + H) ^+
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.75-1.81 (2 H, m), 1.84-1.91 (2 H, m), 3.54 (2 H, t, J = 6.4 Hz), 3.94 (2 H, t, J = 6.4 Hz), 4.51 (2 H, s), 6.65 (2 H, d, J = 8.7 Hz), 7.27-7.37 (5 H, m), 7.53 (2 H, d, J = 8.7 Hz )

（２）実施例９−（１）で得た１−（４−（ベンジルオキシ）ブトキシ）−４−ヨードベンゼン（１．７ｇ）、ＰｄＣｌ_２（ｄｐｐｆ）（０．１３ｇ）、酢酸カリウム（１．３ｇ）及びビス（ピナコラト）ジボロン（１．４ｇ）のＤＭＳＯ（１６ｍｌ）懸濁液を、窒素雰囲気下８５℃で２．５時間攪拌した。反応液を放冷後、水を加えクロロホルムで２回抽出し、無水硫酸マグネシウムで乾燥し乾燥剤を濾別後、溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１０／１）で精製して、無色油状物（１．３ｇ）を得た。この無色油状物（０．１５ｇ）のメタノール（３ｍｌ）溶液に、７．５％パラジウム炭素触媒（５０ｍｇ）を加え水素雰囲気下室温で１３時間攪拌した。セライト濾過により不溶物を濾別し、溶媒を減圧下留去して無色油状物（０．１２ｇ）を得た。この無色油状物（８４ｍｇ）、実施例１−（６）で得た２−（４−ヨードフェニル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（０．１０ｇ）、Ｐｄ（ＰＰｈ_３）_４（２２ｍｇ）、２ｍｏｌ／ｌ−炭酸ナトリウム水溶液（０．３ｍｌ）及び水（１ｍｌ）のＤＭＥ（３ｍｌ）懸濁液を、窒素雰囲気下９０℃で３時間攪拌した。反応液を放冷後、飽和塩化アンモニウム水溶液を加えクロロホルムで２回抽出した。抽出物を無水硫酸マグネシウムで乾燥し乾燥剤を濾別後、溶媒を減圧下留去した。残留物を分取用シリカゲル薄層クロマトグラフィー（クロロホルム／メタノール＝１０／１）で精製し、酢酸エチルで洗浄して２−（４’−（４−ヒドロキシブトキシ）ビフェニル−４−イル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（黄色固体）を得た（８ｍｇ、３工程収率５．９％）。
ＭＳ（ＥＳＩ）：５６０（Ｍ＋Ｈ）^＋，５５８（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆) δppm 1.56 - 1.64 (5 H, m), 1.74 - 1.82 (5 H, m), 3.44 - 3.50 (2 H, m), 3.59 - 3.64 (1 H, m), 3.77 (3 H, s), 4.03 - 4.07 (2 H, m), 4.07 - 4.13 (1 H, m), 4.47 (1 H, t, J=5.0 Hz), 5.20 (1 H, br. s.), 7.06 (2 H, d, J=8.7 Hz), 7.72 (2 H, d, J=8.7 Hz), 7.82 (2 H, d, J=8.3 Hz), 8.02 (1 H, d, J=7.3 Hz), 8.06 (2 H, d, J=8.3 Hz), 8.34 - 8.38 (1 H, m), 8.54 (1 H, s), 11.98 (1 H, br. s.)

(2) 1- (4- (Benzyloxy) butoxy) -4-iodobenzene (1.7 g) obtained in Example 9- (1), PdCl ₂ (dppf) (0.13 g), potassium acetate (1 3 g) and a suspension of bis (pinacolato) diboron (1.4 g) in DMSO (16 ml) was stirred at 85 ° C. for 2.5 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool, water was added, the mixture was extracted twice with chloroform, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1) to give a colorless oil (1.3 g). To a solution of this colorless oil (0.15 g) in methanol (3 ml) was added 7.5% palladium carbon catalyst (50 mg), and the mixture was stirred at room temperature for 13 hours in a hydrogen atmosphere. Insoluble material was filtered off through Celite filtration, and the solvent was evaporated under reduced pressure to give a colorless oil (0.12 g). This colorless oily substance (84 mg), 2- (4-iodophenyl) -3-methoxy-N- (tetrahydro-2H-pyran-2-yloxy) -1,6-naphthyridine obtained in Example 1- (6) A suspension of DME (3 ml) in -4-carboxamide 6-oxide (0.10 g), Pd (PPh ₃ ) ₄ (22 mg), 2 mol / l-aqueous sodium carbonate (0.3 ml) and water (1 ml) The mixture was stirred at 90 ° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool, saturated aqueous ammonium chloride solution was added, and the mixture was extracted twice with chloroform. The extract was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (chloroform / methanol = 10/1), washed with ethyl acetate and 2- (4 ′-(4-hydroxybutoxy) biphenyl-4-yl) -3. -Methoxy-N- (tetrahydro-2H-pyran-2-yloxy) -1,6-naphthyridine-4-carboxamide 6-oxide (yellow solid) was obtained (8 mg, 3-step yield 5.9%).
MS (ESI): 560 (M + H) ⁺ , 558 (M−H) ^−
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 1.56-1.64 (5 H, m), 1.74-1.82 (5 H, m), 3.44-3.50 (2 H, m), 3.59-3.64 (1 H, m), 3.77 (3 H, s), 4.03-4.07 (2 H, m), 4.07-4.13 (1 H, m), 4.47 (1 H, t, J = 5.0 Hz), 5.20 (1 H, br s.), 7.06 (2 H, d, J = 8.7 Hz), 7.72 (2 H, d, J = 8.7 Hz), 7.82 (2 H, d, J = 8.3 Hz), 8.02 (1 H, d , J = 7.3 Hz), 8.06 (2 H, d, J = 8.3 Hz), 8.34-8.38 (1 H, m), 8.54 (1 H, s), 11.98 (1 H, br.s.)

（３）実施例９−（２）で得た２−（４’−（４−ヒドロキシブトキシ）ビフェニル−４−イル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（８ｍｇ）に１，４−ジオキサン（１ｍｌ）及び４ｍｏｌ／ｌ−ＨＣｌ−１，４−ジオキサン溶液（１ｍｌ）を加え、室温で２時間攪拌した。ジエチルエーテルを加え、析出した固体を濾別しジエチルエーテルで洗浄して、Ｎ−ヒドロキシ−２−（４’−（４−ヒドロキシブトキシ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩（黄色固体）を得た（６ｍｇ，７７％）。
ＭＳ（ＥＳＩ）：４７６（Ｍ＋Ｈ）^＋，４７４（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆) δppm 1.56 - 1.62 (2 H, m), 1.75 - 1.81 (2 H, m), 3.47 (2 H, t, J=6.4 Hz), 3.75 (3 H, s), 4.05 (2 H, t, J=6.6 Hz), 7.06 (2 H, d, J=9.2 Hz), 7.72 (2 H, d, J=9.2 Hz), 7.82 (2 H, d, J=8.3 Hz), 8.03 (1 H, d, J=7.1 Hz), 8.05 (2 H, d, J=8.3 Hz), 8.37 (1 H, dd, J=7.1, 2.1 Hz), 8.51 (1 H, d, J=2.1 Hz), 11.40 (1 H, s)
実施例１０
Ｎ−ヒドロキシ−３−メトキシ−２−（４’−（２−（ピペラジン−１−イル）エチル）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド３塩酸塩（化合物３５）

(3) 2- (4 ′-(4-hydroxybutoxy) biphenyl-4-yl) -3-methoxy-N- (tetrahydro-2H-pyran-2-yloxy)-obtained in Example 9- (2) To 1,6-naphthyridine-4-carboxamide 6-oxide (8 mg), 1,4-dioxane (1 ml) and a 4 mol / l-HCl-1,4-dioxane solution (1 ml) were added, and the mixture was stirred at room temperature for 2 hours. Diethyl ether was added, and the precipitated solid was filtered off and washed with diethyl ether, and N-hydroxy-2- (4 ′-(4-hydroxybutoxy) biphenyl-4-yl) -3-methoxy-1,6- Naphthyridine-4-carboxamide 6-oxide hydrochloride (yellow solid) was obtained (6 mg, 77%).
MS (ESI): 476 (M + H) ⁺ , 474 (M−H) ^−
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 1.56-1.62 (2 H, m), 1.75-1.81 (2 H, m), 3.47 (2 H, t, J = 6.4 Hz), 3.75 (3 H , s), 4.05 (2 H, t, J = 6.6 Hz), 7.06 (2 H, d, J = 9.2 Hz), 7.72 (2 H, d, J = 9.2 Hz), 7.82 (2 H, d, J = 8.3 Hz), 8.03 (1 H, d, J = 7.1 Hz), 8.05 (2 H, d, J = 8.3 Hz), 8.37 (1 H, dd, J = 7.1, 2.1 Hz), 8.51 (1 H, d, J = 2.1 Hz), 11.40 (1 H, s)
Example 10
N-hydroxy-3-methoxy-2- (4 ′-(2- (piperazin-1-yl) ethyl) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide trihydrochloride (compound 35)

（１）（４−ブロモフェニル）酢酸（２．２ｇ）のＤＭＦ（３０ｍｌ）溶液に、ＷＳＣ・ＨＣｌ（２．９ｇ）、ＨＯＢｔ・Ｈ_２Ｏ（２．０ｇ）、ＤＩＰＥＡ（４．４ｍｌ）及びピペラジン−１−カルボン酸ｔ−ブチル（１．９ｇ）を加え、室温で５時間攪拌した。反応液に水を加え酢酸エチル／トルエン＝５／１で抽出した。抽出物を水で２回洗浄、無水硫酸ナトリウムで乾燥し乾燥剤を濾別後、溶媒を減圧下留去して、４−（（４−ブロモフェニル）アセチル）ピペラジン−１−カルボン酸ｔ−ブチル（白色固体）を得た（３．６ｇ，９４％）。
ＭＳ（ＥＳＩ）：３８３（Ｍ＋Ｈ）^＋
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.45 (9 H, s), 3.25 - 3.30 (2 H, m), 3.36 - 3.43 (4 H, m), 3.58 - 3.62 (2 H, m), 3.69 (2 H, s), 7.12 (2 H, d, J=8.3 Hz), 7.45 (2 H, d, J=8.3 Hz)

(1) To a solution of (4-bromophenyl) acetic acid (2.2 g) in DMF (30 ml), WSC · HCl (2.9 g), HOBt · H ₂ O (2.0 g), DIPEA (4.4 ml) and Piperazine-1-carboxylate t-butyl (1.9 g) was added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate / toluene = 5/1. The extract was washed twice with water, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The solvent was evaporated under reduced pressure to give 4-((4-bromophenyl) acetyl) piperazine-1-carboxylic acid t- Butyl (white solid) was obtained (3.6 g, 94%).
MS (ESI): 383 (M + H) ^+
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.45 (9 H, s), 3.25-3.30 (2 H, m), 3.36-3.43 (4 H, m), 3.58-3.62 (2 H, m), 3.69 (2 H, s), 7.12 (2 H, d, J = 8.3 Hz), 7.45 (2 H, d, J = 8.3 Hz)

（２）実施例１０−（１）で得た４−（（４−ブロモフェニル）アセチル）ピペラジン−１−カルボン酸ｔ−ブチル（１．５ｇ）のＴＨＦ（３０ｍｌ）溶液に氷冷下水素化ホウ素ナトリウム（５０４ｍｇ）、次いで三フッ化ホウ素ジエチルエーテラート（１．５ｍｌ）を加え氷冷下２時間攪拌した。反応液にエタノール（６０ｍｌ）を加え８５℃で３時間攪拌した。放冷後、溶媒を減圧下留去した。得られた残留物にクロロホルムを加え、水、飽和食塩水で順次洗浄、無水硫酸ナトリウムで乾燥し乾燥剤を濾別後、溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチルの勾配溶離＝５６／３４→０／１００→酢酸エチル／メタノール＝９０／１０）で精製して、４−（２−（４−ブロモフェニル）エチル）ピペラジン−１−カルボン酸ｔ−ブチル（白色固体）を得た（１．４ｇ，９５％）。
ＭＳ（ＥＳＩ）：３６９（Ｍ＋Ｈ）^＋
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.46 (9 H, s), 2.41 - 2.47 (4 H, m), 2.55 - 2.59 (2 H, m), 2.72 - 2.78 (2 H, m), 3.43 - 3.48 (4 H, m), 7.07 (2 H, d, J=8.3 Hz), 7.40 (2 H, d, J=8.3 Hz)

(2) Hydrogenation of a solution of t-butyl 4-((4-bromophenyl) acetyl) piperazine-1-carboxylate (1.5 g) obtained in Example 10- (1) in THF (30 ml) under ice-cooling Sodium boron (504 mg) and then boron trifluoride diethyl etherate (1.5 ml) were added and stirred for 2 hours under ice cooling. Ethanol (60 ml) was added to the reaction solution and stirred at 85 ° C. for 3 hours. After allowing to cool, the solvent was distilled off under reduced pressure. Chloroform was added to the obtained residue, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution of hexane / ethyl acetate = 56/34 → 0/100 → ethyl acetate / methanol = 90/10) to obtain 4- (2- (4-bromo Phenyl) ethyl) piperazine-1-carboxylate t-butyl (white solid) was obtained (1.4 g, 95%).
MS (ESI): 369 (M + H) ^+
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.46 (9 H, s), 2.41-2.47 (4 H, m), 2.55-2.59 (2 H, m), 2.72-2.78 (2 H, m), 3.43-3.48 (4 H, m), 7.07 (2 H, d, J = 8.3 Hz), 7.40 (2 H, d, J = 8.3 Hz)

（３）実施例１０−（２）で得た４−（２−（４−ブロモフェニル）エチル）ピペラジン−１−カルボン酸ｔ−ブチル（７３９ｍｇ）、ＰｄＣｌ_２（ｄｐｐｆ）（８２ｍｇ）、酢酸カリウム（５８９ｍｇ）及びビス（ピナコラト）ジボロン（１．０ｇ）のＤＭＳＯ（１５ｍｌ）懸濁液を、窒素雰囲気下１００℃で５時間攪拌した。反応液を放冷後、水を加え酢酸エチルで抽出し、飽和食塩水洗浄した。水層を酢酸エチルで３回抽出、抽出物を合わせて無水硫酸ナトリウムで乾燥し乾燥剤を濾別後、溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝９９／１→９５／５）で精製して、薄褐色固体（８２３ｍｇ）を得た。この薄褐色固体（１２０ｍｇ）、実施例１−（６）で得た２−（４−ヨードフェニル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（１００ｍｇ）、Ｐｄ（ＰＰｈ_３）_４（２２ｍｇ）、２ｍｏｌ／ｌ−炭酸ナトリウム水溶液（０．３ｍｌ）及び水（１ｍｌ）のＤＭＥ（３ｍｌ）懸濁液を、窒素雰囲気下８５℃で３時間攪拌した。反応液を放冷後、飽和塩化アンモニウム水溶液を加えクロロホルムで２回抽出した。抽出物を無水硫酸マグネシウムで乾燥し乾燥剤を濾別後、溶媒を減圧下留去した。得られた残留物を分取用シリカゲル薄層クロマトグラフィー（クロロホルム／メタノール＝３０／１）で精製して、４−（２−（４’−（３−メトキシ−６−オキシド−４−（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）カルバモイル）−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）エチル）ピペラジン−１−カルボン酸ｔ−ブチル（黄色固体）を得た（５５ｍｇ、２工程収率４１％）。
ＭＳ（ＥＳＩ）：６８５（Ｍ＋Ｈ）^＋，６８３（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆) δppm 1.40 (9 H, s), 1.56 - 1.64 (3 H, m), 1.73 - 1.81 (3 H, m), 2.39 - 2.43 (4 H, m), 2.55 - 2.60 (2 H, m), 2.78 - 2.83 (2 H, m), 3.28 - 3.37 (4 H, m), 3.59 - 3.64 (1 H, m), 3.77 (3 H, s), 4.07 - 4.13 (1 H, m), 5.20 (1 H, br. s.), 7.37 (2 H, d, J=8.3 Hz), 7.70 (2 H, d, J=8.3 Hz), 7.85 (2 H, d, J=8.3 Hz), 8.03 (1 H, d, J=7.3 Hz), 8.07 (2 H, d, J=8.3 Hz), 8.35 - 8.38 (1 H, m), 8.55 (1 H, s), 11.98 (1 H, br)

(3) t-butyl 4- (2- (4-bromophenyl) ethyl) piperazine-1-carboxylate (739 mg) obtained in Example 10- (2), PdCl ₂ (dppf) (82 mg), potassium acetate A suspension of (589 mg) and bis (pinacolato) diboron (1.0 g) in DMSO (15 ml) was stirred at 100 ° C. for 5 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The aqueous layer was extracted three times with ethyl acetate, the extracts were combined, dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol = 99/1 → 95/5) to obtain a light brown solid (823 mg). This light brown solid (120 mg), 2- (4-iodophenyl) -3-methoxy-N- (tetrahydro-2H-pyran-2-yloxy) -1,6-naphthyridine obtained in Example 1- (6) A suspension of DME (3 ml) in -4-carboxamide 6-oxide (100 mg), Pd (PPh ₃ ) ₄ (22 mg), 2 mol / l-aqueous sodium carbonate (0.3 ml) and water (1 ml) in a nitrogen atmosphere The mixture was stirred at 85 ° C. for 3 hours. The reaction mixture was allowed to cool, saturated aqueous ammonium chloride solution was added, and the mixture was extracted twice with chloroform. The extract was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative silica gel thin layer chromatography (chloroform / methanol = 30/1) to give 4- (2- (4 ′-(3-methoxy-6-oxide-4-(( Tetrahydro-2H-pyran-2-yloxy) carbamoyl) -1,6-naphthyridin-2-yl) biphenyl-4-yl) ethyl) piperazine-1-carboxylate t-butyl (yellow solid) was obtained (55 mg, (2 step yield 41%).
MS (ESI): 685 (M + H) ⁺ , 683 (M−H) ^−
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 1.40 (9 H, s), 1.56-1.64 (3 H, m), 1.73-1.81 (3 H, m), 2.39-2.43 (4 H, m) , 2.55-2.60 (2 H, m), 2.78-2.83 (2 H, m), 3.28-3.37 (4 H, m), 3.59-3.64 (1 H, m), 3.77 (3 H, s), 4.07 -4.13 (1 H, m), 5.20 (1 H, br.s.), 7.37 (2 H, d, J = 8.3 Hz), 7.70 (2 H, d, J = 8.3 Hz), 7.85 (2 H , d, J = 8.3 Hz), 8.03 (1 H, d, J = 7.3 Hz), 8.07 (2 H, d, J = 8.3 Hz), 8.35-8.38 (1 H, m), 8.55 (1 H, s), 11.98 (1 H, br)

（４）実施例１０−（３）で得た４−（２−（４’−（３−メトキシ−６−オキシド−４−（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）カルバモイル）−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）エチル）ピペラジン−１−カルボン酸ｔ−ブチル（５５ｍｇ）に１，４−ジオキサン（２ｍｌ）及び４ｍｏｌ／ｌ−ＨＣｌ−１，４−ジオキサン溶液（２ｍｌ）を加え、室温で２時間攪拌した。析出した固体を濾別し１，４−ジオキサンで洗浄して、Ｎ−ヒドロキシ−３−メトキシ−２−（４’−（２−（ピペラジン−１−イル）エチル）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド３塩酸塩（褐色固体）を得た（３１ｍｇ，４９％）。
ＭＳ（ＥＳＩ）：５００（Ｍ＋Ｈ）^＋，４９８（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆) δppm 2.50 - 2.53 (4 H, m), 3.15 - 3.20 (2 H, m), 3.37 - 3.51 (6 H, m), 3.78 (3 H, s), 7.45 (2 H, d, J=7.8 Hz), 7.78 (2 H, d, J=7.8 Hz), 7.88 (2 H, d, J=8.3 Hz), 8.05 - 8.10 (3 H, m), 8.40 - 8.42 (1 H, m), 8.59 (1 H, s), 9.88 - 10.05 (2 H, m), 11.49 (1 H, br. s.), 12.20 (1 H, br. s.)
実施例１１
Ｎ−ヒドロキシ−２−（４−（（４−（（２−ヒドロキシエチル）アミノ）フェニル）エチニル）フェニル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（化合物３６）

(4) 4- (2- (4 ′-(3-methoxy-6-oxide-4-((tetrahydro-2H-pyran-2-yloxy) carbamoyl) -1, -1) obtained in Example 10- (3) 6-naphthyridin-2-yl) biphenyl-4-yl) ethyl) piperazine-1-carboxylate t-butyl (55 mg) in 1,4-dioxane (2 ml) and 4 mol / l-HCl-1,4-dioxane solution (2 ml) was added and stirred at room temperature for 2 hours. The precipitated solid was filtered off and washed with 1,4-dioxane to give N-hydroxy-3-methoxy-2- (4 ′-(2- (piperazin-1-yl) ethyl) biphenyl-4-yl)- 1,6-naphthyridine-4-carboxamide 6-oxide trihydrochloride (brown solid) was obtained (31 mg, 49%).
MS (ESI): 500 (M + H) ⁺ , 498 (M−H) ^−
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 2.50-2.53 (4 H, m), 3.15-3.20 (2 H, m), 3.37-3.51 (6 H, m), 3.78 (3 H, s) , 7.45 (2 H, d, J = 7.8 Hz), 7.78 (2 H, d, J = 7.8 Hz), 7.88 (2 H, d, J = 8.3 Hz), 8.05-8.10 (3 H, m), 8.40-8.42 (1 H, m), 8.59 (1 H, s), 9.88-10.05 (2 H, m), 11.49 (1 H, br.s.), 12.20 (1 H, br.s.)
Example 11
N-hydroxy-2- (4-((4-((2-hydroxyethyl) amino) phenyl) ethynyl) phenyl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide (Compound 36)

（１）４−ヨードアニリン（１０ｇ）のピリジン（５０ｍｌ）溶液に、氷冷下、クロロギ酸（２−クロロエチル）（６．６ｍｌ）を加え、３時間攪拌した。反応液に氷冷下、水を加え、酢酸エチルで抽出、無水硫酸マグネシウムで乾燥し、乾燥剤を濾別した後、溶媒を減圧下留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチルの勾配溶離＝９０／１０→７５／２５）で精製して、４−ヨードフェニルカルバミン酸 ２−クロロエチル（淡桃色固体）を得た（１４ｇ，９５％）。
¹H NMR (600 MHz, CHLOROFORM-d)δppm 3.72 - 3.75 (2 H, m), 4.41 - 4.44 (2 H, m), 6.67 (1 H, s), 7.17 (2 H, d, J=8.3 Hz), 7.61 (2 H, d, J=8.3 Hz)

(1) To a solution of 4-iodoaniline (10 g) in pyridine (50 ml) was added chloroformate (2-chloroethyl) (6.6 ml) under ice cooling, and the mixture was stirred for 3 hours. Water was added to the reaction solution under ice-cooling, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate gradient elution = 90/10 → 75/25) to give 2-chloroethyl 4-iodophenylcarbamate (pale pink solid) (14 g, 95 %).
¹ H NMR (600 MHz, CHLOROFORM-d) δppm 3.72-3.75 (2 H, m), 4.41-4.44 (2 H, m), 6.67 (1 H, s), 7.17 (2 H, d, J = 8.3 Hz), 7.61 (2 H, d, J = 8.3 Hz)

（２）実施例１１−（１）で得た２−クロロエチル（４−ヨードフェニル）カルバマート（１４ｇ）のエタノール（２１０ｍｌ）溶液に水酸化カリウム（１２ｇ）のエタノール（３００ｍｌ）溶液を加え、１２時間加熱還流した。室温まで放冷後、反応液を減圧下濃縮し、水を加え、酢酸エチルで抽出、無水硫酸マグネシウムで乾燥し、乾燥剤を濾別した後、溶媒を減圧下留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチルの勾配溶離＝６５／３５→０／１００）で精製して、２−（（４−ヨードフェニル）アミノ）エタノール（淡褐色固体）を得た（１１ｇ，９６％）。
ＭＳ（ＥＳＩ）：２６４（Ｍ＋Ｈ）^＋
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.60 - 1.67 (1 H, m), 3.22 - 3.30 (2 H, m), 3.79 - 3.90 (2 H, m), 3.95 - 4.09 (1 H, m), 6.44 (2 H, d, J=9.2 Hz), 7.43 (2 H, d, J=9.2 Hz)

(2) To a solution of 2-chloroethyl (4-iodophenyl) carbamate (14 g) obtained in Example 11- (1) in ethanol (210 ml) was added a solution of potassium hydroxide (12 g) in ethanol (300 ml) for 12 hours. Heated to reflux. After allowing to cool to room temperature, the reaction mixture was concentrated under reduced pressure, water was added, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution of hexane / ethyl acetate = 65/35 → 0/100) to obtain 2-((4-iodophenyl) amino) ethanol (light brown solid) ( 11 g, 96%).
MS (ESI): 264 (M + H) ^+
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.60-1.67 (1 H, m), 3.22-3.30 (2 H, m), 3.79-3.90 (2 H, m), 3.95-4.09 (1 H, m ), 6.44 (2 H, d, J = 9.2 Hz), 7.43 (2 H, d, J = 9.2 Hz)

（３）実施例１１−（２）で得た２−（（４−ヨードフェニル）アミノ）エタノール（５．２ｇ）、トリエチルアミン（８．０ｍｌ）、トリメチルシリルアセチレン（４０ｍｌ）のＴＨＦ（５０ｍｌ）溶液に、ＰｄＣｌ_２（ＰＰｈ_３）_２（０．４２ｇ）、ヨウ化銅（Ｉ）（０．２０ｇ）を加え、室温にて１時間攪拌した。反応液に水、酢酸エチルを加え抽出し、抽出物を減圧下濃縮した。残留物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノールの勾配溶離＝１００／０→９２／８）にて２回精製して、２−（（４−（（トリメチルシリル）エチニル）フェニル）アミノ）エタノール（黒色油状物）を得た（３．９ｇ，８５％）。
ＭＳ（ＥＳＩ）：２３４（Ｍ＋Ｈ）^＋，２３２（Ｍ−Ｈ）^−
1H NMR (600 MHz, CHLOROFORM-d) δppm 0.23 (9 H, s), 3.29 - 3.33 (2 H, m), 3.82 - 3.87 (2 H, m), 4.08 - 4.20 (1 H, m), 6.54 (2 H, d, J=8.7 Hz), 7.30 (2 H, d, J=8.7 Hz)

(3) To a THF (50 ml) solution of 2-((4-iodophenyl) amino) ethanol (5.2 g), triethylamine (8.0 ml), and trimethylsilylacetylene (40 ml) obtained in Example 11- (2). , PdCl ₂ (PPh ₃ ) ₂ (0.42 g) and copper (I) iodide (0.20 g) were added, and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution for extraction, and the extract was concentrated under reduced pressure. The residue was purified twice by silica gel column chromatography (gradient elution of chloroform / methanol = 100/0 → 92/8) to give 2-((4-((trimethylsilyl) ethynyl) phenyl) amino) ethanol (black Oil) was obtained (3.9 g, 85%).
MS (ESI): 234 (M + H) ⁺ , 232 (M−H) ^−
1 H NMR (600 MHz, CHLOROFORM-d) δppm 0.23 (9 H, s), 3.29-3.33 (2 H, m), 3.82-3.87 (2 H, m), 4.08-4.20 (1 H, m), 6.54 (2 H, d, J = 8.7 Hz), 7.30 (2 H, d, J = 8.7 Hz)

（４）実施例１１−（３）で得た２−（（４−（（トリメチルシリル）エチニル）フェニル）アミノ）エタノール（３．９ｇ）、炭酸カリウム（４．７ｇ）のメタノール（７５ｍｌ）懸濁液を室温で１７時間攪拌した。反応液を減圧下濃縮し、水、酢酸エチルを加え抽出し、抽出物を減圧下濃縮した。残留物をＮＨ型シリカゲルカラムクロマトグラフィー（クロロホルム／メタノールの勾配溶離＝１００／０→９２／８）で精製して、２−（（４−エチニルフェニル）アミノ）エタノール（黒色油状物）を得た（１．８ｇ，６９％）。
ＭＳ（ＥＳＩ）：１６２（Ｍ＋Ｈ）^＋
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.62 - 1.66 (1 H, m), 2.96 (1 H, s), 3.31 (2 H, t, J=5.3 Hz), 3.82 - 3.87 (2 H, m), 4.14 - 4.22 (1 H, m), 6.56 (2 H, d, J=8.7 Hz), 7.32 (2 H, d, J=8.7 Hz)

(4) Suspension of 2-((4-((trimethylsilyl) ethynyl) phenyl) amino) ethanol (3.9 g) and potassium carbonate (4.7 g) obtained in Example 11- (3) in methanol (75 ml) The solution was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, extracted with water and ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (gradient elution of chloroform / methanol = 100/0 → 92/8) to obtain 2-((4-ethynylphenyl) amino) ethanol (black oil). (1.8 g, 69%).
MS (ESI): 162 (M + H) ^+
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.62-1.66 (1 H, m), 2.96 (1 H, s), 3.31 (2 H, t, J = 5.3 Hz), 3.82-3.87 (2 H, m), 4.14-4.22 (1 H, m), 6.56 (2 H, d, J = 8.7 Hz), 7.32 (2 H, d, J = 8.7 Hz)

（５）実施例１−（６）で得た２−（４−ヨードフェニル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（０．２６ｇ）のＴＨＦ（５．０ｍｌ）溶液に、実施例１１−（４）で得た２−（（４−エチニルフェニル）アミノ）エタノール（０．６４ｇ）、トリエチルアミン（０．３ｍｌ）、ＰｄＣｌ_２（ＰＰｈ_３）_２（２９ｍｇ）、ヨウ化銅（I）（１６ｍｇ）を順次加え、室温で１時間攪拌した。溶媒を減圧下留去し、粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝９０／１０）で精製した。得られた固体をメタノールで洗浄し乾燥して、橙色固体（０．２６ｇ）を得た。さらに、シリカゲルカラムクロマトグラフィー（クロロホルム／メタノール／２５％アンモニア水溶液＝９０／９／１→クロロホルム／メタノールの勾配溶離＝９０／１０→８０／２０）で精製した。得られた固体をジエチルエーテルで洗浄し乾燥して、２−（４−（（４−（（２−ヒドロキシエチル）アミノ）フェニル）エチニル）フェニル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（橙色固体）を得た（０．１５ｇ，５３％）。
ＭＳ（ＥＳＩ）：５５３（Ｍ＋Ｈ）^＋，５５５（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆) δppm 1.55 - 1.66 (3 H, m), 1.71 - 1.81 (3 H, m), 3.14 (2 H, q, J=5.7 Hz), 3.56 (2 H, q, J=5.7 Hz), 3.59 - 3.64 (1 H, m), 3.75 (3 H, s), 4.06 - 4.13 (1 H, m), 4.73 (1 H, t, J=5.7 Hz), 5.20 (1 H, br. s.), 6.16 (1 H, t, J=5.7 Hz), 6.60 - 6.64 (2 H, m), 7.28 - 7.32 (2 H, m), 7.61 - 7.65 (2 H, m), 7.98 - 8.04 (3 H, m), 8.36 (1 H, dd, J=7.3, 2.1 Hz), 8.53 (1 H, d, J=2.1 Hz), 11.97 (1 H, br. s.)

(5) 2- (4-Iodophenyl) -3-methoxy-N- (tetrahydro-2H-pyran-2-yloxy) -1,6-naphthyridine-4-carboxamide obtained in Example 1- (6) 2-((4-Ethynylphenyl) amino) ethanol (0.64 g) obtained in Example 11- (4) and triethylamine (0.3 ml) were added to a solution of oxide (0.26 g) in THF (5.0 ml). ), PdCl ₂ (PPh ₃ ) ₂ (29 mg), and copper (I) iodide (16 mg) were sequentially added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the crude product was purified by silica gel column chromatography (chloroform / methanol = 90/10). The obtained solid was washed with methanol and dried to obtain an orange solid (0.26 g). Furthermore, it was purified by silica gel column chromatography (chloroform / methanol / 25% aqueous ammonia = 90/9/1 → gradient elution of chloroform / methanol = 90/10 → 80/20). The resulting solid was washed with diethyl ether and dried to give 2- (4-((4-((2-hydroxyethyl) amino) phenyl) ethynyl) phenyl) -3-methoxy-N- (tetrahydro-2H- Pyran-2-yloxy) -1,6-naphthyridine-4-carboxamide 6-oxide (orange solid) was obtained (0.15 g, 53%).
MS (ESI): 553 (M + H) ⁺ , 555 (M−H) ^−
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 1.55-1.66 (3 H, m), 1.71-1.81 (3 H, m), 3.14 (2 H, q, J = 5.7 Hz), 3.56 (2 H , q, J = 5.7 Hz), 3.59-3.64 (1 H, m), 3.75 (3 H, s), 4.06-4.13 (1 H, m), 4.73 (1 H, t, J = 5.7 Hz), 5.20 (1 H, br. S.), 6.16 (1 H, t, J = 5.7 Hz), 6.60-6.64 (2 H, m), 7.28-7.32 (2 H, m), 7.61-7.65 (2 H , m), 7.98-8.04 (3 H, m), 8.36 (1 H, dd, J = 7.3, 2.1 Hz), 8.53 (1 H, d, J = 2.1 Hz), 11.97 (1 H, br. s .)

（６）実施例１１−（５）で得た２−（４−（（４−（（２−ヒドロキシエチル）アミノ）フェニル）エチニル）フェニル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（５６ｍｇ）の１，４−ジオキサン（１．０ｍｌ）懸濁液に、４ｍｏｌ／ｌ−ＨＣｌ−１，４−ジオキサン溶液（１．０ｍｌ）を加え室温で２時間攪拌した。ジエチルエーテル（１０ｍｌ）を加え１０分間攪拌した後、析出した固体を濾別した。これをクロロホルム（４．０ｍｌ）に加え攪拌しながら、０．３ｍｏｌ／ｌ−トリエチルアミン−クロロホルム溶液（１．０ｍｌ）を加え１０分間攪拌した。析出した固体を濾別しクロロホルムで洗浄し乾燥して、Ｎ−ヒドロキシ−２−（４−（（４−（（２−ヒドロキシエチル）アミノ）フェニル）エチニル）フェニル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（赤色固体）を得た（３３ｍｇ，７０％）。
ＭＳ（ＥＳＩ）：４７１（Ｍ＋Ｈ）^＋，４６９（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆) δppm 3.14 (2 H, t, J=6.0 Hz), 3.56 (2 H, t, J=6.0 Hz), 3.74 (3 H, s), 6.18 (1 H, br. s.), 6.62 (2 H, d, J=8.7 Hz), 7.30 (2 H, d, J=8.7 Hz), 7.63 (2 H, d, J=8.7 Hz), 7.99 (2 H, d, J=8.7 Hz), 8.02 (1 H, d, J=7.3 Hz), 8.36 (1 H, dd, J=7.3, 2.3 Hz), 8.51 (1 H, d, J=1.8 Hz), 9.57 (1 H, br. s.), 11.39 (1 H, s)
実施例１２
Ｎ−ヒドロキシ−２−（４’−（（テトラヒドロ−２Ｈ−ピラン−４−イル）メチルアミノ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩（化合物３７）

(6) 2- (4-((4-((2-hydroxyethyl) amino) phenyl) ethynyl) phenyl) -3-methoxy-N- (tetrahydro-2H-pyran obtained in Example 11- (5) 2-yloxy) -1,6-naphthyridine-4-carboxamide 6-oxide (56 mg) in 1,4-dioxane (1.0 ml) suspension in 4 mol / l-HCl-1,4-dioxane solution ( 1.0 ml) was added and stirred at room temperature for 2 hours. Diethyl ether (10 ml) was added and stirred for 10 minutes, and the precipitated solid was filtered off. While adding this to chloroform (4.0 ml) and stirring, 0.3 mol / l-triethylamine-chloroform solution (1.0 ml) was added and stirred for 10 minutes. The precipitated solid was filtered off, washed with chloroform and dried to give N-hydroxy-2- (4-((4-((2-hydroxyethyl) amino) phenyl) ethynyl) phenyl) -3-methoxy-1, 6-naphthyridine-4-carboxamide 6-oxide (red solid) was obtained (33 mg, 70%).
MS (ESI): 471 (M + H) ⁺ , 469 (M−H) ^−
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 3.14 (2 H, t, J = 6.0 Hz), 3.56 (2 H, t, J = 6.0 Hz), 3.74 (3 H, s), 6.18 (1 H, br.s.), 6.62 (2 H, d, J = 8.7 Hz), 7.30 (2 H, d, J = 8.7 Hz), 7.63 (2 H, d, J = 8.7 Hz), 7.99 (2 H, d, J = 8.7 Hz), 8.02 (1 H, d, J = 7.3 Hz), 8.36 (1 H, dd, J = 7.3, 2.3 Hz), 8.51 (1 H, d, J = 1.8 Hz) , 9.57 (1 H, br. S.), 11.39 (1 H, s)
Example 12
N-hydroxy-2- (4 ′-((tetrahydro-2H-pyran-4-yl) methylamino) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride Salt (Compound 37)

（１）テトラヒドロ−２Ｈ−ピラン−４−カルボン酸（０．２０ｇ）、４−ブロモアニリン（０．２８ｇ）のＤＭＦ（２．０ｍｌ）溶液に、ＷＳＣ・ＨＣｌ（０．３８ｇ）、ＨＯＢｔ・Ｈ_２Ｏ（０．２６ｇ）、ＤＩＰＥＡ（０．３５ｍｌ）を加え、室温で１６時間攪拌した。反応液に氷冷下、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。溶媒を減圧下留去し、残留物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノールの勾配溶離＝１００／０→９４／６）で精製し、Ｎ−（４−ブロモフェニル）−テトラヒドロ−２Ｈ−ピラン−４−カルボキサミド（白色固体）を得た（０．３５ｇ，９５％）。
ＭＳ（ＥＳＩ）：２８４，２８６（Ｍ＋Ｈ）^＋，２８２，２８４（Ｍ−Ｈ）^−
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.82 - 1.96 (4 H, m), 2.45 - 2.51 (1 H, m), 3.43 - 3.49 (2 H, m), 4.05 - 4.10 (2 H, m), 7.10 (1 H, br. s.), 7.41 - 7.45 (4 H, m)

(1) To a solution of tetrahydro-2H-pyran-4-carboxylic acid (0.20 g) and 4-bromoaniline (0.28 g) in DMF (2.0 ml), WSC · HCl (0.38 g), HOBt · H ₂ O (0.26 g) and DIPEA (0.35 ml) were added, and the mixture was stirred at room temperature for 16 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (gradient elution of chloroform / methanol = 100/0 → 94/6), and N- (4-bromophenyl) -tetrahydro-2H-pyran- 4-Carboxamide (white solid) was obtained (0.35 g, 95%).
MS (ESI): 284, 286 (M + H) ⁺ , 282, 284 (M−H) ^−
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.82-1.96 (4 H, m), 2.45-2.51 (1 H, m), 3.43-3.49 (2 H, m), 4.05-4.10 (2 H, m ), 7.10 (1 H, br. S.), 7.41-7.45 (4 H, m)

（２）実施例１２−（１）で得たＮ−（４−ブロモフェニル）テトラヒドロ−２Ｈ−ピラン−４−カルボキサミド（０．３５ｇ）のＴＨＦ（７．０ｍｌ）溶液に氷冷下、水素化ホウ素ナトリウム（０．１３ｇ）、次いで三フッ化ホウ素ジエチルエーテラート（０．３４ｍｌ）を加え室温で３．５時間攪拌した。反応液にエタノール（１４ｍｌ）を加え３時間加熱還流した。放冷後、溶媒を減圧下留去し、残留物に飽和食塩水を加えて酢酸エチルで抽出し、溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチルの勾配溶離＝９０／１０→６５／３５）で精製して、４−ブロモ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）アニリン（淡黄色固体）を得た（０．２９ｇ，８７％）。
ＭＳ（ＥＳＩ）：２７０，２７２（Ｍ＋Ｈ）^＋
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.30 - 1.40 (2 H, m), 1.66 - 1.72 (2 H, m), 1.77 - 1.88 (1 H, m), 3.00 (2 H, d, J=6.4 Hz), 3.35 - 3.42 (2 H, m), 3.96 - 4.03 (2 H, m), 6.47 (2 H, d, J=8.7 Hz), 7.24 (2 H, d, J=8.7 Hz)

(2) Hydrogenation of a solution of N- (4-bromophenyl) tetrahydro-2H-pyran-4-carboxamide (0.35 g) obtained in Example 12- (1) in THF (7.0 ml) under ice-cooling Sodium boron (0.13 g) and then boron trifluoride diethyl etherate (0.34 ml) were added, and the mixture was stirred at room temperature for 3.5 hours. Ethanol (14 ml) was added to the reaction mixture, and the mixture was heated to reflux for 3 hours. After allowing to cool, the solvent was evaporated under reduced pressure, saturated brine was added to the residue, and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution of hexane / ethyl acetate = 90/10 → 65/35) to give 4-bromo-N- (tetrahydro-2H-pyran-4-ylmethyl) aniline. (Pale yellow solid) was obtained (0.29 g, 87%).
MS (ESI): 270, 272 (M + H) ^+
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.30-1.40 (2 H, m), 1.66-1.72 (2 H, m), 1.77-1.88 (1 H, m), 3.00 (2 H, d, J = 6.4 Hz), 3.35-3.42 (2 H, m), 3.96-4.03 (2 H, m), 6.47 (2 H, d, J = 8.7 Hz), 7.24 (2 H, d, J = 8.7 Hz)

（３）実施例１２−（２）で得た４−ブロモ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）アニリン（０．２９ｇ）、ＰｄＣｌ_２（ｄｐｐｆ）（６３ｍｇ）、酢酸カリウム（０．３６ｇ）及びビス（ピナコラト）ジボロン（０．４３ｇ）のＤＭＳＯ（２．９ｍｌ）懸濁液を、窒素雰囲気下１００℃で４時間攪拌した。反応液を放冷後、水を加え酢酸エチルで２回抽出し、溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチルの勾配溶離＝９０／１０→６５／３５）で精製して、褐色油状物（９５ｍｇ）を得た。この褐色油状物（９５ｍｇ）、実施例１−（６）で得た２−（４−ヨードフェニル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（０．１１ｇ）、Ｐｄ（ＰＰｈ_３）_４（２４ｍｇ）、２ｍｏｌ／ｌ−炭酸ナトリウム水溶液（０．３ｍｌ）及び水（３ｍｌ）のＤＭＥ（１ｍｌ）懸濁液を、窒素雰囲気下８５℃で３時間攪拌した。反応液を放冷後、飽和食塩水を加えクロロホルムで３回抽出した。溶媒を減圧下留去し、得られた残留物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノールの勾配溶離＝９９／１→９４／６）で精製し、酢酸エチルで洗浄して３−メトキシ−２−（４’−（（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）アミノ）ビフェニル−４−イル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（橙色固体）を得た（７３ｍｇ，２８％）。
ＭＳ（ＥＳＩ）：５８５（Ｍ＋Ｈ）^＋，５８３（Ｍ−Ｈ）^−
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.35 - 1.46 (2 H, m), 1.65 - 2.03 (8 H, m), 2.07 - 2.13 (1 H, m), 3.12 (2 H, br. s.), 3.42 (2 H, t, J=10.8 Hz), 3.81 - 3.86 (1 H, m), 3.87 (3 H, s), 3.91 - 3.97 (1 H, m), 3.99 - 4.05 (2 H, m), 4.19 - 4.25 (1 H, m), 5.50 (1 H, br. s.), 6.72 (2 H, d, J=8.3 Hz), 7.52 (1 H, d, J=6.9 Hz), 7.56 (2 H, d, J=8.3 Hz), 7.60 (1 H, d, J=6.9 Hz), 7.72 (2 H, d, J=8.3 Hz), 8.11 (2 H, d, J=8.3 Hz), 8.78 (1 H, s), 11.71 (1 H, br. s.)

(3) 4-Bromo-N- (tetrahydro-2H-pyran-4-ylmethyl) aniline (0.29 g) obtained in Example 12- (2), PdCl ₂ (dppf) (63 mg), potassium acetate (0 .36 g) and bis (pinacolato) diboron (0.43 g) in DMSO (2.9 ml) were stirred at 100 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool, water was added, and the mixture was extracted twice with ethyl acetate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate gradient elution = 90/10 → 65/35) to give a brown oil (95 mg). This brown oil (95 mg), 2- (4-iodophenyl) -3-methoxy-N- (tetrahydro-2H-pyran-2-yloxy) -1,6-naphthyridine obtained in Example 1- (6) A suspension of DME (1 ml) in -4-carboxamide 6-oxide (0.11 g), Pd (PPh ₃ ) ₄ (24 mg), 2 mol / l-sodium carbonate aqueous solution (0.3 ml) and water (3 ml) The mixture was stirred at 85 ° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool, saturated brine was added, and the mixture was extracted 3 times with chloroform. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (gradient elution of chloroform / methanol = 99/1 → 94/6), washed with ethyl acetate and washed with 3-methoxy-2- (4 ′-((Tetrahydro-2H-pyran-4-ylmethyl) amino) biphenyl-4-yl) -N- (tetrahydro-2H-pyran-2-yloxy) -1,6-naphthyridine-4-carboxamide 6 The oxide (orange solid) was obtained (73 mg, 28%).
MS (ESI): 585 (M + H) ⁺ , 583 (M−H) ^−
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.35-1.46 (2 H, m), 1.65-2.03 (8 H, m), 2.07-2.13 (1 H, m), 3.12 (2 H, br. S .), 3.42 (2 H, t, J = 10.8 Hz), 3.81-3.86 (1 H, m), 3.87 (3 H, s), 3.91-3.97 (1 H, m), 3.99-4.05 (2 H , m), 4.19-4.25 (1 H, m), 5.50 (1 H, br.s.), 6.72 (2 H, d, J = 8.3 Hz), 7.52 (1 H, d, J = 6.9 Hz) , 7.56 (2 H, d, J = 8.3 Hz), 7.60 (1 H, d, J = 6.9 Hz), 7.72 (2 H, d, J = 8.3 Hz), 8.11 (2 H, d, J = 8.3 Hz), 8.78 (1 H, s), 11.71 (1 H, br.s.)

（４）実施例１２−（３）で得た３−メトキシ−２−（４’−（（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）アミノ）ビフェニル−４−イル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（１０ｍｇ）のメタノール（０．１０ｍｌ）、１，４−ジオキサン（０．２０ｍｌ）の溶液に、４ｍｏｌ／ｌ−ＨＣｌ−１，４−ジオキサン溶液（０．１０ｍｌ）を加え、室温で３０分間攪拌した。反応液を濃縮し、クロロホルム及びジエチルエーテルを加え析出した固体を濾別、乾燥し、Ｎ−ヒドロキシ−３−メトキシ−２−（４’−（（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）アミノ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩（褐色固体）を得た（７．４ｍｇ，７２％）。
ＭＳ（ＥＳＩ）：５０１（Ｍ＋Ｈ）^＋，４９９（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆) δppm 1.18 - 1.29 (2 H, m), 1.66 - 1.74 (2 H, m), 1.76 - 1.88 (1 H, m), 2.95 - 3.02 (2 H, m), 3.25 - 3.32 (2 H, m), 3.74 (3 H, s), 3.87 (2 H, dd, J=11.2, 3.0 Hz), 6.74 (2 H, d, J=7.8 Hz), 7.56 (2 H, d, J=8.7 Hz), 7.75 (2 H, d, J=8.7 Hz), 7.99 - 8.04 (3 H, m), 8.35 (1 H, dd, J=7.3, 1.8 Hz), 8.50 (1 H, d, J=1.8 Hz), 11.39 (1 H, s)
実施例１３
Ｎ−ヒドロキシ−７−（４’−（４−ヒドロキシブチルアミノ）ビフェニル−４−イル）−１，８−ナフチリジン−５−カルボキサミド １−オキシド２塩酸塩（化合物３８）

(4) 3-methoxy-2- (4 ′-((tetrahydro-2H-pyran-4-ylmethyl) amino) biphenyl-4-yl) -N- (tetrahydro-2H obtained in Example 12- (3) -Pyran-2-yloxy) -1,6-naphthyridine-4-carboxamide 6 mol (10 mg) in methanol (0.10 ml), 1,4-dioxane (0.20 ml) in a solution of 4 mol / l-HCl A -1,4-dioxane solution (0.10 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, chloroform and diethyl ether were added, and the precipitated solid was filtered off and dried, and N-hydroxy-3-methoxy-2- (4 ′-((tetrahydro-2H-pyran-4-ylmethyl) amino) Biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride (brown solid) was obtained (7.4 mg, 72%).
MS (ESI): 501 (M + H) ⁺ , 499 (M−H) ^−
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 1.18-1.29 (2 H, m), 1.66-1.74 (2 H, m), 1.76-1.88 (1 H, m), 2.95-3.02 (2 H, m), 3.25-3.32 (2 H, m), 3.74 (3 H, s), 3.87 (2 H, dd, J = 11.2, 3.0 Hz), 6.74 (2 H, d, J = 7.8 Hz), 7.56 (2 H, d, J = 8.7 Hz), 7.75 (2 H, d, J = 8.7 Hz), 7.99-8.04 (3 H, m), 8.35 (1 H, dd, J = 7.3, 1.8 Hz), 8.50 (1 H, d, J = 1.8 Hz), 11.39 (1 H, s)
Example 13
N-hydroxy-7- (4 ′-(4-hydroxybutylamino) biphenyl-4-yl) -1,8-naphthyridine-5-carboxamide 1-oxide dihydrochloride (Compound 38)

（１）２，２−ジメチル−Ｎ−（ピリジン−２−イル）プロパンアミド（４．１ｇ）のＴＨＦ（５５ｍｌ）溶液に、−７０℃で２．６ｍｏｌ／ｌ−ｎ−ブチルリチウム−ヘキサン溶液（２２ｍｌ）を滴下し、０℃で４時間攪拌した。その後−７０℃でシュウ酸ジエチル（８．３ｇ）のＴＨＦ（１０ｍｌ）溶液を加え、室温まで昇温し、１時間攪拌した。反応液を１ｍｏｌ／ｌ−塩酸水溶液に注ぎ酢酸エチルで抽出した。抽出物を無水硫酸マグネシウムで乾燥し、乾燥剤を濾別した後、溶媒を減圧下留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチルの勾配溶離＝５７／４３→３６／６４）で精製して、（２−（（２，２−ジメチルプロパノイル）アミノ）ピリジン−３−イル）（オキソ）酢酸エチル（橙色油状物）を得た（３．７ｇ，５７％）。
ＭＳ（ＥＳＩ）：２７７（Ｍ−Ｈ）^−
1H NMR (600 MHz, CHLOROFORM-d)δppm 1.34 (9 H, s), 1.43 (3 H, t, J=7.0 Hz), 4.42 (2 H, q, J=7.0 Hz), 7.17 (1 H, dd, J=7.8, 5.0 Hz), 8.08 (1 H, dd, J=7.8, 1.8 Hz), 8.62 (1 H, dd, J=5.0, 1.8 Hz), 9.92 (1 H, s)

(1) 2,2-dimethyl-N- (pyridin-2-yl) propanamide (4.1 g) in a THF (55 ml) solution at −70 ° C. in a 2.6 mol / l-n-butyllithium-hexane solution (22 ml) was added dropwise and stirred at 0 ° C. for 4 hours. Thereafter, a solution of diethyl oxalate (8.3 g) in THF (10 ml) was added at −70 ° C., and the mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was poured into a 1 mol / l-hydrochloric acid aqueous solution and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate gradient elution = 57/43 → 36/64) to give (2-((2,2-dimethylpropanoyl) amino) pyridin-3-yl). Ethyl (oxo) acetate (orange oil) was obtained (3.7 g, 57%).
MS (ESI): 277 (M−H) ^−
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.34 (9 H, s), 1.43 (3 H, t, J = 7.0 Hz), 4.42 (2 H, q, J = 7.0 Hz), 7.17 (1 H , dd, J = 7.8, 5.0 Hz), 8.08 (1 H, dd, J = 7.8, 1.8 Hz), 8.62 (1 H, dd, J = 5.0, 1.8 Hz), 9.92 (1 H, s)

（２）実施例１３−（１）で得た（２−（（２，２−ジメチルプロパノイル）アミノ）ピリジン−３−イル）（オキソ）酢酸エチル（３．０ｇ）の５０％エタノール水溶液（３０ｍｌ）に水酸化カリウム（２．８ｇ）を加え、室温で２０分攪拌後、４’−ブロモアセトフェノン（２．９ｇ）を加え、６時間加熱還流した。室温まで放冷後、水及び酢酸を加えて析出した固体を濾別し、乾燥して、２−（４−ブロモフェニル）−１，８−ナフチリジン−４−カルボン酸（淡褐色固体）を得た（２．９ｇ，８２％）。
ＭＳ（ＥＳＩ）： ３２９（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆) δppm 7.72 (1 H, dd, J=8.7, 4.1 Hz), 7.81 (2 H, d, J=8.7 Hz), 8.31 (2 H, d, J=8.7 Hz), 8.56 (1 H, s), 9.13 (1 H, dd, J=8.7, 1.8 Hz), 9.16 (1 H, dd, J=4.1, 1.8 Hz)

(2) 50% aqueous ethanol solution of (2-((2,2-dimethylpropanoyl) amino) pyridin-3-yl) (oxo) acetate (3.0 g) obtained in Example 13- (1) ( 30 ml) was added potassium hydroxide (2.8 g), stirred at room temperature for 20 minutes, 4′-bromoacetophenone (2.9 g) was added, and the mixture was heated to reflux for 6 hours. After allowing to cool to room temperature, water and acetic acid were added and the precipitated solid was filtered off and dried to give 2- (4-bromophenyl) -1,8-naphthyridine-4-carboxylic acid (light brown solid). (2.9 g, 82%).
MS (ESI): 329 (M−H) ^−
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 7.72 (1 H, dd, J = 8.7, 4.1 Hz), 7.81 (2 H, d, J = 8.7 Hz), 8.31 (2 H, d, J = 8.7 Hz), 8.56 (1 H, s), 9.13 (1 H, dd, J = 8.7, 1.8 Hz), 9.16 (1 H, dd, J = 4.1, 1.8 Hz)

（３）実施例１３−（２）で得た２−（４−ブロモフェニル）−１，８−ナフチリジン−４−カルボン酸（２．８ｇ）のＤＭＦ（２０ｍｌ）溶液に、Ｏ−（テトラヒドロ−２Ｈ−ピラン−２−イル）ヒドロキシルアミン（１．３ｇ）、ＷＳＣ・ＨＣｌ（２．０ｇ）、ＨＯＢｔ・Ｈ_２Ｏ（１．４ｇ）、ＤＩＰＥＡ（１．９ｇ）を加え、室温で７時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて酢酸エチルで抽出した。抽出物を無水硫酸マグネシウムで乾燥し、乾燥剤を濾別した後、溶媒を減圧下留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチルの勾配溶離＝２５／７５→０／１００）で精製して、２−（４−ブロモフェニル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，８−ナフチリジン−４−カルボキサミド（淡黄色固体）を得た（３．１ｇ，８４％）。
ＭＳ（ＥＳＩ）：４２８（Ｍ＋Ｈ）^＋，４２６（Ｍ−Ｈ）^−
1H NMR (600 MHz, CHLOROFORM-d)δppm 1.51 - 2.12 (6 H, m), 3.70 - 3.80 (1 H, m), 4.15 - 4.23 (1 H, m), 5.31 - 5.42 (1 H, m), 7.35 - 7.43 (1 H, m), 7.52 - 7.67 (2 H, m), 7.81 - 7.90 (1 H, m), 7.93 - 8.07 (2 H, m), 8.52 (1 H, d, J=4.6 Hz), 9.01 - 9.11 (1 H, m), 9.91 (1 H, s)

(3) To a solution of 2- (4-bromophenyl) -1,8-naphthyridine-4-carboxylic acid (2.8 g) obtained in Example 13- (2) in DMF (20 ml), O- (tetrahydro- 2H-pyran-2-yl) hydroxylamine (1.3 g), WSC · HCl (2.0 g), HOBt · H ₂ O (1.4 g), DIPEA (1.9 g) were added, and the mixture was stirred at room temperature for 7 hours. did. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution of hexane / ethyl acetate = 25/75 → 0/100) to give 2- (4-bromophenyl) -N- (tetrahydro-2H-pyran-2-yloxy). ) -1,8-naphthyridine-4-carboxamide (pale yellow solid) was obtained (3.1 g, 84%).
MS (ESI): 428 (M + H) ⁺ , 426 (M−H) ^−
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.51-2.12 (6 H, m), 3.70-3.80 (1 H, m), 4.15-4.23 (1 H, m), 5.31-5.42 (1 H, m ), 7.35-7.43 (1 H, m), 7.52-7.67 (2 H, m), 7.81-7.90 (1 H, m), 7.93-8.07 (2 H, m), 8.52 (1 H, d, J = 4.6 Hz), 9.01-9.11 (1 H, m), 9.91 (1 H, s)

（４）実施例１３−（３）で得た２−（４−ブロモフェニル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，８−ナフチリジン−４−カルボキサミド（０．４３ｇ）のクロロホルム（５ｍｌ）溶液に、０℃でｍＣＰＢＡ（＞６５％）（０．４０ｇ）、炭酸水素ナトリウム（０．２１ｇ）を加え、０℃で３０分間次いで室温で２時間攪拌した。反応液にチオ硫酸ナトリウム水溶液を加えてクロロホルムで抽出、無水硫酸マグネシウムで乾燥し、乾燥剤を濾別した後、溶媒を減圧下留去した。残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル→クロロホルム／メタノールの勾配溶離＝９７／３→９０／１０）で精製して、７−（４−ブロモフェニル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，８−ナフチリジン−５−カルボキサミド １−オキシド（黄色固体）を得た（０．３８ｇ，８６％）。
ＭＳ（ＥＳＩ）：４４４，４４６（Ｍ＋Ｈ）^＋，４４２，４４４（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆) δppm 1.44 - 1.84 (6 H, m) 3.50 - 3.64 (1 H, m) 3.85 - 4.10 (1 H, m) 5.09 - 5.17 (1 H, m) 7.53 (1 H, dd, J=8.5, 6.2 Hz) 7.81 (2 H, d, J=8.7 Hz) 7.95 (1 H, d, J=8.5 Hz) 8.31 (2 H, d, J=8.7 Hz) 8.44 (1 H, s) 8.77 (1 H, d, J=6.2 Hz) 12.01 (1 H, br. s.)

(4) 2- (4-Bromophenyl) -N- (tetrahydro-2H-pyran-2-yloxy) -1,8-naphthyridine-4-carboxamide (0.43 g) obtained in Example 13- (3) MCPBA (> 65%) (0.40 g) and sodium hydrogen carbonate (0.21 g) were added at 0 ° C. to a chloroform (5 ml) solution, and the mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for 2 hours. To the reaction solution was added an aqueous sodium thiosulfate solution, extracted with chloroform, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution of ethyl acetate → chloroform / methanol = 97/3 → 90/10) to give 7- (4-bromophenyl) -N- (tetrahydro-2H-pyran-2 -Iyloxy) -1,8-naphthyridine-5-carboxamide 1-oxide (yellow solid) was obtained (0.38 g, 86%).
MS (ESI): 444, 446 (M + H) ⁺ , 442, 444 (M−H) ^−
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 1.44-1.84 (6 H, m) 3.50-3.64 (1 H, m) 3.85-4.10 (1 H, m) 5.09-5.17 (1 H, m) 7.53 (1 H, dd, J = 8.5, 6.2 Hz) 7.81 (2 H, d, J = 8.7 Hz) 7.95 (1 H, d, J = 8.5 Hz) 8.31 (2 H, d, J = 8.7 Hz) 8.44 (1 H, s) 8.77 (1 H, d, J = 6.2 Hz) 12.01 (1 H, br.s.)

（５）実施例１３−（４）で得た７−（４−ブロモフェニル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，８−ナフチリジン−５−カルボキサミド １−オキシド（０．１０ｇ）、実施例３−（１）で得た４−（（４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェニル）アミノ）ブタン−１−オール（８５ｍｇ）、Ｐｄ（ＰＰｈ_３）_４（２６ｍｇ）、２ｍｏｌ／ｌ−炭酸ナトリウム水溶液（０．５ｍｌ）のＤＭＦ（２ｍｌ）懸濁液を窒素雰囲気下８５℃で７時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えてクロロホルムで抽出した。無水硫酸マグネシウムで乾燥し、乾燥剤を濾別した後、溶媒を減圧下留去した。得られた残留物を分取用シリカゲル薄層クロマトグラフィー（クロロホルム／メタノール＝８／１）で精製して、７−（４’−（４−ヒドロキシブチルアミノ）ビフェニル−４−イル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，８−ナフチリジン−５−カルボキサミド １−オキシド（褐色固体）を得た（２４ｍｇ，２０％）。
ＭＳ（ＥＳＩ）：５２９（Ｍ＋Ｈ）^＋，５２７（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆) δppm 1.44 - 1.64 (7 H, m) 1.67 - 1.80 (3 H, m) 2.97 - 3.08 (2 H, m) 3.39 - 3.43 (2 H, m) 3.53 - 3.61 (1 H, m) 3.98 - 4.08 (1 H, m) 4.40 (1 H, t, J=5.0 Hz) 5.10 - 5.17 (1 H, m) 5.91 (1 H, t, J=5.5 Hz) 6.65 (2 H, d, J=8.7 Hz) 7.48 (1 H, dd, J=8.5, 6.4 Hz) 7.56 (2 H, d, J=8.7 Hz) 7.79 (2 H, d, J=8.7 Hz) 7.93 - 8.03 (1 H, m) 8.36 (2 H, d, J=8.7 Hz) 8.41 (1 H, s) 8.75 (1 H, d, J=6.4 Hz) 12.04 (1 H, br. s.)

(5) 7- (4-Bromophenyl) -N- (tetrahydro-2H-pyran-2-yloxy) -1,8-naphthyridine-5-carboxamide 1-oxide (0) obtained in Example 13- (4) 10 g), 4-((4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) amino) butane- obtained in Example 3- (1) A suspension of 1-ol (85 mg), Pd (PPh ₃ ) ₄ (26 mg), 2 mol / l-sodium carbonate aqueous solution (0.5 ml) in DMF (2 ml) was stirred at 85 ° C. under a nitrogen atmosphere for 7 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. After drying over anhydrous magnesium sulfate and filtering off the desiccant, the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative silica gel thin layer chromatography (chloroform / methanol = 8/1) to give 7- (4 ′-(4-hydroxybutylamino) biphenyl-4-yl) -N—. (Tetrahydro-2H-pyran-2-yloxy) -1,8-naphthyridine-5-carboxamide 1-oxide (brown solid) was obtained (24 mg, 20%).
MS (ESI): 529 (M + H) ⁺ , 527 (M−H) ^−
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 1.44-1.64 (7 H, m) 1.67-1.80 (3 H, m) 2.97-3.08 (2 H, m) 3.39-3.43 (2 H, m) 3.53 -3.61 (1 H, m) 3.98-4.08 (1 H, m) 4.40 (1 H, t, J = 5.0 Hz) 5.10-5.17 (1 H, m) 5.91 (1 H, t, J = 5.5 Hz) 6.65 (2 H, d, J = 8.7 Hz) 7.48 (1 H, dd, J = 8.5, 6.4 Hz) 7.56 (2 H, d, J = 8.7 Hz) 7.79 (2 H, d, J = 8.7 Hz) 7.93-8.03 (1 H, m) 8.36 (2 H, d, J = 8.7 Hz) 8.41 (1 H, s) 8.75 (1 H, d, J = 6.4 Hz) 12.04 (1 H, br.s.)

（６）実施例１３−（５）で得た７−（４’−（４−ヒドロキシブチルアミノ）ビフェニル−４−イル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，８−ナフチリジン−５−カルボキサミド １−オキシド（２１ｍｇ）にメタノール（１ｍｌ）及び４ｍｏｌ／ｌ−ＨＣｌ−１，４−ジオキサン溶液（１ｍｌ）を加え、室温で１時間攪拌した。反応液にジエチルエーテルを加え析出した固体を濾別しジエチルエーテルで洗浄して、Ｎ−ヒドロキシ−７−（４’−（４−ヒドロキシブチルアミノ）ビフェニル−４−イル）−１，８−ナフチリジン−５−カルボキサミド １−オキシド２塩酸塩（黄土色固体）を得た（７．０ｍｇ，４０％）。
ＭＳ（ＥＳＩ）：４４５（Ｍ＋Ｈ）^＋，４４３（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆+D₂O) δppm 1.38 - 1.55 (2 H, m) 1.55 - 1.67 (2 H, m) 3.15 (2 H, t, J=6.9 Hz) 3.39 - 3.42 (2 H, m) 6.90 - 7.13 (2 H, m) 7.56 (1 H, dd, J=8.7, 6.0 Hz) 7.65 - 7.76 (2 H, m) 7.85 (2 H, d, J=8.3 Hz) 8.07 (1 H, d, J=8.7 Hz) 8.34 - 8.47 (3 H, m) 8.84 (1 H, d, J=6.0 Hz)
実施例１４
Ｎ−ヒドロキシ−２−（４−（４−（３−ヒドロキシプロピル）ピペリジン−１−イル）フェニル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩（化合物５５）

(6) 7- (4 ′-(4-hydroxybutylamino) biphenyl-4-yl) -N- (tetrahydro-2H-pyran-2-yloxy) -1,8 obtained in Example 13- (5) -Naphthyridine-5-carboxamide 1-oxide (21 mg) was added with methanol (1 ml) and 4 mol / l-HCl-1,4-dioxane solution (1 ml), and stirred at room temperature for 1 hour. Diethyl ether was added to the reaction solution, and the precipitated solid was separated by filtration, washed with diethyl ether, and N-hydroxy-7- (4 ′-(4-hydroxybutylamino) biphenyl-4-yl) -1,8-naphthyridine. -5-carboxamide 1-oxide dihydrochloride (ocher solid) was obtained (7.0 mg, 40%).
MS (ESI): 445 (M + H) ⁺ , 443 (M−H) ^−
1 H NMR (600 MHz, DMSO-d ₆ + D ₂ O) δppm 1.38-1.55 (2 H, m) 1.55-1.67 (2 H, m) 3.15 (2 H, t, J = 6.9 Hz) 3.39-3.42 (2 H, m) 6.90-7.13 (2 H, m) 7.56 (1 H, dd, J = 8.7, 6.0 Hz) 7.65-7.76 (2 H, m) 7.85 (2 H, d, J = 8.3 Hz) 8.07 (1 H, d, J = 8.7 Hz) 8.34-8.47 (3 H, m) 8.84 (1 H, d, J = 6.0 Hz)
Example 14
N-hydroxy-2- (4- (4- (3-hydroxypropyl) piperidin-1-yl) phenyl) -1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride (Compound 55)

（１）４’−フルオロアセトフェノン（０．４０ｇ）、３−（ピペリジン−４−イル）プロパン−１−オール（０．４１ｇ）のＤＭＳＯ（１０ｍｌ）溶液に、ＤＩＰＥＡ（０．７３ｇ）を加え、１５０℃で３日間攪拌した。室温に放冷後、水を加えて酢酸エチルで抽出した。抽出物を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別した後、溶媒を減圧下留去した。残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製して、１−（４−（４−（３−ヒドロキシプロピル）ピペリジン−１−イル）フェニル）エタノン（褐色固体）を得た（０．２２ｇ，３０％）。
ＭＳ（ＥＳＩ）：２６２（Ｍ＋Ｈ）^＋
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.16 - 1.39 (4 H, m), 1.40 - 1.55 (1 H, m), 1.56 - 1.67 (2 H, m), 1.72 - 1.87 (2 H, m), 2.50 (3 H, s), 2.73 - 2.93 (2 H, m), 3.60 - 3.69 (2 H, m), 3.81 - 3.95 (2 H, m), 6.85 (2 H, d, J=9.2 Hz), 7.84 (2 H, d, J=9.2 Hz)

(1) DIPEA (0.73 g) was added to a solution of 4′-fluoroacetophenone (0.40 g), 3- (piperidin-4-yl) propan-1-ol (0.41 g) in DMSO (10 ml), The mixture was stirred at 150 ° C. for 3 days. After allowing to cool to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 1- (4- (4- (3-hydroxypropyl) piperidin-1-yl) phenyl) ethanone (brown solid) (0.22 g). , 30%).
MS (ESI): 262 (M + H) ^+
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.16-1.39 (4 H, m), 1.40-1.55 (1 H, m), 1.56-1.67 (2 H, m), 1.72-1.87 (2 H, m ), 2.50 (3 H, s), 2.73-2.93 (2 H, m), 3.60-3.69 (2 H, m), 3.81-3.95 (2 H, m), 6.85 (2 H, d, J = 9.2 Hz), 7.84 (2 H, d, J = 9.2 Hz)

（２）実施例１４−（１）で得た１−（４−（４−（３−ヒドロキシプロピル）ピペリジン−１−イル）フェニル）エタノン（０．２２ｇ）、実施例６−（２）で得た（４−（（２，２−ジメチルプロパノイル）アミノ）ピリジン−３−イル）（オキソ）酢酸エチル（０．２３ｇ）の５０％エタノール水溶液（４．０ｍｌ）に水酸化カリウム（０．２６ｇ）を加え、８時間加熱還流した。室温まで放冷し酢酸を加えた後、固体が析出するまで溶媒を減圧下留去した。析出した固体を濾別、クロロホルム及び水で洗浄、乾燥して、２−（４−（４−（３−ヒドロキシプロピル）ピペリジン−１−イル）フェニル）−１，６−ナフチリジン−４−カルボン酸（褐色固体）を得た（８３ｍｇ，２５％）。
ＭＳ（ＥＳＩ）：３９２（Ｍ＋Ｈ）^＋，３９０（Ｍ−Ｈ）^−
1H NMR (600 MHz, DMSO-d₆) δppm 1.17 - 1.29 (4 H, m), 1.39 - 1.51 (3 H, m), 1.69 - 1.80 (2 H, m), 2.73 - 2.85 (2 H, m), 3.32 - 3.42 (2 H, m), 3.87 - 3.95 (2 H, m), 4.41 (1 H, s), 7.07 (2 H, d, J=8.7 Hz), 7.72 - 7.79 (2 H, m), 8.05 (1 H, s), 8.14 (2 H, d, J=8.7 Hz), 8.55 (1 H, d, J=6.0 Hz), 9.95 (1 H, s)

(2) 1- (4- (4- (3-hydroxypropyl) piperidin-1-yl) phenyl) ethanone (0.22 g) obtained in Example 14- (1), in Example 6- (2) The obtained (4-((2,2-dimethylpropanoyl) amino) pyridin-3-yl) (oxo) ethyl acetate (0.23 g) in 50% ethanol aqueous solution (4.0 ml) was added with potassium hydroxide (0. 26 g) was added and heated to reflux for 8 hours. After cooling to room temperature and adding acetic acid, the solvent was distilled off under reduced pressure until a solid precipitated. The precipitated solid was separated by filtration, washed with chloroform and water and dried to give 2- (4- (4- (3-hydroxypropyl) piperidin-1-yl) phenyl) -1,6-naphthyridine-4-carboxylic acid (Brown solid) was obtained (83 mg, 25%).
MS (ESI): 392 (M + H) ⁺ , 390 (M−H) ^−
1 H NMR (600 MHz, DMSO-d ₆ ) δppm 1.17-1.29 (4 H, m), 1.39-1.51 (3 H, m), 1.69-1.80 (2 H, m), 2.73-2.85 (2 H, m), 3.32-3.42 (2 H, m), 3.87-3.95 (2 H, m), 4.41 (1 H, s), 7.07 (2 H, d, J = 8.7 Hz), 7.72-7.79 (2 H , m), 8.05 (1 H, s), 8.14 (2 H, d, J = 8.7 Hz), 8.55 (1 H, d, J = 6.0 Hz), 9.95 (1 H, s)

（３）実施例１４−（２）で得た２−（４−（４−（３−ヒドロキシプロピル）ピペリジン−１−イル）フェニル）−１，６−ナフチリジン−４−カルボン酸（８０ｍｇ）のＤＭＦ（２．０ｍｌ）溶液に、Ｏ−（テトラヒドロ−２Ｈ−ピラン−２−イル）ヒドロキシルアミン（３６ｍｇ）、ＷＳＣ・ＨＣｌ（５９ｍｇ）、ＨＯＢｔ・Ｈ_２Ｏ（４７ｍｇ）を加え、６０℃で４時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。抽出物に飽和炭酸水素ナトリウム水溶液を加えて酢酸エチルで抽出し、飽和食塩水で洗浄した。抽出物を無水硫酸マグネシウムで乾燥し、乾燥剤を濾別した後、溶媒を減圧下留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／１）で精製して、２−（４−（４−（３−ヒドロキシプロピル）ピペリジン−１−イル）フェニル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド（褐色固体）を得た（４５ｍｇ，４５％）。
ＭＳ（ＥＳＩ）：４９１（Ｍ＋Ｈ）^＋，４８９（Ｍ−Ｈ）^−
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.29 - 2.14 (15 H, m), 2.88 (2 H, s), 3.62 - 3.75 (3 H, m), 3.86 - 3.96 (3 H, m), 4.03 - 4.10 (1 H, m), 5.25 - 5.35 (1 H, m), 7.00 (2 H, d, J=8.3 Hz), 7.86 (1 H, d, J=6.0 Hz), 7.93 (1 H, s), 8.08 (2 H, d, J=8.3 Hz), 8.26 (1 H, s), 8.69 (1 H, d, J=6.0 Hz), 9.54 (1 H, s)

(3) 2- (4- (4- (3-hydroxypropyl) piperidin-1-yl) phenyl) -1,6-naphthyridine-4-carboxylic acid (80 mg) obtained in Example 14- (2) To a DMF (2.0 ml) solution, O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (36 mg), WSC · HCl (59 mg), HOBt · H ₂ O (47 mg) were added, and the mixture was stirred at 60 ° C. for 4 hours. Stir for hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. To the extract was added saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, and washed with saturated brine. The extract was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 2- (4- (4- (3-hydroxypropyl) piperidin-1-yl) phenyl) -N- (tetrahydro- 2H-pyran-2-yloxy) -1,6-naphthyridine-4-carboxamide (brown solid) was obtained (45 mg, 45%).
MS (ESI): 491 (M + H) ⁺ , 489 (M−H) ^−
1 H NMR (600 MHz, CHLOROFORM-d) δppm 1.29-2.14 (15 H, m), 2.88 (2 H, s), 3.62-3.75 (3 H, m), 3.86-3.96 (3 H, m), 4.03-4.10 (1 H, m), 5.25-5.35 (1 H, m), 7.00 (2 H, d, J = 8.3 Hz), 7.86 (1 H, d, J = 6.0 Hz), 7.93 (1 H , s), 8.08 (2 H, d, J = 8.3 Hz), 8.26 (1 H, s), 8.69 (1 H, d, J = 6.0 Hz), 9.54 (1 H, s)

（４）実施例１４−（３）で得た２−（４−（４−（３−ヒドロキシプロピル）ピペリジン−１−イル）フェニル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド（２００ｍｇ）のクロロホルム（２．０ｍｌ）溶液に、炭酸水素ナトリウム（１０３ｍｇ）を加え、氷冷下ｍＣＰＢＡ（＞６５％）（１８４ｍｇ）を加え、室温で２０分間攪拌した。反応液を分取用シリカゲル薄層クロマトグラフィー（クロロホルム／メタノール＝１０／１）で精製して、２−（４−（４−（３−ヒドロキシプロピル）ピペリジン−１−イル）フェニル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（黄色油状物）を得た（９ｍｇ，４％）。
¹H NMR (400 MHz, CD₃OD) δppm 1.40 - 1.55 (2H, m), 1.55 - 2.05 (11H, m), 2.10 - 2.30 (2H, m), 3.20 - 3.40 (2H, m), 3.55 - 3.65 (2H, m), 3.65 - 3.75 (1H, m),3.95 - 4.10 (2H, m), 4.10 - 4.25 (1H, m), 5.22 - 5.32 (1H, m), 8.06 (1H, dd, J=6.0, 0.9 Hz), 8.22 (2H, d, J=9.0 Hz), 8.35 (1H, s), 8.47 (2H, d, J=9.0 Hz), 8.75 (1H, d, J=6.0 Hz), 9.59 (1H, s)

(4) 2- (4- (4- (3-hydroxypropyl) piperidin-1-yl) phenyl) -N- (tetrahydro-2H-pyran-2-yloxy)-obtained in Example 14- (3) To a solution of 1,6-naphthyridine-4-carboxamide (200 mg) in chloroform (2.0 ml) was added sodium bicarbonate (103 mg), mCPBA (> 65%) (184 mg) was added under ice cooling, and the mixture was stirred at room temperature for 20 minutes. Stir. The reaction solution was purified by preparative silica gel thin layer chromatography (chloroform / methanol = 10/1) to give 2- (4- (4- (3-hydroxypropyl) piperidin-1-yl) phenyl) -N- (Tetrahydro-2H-pyran-2-yloxy) -1,6-naphthyridine-4-carboxamide 6-oxide (yellow oil) was obtained (9 mg, 4%).
¹ H NMR (400 MHz, CD ₃ OD) δppm 1.40-1.55 (2H, m), 1.55-2.05 (11H, m), 2.10-2.30 (2H, m), 3.20-3.40 (2H, m), 3.55- 3.65 (2H, m), 3.65-3.75 (1H, m), 3.95-4.10 (2H, m), 4.10-4.25 (1H, m), 5.22-5.32 (1H, m), 8.06 (1H, dd, J = 6.0, 0.9 Hz), 8.22 (2H, d, J = 9.0 Hz), 8.35 (1H, s), 8.47 (2H, d, J = 9.0 Hz), 8.75 (1H, d, J = 6.0 Hz), 9.59 (1H, s)

（５）実施例１４−（４）で得た２−（４−（４−（３−ヒドロキシプロピル）ピペリジン−１−イル）フェニル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（３４ｍｇ）のエタノール（１．０ｍｌ）溶液に４ｍｏｌ／ｌ−ＨＣｌ−１，４−ジオキサン溶液（１．０ｍｌ）を加え、室温で３０分間攪拌した。溶媒を減圧下留去し、残留物にジイソプロピルエーテルを加え、固体を濾別して、Ｎ−ヒドロキシ−２−（４−（４−（３−ヒドロキシプロピル）ピペリジン−１−イル）フェニル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩（暗褐色固体）を得た（８ｍｇ，２４％）。
ＭＳ（ＥＳＩ）：４２３（Ｍ＋Ｈ）^＋，４２１（Ｍ−Ｈ）^−
1H NMR (400 MHz, CD₃OD) δppm 1.42 - 1.58 (2H, m), 1.58 - 1.74 (2H, m), 1.82 - 2.00 (1H, m), 2.00 - 2.18 (4H, m), 3.52 - 3.68 (2H, m), 3.94 - 4.12 (2H, m), 4.24 - 4.42 (2H, m), 8.26 (2H, d, J=8.5 Hz), 8.48 - 8.60 (1H, m), 8.60 - 8.70 (1H, m), 8.73 (2H, d, J=8.5 Hz), 8.84 - 8.94 (1H, m), 9.96 - 10.16 (1H, m)

実施例１５
３−アミノ−２−（ビフェニル−４−イル）−Ｎ−ヒドロキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩（化合物６２）

(5) 2- (4- (4- (3-hydroxypropyl) piperidin-1-yl) phenyl) -N- (tetrahydro-2H-pyran-2-yloxy)-obtained in Example 14- (4) To a solution of 1,6-naphthyridine-4-carboxamide 6-oxide (34 mg) in ethanol (1.0 ml) was added 4 mol / l-HCl-1,4-dioxane solution (1.0 ml), and the mixture was stirred at room temperature for 30 minutes. . The solvent was distilled off under reduced pressure, diisopropyl ether was added to the residue, the solid was filtered off, and N-hydroxy-2- (4- (4- (3-hydroxypropyl) piperidin-1-yl) phenyl) -1, 6-naphthyridine-4-carboxamide 6-oxide dihydrochloride (dark brown solid) was obtained (8 mg, 24%).
MS (ESI): 423 (M + H) ⁺ , 421 (M−H) ^−
1 H NMR (400 MHz, CD ₃ OD) δppm 1.42-1.58 (2H, m), 1.58-1.74 (2H, m), 1.82-2.00 (1H, m), 2.00-2.18 (4H, m), 3.52- 3.68 (2H, m), 3.94-4.12 (2H, m), 4.24-4.42 (2H, m), 8.26 (2H, d, J = 8.5 Hz), 8.48-8.60 (1H, m), 8.60-8.70 ( 1H, m), 8.73 (2H, d, J = 8.5 Hz), 8.84-8.94 (1H, m), 9.96-10.16 (1H, m)

Example 15
3-Amino-2- (biphenyl-4-yl) -N-hydroxy-1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride (Compound 62)

（１）実施例１−（２）で得た（４−（（２，２−ジメチルプロパノイル）アミノ）ピリジン−３−イル）（オキソ）酢酸エチル（４．０ｇ）のエタノール（６０ｍｌ）及び水（６０ｍｌ）溶液に、４０℃で水酸化カリウム（８．１ｇ）を加え、１時間２０分加熱還流した。７５℃に冷却し、Ｎ−（２−（４−ブロモフェニル）−２−オキソエチル）アセタミド（３．７ｇ）を添加し、１時間加熱還流した。室温に冷却後、減圧下で濃縮し、６ｍｏｌ／ｌ−塩酸でｐＨ４．２に調整した。析出物を濾別し、ＩＰＥ次いで水（３回）で洗浄し、３−（アセチルアミノ）−２−（４−ブロモフェニル）−１，６−ナフチリジン−４−カルボン酸（黄色固体）を得た（４．４ｇ）。
¹H NMR (400 MHz, DMSO-d₆) δppm 1.87 (3H, s), 7.68 (2H, d, J=8.5 Hz), 7.73 (2H, d, J=8.5 Hz), 8.00 (1H, d, J=5.8 Hz), 8.82 (1H, d, J=5.8 Hz), 9.38 (1 H, s), 10.12 (1 H, s)

(1) Ethanol (60 ml) of (4-((2,2-dimethylpropanoyl) amino) pyridin-3-yl) (oxo) acetate (4.0 g) obtained in Example 1- (2) and To a water (60 ml) solution was added potassium hydroxide (8.1 g) at 40 ° C., and the mixture was heated to reflux for 1 hour and 20 minutes. The mixture was cooled to 75 ° C., N- (2- (4-bromophenyl) -2-oxoethyl) acetamide (3.7 g) was added, and the mixture was heated to reflux for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure and adjusted to pH 4.2 with 6 mol / l-hydrochloric acid. The precipitate was filtered off and washed with IPE and then water (3 times) to give 3- (acetylamino) -2- (4-bromophenyl) -1,6-naphthyridine-4-carboxylic acid (yellow solid). (4.4 g).
¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 1.87 (3H, s), 7.68 (2H, d, J = 8.5 Hz), 7.73 (2H, d, J = 8.5 Hz), 8.00 (1H, d, J = 5.8 Hz), 8.82 (1H, d, J = 5.8 Hz), 9.38 (1 H, s), 10.12 (1 H, s)

（２）実施例１５−（１）で得た３−（アセチルアミノ）−２−（４−ブロモフェニル）−１，６−ナフチリジン−４−カルボン酸（１．６ｇ）の水（１５ｍｌ）懸濁液に、水酸化カリウム（２．３ｇ）を加え、７時間加熱還流した。室温に冷却し、２ｍｏｌ／ｌ−塩酸でｐＨ７に調整した後、水を加え、析出物を濾別し、３−アミノ−２−（４−ブロモフェニル）−１，６−ナフチリジン−４−カルボン酸（黄色固体）を得た（１．４ｇ）。
¹H NMR (400 MHz, DMSO-d₆) δppm 7.66 (2H, d, J=8.4 Hz), 7.72 (1H, d, J=5.5 Hz), 7.78 (2H, d, J=8.4 Hz), 8.44 (1H, d, J=5.5 Hz), 9.83 (1 H, s)

(2) Water of 3- (acetylamino) -2- (4-bromophenyl) -1,6-naphthyridine-4-carboxylic acid (1.6 g) obtained in Example 15- (1) (15 ml) To the suspension, potassium hydroxide (2.3 g) was added and heated to reflux for 7 hours. After cooling to room temperature and adjusting to pH 7 with 2 mol / l-hydrochloric acid, water was added, the precipitate was filtered off, and 3-amino-2- (4-bromophenyl) -1,6-naphthyridine-4-carboxylic acid was added. The acid (yellow solid) was obtained (1.4 g).
¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 7.66 (2H, d, J = 8.4 Hz), 7.72 (1H, d, J = 5.5 Hz), 7.78 (2H, d, J = 8.4 Hz), 8.44 (1H, d, J = 5.5 Hz), 9.83 (1 H, s)

（３）実施例１５−（２）で得た３−アミノ−２−（４−ブロモフェニル）−１，６−ナフチリジン−４−カルボン酸（０．２９ｇ）のＤＭＦ（２．０ｍｌ）溶液に、Ｏ−（テトラヒドロ−２Ｈ−ピラン−２−イル）ヒドロキシルアミン（０．５９ｇ）、ＤＩＰＥＡ（０．４３ｍｌ）、ＨＯＢｔ・Ｈ_２Ｏ（０．１３ｇ）及びＷＳＣ・ＨＣｌ（０．３２ｇ）を加え、室温で２７時間攪拌した。反応液に水を加え，不溶物を濾別した。濾液に酢酸エチルを加え，６ｍｏｌ／ｌ−塩酸でｐＨ４に調整後，抽出液を水及び飽和食塩水で洗浄し，無水硫酸ナトリウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し，残留物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝２０／１）で精製して、３−アミノ−２−（４−ブロモフェニル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド（橙色固体）を得た（０．１６ｇ，４２％）。
¹H NMR (400 MHz, CHLOROFORM-d) δppm 1.50 - 2.05 (6H, m), 3.62 - 3.72 (1H, m), 4.01 - 4.14 (1H, m), 5.16 - 5.39 (3H, m), 7.56 - 7.64 (2H, m), 7.67 - 7.73 (2H, m), 7.74 (1H, d, J=5.8 Hz), 8.26 - 8.36 (1H, m), 9.45 (1H, s)

(3) To a DMF (2.0 ml) solution of 3-amino-2- (4-bromophenyl) -1,6-naphthyridine-4-carboxylic acid (0.29 g) obtained in Example 15- (2) , O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (0.59 g), DIPEA (0.43 ml), HOBt.H ₂ O (0.13 g) and WSC · HCl (0.32 g) were added. And stirred at room temperature for 27 hours. Water was added to the reaction solution, and the insoluble material was filtered off. Ethyl acetate was added to the filtrate, the pH was adjusted to 4 with 6 mol / l-hydrochloric acid, and the extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 20/1) to give 3-amino-2- (4-bromophenyl) -N -(Tetrahydro-2H-pyran-2-yloxy) -1,6-naphthyridine-4-carboxamide (orange solid) was obtained (0.16 g, 42%).
¹ H NMR (400 MHz, CHLOROFORM-d) δppm 1.50-2.05 (6H, m), 3.62-3.72 (1H, m), 4.01-4.14 (1H, m), 5.16-5.39 (3H, m), 7.56- 7.64 (2H, m), 7.67-7.73 (2H, m), 7.74 (1H, d, J = 5.8 Hz), 8.26-8.36 (1H, m), 9.45 (1H, s)

（４）実施例１５−（３）で得た３−アミノ−２−（４−ブロモフェニル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド（０．１５ｇ）のクロロホルム（１．５ｍｌ）溶液に、炭酸水素ナトリウム（８５ｍｇ）及びｍＣＰＢＡ（＞６５％）（０．１６ｇ）を加え、室温で３０分間攪拌した。反応液をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝１０／１）で精製して、３−アミノ−２−（４−ブロモフェニル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（黄色固体）を得た（５３ｍｇ，３４％）。
ＭＳ（ＥＳＩ）：４６１，４５９（Ｍ＋Ｈ）^＋，４５９，４５７（Ｍ−Ｈ）^−
1H NMR (400 MHz, CHLOROFORM-d) δppm 1.50 - 2.10 (6H, m), 3.71 - 3.80 (1H, m), 4.13 - 4.24 (1H, m), 5.34 - 5.51 (3H, m), 7.48 - 7.59 (2H, m), 7.62 (2H, d, J=8.4 Hz), 7.73 (2H, d, J=8.4 Hz), 8.96 (1H, s)

(4) 3-amino-2- (4-bromophenyl) -N- (tetrahydro-2H-pyran-2-yloxy) -1,6-naphthyridine-4-carboxamide obtained in Example 15- (3) Sodium hydrogen carbonate (85 mg) and mCPBA (> 65%) (0.16 g) were added to a chloroform (1.5 ml) solution of 0.15 g), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was purified by silica gel column chromatography (chloroform / methanol = 10/1) to give 3-amino-2- (4-bromophenyl) -N- (tetrahydro-2H-pyran-2-yloxy) -1, 6-naphthyridine-4-carboxamide 6-oxide (yellow solid) was obtained (53 mg, 34%).
MS (ESI): 461, 459 (M + H) ⁺ , 459, 457 (M−H) ^−
1 H NMR (400 MHz, CHLOROFORM-d) δppm 1.50-2.10 (6H, m), 3.71-3.80 (1H, m), 4.13-4.24 (1H, m), 5.34-5.51 (3H, m), 7.48- 7.59 (2H, m), 7.62 (2H, d, J = 8.4 Hz), 7.73 (2H, d, J = 8.4 Hz), 8.96 (1H, s)

（５）実施例１５−（４）で得た３−アミノ−２−（４−ブロモフェニル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（２８ｍｇ）の１，４−ジオキサン（１．０ｍｌ）溶液に、フェニルボロン酸（１５ｍｇ）、Ｐｄ（ＰＰｈ_３）_４（７ｍｇ）、炭酸ナトリウム（１９ｍｇ）及び水（１．０ｍｌ）を加え、１．５時間加熱還流した。室温に冷却後、クロロホルム及び水を加え、１ｍｏｌ／ｌ−塩酸でｐＨ５に調整し、クロロホルムで２回抽出した。得られた抽出物を無水硫酸ナトリウムで乾燥し、乾燥剤を濾別後、溶媒を減圧下留去した。得られた残留物を分取用シリカゲルクロマトグラフィー（クロロホルム／メタノール＝１０／１）で精製し、３−アミノ−２−（ビフェニル−４−イル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（黄色油状物）を得た（１７ｍｇ，６１％）。
¹H NMR (400 MHz, CHLOROFORM-d) δppm 1.58 - 2.00 (6H, m), 3.75 - 3.84 (1H, m), 4.14 - 4.25 (1H, m), 5.38 - 5.50 (3H, m), 7.38 - 7.46 (1H, m), 7.46 - 7.76 (6H, m), 7.76 - 7.86 (4H, m), 8.90 (1H, s)

(5) 3-Amino-2- (4-bromophenyl) -N- (tetrahydro-2H-pyran-2-yloxy) -1,6-naphthyridine-4-carboxamide obtained in Example 15- (4) 6 -To a solution of oxide (28 mg) in 1,4-dioxane (1.0 ml), phenylboronic acid (15 mg), Pd (PPh ₃ ) ₄ (7 mg), sodium carbonate (19 mg) and water (1.0 ml) were added. For 1.5 hours. After cooling to room temperature, chloroform and water were added, adjusted to pH 5 with 1 mol / l-hydrochloric acid, and extracted twice with chloroform. The obtained extract was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative silica gel chromatography (chloroform / methanol = 10/1) to give 3-amino-2- (biphenyl-4-yl) -N- (tetrahydro-2H-pyran-2- (Iloxy) -1,6-naphthyridine-4-carboxamide 6-oxide (yellow oil) was obtained (17 mg, 61%).
¹ H NMR (400 MHz, CHLOROFORM-d) δppm 1.58-2.00 (6H, m), 3.75-3.84 (1H, m), 4.14-4.25 (1H, m), 5.38-5.50 (3H, m), 7.38- 7.46 (1H, m), 7.46-7.76 (6H, m), 7.76-7.86 (4H, m), 8.90 (1H, s)

（６）実施例１５−（５）で得た３−アミノ−２−（ビフェニル−４−イル）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（１７ｍｇ）のエタノール（０．３ｍｌ）懸濁液に、４ｍｏｌ／ｌ−ＨＣｌ−１，４−ジオキサン溶液（０．３ｍｌ）を加え、室温で１．５時間攪拌した。反応液にＩＰＡ及びＩＰＥを加え、固体を濾別し、ＩＰＡ及びＩＰＥで洗浄し、３−アミノ−２−（ビフェニル−４−イル）−Ｎ−ヒドロキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩（黄色固体）を得た（６ｍｇ，３６％）。
ＭＳ（ＥＳＩ）：３７３（Ｍ＋Ｈ）^＋，３７１（Ｍ−Ｈ）^−
1H NMR (400 MHz, DMSO-d₆) δppm 5.65 - 5.85 (2H, m), 7.39 - 7.46 (1H, m), 7.49 - 7.55 (2H, m), 7.74 - 7.80 (2H, m), 7.80 - 7.84 (3H, m), 7.85 - 7.90 (2H, m), 8.09 (1H, dd, J=7.1, 2.0 Hz), 8.44 - 8.50 (1H, m), 11.40 (1H, s)
実施例１６
４−（４−（（４’−（４−（（ヒドロキシアミノ）カルボニル）−３−メトキシ−６−オキシド−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブトキシ）−４−オキソ酪酸塩酸塩（化合物７４）

(6) 3-Amino-2- (biphenyl-4-yl) -N- (tetrahydro-2H-pyran-2-yloxy) -1,6-naphthyridine-4-carboxamide obtained in Example 15- (5) To a suspension of 6-oxide (17 mg) in ethanol (0.3 ml) was added 4 mol / l-HCl-1,4-dioxane solution (0.3 ml), and the mixture was stirred at room temperature for 1.5 hours. IPA and IPE were added to the reaction solution, the solid was filtered off, washed with IPA and IPE, and 3-amino-2- (biphenyl-4-yl) -N-hydroxy-1,6-naphthyridine-4-carboxamide 6 -Oxide dihydrochloride (yellow solid) was obtained (6 mg, 36%).
MS (ESI): 373 (M + H) ⁺ , 371 (M−H) ^−
1 H NMR (400 MHz, DMSO-d ₆ ) δppm 5.65-5.85 (2H, m), 7.39-7.46 (1H, m), 7.49-7.55 (2H, m), 7.74-7.80 (2H, m), 7.80 -7.84 (3H, m), 7.85-7.90 (2H, m), 8.09 (1H, dd, J = 7.1, 2.0 Hz), 8.44-8.50 (1H, m), 11.40 (1H, s)
Example 16
4- (4-((4 '-(4-((hydroxyamino) carbonyl) -3-methoxy-6-oxide-1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butoxy)- 4-Oxobutyric acid hydrochloride (Compound 74)

（１）４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェノール（４．００ｇ）のＤＭＦ（１２ｍｌ）溶液に、炭酸カリウム（７．５４ｇ）及び２−（４−ブロモブトキシ）テトラヒドロ−２Ｈ−ピラン（５．００ｇ）を加え、５０〜６０℃で３０分間攪拌した後、ＤＭＦ（４．０ｍｌ）を追加し、８０℃で３０分間攪拌した。放冷後、反応液に酢酸エチル及び水を加え、６ｍｏｌ／ｌ−塩酸でｐＨ６に調整し、有機層を分取した。抽出物を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した後に乾燥剤を濾別し、溶媒を減圧下留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝９０／１０）で精製して、２−（４−（４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェノキシ）ブトキシ）テトラヒドロ−２Ｈ−ピラン（淡黄色油状物）を得た（７．７０ｇ，１００％）。
¹H NMR (400 MHz, CHLOROFORM-d) δppm 1.33 (12H, s), 1.45 - 2.02 (10H, m), 3.39 - 3.54 (2H, m), 3.74 - 3.92 (2H, m), 4.02 (2H, t, J=6.5 Hz), 4.56 - 4.63 (1H, m), 6.86 - 6.92 (2H, m), 7.71 - 7.77 (2H, m)

(1) To a solution of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (4.00 g) in DMF (12 ml), potassium carbonate (7.54 g) And 2- (4-bromobutoxy) tetrahydro-2H-pyran (5.00 g) was added, and the mixture was stirred at 50-60 ° C. for 30 minutes, then DMF (4.0 ml) was added, and the mixture was stirred at 80 ° C. for 30 minutes. . After allowing to cool, ethyl acetate and water were added to the reaction solution, adjusted to pH 6 with 6 mol / l-hydrochloric acid, and the organic layer was separated. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 90/10) to give 2- (4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-). 2-yl) phenoxy) butoxy) tetrahydro-2H-pyran (pale yellow oil) was obtained (7.70 g, 100%).
¹ H NMR (400 MHz, CHLOROFORM-d) δppm 1.33 (12H, s), 1.45-2.02 (10H, m), 3.39-3.54 (2H, m), 3.74-3.92 (2H, m), 4.02 (2H, t, J = 6.5 Hz), 4.56-4.63 (1H, m), 6.86-6.92 (2H, m), 7.71-7.77 (2H, m)

（２）実施例１６−（１）で得た２−（４−（４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェノキシ）ブトキシ）テトラヒドロ−２Ｈ−ピラン（３．６０ｇ）の１，４−ジオキサン（９．０ｍｌ）溶液に、６ｍｏｌ／ｌ−塩酸（１．０ｍｌ）を加えて室温で２．５時間攪拌後１，４−ジオキサン（９．０ｍｌ）及び６ｍｏｌ／ｌ−塩酸（４．０ｍｌ）を加え、室温で４時間攪拌した。反応液に水を加え２０％水酸化ナトリウム水溶液でｐＨ６に調整し、酢酸エチルで抽出した。抽出物を水で洗浄し、無水硫酸マグネシウムで乾燥後に乾燥剤を濾別し、溶媒を減圧下留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチルの勾配溶離＝９０／１０→５０／５０）で精製して、４−（４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェノキシ）ブタン−１−オール（無色油状物）を得た（０．８８ｇ，３１％）。
¹H NMR (400 MHz, CHLOROFORM-d) δppm 1.33 (12H, s), 1.71 - 1.80 (2H, m), 1.84 - 1.94 (2H, m), 3.68 - 3.77 (2H, m), 4.03 (2H, t, J=6.1 Hz), 6.86 - 6.92 (2H, m), 7.70 - 7.78 (2H, m)

(2) 2- (4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) butoxy) tetrahydro obtained in Example 16- (1) 6 mol / l-hydrochloric acid (1.0 ml) was added to a solution of -2H-pyran (3.60 g) in 1,4-dioxane (9.0 ml) and stirred at room temperature for 2.5 hours. 9.0 ml) and 6 mol / l-hydrochloric acid (4.0 ml) were added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, the pH was adjusted to 6 with a 20% aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution of hexane / ethyl acetate = 90/10 → 50/50) to give 4- (4- (4,4,5,5-tetramethyl-1,3,3). 2-Dioxaborolan-2-yl) phenoxy) butan-1-ol (colorless oil) was obtained (0.88 g, 31%).
¹ H NMR (400 MHz, CHLOROFORM-d) δppm 1.33 (12H, s), 1.71-1.80 (2H, m), 1.84-1.94 (2H, m), 3.68-3.77 (2H, m), 4.03 (2H, t, J = 6.1 Hz), 6.86-6.92 (2H, m), 7.70-7.78 (2H, m)

（３）実施例１−（５）で得た２−（４−ヨードフェニル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド（４００ｍｇ）及び実施例１６−（２）で得た４−（４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェノキシ）ブタン−１−オール（２７８ｍｇ）の１，４−ジオキサン（４．０ｍｌ）溶液に、Ｐｄ（ＰＰｈ_３）_４（９１ｍｇ）、炭酸ナトリウム（２５０ｍｇ）及び水（４．０ｍｌ）を加え、窒素雰囲気下３０分間加熱還流した。反応液を放冷後、水及び酢酸エチルを加え、１ｍｏｌ／ｌ−塩酸でｐＨ５．５に調整し有機層を分取した。抽出物を無水硫酸ナトリウムで乾燥し乾燥剤を濾別した後、溶媒を減圧下留去した。残留物をＮＨ型シリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝１００／１）で精製して、２−（４’−（４−ヒドロキシブトキシ）ビフェニル−４−イル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド（黄色泡状物）を得た（２７２ｍｇ，６３％）。
¹H NMR (400 MHz, CHLOROFORM-d) δppm 1.40 - 2.10 (10H, m), 3.68 - 3.80 (3H, m), 3.75 (3H, s), 4.03 - 4.12 (3H, m), 5.29 (1H, br. s.), 6.98 - 7.05 (2H, m), 7.58 - 7.65 (2H, m), 7.72 (2H, d, J=8.3 Hz), 7.92 (1H, d, J=5.8 Hz), 8.12 (2H, d, J=8.3 Hz), 8.73 (1H, d, J=5.8 Hz), 9.16 (1H, s), 9.50 (1H, s)

(3) 2- (4-Iodophenyl) -3-methoxy-N- (tetrahydro-2H-pyran-2-yloxy) -1,6-naphthyridine-4-carboxamide obtained in Example 1- (5) 400 mg) and 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) butan-1-ol obtained in Example 16- (2) Pd (PPh ₃ ) ₄ (91 mg), sodium carbonate (250 mg) and water (4.0 ml) were added to a solution of 278 mg) in 1,4-dioxane (4.0 ml), and the mixture was heated to reflux for 30 minutes under a nitrogen atmosphere. The reaction solution was allowed to cool, water and ethyl acetate were added, the pH was adjusted to 5.5 with 1 mol / l-hydrochloric acid, and the organic layer was separated. The extract was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (chloroform / methanol = 100/1) to give 2- (4 ′-(4-hydroxybutoxy) biphenyl-4-yl) -3-methoxy-N- (tetrahydro -2H-pyran-2-yloxy) -1,6-naphthyridine-4-carboxamide (yellow foam) was obtained (272 mg, 63%).
¹ H NMR (400 MHz, CHLOROFORM-d) δppm 1.40-2.10 (10H, m), 3.68-3.80 (3H, m), 3.75 (3H, s), 4.03-4.12 (3H, m), 5.29 (1H, br. s.), 6.98-7.05 (2H, m), 7.58-7.65 (2H, m), 7.72 (2H, d, J = 8.3 Hz), 7.92 (1H, d, J = 5.8 Hz), 8.12 ( 2H, d, J = 8.3 Hz), 8.73 (1H, d, J = 5.8 Hz), 9.16 (1H, s), 9.50 (1H, s)

（４）実施例１６−（３）で得た２−（４’−（４−ヒドロキシブトキシ）ビフェニル−４−イル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド（２７０ｍｇ）のＤＭＦ（３．０ｍｌ）懸濁液に、ＤＩＰＥＡ（０．２６ｍｌ）、コハク酸モノ−ｔｅｒｔ−ブチル（１３０ｍｇ）、ＨＯＢｔ・Ｈ_２Ｏ（７６ｍｇ）及びＷＳＣ・ＨＣｌ（１１０ｍｇ）を加え、室温で５．５時間攪拌した。コハク酸モノ−ｔｅｒｔ−ブチル（１３０ｍｇ）及びＷＳＣ・ＨＣｌ（１１０ｍｇ）を追加し、室温で１．５時間攪拌した。反応液に水を加え１ｍｏｌ／ｌ−塩酸でｐＨ５．５に調整後、酢酸エチルを加えて有機層を分取し、抽出物を水及び飽和食塩水で順次洗浄した。無水硫酸マグネシウムで乾燥して乾燥剤を濾別後、溶媒を減圧下留去し、残留物をＮＨ型シリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝１０／１）で精製して、コハク酸＝ｔｅｒｔ−ブチル＝４−（（４’−（３−メトキシ−４−（（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）アミノ）カルボニル）−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル（黄色油状物）を得た（８１ｍｇ，２３％）。
¹H NMR (400 MHz, CHLOROFORM-d) δppm 1.45 (9H, s), 1.50 - 2.10 (10H, m), 2.50 - 2.62 (4H, m), 3.60 - 3.80 (1H, m), 3.75 (3H, s), 4.02 - 4.13 (3H, m), 4.14 - 4.24 (2H, m), 5.31 (1H, br. s.), 7.00 (2H, d, J=8.8 Hz), 7.61 (2H, d, J=8.8 Hz), 7.72 (2H, d, J=8.3 Hz), 7.88 (1H, d, J=5.9 Hz), 8.11 (2H, d, J=8.3 Hz), 8.68 (1H, d, J=5.9 Hz), 9.35 (1H, br. s.), 9.48 (1H, br. s.)

(4) 2- (4 ′-(4-hydroxybutoxy) biphenyl-4-yl) -3-methoxy-N- (tetrahydro-2H-pyran-2-yloxy)-obtained in Example 16- (3) To a suspension of 1,6-naphthyridine-4-carboxamide (270 mg) in DMF (3.0 ml), DIPEA (0.26 ml), mono-tert-butyl succinate (130 mg), HOBt · H ₂ O (76 mg) And WSC · HCl (110 mg) were added, and the mixture was stirred at room temperature for 5.5 hours. Mono-tert-butyl succinate (130 mg) and WSC · HCl (110 mg) were added, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction solution and adjusted to pH 5.5 with 1 mol / l-hydrochloric acid, ethyl acetate was added to separate the organic layer, and the extract was washed successively with water and saturated brine. After drying over anhydrous magnesium sulfate and filtering off the desiccant, the solvent was distilled off under reduced pressure, the residue was purified by NH silica gel column chromatography (chloroform / methanol = 10/1), and succinic acid = tert- Butyl = 4-((4 ′-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yloxy) amino) carbonyl) -1,6-naphthyridin-2-yl) biphenyl-4-yl) Oxy) butyl ester (yellow oil) was obtained (81 mg, 23%).
¹ H NMR (400 MHz, CHLOROFORM-d) δppm 1.45 (9H, s), 1.50-2.10 (10H, m), 2.50-2.62 (4H, m), 3.60-3.80 (1H, m), 3.75 (3H, s), 4.02-4.13 (3H, m), 4.14-4.24 (2H, m), 5.31 (1H, br.s.), 7.00 (2H, d, J = 8.8 Hz), 7.61 (2H, d, J = 8.8 Hz), 7.72 (2H, d, J = 8.3 Hz), 7.88 (1H, d, J = 5.9 Hz), 8.11 (2H, d, J = 8.3 Hz), 8.68 (1H, d, J = 5.9 Hz), 9.35 (1H, br.s.), 9.48 (1H, br.s.)

（５）実施例１６−（４）で得たコハク酸＝ｔｅｒｔ−ブチル＝４−（（４’−（３−メトキシ−４−（（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）アミノ）カルボニル）−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル（８０ｍｇ）のクロロホルム（１．０ｍｌ）溶液に、氷冷下７７％ｍＣＰＢＡ（５１ｍｇ）及び炭酸水素ナトリウム（２９ｍｇ）を加えて１０分間攪拌後、室温で１時間攪拌した。反応液を分取用シリカゲル薄層クロマトグラフィー（クロロホルム／メタノール＝１０／１）で精製して、コハク酸＝ｔｅｒｔ−ブチル＝４−（（４’−（３−メトキシ−６−オキシド−４−（（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）アミノ）カルボニル）−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル（黄色固体）を得た（７６ｍｇ，９３％）。
¹H NMR (400 MHz, CHLOROFORM-d) δppm 1.35 - 2.15 (10H, m), 1.45 (9H, s), 2.51 - 2.63 (4H, m), 3.75 - 3.88 (1H, m), 3.85 (3H, s), 4.03 - 4.09 (2H, m), 4.11 - 4.23 (3H, m), 5.43 (1H, br. s.), 6.97 - 7.04 (2H, m), 7.55 - 7.66 (3H, m), 7.74 (2H, d, J=8.3 Hz), 7.75 - 7.81 (1H, m), 8.12 (2H, d, J=8.6 Hz), 8.88 (1H, s), 11.00 - 11.15 (1H, m)

(5) Succinic acid obtained in Example 16- (4) = tert-butyl = 4-((4 ′-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yloxy) amino) carbonyl) ) -1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butyl ester (80 mg) in chloroform (1.0 ml) was added to 77% mCPBA (51 mg) and sodium bicarbonate ( 29 mg) was added and the mixture was stirred for 10 minutes and then stirred at room temperature for 1 hour. The reaction solution was purified by preparative silica gel thin layer chromatography (chloroform / methanol = 10/1), and succinic acid = tert-butyl = 4-((4 ′-(3-methoxy-6-oxide-4- (((Tetrahydro-2H-pyran-2-yloxy) amino) carbonyl) -1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butyl ester (yellow solid) was obtained (76 mg, 93 %).
¹ H NMR (400 MHz, CHLOROFORM-d) δppm 1.35-2.15 (10H, m), 1.45 (9H, s), 2.51-2.63 (4H, m), 3.75-3.88 (1H, m), 3.85 (3H, s), 4.03-4.09 (2H, m), 4.11-4.23 (3H, m), 5.43 (1H, br.s.), 6.97-7.04 (2H, m), 7.55-7.66 (3H, m), 7.74 (2H, d, J = 8.3 Hz), 7.75-7.81 (1H, m), 8.12 (2H, d, J = 8.6 Hz), 8.88 (1H, s), 11.00-11.15 (1H, m)

（６）実施例１６−（５）で得たコハク酸＝ｔｅｒｔ−ブチル＝４−（（４’−（３−メトキシ−６−オキシド−４−（（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）アミノ）カルボニル）−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル（７０ｍｇ）に、４ｍｏｌ／ｌ−ＨＣｌ−１，４−ジオキサン溶液（１．０ｍｌ）を加えて室温で１時間攪拌後、１，４−ジオキサン（１．０ｍｌ）及び水（５０μｌ）を加えて室温で１０分間攪拌した。反応液にＩＰＥを加えて上澄液を除去する操作を４回繰り返しすことで黄色固体（３０ｍｇ）を得た。得られた固体に４ｍｏｌ／ｌ−ＨＣｌ−１，４−ジオキサン溶液（０．５ｍｌ）、１，４−ジオキサン（０．５ｍｌ）及び水（５０μｌ）を加えて室温で２時間攪拌し、ＴＦＡ（０．３ｍｌ）を加えて室温で７．５時間攪拌後、室温で１４時間放置した。析出物を濾別して、１，４−ジオキサン及びＩＰＥで洗浄し、４−（４−（（４’−（４−（（ヒドロキシアミノ）カルボニル）−３−メトキシ−６−オキシド−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブトキシ）−４−オキソ酪酸塩酸塩（黄色固体）を得た（１２ｍｇ，２０％）。
ＭＳ（ＥＳＩ）：５７６（Ｍ＋Ｈ）^＋，５７４（Ｍ−Ｈ）^−
1H NMR (400 MHz, DMSO-d₆) δppm 1.70 - 1.86 (4H, m), 2.30 - 2.70 (4H, m), 3.75 (3H, s), 4.02 - 4.14 (4H, m), 7.07 (2H, d, J=8.8 Hz), 7.73 (2H, d, J=8.8 Hz), 7.82 (2H, d, J=8.5 Hz), 8.03 (1H, d, J=7.1 Hz), 8.05 (2H, d, J=8.5 Hz), 8.36 (1H, dd, J=7.1, 2.1 Hz), 8.52 (1H, d, J=2.1 Hz), 11.40 (1H, s)
実施例１７
４−（ジメチルアミノ）酪酸＝４−（（４’−（４−（（ヒドロキシアミノ）カルボニル）−３−メトキシ−６−オキシド−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル２塩酸塩（化合物７８）

(6) Succinic acid obtained in Example 16- (5) = tert-butyl = 4-((4 ′-(3-methoxy-6-oxide-4-(((tetrahydro-2H-pyran-2-yloxy) ) Amino) carbonyl) -1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butyl ester (70 mg) with 4 mol / l-HCl-1,4-dioxane solution (1.0 ml). In addition, after stirring at room temperature for 1 hour, 1,4-dioxane (1.0 ml) and water (50 μl) were added and stirred at room temperature for 10 minutes. The operation of adding IPE to the reaction solution and removing the supernatant was repeated 4 times to obtain a yellow solid (30 mg). A 4 mol / l-HCl-1,4-dioxane solution (0.5 ml), 1,4-dioxane (0.5 ml) and water (50 μl) were added to the obtained solid, and the mixture was stirred at room temperature for 2 hours. 0.3 ml) was added and the mixture was stirred at room temperature for 7.5 hours and then allowed to stand at room temperature for 14 hours. The precipitate was filtered off and washed with 1,4-dioxane and IPE to give 4- (4-((4 ′-(4-((hydroxyamino) carbonyl) -3-methoxy-6-oxide-1,6- Naphthyridin-2-yl) biphenyl-4-yl) oxy) butoxy) -4-oxobutyric acid hydrochloride (yellow solid) was obtained (12 mg, 20%).
MS (ESI): 576 (M + H) ⁺ , 574 (M−H) ^−
1 H NMR (400 MHz, DMSO-d ₆ ) δppm 1.70-1.86 (4H, m), 2.30-2.70 (4H, m), 3.75 (3H, s), 4.02-4.14 (4H, m), 7.07 (2H , d, J = 8.8 Hz), 7.73 (2H, d, J = 8.8 Hz), 7.82 (2H, d, J = 8.5 Hz), 8.03 (1H, d, J = 7.1 Hz), 8.05 (2H, d , J = 8.5 Hz), 8.36 (1H, dd, J = 7.1, 2.1 Hz), 8.52 (1H, d, J = 2.1 Hz), 11.40 (1H, s)
Example 17
4- (Dimethylamino) butyric acid = 4-((4 ′-(4-((hydroxyamino) carbonyl) -3-methoxy-6-oxide-1,6-naphthyridin-2-yl) biphenyl-4-yl) Oxy) butyl ester dihydrochloride (Compound 78)

（１）実施例９−（２）で得た２−（４’−（４−ヒドロキシブトキシ）ビフェニル−４−イル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド（９１２ｍｇ）のＤＭＦ（５．０ｍｌ）懸濁液に、４−（ジメチルアミノ）酪酸塩酸塩（０．３３ｇ）、ＤＩＰＥＡ（０．５６ｍｌ）及びＷＳＣ・ＨＣｌ（０．３７ｇ）を加え、室温で５．５時間攪拌した。反応液に水を加え析出物を濾別し、４−（ジメチルアミノ）酪酸＝４−（（４’−（３−メトキシ−６−オキシド−４−（（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）アミノ）カルボニル）−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル（黄色固体）を得た（３１５ｍｇ，２９％）。また、濾液を酢酸エチルで６回逆抽出し、合わせた抽出物を減圧下濃縮した。残留物にＩＰＥを加えて濾別し、ＩＰＥで洗浄することで４−（ジメチルアミノ）酪酸＝４−（（４’−（３−メトキシ−６−オキシド−４−（（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）アミノ）カルボニル）−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル（黄色固体）を得た（２６６ｍｇ，２４％）。
¹H NMR (400 MHz, CHLOROFORM-d) δppm 1.40 - 2.15 (12H, m), 2.20 - 2.42 (10H, m), 3.75 - 3.89 (1H, m), 3.86 (3H, s), 4.07 (2H, t, J=5.7 Hz), 4.15 - 4.24 (3H, m), 5.44 - 5.48 (1H, m), 6.97 - 7.06 (2H, m), 7.59 (1H, d, J=7.3 Hz), 7.63 (2H, d, J=8.8 Hz), 7.69 - 7.77 (1H, m), 7.74 (2H, d, J=8.3 Hz), 8.13 (2H, d, J=8.3 Hz), 8.84 (1H, d, J=1.7 Hz)

(1) 2- (4 ′-(4-hydroxybutoxy) biphenyl-4-yl) -3-methoxy-N- (tetrahydro-2H-pyran-2-yloxy)-obtained in Example 9- (2) To a suspension of 1,6-naphthyridine-4-carboxamide 6-oxide (912 mg) in DMF (5.0 ml) was added 4- (dimethylamino) butyric acid hydrochloride (0.33 g), DIPEA (0.56 ml) and WSC. -HCl (0.37 g) was added and stirred at room temperature for 5.5 hours. Water was added to the reaction mixture, and the precipitate was filtered off, and 4- (dimethylamino) butyric acid = 4-((4 ′-(3-methoxy-6-oxide-4-(((tetrahydro-2H-pyran-2- (Iloxy) amino) carbonyl) -1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butyl ester (yellow solid) was obtained (315 mg, 29%). The filtrate was back-extracted 6 times with ethyl acetate, and the combined extracts were concentrated under reduced pressure. IPE was added to the residue, filtered, and washed with IPE to give 4- (dimethylamino) butyric acid = 4-((4 ′-(3-methoxy-6-oxide-4-(((tetrahydro-2H- Pyran-2-yloxy) amino) carbonyl) -1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butyl ester (yellow solid) was obtained (266 mg, 24%).
¹ H NMR (400 MHz, CHLOROFORM-d) δppm 1.40-2.15 (12H, m), 2.20-2.42 (10H, m), 3.75-3.89 (1H, m), 3.86 (3H, s), 4.07 (2H, t, J = 5.7 Hz), 4.15-4.24 (3H, m), 5.44-5.48 (1H, m), 6.97-7.06 (2H, m), 7.59 (1H, d, J = 7.3 Hz), 7.63 (2H , d, J = 8.8 Hz), 7.69-7.77 (1H, m), 7.74 (2H, d, J = 8.3 Hz), 8.13 (2H, d, J = 8.3 Hz), 8.84 (1H, d, J = 1.7 Hz)

（２）４ｍｏｌ／ｌ−ＨＣｌ−１，４−ジオキサン溶液（８．０ｍｌ）に実施例１７−（１）で得た４−（ジメチルアミノ）酪酸＝４−（（４’−（３−メトキシ−６−オキシド−４−（（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）アミノ）カルボニル）−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル（１５０ｍｇ）の１，４−ジオキサン（８．０ｍｌ）溶液を加え、室温で３０分間攪拌した。反応液にＩＰＥを加えて上澄液を除去する操作を２回繰り返した後、残留物に酢酸エチルを加えて上澄液を除去する操作を２回繰り返した。得られた残留物に酢酸エチルを加えて攪拌し、析出物を濾別して、４−（ジメチルアミノ）酪酸＝４−（（４’−（４−（（ヒドロキシアミノ）カルボニル）−３−メトキシ−６−オキシド−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル２塩酸塩（黄色固体）を得た（１３３ｍｇ，９０％）。
ＭＳ（ＥＳＩ）：５８９（Ｍ＋Ｈ）^＋，５８７（Ｍ−Ｈ）^−
1H NMR (400 MHz, DMSO-d₆) δppm 1.72 - 1.94 (6H, m), 2.43 (2H, t, J=7.3 Hz), 2.75 (3H, s), 2.76 (3H, s), 3.01 - 3.08 (2H, m), 3.75 (3H, s), 4.04 - 4.16 (4H, m), 7.07 (2H, d, J=8.9 Hz), 7.73 (2H, d, J=8.9 Hz), 7.82 (2H, d, J=8.5 Hz), 8.02 (1H, d, J=7.3 Hz), 8.06 (2H, d, J=8.5 Hz), 8.37 (1H, dd, J=7.3, 2.0 Hz), 8.52 (1H, d, J=2.0 Hz), 9.76 (1H, br. s.), 11.41 (1H, s)
実施例１８
Ｎ−（カルボキシメチル）−４−（４−（（４’−（４−（（ヒドロキシアミノ）カルボニル）−３−メトキシ−６−オキシド−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブトキシ）−Ｎ，Ｎ−ジメチル−４−オキソブタン−１−アミニウム（化合物７９）

(2) 4- (dimethylamino) butyric acid 4-((4 ′-(3-methoxy) obtained in Example 17- (1) in a 4 mol / l-HCl-1,4-dioxane solution (8.0 ml) Of -6-oxide-4-(((tetrahydro-2H-pyran-2-yloxy) amino) carbonyl) -1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butyl ester (150 mg) 1,4-Dioxane (8.0 ml) solution was added and stirred at room temperature for 30 minutes. The operation of adding IPE to the reaction solution and removing the supernatant was repeated twice, and then the operation of adding ethyl acetate to the residue and removing the supernatant was repeated twice. Ethyl acetate was added to the obtained residue and stirred, and the precipitate was filtered off, and 4- (dimethylamino) butyric acid = 4-((4 ′-(4-((hydroxyamino) carbonyl) -3-methoxy- 6-oxide-1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butyl = ester dihydrochloride (yellow solid) was obtained (133 mg, 90%).
MS (ESI): 589 (M + H) ⁺ , 587 (M−H) ^−
1 H NMR (400 MHz, DMSO-d ₆ ) δppm 1.72-1.94 (6H, m), 2.43 (2H, t, J = 7.3 Hz), 2.75 (3H, s), 2.76 (3H, s), 3.01- 3.08 (2H, m), 3.75 (3H, s), 4.04-4.16 (4H, m), 7.07 (2H, d, J = 8.9 Hz), 7.73 (2H, d, J = 8.9 Hz), 7.82 (2H , d, J = 8.5 Hz), 8.02 (1H, d, J = 7.3 Hz), 8.06 (2H, d, J = 8.5 Hz), 8.37 (1H, dd, J = 7.3, 2.0 Hz), 8.52 (1H , d, J = 2.0 Hz), 9.76 (1H, br.s.), 11.41 (1H, s)
Example 18
N- (carboxymethyl) -4- (4-((4 ′-(4-((hydroxyamino) carbonyl) -3-methoxy-6-oxide-1,6-naphthyridin-2-yl) biphenyl-4- Yl) oxy) butoxy) -N, N-dimethyl-4-oxobutane-1-aminium (Compound 79)

（１）実施例１７−（１）で得た４−（ジメチルアミノ）酪酸＝４−（（４’−（３−メトキシ−６−オキシド−４−（（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）アミノ）カルボニル）−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル（７００ｍｇ）のＴＨＦ（１４ｍｌ）懸濁液に、ブロモ酢酸ｔｅｒｔ−ブチル（０．１５ｍｌ）を加え室温で６６時間攪拌した。ＴＨＦ（７．０ｍｌ）及びブロモ酢酸ｔｅｒｔ−ブチル（７５μｌ）を加えて室温で８時間攪拌した後、ＴＨＦ（３．５ｍｌ）及びブロモ酢酸ｔｅｒｔ−ブチル（３１μｌ）を追加して室温で３時間攪拌した。析出物を濾別し、ＴＨＦ及びクロロホルムで洗浄することによりＮ−（２−ｔｅｒｔ−ブトキシ−２−オキソエチル）−４−（４−（（４’−（３−メトキシ−６−オキシド−４−（（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）アミノ）カルボニル）−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブトキシ）−Ｎ，Ｎ−ジメチル−４−オキソブタン−１−アミニウムブロミド（黄色固体）を得た（８４０ｍｇ，９３％）。
¹H NMR (400 MHz, CHLOROFORM-d) δppm 1.35 - 2.15 (12H, m), 1.51 (9H, s), 2.46 - 2.56 (2H, m), 3.59 (6H, s), 3.78 - 3.92 (1H, m), 3.88 (3H, s), 3.94 - 4.11 (4H, m), 4.14 - 4.27 (3H, m), 4.61 (2H, s), 5.49 (1H, br. s.), 7.01 (2H, d, J=8.8 Hz), 7.54 (1H, d, J=7.6 Hz), 7.57 - 7.69 (3H, m), 7.73 (2H, d, J=8.3 Hz), 8.12 (2H, d, J=8.3 Hz), 8.75 - 8.83 (1H, m), 11.67 (1H, br. s.)

(1) 4- (Dimethylamino) butyric acid obtained in Example 17- (1) = 4-((4 ′-(3-methoxy-6-oxide-4-(((tetrahydro-2H-pyran-2- A suspension of yloxy) amino) carbonyl) -1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butyl ester (700 mg) in THF (14 ml) was added to tert-butyl bromoacetate (0.15 ml). ) And stirred at room temperature for 66 hours. THF (7.0 ml) and tert-butyl bromoacetate (75 μl) were added and stirred at room temperature for 8 hours, and then THF (3.5 ml) and tert-butyl bromoacetate (31 μl) were added and stirred at room temperature for 3 hours. did. The precipitate was filtered off and washed with THF and chloroform to give N- (2-tert-butoxy-2-oxoethyl) -4- (4-((4 ′-(3-methoxy-6-oxide-4- (((Tetrahydro-2H-pyran-2-yloxy) amino) carbonyl) -1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butoxy) -N, N-dimethyl-4-oxobutane-1 -Aminium bromide (yellow solid) was obtained (840 mg, 93%).
¹ H NMR (400 MHz, CHLOROFORM-d) δppm 1.35-2.15 (12H, m), 1.51 (9H, s), 2.46-2.56 (2H, m), 3.59 (6H, s), 3.78-3.92 (1H, m), 3.88 (3H, s), 3.94-4.11 (4H, m), 4.14-4.27 (3H, m), 4.61 (2H, s), 5.49 (1H, br.s.), 7.01 (2H, d , J = 8.8 Hz), 7.54 (1H, d, J = 7.6 Hz), 7.57-7.69 (3H, m), 7.73 (2H, d, J = 8.3 Hz), 8.12 (2H, d, J = 8.3 Hz) ), 8.75-8.83 (1H, m), 11.67 (1H, br.s.)

（２）実施例１８−（１）で得たＮ−（２−ｔｅｒｔ−ブトキシ−２−オキソエチル）−４−（４−（（４’−（３−メトキシ−６−オキシド−４−（（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）アミノ）カルボニル）−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブトキシ）−Ｎ，Ｎ−ジメチル−４−オキソブタン−１−アミニウムブロミド（２９７ｍｇ）のアニソール（０．５ｍｌ）懸濁液に、ＴＦＡ（２．５ｍｌ）を加えて室温で４．５時間攪拌後、３９時間室温で放置した。反応液にＩＰＥを加えて上澄液を除去する操作を２回繰り返した後、残留物に酢酸エチルを加えて上澄液を除去する操作を２回繰り返して黄色固体（２８０ｍｇ）を得た。得られた固体（１４０ｍｇ）の水（１００ｍｌ）懸濁液に１ｍｏｌ／ｌ−水酸化ナトリウム水溶液を加えてｐＨ８に調整し溶解させ、逆相シリカゲルカラムクロマトグラフィー（水→水／アセトニトリル＝７０／３０）で精製し、Ｎ−（カルボキシメチル）−４−（４−（（４’−（４−（（ヒドロキシアミノ）カルボニル）−３−メトキシ−６−オキシド−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブトキシ）−Ｎ，Ｎ−ジメチル−４−オキソブタン−１−アミニウム（黄色固体）を得た（６１ｍｇ，５５％）。
ＭＳ（ＥＳＩ）：６４７（Ｍ）^＋，６４６（Ｍ−Ｈ）^−
1H NMR (400 MHz, DMSO-d₆) δppm 1.68 - 1.95 (6H, m), 2.26 - 2.40 (2H, m), 3.10 (6H, s), 3.41 - 3.55 (4H, m), 3.76 (3H, s), 3.99 - 4.17 (4H, m), 6.99 - 7.09 (2H, m), 7.64 - 7.87 (4H, m), 7.96 - 8.10 (3H, m), 8.27 - 8.38 (1H, m), 8.52 (1H, br. s.), 9.50 - 9.60 (1H, m), 10.20 (1H, br. s.)
実施例１９
リン酸＝４−（（４’−（４−（（ヒドロキシアミノ）カルボニル）−３−メトキシ−６−オキシド−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル２ナトリウム塩（化合物８５）

(2) N- (2-tert-butoxy-2-oxoethyl) -4- (4-((4 ′-(3-methoxy-6-oxide-4-(( (Tetrahydro-2H-pyran-2-yloxy) amino) carbonyl) -1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butoxy) -N, N-dimethyl-4-oxobutane-1-ami TFA (2.5 ml) was added to a suspension of nium bromide (297 mg) in anisole (0.5 ml), stirred at room temperature for 4.5 hours, and then allowed to stand at room temperature for 39 hours. The operation of adding IPE to the reaction solution and removing the supernatant was repeated twice, and then the operation of adding ethyl acetate to the residue and removing the supernatant was repeated twice to obtain a yellow solid (280 mg). A 1 mol / l-aqueous sodium hydroxide solution was added to a suspension of the obtained solid (140 mg) in water (100 ml) to adjust to pH 8 and dissolved, and reverse phase silica gel column chromatography (water → water / acetonitrile = 70/30). N- (carboxymethyl) -4- (4-((4 ′-(4-((hydroxyamino) carbonyl) -3-methoxy-6-oxide-1,6-naphthyridin-2-yl) ) Biphenyl-4-yl) oxy) butoxy) -N, N-dimethyl-4-oxobutane-1-aminium (yellow solid) was obtained (61 mg, 55%).
MS (ESI): 647 (M) ⁺ , 646 (M−H) ^−
1 H NMR (400 MHz, DMSO-d ₆ ) δppm 1.68-1.95 (6H, m), 2.26-2.40 (2H, m), 3.10 (6H, s), 3.41-3.55 (4H, m), 3.76 (3H , s), 3.99-4.17 (4H, m), 6.99-7.09 (2H, m), 7.64-7.87 (4H, m), 7.96-8.10 (3H, m), 8.27-8.38 (1H, m), 8.52 (1H, br.s.), 9.50-9.60 (1H, m), 10.20 (1H, br.s.)
Example 19
Phosphoric acid = 4-((4 ′-(4-((hydroxyamino) carbonyl) -3-methoxy-6-oxide-1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butyl ester Disodium salt (compound 85)

（１）実施例１６−（３）で得た２−（４’−（４−ヒドロキシブトキシ）ビフェニル−４−イル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド（１．７１ｇ）の塩化メチレン（２５ｍｌ）、アセトニトリル（２５ｍｌ）及びＴＨＦ（２５ｍｌ）溶液に、窒素雰囲気下Ｎ，Ｎ−ジイソプロピルホスホルアミド酸ジ−ｔｅｒｔ−ブチルエステル（２．０ｍｌ）及び１Ｈ−テトラゾール（０．６６ｇ）を加え、室温で１．５時間攪拌した。氷冷下７７％ｍＣＰＢＡ（１．４１ｇ）を添加して１０分間攪拌後、室温で４５分間攪拌した。溶媒を減圧下留去し、塩化メチレンを加え、チオ硫酸ナトリウム水溶液及び飽和炭酸水素ナトリウム水溶液で順次洗浄した。無水硫酸ナトリウムで乾燥後、乾燥剤を濾別し、溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（クロロホルム／アセトン＝５／１）で精製して、リン酸＝ジ−ｔｅｒｔ−ブチル＝４−（（４’−（３−メトキシ−４−（（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）アミノ）カルボニル）−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル（黄色固体）を得た（１．３７ｇ，５９％）。
ＭＳ（ＥＳＩ）：７３６（Ｍ＋Ｈ）^＋，７３４（Ｍ−Ｈ）^−
1H NMR (400 MHz, CHLOROFORM-d) δppm 1.48 (18H, s), 1.56 - 2.10 (10H, m), 3.60 - 3.80 (1H, m), 3.76 (3H, s), 3.96 - 4.18 (5H, m), 5.28 - 5.35 (1H, m), 6.96 - 7.04 (2H, m), 7.58 - 7.64 (2H, m), 7.68 - 7.75 (2H, m), 7.87 (1H, d, J=6.0 Hz), 8.11 (2H, d, J=8.3 Hz), 8.65 (1H, d, J=6.0 Hz), 9.47 (1H, s), 9.55 (1H, s)

(1) 2- (4 ′-(4-hydroxybutoxy) biphenyl-4-yl) -3-methoxy-N- (tetrahydro-2H-pyran-2-yloxy)-obtained in Example 16- (3) To a solution of 1,6-naphthyridine-4-carboxamide (1.71 g) in methylene chloride (25 ml), acetonitrile (25 ml) and THF (25 ml) was added N-N-diisopropylphosphoramidate di-tert-butyl under nitrogen atmosphere. Ester (2.0 ml) and 1H-tetrazole (0.66 g) were added, and the mixture was stirred at room temperature for 1.5 hours. Under ice cooling, 77% mCPBA (1.41 g) was added and stirred for 10 minutes, and then stirred at room temperature for 45 minutes. The solvent was distilled off under reduced pressure, methylene chloride was added, and the mixture was washed successively with an aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution. After drying over anhydrous sodium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / acetone = 5/1), and phosphoric acid = di-tert-butyl = 4-((4 ′-(3-methoxy-4-(((( Tetrahydro-2H-pyran-2-yloxy) amino) carbonyl) -1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butyl ester (yellow solid) was obtained (1.37 g, 59%). ).
MS (ESI): 736 (M + H) ⁺ , 734 (M−H) ^−
1 H NMR (400 MHz, CHLOROFORM-d) δppm 1.48 (18H, s), 1.56-2.10 (10H, m), 3.60-3.80 (1H, m), 3.76 (3H, s), 3.96-4.18 (5H, m), 5.28-5.35 (1H, m), 6.96-7.04 (2H, m), 7.58-7.64 (2H, m), 7.68-7.75 (2H, m), 7.87 (1H, d, J = 6.0 Hz) , 8.11 (2H, d, J = 8.3 Hz), 8.65 (1H, d, J = 6.0 Hz), 9.47 (1H, s), 9.55 (1H, s)

（２）実施例１９−（１）で得たリン酸＝ジ−ｔｅｒｔ−ブチル＝４−（（４’−（３−メトキシ−４−（（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）アミノ）カルボニル）−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル（１．３７ｇ）のクロロホルム（６．５ｍｌ）溶液に、氷冷下７７％ｍＣＰＢＡ（０．８３ｇ）及び炭酸水素ナトリウム（０．４７ｇ）を加えて１０分間攪拌した後、室温で１時間攪拌した。反応液をシリカゲルカラムクロマトグラフィー（酢酸エチル→クロロホルム／メタノール＝１０／１）で精製し、リン酸＝ジ−ｔｅｒｔ−ブチル＝４−（（４’−（３−メトキシ−６−オキシド−４−（（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）アミノ）カルボニル）−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル（黄色固体）を得た（１．０１ｇ，７２％）。
ＭＳ（ＥＳＩ）：７５２（Ｍ＋Ｈ）^＋，７５０（Ｍ−Ｈ）^−
1H NMR (400 MHz, CHLOROFORM-d) δppm 1.50 (18H, s), 1.62 - 2.16 (10H, m), 3.78 - 3.94 (1H, m), 3.89 (3H, s), 4.02 - 4.28 (5H, m), 5.51 (1H, br. s.), 6.95 - 7.05 (2H, m), 7.53 (1H, d, J=7.3 Hz), 7.55 - 7.70 (3H, m), 7.74 (2H, d, J=8.5 Hz), 8.14 (2H, d, J=8.5 Hz), 8.80 (1H, d, J=1.7 Hz), 11.76 (1H, br. s.)

(2) Phosphate = di-tert-butyl = 4-((4 ′-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yloxy) amino) obtained in Example 19- (1) To a solution of) carbonyl) -1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butyl ester (1.37 g) in chloroform (6.5 ml) was added 77% mCPBA (0.83 g) under ice cooling. ) And sodium bicarbonate (0.47 g) were added and stirred for 10 minutes, followed by stirring at room temperature for 1 hour. The reaction solution was purified by silica gel column chromatography (ethyl acetate → chloroform / methanol = 10/1), and phosphoric acid = di-tert-butyl = 4-((4 ′-(3-methoxy-6-oxide-4-). (((Tetrahydro-2H-pyran-2-yloxy) amino) carbonyl) -1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butyl ester (yellow solid) was obtained (1.01 g). 72%).
MS (ESI): 752 (M + H) ⁺ , 750 (M−H) ^−
1 H NMR (400 MHz, CHLOROFORM-d) δppm 1.50 (18H, s), 1.62-2.16 (10H, m), 3.78-3.94 (1H, m), 3.89 (3H, s), 4.02-4.28 (5H, m), 5.51 (1H, br.s.), 6.95-7.05 (2H, m), 7.53 (1H, d, J = 7.3 Hz), 7.55-7.70 (3H, m), 7.74 (2H, d, J = 8.5 Hz), 8.14 (2H, d, J = 8.5 Hz), 8.80 (1H, d, J = 1.7 Hz), 11.76 (1H, br.s.)

（３）実施例１９−（２）で得たリン酸＝ジ−ｔｅｒｔ−ブチル＝４−（（４’−（３−メトキシ−６−オキシド−４−（（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）アミノ）カルボニル）−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル（５００ｍｇ）のアニソール（１．０ｍｌ）懸濁液に、ＴＦＡ（５．０ｍｌ）を加え室温で３．５時間攪拌後、アニソール（１．０ｍｌ）を追加し３．５時間攪拌した。反応液にＩＰＥを加えて６４時間室温で放置して上澄液を除去後、残留物にＩＰＥを加えて上澄液を除去した。得られた残留物（０．３７ｇ）の水（２０ｍｌ）懸濁液に０．５ｍｏｌ／ｌ−水酸化ナトリウム水溶液を加えてｐＨ７に調整し溶解させ、逆相シリカゲルカラムクロマトグラフィー（水→水／アセトニトリル＝９０／１０）で精製し、リン酸＝４−（（４’−（４−（（ヒドロキシアミノ）カルボニル）−３−メトキシ−６−オキシド−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル２ナトリウム塩（黄色固体）を得た（２９０ｍｇ，７３％）。
ＭＳ（ＥＳＩ）：５５４（Ｍ−Ｈ）^−
1H NMR (400 MHz, D₂O) δppm 1.62 - 1.83 (4H, m), 3.65 (3H, s), 3.73 - 3.80 (2H, m), 4.00 - 4.07 (2H, m), 6.98 (2H, d, J=8.7 Hz), 7.57 (2H, d, J=8.7 Hz), 7.65 (2H, d, J=8.2 Hz), 7.80 (2H, d, J=8.2 Hz), 7.96 (1H, d, J=7.3 Hz), 8.25 (1H, dd, J=7.3, 2.1 Hz), 8.75 (1H, d, J=2.1 Hz)
実施例２０
リン酸＝３−（４−（（４’−（４−（（ヒドロキシアミノ）カルボニル）−３−メトキシ−６−オキシド−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブトキシ）−１−メチル−３−オキソプロピル＝エステルナトリウム塩（化合物９５）

(3) Phosphate = di-tert-butyl = 4-((4 ′-(3-methoxy-6-oxide-4-(((tetrahydro-2H-pyran-2) obtained in Example 19- (2)) -Anyl (1.0 ml) suspension of -yloxy) amino) carbonyl) -1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butyl ester (500 mg) in TFA (5.0 ml) After stirring at room temperature for 3.5 hours, anisole (1.0 ml) was added and stirred for 3.5 hours. IPE was added to the reaction solution and allowed to stand at room temperature for 64 hours to remove the supernatant, and then IPE was added to the residue to remove the supernatant. A 0.5 mol / l-sodium hydroxide aqueous solution was added to a suspension of the obtained residue (0.37 g) in water (20 ml) to adjust to pH 7 and dissolved, and reverse phase silica gel column chromatography (water → water / Purified with acetonitrile = 90/10) and phosphoric acid = 4-((4 ′-(4-((hydroxyamino) carbonyl) -3-methoxy-6-oxide-1,6-naphthyridin-2-yl) biphenyl -4-yl) oxy) butyl = ester disodium salt (yellow solid) was obtained (290 mg, 73%).
MS (ESI): 554 (M-H) ^−
1 H NMR (400 MHz, D ₂ O) δppm 1.62-1.83 (4H, m), 3.65 (3H, s), 3.73-3.80 (2H, m), 4.00-4.07 (2H, m), 6.98 (2H, d, J = 8.7 Hz), 7.57 (2H, d, J = 8.7 Hz), 7.65 (2H, d, J = 8.2 Hz), 7.80 (2H, d, J = 8.2 Hz), 7.96 (1H, d, J = 7.3 Hz), 8.25 (1H, dd, J = 7.3, 2.1 Hz), 8.75 (1H, d, J = 2.1 Hz)
Example 20
Phosphoric acid = 3- (4-((4 ′-(4-((hydroxyamino) carbonyl) -3-methoxy-6-oxide-1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) Butoxy) -1-methyl-3-oxopropyl ester sodium salt (Compound 95)

（１）実施例１６−（３）で得た２−（４’−（４−ヒドロキシブトキシ）ビフェニル−４−イル）−３−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）−１，６−ナフチリジン−４−カルボキサミド（１．５９ｇ）のＴＨＦ（３２ｍｌ）懸濁液に、氷冷下ＤＩＰＥＡ（１．０１ｍｌ）及びＭｓＣｌ（０．３４ｍｌ）を加え、氷冷下１時間攪拌した後、ＤＩＰＥＡ（１．０１ｍｌ）及びＭｓＣｌ（０．３４ｍｌ）を追加し、１時間攪拌した。さらにＤＩＰＥＡ（１．０１ｍｌ）及びＭｓＣｌ（０．３４ｍｌ）を追加し、１時間攪拌した。反応液に酢酸エチル及び水を加えて有機層を分取し、抽出物を水及び飽和食塩水で順次洗浄した。無水硫酸マグネシウムで乾燥して乾燥剤を濾別後、溶媒を減圧下留去し、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／トルエン＝３／１）で精製して、メタンスルホン酸＝４−（（４’−（３−メトキシ−４−（（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）アミノ）カルボニル）−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル（黄色固体）を得た（４６３ｍｇ，２５％）。
ＭＳ（ＥＳＩ）：６２２（Ｍ＋Ｈ）^＋，６２０（Ｍ−Ｈ）^−
1H NMR (400 MHz, CHLOROFORM-d) δppm 1.54 - 2.10 (10H, m), 3.03 (3H, s), 3.53 - 3.56 (1H, m), 3.76 (3H, s), 4.04 - 4.14 (3H, m), 4.35 (2H, t, J=6.0 Hz), 5.31 (1H, br. s.), 6.98 - 7.05 (2H, m), 7.58 - 7.67 (2H, m), 7.72 (2H, d, J=8.3 Hz), 7.88 (1H, d, J=5.9 Hz), 8.11 (2H, d, J=8.3 Hz), 8.66 (1H, d, J=5.9 Hz), 9.41 (1H, s), 9.46 (1H, s)

(1) 2- (4 ′-(4-hydroxybutoxy) biphenyl-4-yl) -3-methoxy-N- (tetrahydro-2H-pyran-2-yloxy)-obtained in Example 16- (3) To a suspension of 1,6-naphthyridine-4-carboxamide (1.59 g) in THF (32 ml) were added DIPEA (1.01 ml) and MsCl (0.34 ml) under ice cooling, and the mixture was stirred for 1 hour under ice cooling. Thereafter, DIPEA (1.01 ml) and MsCl (0.34 ml) were added, and the mixture was stirred for 1 hour. Further, DIPEA (1.01 ml) and MsCl (0.34 ml) were added and stirred for 1 hour. Ethyl acetate and water were added to the reaction solution, the organic layer was separated, and the extract was washed successively with water and saturated brine. After drying over anhydrous magnesium sulfate and filtering off the desiccant, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / toluene = 3/1), and methanesulfonic acid = 4- ((4 ′-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yloxy) amino) carbonyl) -1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butyl = The ester (yellow solid) was obtained (463 mg, 25%).
MS (ESI): 622 (M + H) ⁺ , 620 (M−H) ^−
1 H NMR (400 MHz, CHLOROFORM-d) δppm 1.54-2.10 (10H, m), 3.03 (3H, s), 3.53-3.56 (1H, m), 3.76 (3H, s), 4.04-4.14 (3H, m), 4.35 (2H, t, J = 6.0 Hz), 5.31 (1H, br.s.), 6.98-7.05 (2H, m), 7.58-7.67 (2H, m), 7.72 (2H, d, J = 8.3 Hz), 7.88 (1H, d, J = 5.9 Hz), 8.11 (2H, d, J = 8.3 Hz), 8.66 (1H, d, J = 5.9 Hz), 9.41 (1H, s), 9.46 ( 1H, s)

（２）実施例２０−（１）で得たメタンスルホン酸＝４−（（４’−（３−メトキシ−４−（（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）アミノ）カルボニル）−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル（０．４６ｇ）のＤＭＦ（２．０ｍｌ）溶液に、３−ヒドロキシ酪酸（０．２１ｇ）のＤＭＦ（０．５ｍｌ）溶液及び炭酸カリウム（０．３１ｇ）を加え、室温で２．５時間攪拌した後４０〜５０℃で８．５時間攪拌した。放冷後、反応液に酢酸エチル及び水を加え１ｍｏｌ／ｌ−塩酸でｐＨ５に調整し、有機層を分取した。水層を酢酸エチルで逆抽出し、合わせた抽出物を水及び飽和食塩水で順次洗浄した。無水硫酸マグネシウムで乾燥して乾燥剤を濾別後、溶媒を減圧下留去し、残留物をシリカゲルカラムクロマトグラフィー（クロロホルム／アセトン＝１０／１）で精製後、分取用シリカゲル薄層クロマトグラフィー（クロロホルム／アセトン＝５／１）で精製し、さらに分取用シリカゲル薄層クロマトグラフィー（酢酸エチル／トルエン＝３／１）で精製し、３−ヒドロキシ酪酸＝４−（（４’−（３−メトキシ−４−（（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）アミノ）カルボニル）−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル（黄色固体）を得た（０．１９ｇ，４１％）。
¹H NMR (400 MHz, CHLOROFORM-d) δppm 1.18 - 1.35 (3H, m), 1.50 - 2.10 (10H, m), 2.35 - 2.69 (2H, m), 3.53 - 3.56 (1H, m), 3.76 (3H, s), 4.02 - 4.26 (6H, m), 5.20 - 5.40 (1H, m), 6.58 - 7.04 (2H, m), 7.58 - 7.66 (2H, m), 7.72 (2H, d, J=8.3 Hz), 7.87 (1H, d, J=5.9 Hz), 8.11 (2H, d, J=8.3 Hz), 8.65 (1H, d, J=5.9 Hz), 9.46 (1H, s), 9.47 (1H, br. s.)

(2) Methanesulfonic acid obtained in Example 20- (1) = 4-((4 ′-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yloxy) amino) carbonyl) -1 , 6-Naphthyridin-2-yl) biphenyl-4-yl) oxy) butyl ester (0.46 g) in DMF (2.0 ml) was added 3-hydroxybutyric acid (0.21 g) in DMF (0.5 ml). ) Solution and potassium carbonate (0.31 g) were added, and the mixture was stirred at room temperature for 2.5 hours, and then stirred at 40 to 50 ° C. for 8.5 hours. After allowing to cool, ethyl acetate and water were added to the reaction solution, adjusted to pH 5 with 1 mol / l-hydrochloric acid, and the organic layer was separated. The aqueous layer was back-extracted with ethyl acetate, and the combined extracts were washed successively with water and saturated brine. After drying over anhydrous magnesium sulfate and filtering off the desiccant, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / acetone = 10/1), and then preparative silica gel thin layer chromatography. Purified with (chloroform / acetone = 5/1) and further purified with preparative silica gel thin layer chromatography (ethyl acetate / toluene = 3/1) to give 3-hydroxybutyric acid = 4-((4 ′-(3 -Methoxy-4-(((tetrahydro-2H-pyran-2-yloxy) amino) carbonyl) -1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butyl ester (yellow solid) is obtained. (0.19 g, 41%).
¹ H NMR (400 MHz, CHLOROFORM-d) δppm 1.18-1.35 (3H, m), 1.50-2.10 (10H, m), 2.35-2.69 (2H, m), 3.53-3.56 (1H, m), 3.76 ( 3H, s), 4.02-4.26 (6H, m), 5.20-5.40 (1H, m), 6.58-7.04 (2H, m), 7.58-7.66 (2H, m), 7.72 (2H, d, J = 8.3 Hz), 7.87 (1H, d, J = 5.9 Hz), 8.11 (2H, d, J = 8.3 Hz), 8.65 (1H, d, J = 5.9 Hz), 9.46 (1H, s), 9.47 (1H, br.s.)

（３）実施例２０−（２）で得た３−ヒドロキシ酪酸＝４−（（４’−（３−メトキシ−４−（（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）アミノ）カルボニル）−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル（１３４ｍｇ）の塩化メチレン（２．０ｍｌ）溶液に、窒素雰囲気下Ｎ，Ｎ−ジイソプロピルホスホルアミド酸ジ−ｔｅｒｔ−ブチルエステル（１３４μｌ）及び１Ｈ−テトラゾール（４５ｍｇ）を加え、室温で１時間攪拌した。氷冷下７７％ｍＣＰＢＡ（９５ｍｇ）を添加し、室温で１時間攪拌した後、氷冷下７７％ｍＣＰＢＡ（９５ｍｇ）を追加し、室温で１時間攪拌した。反応液を分取用シリカゲル薄層クロマトグラフィー（酢酸エチル→クロロホルム／メタノール＝１０／１）で精製して、３−（（ジ−ｔｅｒｔ−ブトキシホスホリル）オキシ）酪酸＝４−（（４’−（３−メトキシ−６−オキシド−４−（（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）アミノ）カルボニル）−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル（黄色固体）を得た（３４ｍｇ，１９％）。
¹H NMR (400 MHz, CHLOROFORM-d) δppm 1.20 - 2.17 (13H, m), 1.48 (18H, s), 2.40 - 2.90 (2H, m), 3.65 - 3.95 (1H, m), 3.89 (3H, s), 3.95 - 4.30 (5H, m), 4.70 - 5.40 (1H, m), 5.51 (1H, br. s.), 7.02 (2H, d, J=8.5 Hz), 7.53 (1H, d, J=7.3 Hz), 7.57 - 7.68 (3H, m), 7.74 (2H, d, J=8.3 Hz), 8.14 (2H, d, J=8.3 Hz), 8.79 (1H, s), 11.76 (1H, br. s.)

(3) 3-hydroxybutyric acid obtained in Example 20- (2) = 4-((4 ′-(3-methoxy-4-(((tetrahydro-2H-pyran-2-yloxy) amino) carbonyl)- To a solution of 1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butyl ester (134 mg) in methylene chloride (2.0 ml) was added N, N-diisopropylphosphoramidic acid di-tert under nitrogen atmosphere. -Butyl ester (134 μl) and 1H-tetrazole (45 mg) were added, and the mixture was stirred at room temperature for 1 hour. 77% mCPBA (95 mg) was added under ice-cooling and stirred at room temperature for 1 hour, 77% mCPBA (95 mg) was added under ice-cooling and stirred at room temperature for 1 hour. The reaction solution was purified by preparative silica gel thin layer chromatography (ethyl acetate → chloroform / methanol = 10/1) to give 3-((di-tert-butoxyphosphoryl) oxy) butyric acid = 4-((4′- (3-Methoxy-6-oxide-4-(((tetrahydro-2H-pyran-2-yloxy) amino) carbonyl) -1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butyl ester (Yellow solid) was obtained (34 mg, 19%).
¹ H NMR (400 MHz, CHLOROFORM-d) δppm 1.20-2.17 (13H, m), 1.48 (18H, s), 2.40-2.90 (2H, m), 3.65-3.95 (1H, m), 3.89 (3H, s), 3.95-4.30 (5H, m), 4.70-5.40 (1H, m), 5.51 (1H, br.s.), 7.02 (2H, d, J = 8.5 Hz), 7.53 (1H, d, J = 7.3 Hz), 7.57-7.68 (3H, m), 7.74 (2H, d, J = 8.3 Hz), 8.14 (2H, d, J = 8.3 Hz), 8.79 (1H, s), 11.76 (1H, br .s.)

（４）実施例２０−（３）で得た３−（（ジ−ｔｅｒｔ−ブトキシホスホリル）オキシ）酪酸＝４−（（４’−（３−メトキシ−６−オキシド−４−（（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）アミノ）カルボニル）−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル（６５ｍｇ）のアニソール（０．４ｍｌ）懸濁液に、ＴＦＡ（１．０ｍｌ）を加え室温で２日間攪拌した後、反応液にＩＰＥを加えて析出物を濾別した。得られた固体の水懸濁液に０．１ｍｏｌ／ｌ−水酸化ナトリウム水溶液を加えてｐＨ７．５に調整し溶解させ、逆相シリカゲルカラムクロマトグラフィー（水→水／アセトニトリル＝７５／２５）で精製した。得られた固体を水に溶解させ０．１ｍｏｌ／ｌ−塩酸及び０．１ｍｏｌ／ｌ−水酸化ナトリウム水溶液でｐＨ４に調整し、減圧下濃縮した。残留物にメタノールを加えて不溶物を濾別し、濾液を減圧下濃縮した後アセトンを加えて濾別し、リン酸＝３−（４−（（４’−（４−（（ヒドロキシアミノ）カルボニル）−３−メトキシ−６−オキシド−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブトキシ）−１−メチル−３−オキソプロピル＝エステルナトリウム塩（黄色固体）を得た（１２ｍｇ，２３％）。
ＭＳ（ＥＳＩ）：６４０（Ｍ−Ｈ）^−
1H NMR (400 MHz, CD₃OD) δppm 1.30 - 1.39 (3H, m), 1.75 - 1.95 (4H, m), 2.46 - 2.80 (2H, m), 3.81 (3H, s), 4.00 - 4.35 (4H, m), 4.63 - 4.82 (1H, m), 7.04 (2H, d, J=8.3 Hz), 7.63 - 7.70 (2H, m), 7.77 (2H, d, J=8.1 Hz), 8.08 - 8.16 (3H, m), 8.40 (1H, dd, J=7.3, 1.9 Hz), 8.81 - 8.84 (1H, m)
以下、前記実施例１から２０の方法と同様にして、表１に示す化合物をそれぞれ対応する原料を使用して製造した。表１中の実施例番号とは、前記の実施例自体又は前記のいずれの実施例に基づいて表１に示す化合物を製造したかを示すものである。
表１中の略語を以下に示す。
Ｆｒｅｅ：塩を形成していない（フリー体）
ＨＣｌ：塩酸塩
Ｎａ：ナトリウム塩

(4) 3-((Di-tert-butoxyphosphoryl) oxy) butyric acid obtained in Example 20- (3) = 4-((4 ′-(3-methoxy-6-oxide-4-(((tetrahydro -2H-pyran-2-yloxy) amino) carbonyl) -1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butyl ester (65 mg) in a suspension of anisole (0.4 ml) After adding TFA (1.0 ml) and stirring at room temperature for 2 days, IPE was added to the reaction solution and the precipitate was separated by filtration. 0.1 mol / l-sodium hydroxide aqueous solution was added to the obtained solid aqueous suspension to adjust to pH 7.5 and dissolved, and reverse phase silica gel column chromatography (water → water / acetonitrile = 75/25) Purified. The obtained solid was dissolved in water, adjusted to pH 4 with 0.1 mol / l-hydrochloric acid and 0.1 mol / l-sodium hydroxide aqueous solution, and concentrated under reduced pressure. Methanol was added to the residue, insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, then acetone was added and filtered off, and phosphoric acid = 3- (4-((4 '-(4-((hydroxyamino)) Carbonyl) -3-methoxy-6-oxide-1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butoxy) -1-methyl-3-oxopropyl ester sodium salt (yellow solid) (12 mg, 23%).
MS (ESI): 640 (M−H) ^−
1 H NMR (400 MHz, CD ₃ OD) δppm 1.30-1.39 (3H, m), 1.75-1.95 (4H, m), 2.46-2.80 (2H, m), 3.81 (3H, s), 4.00-4.35 ( 4H, m), 4.63-4.82 (1H, m), 7.04 (2H, d, J = 8.3 Hz), 7.63-7.70 (2H, m), 7.77 (2H, d, J = 8.1 Hz), 8.08-8.16 (3H, m), 8.40 (1H, dd, J = 7.3, 1.9 Hz), 8.81-8.84 (1H, m)
Thereafter, in the same manner as in Examples 1 to 20, the compounds shown in Table 1 were produced using the corresponding raw materials. The Example number in Table 1 indicates whether the compound shown in Table 1 was produced based on the above Example itself or any of the above Examples.
Abbreviations in Table 1 are shown below.
Free: No salt is formed (free body)
HCl: hydrochloride Na: sodium salt

表１で記載されている化合物名は、以下の通りである。
化合物１ ２−（ビフェニル−４−イル）−Ｎ−ヒドロキシ−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物２ Ｎ−ヒドロキシ−２−（４’−（２−ヒドロキシエトキシ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物３ Ｎ−ヒドロキシ−２−（４’−（（２−ヒドロキシエチル）アミノ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物４ Ｎ−ヒドロキシ−３−メトキシ−２−（４−（ピリジン−４−イル）フェニル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物５ ２−（４’−（３，４−ジヒドロキシブトキシ）ビフェニル−４−イル）−Ｎ−ヒドロキシ−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物６ ２−（４’−（シアノメチル）ビフェニル−４−イル）−Ｎ−ヒドロキシ−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物７ Ｎ−ヒドロキシ−３−メトキシ−２−（４−（キノリン−６−イル）フェニル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物８ Ｎ−ヒドロキシ−３−メトキシ−２−（４’−メトキシビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物９ Ｎ−ヒドロキシ−３−メトキシ−２−（３’−メトキシビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物１０ Ｎ−ヒドロキシ−２−（４’−（３−ヒドロキシプロピル）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物１１ ２−（４−（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イル）フェニル）−Ｎ−ヒドロキシ−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物１２ Ｎ−ヒドロキシ−２−（４’−（（４−ヒドロキシブチル）アミノ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物１３ Ｎ−ヒドロキシ−２−（４’−ヒドロキシビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物１４ ２−（４−（６−シアノピリジン−３−イル）フェニル）−Ｎ−ヒドロキシ−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物１５ Ｎ−ヒドロキシ−３−メトキシ−２−（４−（６−メトキシピリジン−３−イル）フェニル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物１６ Ｎ−ヒドロキシ−２−（４’−（３−ヒドロキシプロピル）ビフェニル−４−イル）−３，８−ジメトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物１７ ８−ブロモ−Ｎ−ヒドロキシ−２−（４’−（２−ヒドロキシエトキシ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物１８ ３−クロロ−Ｎ−ヒドロキシ−２−（４’−（２−ヒドロキシエトキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物１９ Ｎ−ヒドロキシ−３−メトキシ−２−（４’−（トリフルオロメトキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物２０ Ｎ−ヒドロキシ−３−メトキシ−２−（４’−（２−メトキシエトキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物２１ Ｎ−ヒドロキシ−３−メトキシ−２−（４’−プロピルビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物２２ ２−（４’−フルオロビフェニル−４−イル）−Ｎ−ヒドロキシ−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物２３ Ｎ−ヒドロキシ−３−メトキシ−２−（４’−メチルビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物２４ ２−（４’−アセチルビフェニル−４−イル）−Ｎ−ヒドロキシ−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物２５ Ｎ−ヒドロキシ−３−メトキシ−２−（４’−（メチルスルホニル）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物２６ Ｎ−ヒドロキシ−３−メトキシ−２−（４’−（メトキシアセチル）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物２７ Ｎ−ヒドロキシ−３−メトキシ−２−（４’−（トリフルオロメチル）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物２８ ２−（４−（３，４−ジヒドロ−２Ｈ−１，５−ベンゾジオキセピン−７−イル）フェニル）−Ｎ−ヒドロキシ−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物２９ ２−（３’−フルオロ−４’−メトキシビフェニル−４−イル）−Ｎ−ヒドロキシ−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物３０ Ｎ−ヒドロキシ−３−メトキシ−２−（４’−（モルホリン−４−イル）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物３１ Ｎ−ヒドロキシ−２−（４’−（（４−ヒドロキシブチル）アミノ）ビフェニル−４−イル）−１，７−ナフチリジン−４−カルボキサミド ７−オキシド２塩酸塩、
化合物３２ Ｎ−ヒドロキシ−２−（４’−（４−ヒドロキシブトキシ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物３３ Ｎ−ヒドロキシ−２−（４’−（（６−ヒドロキシヘキシル）アミノ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物３４ Ｎ−ヒドロキシ−２−（４’−（（３−ヒドロキシプロピル）アミノ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物３５ Ｎ−ヒドロキシ−３−メトキシ−２−（４’−（２−（ピペラジン−１−イル）エチル）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド３塩酸塩、
化合物３６ Ｎ−ヒドロキシ−２−（４−（（４−（（２−ヒドロキシエチル）アミノ）フェニル）エチニル）フェニル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド、
化合物３７ Ｎ−ヒドロキシ−２−（４’−（（テトラヒドロ−２Ｈ−ピラン−４−イル）メチルアミノ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物３８ Ｎ−ヒドロキシ−７−（４’−（４−ヒドロキシブチルアミノ）ビフェニル−４−イル）−１，８−ナフチリジン−５−カルボキサミド １−オキシド２塩酸塩、
化合物３９ Ｎ−ヒドロキシ−２−（４−（６−（（５−ヒドロキシペンチル）オキシ）ピリジン−３−イル）フェニル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物４０ ４’−（４−（ヒドロキシカルバモイル）−３−メトキシ−６−オキシド−１，６−ナフチリジン−２−イル）ビフェニル−４−カルボン酸塩酸塩、
化合物４１ Ｎ−ヒドロキシ−２−（４’−（ヒドロキシカルバモイル）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物４２ ４’−（４−（ヒドロキシカルバモイル）−３−メトキシ−６−オキシド−１，６−ナフチリジン−２−イル）ビフェニル−４−カルボン酸メチル塩酸塩、
化合物４３ Ｎ−ヒドロキシ−３−メトキシ−２−（４−（（４−（モルホリン−４−イルメチル）フェニル）エチニル）フェニル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド、
化合物４４ Ｎ−ヒドロキシ−３−メトキシ−２−（４’−（３−（モルホリン−４−イル）プロポキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物４５ ４’−（４−（ヒドロキシカルバモイル）−３−メトキシ−６−オキシド−１，６−ナフチリジン−２−イル）ビフェニル−４−カルボン酸 ｔｅｒｔ−ブチル塩酸塩、
化合物４６ Ｎ−ヒドロキシ−３−メトキシ−２−（４’−（プロピルカルバモイル）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物４７ Ｎ−ヒドロキシ−２−（４’−（３−（２−ヒドロキシエトキシ）プロポキシ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物４８ Ｎ−ヒドロキシ−２−（４’−（３−（１Ｈ−イミダゾール−１−イル）プロポキシ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物４９ ２−（４−シクロプロピルフェニル）−Ｎ−ヒドロキシ−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物５０ ２−（４−（フラン−２−イル）フェニル）−Ｎ−ヒドロキシ−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物５１ Ｎ−ヒドロキシ−３−メトキシ−２−（４’−（メチルアミノ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物５２ Ｎ−ヒドロキシ−３−メトキシ−２−（４−（２−フェニルエチル）フェニル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物５３ ２−（４’−（２−（シクロプロピルアミノ）エトキシ）ビフェニル−４−イル）−Ｎ−ヒドロキシ−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物５４ ２−（ビフェニル−４−イル）−Ｎ−ヒドロキシ−３−メチル−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物５５ Ｎ−ヒドロキシ−２−（４−（４−（３−ヒドロキシプロピル）ピペリジン−１−イル）フェニル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物５６ Ｎ−ヒドロキシ−２−（４’−（３−ヒドロキシアゼチジン−１−イル）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物５７ Ｎ−ヒドロキシ−３−メトキシ−２−（４’−ニトロビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物５８ ２−（４’−（（３−シアノプロピル）アミノ）ビフェニル−４−イル）−Ｎ−ヒドロキシ−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物５９ Ｎ−ヒドロキシ−２−（４’−（（２−ヒドロキシエチル）アミノ）ビフェニル−４−イル）−３−メチル−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物６０ ２−（４’−アミノビフェニル−４−イル）−Ｎ−ヒドロキシ−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物６１ ２−（３’−フルオロ−４’−（（２−ヒドロキシエチル）アミノ）ビフェニル−４−イル）−Ｎ−ヒドロキシ−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物６２ ３−アミノ−２−（ビフェニル−４−イル）−Ｎ−ヒドロキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物６３ ２−（４’−ｔｅｒｔ−ブチルビフェニル−４−イル）−Ｎ−ヒドロキシ−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物６４ Ｎ−ヒドロキシ−２−（４’−（４−ヒドロキシピペリジン−１−イル）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物６５ Ｎ−ヒドロキシ−３−メトキシ−２−（４’−（４−（モルホリン−４−イル）ブトキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物６６ Ｎ−ヒドロキシ−２−（４’−（３−（（２−ヒドロキシエチル）（メチル）アミノ）プロポキシ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物６７ Ｎ−ヒドロキシ−２−（４’−（（５−ヒドロキシ−４−（ヒドロキシメチル）ペンチル）オキシ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物６８ Ｎ−ヒドロキシ−２−（４’−（（５−ヒドロキシペンタノイル）アミノ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物６９ Ｎ−ヒドロキシ−２−（４’−（（４−ヒドロキシペンチル）アミノ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物７０ Ｎ−ヒドロキシ−３−メトキシ−２−（４’−（３−（ピペリジン−４−イル）プロポキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物７１ Ｎ−ヒドロキシ−２−（４’−（４−（３−ヒドロキシアゼチジン−１−イル）ブトキシ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物７２ Ｎ−ヒドロキシ−３−メトキシ−２−（４’−（３−（ピリジン−３−イル）プロポキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物７３ １，４’−ビピペリジン−１’−カルボン酸＝４−（（４’−（４−（ヒドロキシカルバモイル）−３−メトキシ−６−オキシド−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル２塩酸塩、
化合物７４ ４−（４−（（４’−（４−（（ヒドロキシアミノ）カルボニル）−３−メトキシ−６−オキシド−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブトキシ）−４−オキソ酪酸塩酸塩、
化合物７５ Ｎ−ヒドロキシ−３−メトキシ−２−（４’−（４−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）ブトキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド、
化合物７６ Ｎ−ヒドロキシ−２−（４’−（４−ヒドロキシブトキシ）ビフェニル−４−イル）−３−メチル−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物７７ Ｎ−ヒドロキシ−２−（４’−（（４−ヒドロキシペンチル）オキシ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物７８ ４−（ジメチルアミノ）酪酸＝４−（（４’−（４−（（ヒドロキシアミノ）カルボニル）−３−メトキシ−６−オキシド−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル２塩酸塩、
化合物７９ Ｎ−（カルボキシメチル）−４−（４−（（４’−（４−（（ヒドロキシアミノ）カルボニル）−３−メトキシ−６−オキシド−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブトキシ）−Ｎ，Ｎ−ジメチル−４−オキソブタン−１−アミニウム、
化合物８０ Ｎ−ヒドロキシ−２−（４’−（（４−ヒドロキシ−４−メチルペンチル）オキシ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物８１ Ｎ−ヒドロキシ−２−（４’−（２−ヒドロキシプロポキシ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物８２ Ｎ−ヒドロキシ−２−（４’−（２−ヒドロキシ−２−メチルプロポキシ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物８３ Ｎ−ヒドロキシ−３−メトキシ−２−（４−（（４−（１，４−オキサゼパン−４−イルメチル）フェニル）エチニル）フェニル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド、
化合物８４ Ｎ−ヒドロキシ−２−（４−（（４−（（３−ヒドロキシアゼチジン−１−イル）メチル）フェニル）エチニル）フェニル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド、
化合物８５ リン酸＝４−（（４’−（４−（（ヒドロキシアミノ）カルボニル）−３−メトキシ−６−オキシド−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブチル＝エステル２ナトリウム塩、
化合物８６ Ｎ−ヒドロキシ−３−メトキシ−２−（４’−（３−（１，４−オキサゼパン−４−イル）プロポキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物８７ Ｎ−ヒドロキシ−３−メトキシ−２−（４’−（２−（モルホリン−４−イル）エトキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物８８ Ｎ−ヒドロキシ−３−メトキシ−２−（４’−（３−（チオモルホリン−４−イル）プロポキシ）ビフェニル−４−イル）−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物８９ ２−（４’−（３−（アゼチジン−１−イル）プロポキシ）ビフェニル−４−イル）−Ｎ−ヒドロキシ−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物９０ ４−（３−（（４’−（４−（ヒドロキシカルバモイル）−３−メトキシ−６−オキシド−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）プロピル）チオモルホリン １−オキシド２塩酸塩、
化合物９１ ２−（４’−（３−（３，３−ジフルオロアゼチジン−１−イル）プロポキシ）ビフェニル−４−イル）−Ｎ−ヒドロキシ−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド２塩酸塩、
化合物９２ Ｎ−ヒドロキシ−２−（４’−（３−ヒドロキシプロポキシ）ビフェニル−４−イル）−３−メトキシ−１，６−ナフチリジン−４−カルボキサミド ６−オキシド塩酸塩、
化合物９３ リン酸＝３−（（４’−（４−（ヒドロキシカルバモイル）−３−メトキシ−６−オキシド−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）プロピル＝エステル２ナトリウム塩、
化合物９４ リン酸＝２−（（４’−（４−（ヒドロキシカルバモイル）−３−メトキシ−６−オキシド−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）エチル＝エステル２ナトリウム塩、
化合物９５ リン酸＝３−（４−（（４’−（４−（（ヒドロキシアミノ）カルボニル）−３−メトキシ−６−オキシド−１，６−ナフチリジン−２−イル）ビフェニル−４−イル）オキシ）ブトキシ）−１−メチル−３−オキソプロピル＝エステルナトリウム塩。

The compound names described in Table 1 are as follows.
Compound 1 2- (biphenyl-4-yl) -N-hydroxy-3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 2 N-hydroxy-2- (4 ′-(2-hydroxyethoxy) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 3 N-hydroxy-2- (4 ′-((2-hydroxyethyl) amino) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride,
Compound 4 N-hydroxy-3-methoxy-2- (4- (pyridin-4-yl) phenyl) -1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride,
Compound 5 2- (4 ′-(3,4-dihydroxybutoxy) biphenyl-4-yl) -N-hydroxy-3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 6 2- (4 ′-(cyanomethyl) biphenyl-4-yl) -N-hydroxy-3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 7 N-hydroxy-3-methoxy-2- (4- (quinolin-6-yl) phenyl) -1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride,
Compound 8 N-hydroxy-3-methoxy-2- (4′-methoxybiphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 9 N-hydroxy-3-methoxy-2- (3′-methoxybiphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 10 N-hydroxy-2- (4 ′-(3-hydroxypropyl) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 11 2- (4- (2,3-Dihydro-1,4-benzodioxin-6-yl) phenyl) -N-hydroxy-3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride ,
Compound 12 N-hydroxy-2- (4 ′-((4-hydroxybutyl) amino) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride,
Compound 13 N-hydroxy-2- (4′-hydroxybiphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 14 2- (4- (6-Cyanopyridin-3-yl) phenyl) -N-hydroxy-3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride,
Compound 15 N-hydroxy-3-methoxy-2- (4- (6-methoxypyridin-3-yl) phenyl) -1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride,
Compound 16 N-hydroxy-2- (4 ′-(3-hydroxypropyl) biphenyl-4-yl) -3,8-dimethoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 17 8-bromo-N-hydroxy-2- (4 ′-(2-hydroxyethoxy) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 18 3-chloro-N-hydroxy-2- (4 ′-(2-hydroxyethoxy) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 19 N-hydroxy-3-methoxy-2- (4 ′-(trifluoromethoxy) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 20 N-hydroxy-3-methoxy-2- (4 ′-(2-methoxyethoxy) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 21 N-hydroxy-3-methoxy-2- (4′-propylbiphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 22 2- (4′-fluorobiphenyl-4-yl) -N-hydroxy-3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 23 N-hydroxy-3-methoxy-2- (4′-methylbiphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 24 2- (4′-acetylbiphenyl-4-yl) -N-hydroxy-3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 25 N-hydroxy-3-methoxy-2- (4 ′-(methylsulfonyl) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 26 N-hydroxy-3-methoxy-2- (4 ′-(methoxyacetyl) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 27 N-hydroxy-3-methoxy-2- (4 ′-(trifluoromethyl) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 28 2- (4- (3,4-Dihydro-2H-1,5-benzodioxepin-7-yl) phenyl) -N-hydroxy-3-methoxy-1,6-naphthyridine-4-carboxamide 6 -Oxide hydrochloride,
Compound 29 2- (3′-fluoro-4′-methoxybiphenyl-4-yl) -N-hydroxy-3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 30 N-hydroxy-3-methoxy-2- (4 ′-(morpholin-4-yl) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 31 N-hydroxy-2- (4 ′-((4-hydroxybutyl) amino) biphenyl-4-yl) -1,7-naphthyridine-4-carboxamide 7-oxide dihydrochloride,
Compound 32 N-hydroxy-2- (4 ′-(4-hydroxybutoxy) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 33 N-hydroxy-2- (4 ′-((6-hydroxyhexyl) amino) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride,
Compound 34 N-hydroxy-2- (4 ′-((3-hydroxypropyl) amino) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride,
Compound 35 N-hydroxy-3-methoxy-2- (4 ′-(2- (piperazin-1-yl) ethyl) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide trihydrochloride ,
Compound 36 N-hydroxy-2- (4-((4-((2-hydroxyethyl) amino) phenyl) ethynyl) phenyl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide,
Compound 37 N-hydroxy-2- (4 ′-((tetrahydro-2H-pyran-4-yl) methylamino) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide Dihydrochloride,
Compound 38 N-hydroxy-7- (4 ′-(4-hydroxybutylamino) biphenyl-4-yl) -1,8-naphthyridine-5-carboxamide 1-oxide dihydrochloride,
Compound 39 N-hydroxy-2- (4- (6-((5-hydroxypentyl) oxy) pyridin-3-yl) phenyl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide 2 hydrochloric acid salt,
Compound 40 4 ′-(4- (hydroxycarbamoyl) -3-methoxy-6-oxide-1,6-naphthyridin-2-yl) biphenyl-4-carboxylic acid hydrochloride,
Compound 41 N-hydroxy-2- (4 ′-(hydroxycarbamoyl) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 42 4 ′-(4- (hydroxycarbamoyl) -3-methoxy-6-oxide-1,6-naphthyridin-2-yl) biphenyl-4-carboxylic acid methyl hydrochloride,
Compound 43 N-hydroxy-3-methoxy-2- (4-((4- (morpholin-4-ylmethyl) phenyl) ethynyl) phenyl) -1,6-naphthyridine-4-carboxamide 6-oxide,
Compound 44 N-hydroxy-3-methoxy-2- (4 ′-(3- (morpholin-4-yl) propoxy) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride ,
Compound 45 4 ′-(4- (hydroxycarbamoyl) -3-methoxy-6-oxide-1,6-naphthyridin-2-yl) biphenyl-4-carboxylic acid tert-butyl hydrochloride,
Compound 46 N-hydroxy-3-methoxy-2- (4 ′-(propylcarbamoyl) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 47 N-hydroxy-2- (4 ′-(3- (2-hydroxyethoxy) propoxy) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 48 N-hydroxy-2- (4 ′-(3- (1H-imidazol-1-yl) propoxy) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide 2 Hydrochloride,
Compound 49 2- (4-cyclopropylphenyl) -N-hydroxy-3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 50 2- (4- (furan-2-yl) phenyl) -N-hydroxy-3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 51 N-hydroxy-3-methoxy-2- (4 ′-(methylamino) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride,
Compound 52 N-hydroxy-3-methoxy-2- (4- (2-phenylethyl) phenyl) -1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 53 2- (4 ′-(2- (cyclopropylamino) ethoxy) biphenyl-4-yl) -N-hydroxy-3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride,
Compound 54 2- (biphenyl-4-yl) -N-hydroxy-3-methyl-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 55 N-hydroxy-2- (4- (4- (3-hydroxypropyl) piperidin-1-yl) phenyl) -1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride,
Compound 56 N-hydroxy-2- (4 ′-(3-hydroxyazetidin-1-yl) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride,
Compound 57 N-hydroxy-3-methoxy-2- (4′-nitrobiphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 58 2- (4 ′-((3-cyanopropyl) amino) biphenyl-4-yl) -N-hydroxy-3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride,
Compound 59 N-hydroxy-2- (4 ′-((2-hydroxyethyl) amino) biphenyl-4-yl) -3-methyl-1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride,
Compound 60 2- (4′-aminobiphenyl-4-yl) -N-hydroxy-3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride,
Compound 61 2- (3′-fluoro-4 ′-((2-hydroxyethyl) amino) biphenyl-4-yl) -N-hydroxy-3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide 2 Hydrochloride,
Compound 62 3-amino-2- (biphenyl-4-yl) -N-hydroxy-1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride,
Compound 63 2- (4′-tert-butylbiphenyl-4-yl) -N-hydroxy-3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 64 N-hydroxy-2- (4 ′-(4-hydroxypiperidin-1-yl) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride,
Compound 65 N-hydroxy-3-methoxy-2- (4 ′-(4- (morpholin-4-yl) butoxy) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride ,
Compound 66 N-hydroxy-2- (4 ′-(3-((2-hydroxyethyl) (methyl) amino) propoxy) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6 -Oxide dihydrochloride,
Compound 67 N-hydroxy-2- (4 ′-((5-hydroxy-4- (hydroxymethyl) pentyl) oxy) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6 Oxide hydrochloride,
Compound 68 N-hydroxy-2- (4 ′-((5-hydroxypentanoyl) amino) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 69 N-hydroxy-2- (4 ′-((4-hydroxypentyl) amino) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride,
Compound 70 N-hydroxy-3-methoxy-2- (4 ′-(3- (piperidin-4-yl) propoxy) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride ,
Compound 71 N-hydroxy-2- (4 ′-(4- (3-hydroxyazetidin-1-yl) butoxy) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6 Oxide dihydrochloride,
Compound 72 N-hydroxy-3-methoxy-2- (4 ′-(3- (pyridin-3-yl) propoxy) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride ,
Compound 73 1,4′-bipiperidine-1′-carboxylic acid = 4-((4 ′-(4- (hydroxycarbamoyl) -3-methoxy-6-oxide-1,6-naphthyridin-2-yl) biphenyl- 4-yl) oxy) butyl = ester dihydrochloride,
Compound 74 4- (4-((4 ′-(4-((hydroxyamino) carbonyl) -3-methoxy-6-oxide-1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butoxy ) -4-oxobutyric acid hydrochloride,
Compound 75 N-hydroxy-3-methoxy-2- (4 ′-(4- (tetrahydro-2H-pyran-2-yloxy) butoxy) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6 Oxide,
Compound 76 N-hydroxy-2- (4 ′-(4-hydroxybutoxy) biphenyl-4-yl) -3-methyl-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 77 N-hydroxy-2- (4 ′-((4-hydroxypentyl) oxy) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 78 4- (Dimethylamino) butyric acid = 4-((4 ′-(4-((hydroxyamino) carbonyl) -3-methoxy-6-oxide-1,6-naphthyridin-2-yl) biphenyl-4- Yl) oxy) butyl = ester dihydrochloride,
Compound 79 N- (carboxymethyl) -4- (4-((4 ′-(4-((hydroxyamino) carbonyl) -3-methoxy-6-oxide-1,6-naphthyridin-2-yl) biphenyl- 4-yl) oxy) butoxy) -N, N-dimethyl-4-oxobutane-1-aminium,
Compound 80 N-hydroxy-2- (4 ′-((4-hydroxy-4-methylpentyl) oxy) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride ,
Compound 81 N-hydroxy-2- (4 ′-(2-hydroxypropoxy) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 82 N-hydroxy-2- (4 ′-(2-hydroxy-2-methylpropoxy) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 83 N-hydroxy-3-methoxy-2- (4-((4- (1,4-oxazepan-4-ylmethyl) phenyl) ethynyl) phenyl) -1,6-naphthyridine-4-carboxamide 6-oxide,
Compound 84 N-hydroxy-2- (4-((4-((3-hydroxyazetidin-1-yl) methyl) phenyl) ethynyl) phenyl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6 -Oxides,
Compound 85 Phosphoric acid = 4-((4 ′-(4-((hydroxyamino) carbonyl) -3-methoxy-6-oxide-1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) butyl = Ester disodium salt,
Compound 86 N-hydroxy-3-methoxy-2- (4 ′-(3- (1,4-oxazepan-4-yl) propoxy) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6 Oxide dihydrochloride,
Compound 87 N-hydroxy-3-methoxy-2- (4 ′-(2- (morpholin-4-yl) ethoxy) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride ,
Compound 88 N-hydroxy-3-methoxy-2- (4 ′-(3- (thiomorpholin-4-yl) propoxy) biphenyl-4-yl) -1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride salt,
Compound 89 2- (4 ′-(3- (azetidin-1-yl) propoxy) biphenyl-4-yl) -N-hydroxy-3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride ,
Compound 90 4- (3-((4 ′-(4- (hydroxycarbamoyl) -3-methoxy-6-oxide-1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) propyl) thiomorpholine 1-oxide dihydrochloride,
Compound 91 2- (4 ′-(3- (3,3-difluoroazetidin-1-yl) propoxy) biphenyl-4-yl) -N-hydroxy-3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide dihydrochloride,
Compound 92 N-hydroxy-2- (4 ′-(3-hydroxypropoxy) biphenyl-4-yl) -3-methoxy-1,6-naphthyridine-4-carboxamide 6-oxide hydrochloride,
Compound 93 Phosphoric acid = 3-((4 ′-(4- (hydroxycarbamoyl) -3-methoxy-6-oxide-1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) propyl ester 2 Sodium salt,
Compound 94 Phosphoric acid = 2-((4 ′-(4- (hydroxycarbamoyl) -3-methoxy-6-oxide-1,6-naphthyridin-2-yl) biphenyl-4-yl) oxy) ethyl ester 2 Sodium salt,
Compound 95 Phosphoric acid = 3- (4-((4 ′-(4-((hydroxyamino) carbonyl) -3-methoxy-6-oxide-1,6-naphthyridin-2-yl) biphenyl-4-yl) Oxy) butoxy) -1-methyl-3-oxopropyl ester sodium salt.

Test Example The action of the compound of the present invention was confirmed by the following test.

Test Example 1 LpxC Enzyme Inhibitory Activity Evaluation Test LpxC enzyme activity is a reaction between LpxC and its substrate UDP-3-O- (R-3-hydroxydecanoyl) -N-acetylglucosamine, and the amount of the reaction product. Was determined by quantifying the amino groups present in the product.
Specifically, 12.5 ng of Pseudomonas aeruginosa LpxC enzyme (preparing chromosomal DNA from Pseudomonas aeruginosa and obtaining P. aeruginosa LpxC gene by PCR method (polymerase chain reaction method) using LpxC-specific primers, 80 μmol / l UDP-3-O- (R-3-hydroxydecanoyl) -N-acetylglucosamine (Wako Pure Chemical Industries, Ltd.) was added to the vector and expressed using E. coli. Incubated for 40 minutes at room temperature. This reaction was carried out in 40 mmol / l-Hepes buffer (pH 8.0) containing 0.02% bridge 35 and 80 μmol / l-dithiothreitol. After completion of the reaction by adding 0.2 mol / l-borax to the reaction solution, 0.5 mg / ml-fluorescamine dissolved in anhydrous dioxane was added, and the amount of the reaction product was determined as excitation wavelength / fluorescence wavelength = 390 nm / 495 nm. Detected with. Inhibition curves were obtained by allowing test compounds of various concentrations to coexist during the reaction. From the inhibition curve, the concentration (IC ₅₀ value) of the test compound when the amount of the reaction product was suppressed by 50% was determined and used as an index of LpxC enzyme inhibitory activity. Table 2 shows the test results of representative compounds. As shown in the table, the test compound showed inhibitory activity against the LpxC enzyme.

Test Example 2 Antibacterial Activity Evaluation Test Minimum growth inhibitory concentration (MIC) was measured according to the CLSI (Clinical and Laboratory Standards Institute) standard method using the following micro liquid dilution method.

  As a bacterium, Pseudomonas aeruginosa (ATCC 27853 strain) was used. The test cells cultured overnight on the heart infusion agar medium were scraped off and suspended in McFarland 0.5 equivalent, which was diluted 10 times to obtain an inoculum solution. 0.005 ml of the inoculated bacterial solution was inoculated into a cation-adjusted Mueller Hinton medium containing a test compound and cultured at 35 ° C. for 18 hours. The MIC was defined as the minimum drug concentration at which no bacterial growth was observed. Table 2 shows the test results of representative compounds. As shown in the table, the test compound showed antibacterial activity against Pseudomonas aeruginosa.

試験例３ 生理食塩水への溶解度測定試験
過剰量の披験化合物に生理食塩水を加え懸濁させ、１ｍｏｌ／ｌ−水酸化ナトリウム水溶液を用いてｐＨ７〜８付近に調整した後、室温で２４時間振とうした。この懸濁液を遠心処理（１１０００ｒｐｍ）し、得られた上清を５０％アセトニトリル／水混液で希釈し、ＨＰＬＣにて定量した。実施例７９、８５、９３および９４の化合物の生理食塩水（ｐH７〜８）に対する溶解度は、５ｍｇ／ｍｌ以上であった。

Test Example 3 Solubility measurement test in physiological saline After adding physiological saline to an excessive amount of the test compound and suspending it, the pH was adjusted to around 7-8 using a 1 mol / l-sodium hydroxide aqueous solution, and then 24 hours at room temperature. I shake time. This suspension was centrifuged (11000 rpm), and the resulting supernatant was diluted with a 50% acetonitrile / water mixture and quantified by HPLC. The solubility of the compounds of Examples 79, 85, 93 and 94 in physiological saline (pH 7 to 8) was 5 mg / ml or more.

Test Example 4 Mouse Systemic Infection Prevention Test Using Pseudomonas aeruginosa (1) Preparation of Inoculum Bacterial Pseudomonas aeruginosa clinical isolate (TS88 strain) cultured at 37 ° C. for 16 hours in a heart infusion agar medium with 5% mucin- It was suspended in a physiological saline solution and used as an inoculum.
(2) 0.5 ml of the inoculated bacterial solution was inoculated intraperitoneally into male ICR mice (4 weeks old, Japan SLC) (3-6 × 10 ⁵ CFU / mouse).
(3) One hour after inoculation of the treatment bacteria, 10% hydroxypropylated β-cyclodextrin / 2.5% mannitol aqueous solution (solution A) or physiological saline solution of the test compound was administered into the tail vein. One group consisted of 6 or 8 animals, and the dose of the test compound was 25 mg / kg. For the administration groups of compounds 79 and 85, which are prodrugs, 32 mg / kg each was administered so that the compound 32 was 25 mg / kg when converted to compound 32, the active substance.
(4) Judgment of effect The infection treatment effect was based on the survival rate (survival number / treatment number) 7 days after bacterial inoculation. In the non-treated group, all cases died 1 to 2 days after the bacterial inoculation, but in the test compound administration group, the survival cases shown in Table 3 were observed 7 days after the bacterial inoculation, and in vivo anti-Pseudomonas aeruginosa activity was observed. It was.

Claims (12)

General formula [1]

(Where
V ² is, ^{C-R 2} or ^N + -O ^- indicates,
V ³ is, ^{C-R 3} or ^N + -O ^- indicates,
V ⁴ represents C—R ⁴ or N ⁺ —O ⁻ .
V ⁵ represents C—R ⁵ or N ⁺ —O ⁻ .
Provided that any one of V ² , V ³ , V ⁴ and V ⁵ is N ⁺ -O ⁻ .
R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same or different and are a hydrogen atom, halogen atom, hydroxy group, cyano group, carboxy group, carbamoyl group, C _1-6 alkyl group, C _3-8. Cycloalkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 alkoxy group, C _3-8 cycloalkoxy group, aryloxy group, C _1-6 alkylthio group, C _1-6 alkoxycarbonyl Group, aryl group, heterocyclic group (the C _1-6 alkyl group, C _3-8 cycloalkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 alkoxy group, C _3-8 cycloalkoxy group, an aryloxy group, C _1-6 alkylthio group, C _1-6 alkoxycarbonyl group, aryl group and heterocyclic group are the same or selected from substituent group R ^a below May be substituted with 1 to 4 different substituents), -NR ⁶ R ⁷ or -CONR ⁶ R ⁷ ,
The substituent group R ^a is a halogen atom, a hydroxy group, a carboxy group, an amino group (the amino group may be substituted with 1 or 2 C _1-6 alkyl groups), a C _1-6 alkyl group. , C _3-8 cycloalkyl group, C _1-6 alkoxy group, aryl group or heterocyclic group,
R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkanoyl group, a C _1-6 alkylsulfonyl group, an aryl group or a heterocyclic ring. Group (the C _1-6 alkyl group, C _3-8 cycloalkyl group, C _2-6 alkanoyl group, C _1-6 alkylsulfonyl group, aryl group and heterocyclic group are “halogen atom, hydroxy group, amino group, And may be substituted with the same or different 1 to 4 substituents selected from “group, carboxy group and C _1-6 alkyl group”.
R ⁶ and R ⁷ are formed together with a nitrogen atom to be bonded, and form a saturated or unsaturated 5- or 6-membered ring that may further contain one or more nitrogen atoms, oxygen atoms, or sulfur atoms. You can,
A ¹ represents a divalent aryl group, a divalent monocyclic heterocyclic group (the divalent aryl group and divalent monocyclic heterocyclic group are the same or selected from the following substituent group R ^b , or May be substituted with 1 to 4 different substituents) or -C≡C-
The substituent group R ^b is a halogen atom, a hydroxy group, an amino group (the amino group may be substituted with a C _2-6 alkanoyl group or 1 or 2 C _1-6 alkyl groups), a carboxy group. , Carbamoyl group, C _1-6 alkyl group, C _3-8 cycloalkyl group, C _2-6 alkenyl group or C _1-6 alkoxy group (the C _1-6 alkyl group, C _3-8 cycloalkyl group, C _{The 2-6} alkenyl group and the C _1-6 alkoxy group are the same or different selected from “halogen atom, hydroxy group, amino group, carboxy group, C _1-6 alkylaminocarbonyl group and C _1-6 alkoxycarbonyl group”. And optionally substituted with 1 to 4 substituents)
L is —C≡C—, —C≡C—C≡C—, —O—, —S—, —NR ⁸ —, —CONR ⁸ —, —NR ⁸ CO—, a divalent heterocyclic group, _{^{- (CH 2) m -NR 8}} -, - (CH 2) m -O -, - NR 8 - (CH 2) m -, - O- (CH 2) m -, - ON = CH-, C 2 _{-4 represents an} alkylene group or a bond,
R ⁸ represents a hydrogen atom, a C _1-6 alkyl group, a C _3-8 cycloalkyl group or an aryl group,
m represents 1, 2 or 3,
A ² represents a divalent aryl group, a divalent heterocyclic group, a divalent partially saturated condensed polycyclic hydrocarbon ring group, a C _3-8 cycloalkylene group, a C _1-4 alkylene group or C _2-4 alkenylene group (the divalent aryl group, divalent heterocyclic group, divalent partially saturated condensed polycyclic hydrocarbon ring group, C _3-8 cycloalkylene group, C _{1- 4} alkylene group and C _2-4 alkenylene group may be substituted with the same or different 1 to 4 substituents selected from the following substituent group R ^c ):
The substituent group R ^c is a halogen atom, a hydroxy group that may be protected, a mercapto group, a cyano group, a nitro group, an amino group that may be protected, a formyl group that may be protected, or a carboxy group that may be protected. Carbamoyl group, sulfo group, ureido group, guanidide group, C _1-6 alkyl group, C _3-8 cycloalkyl group, C _1-6 haloalkyl group, C _1-6 hydroxyalkyl group, C _1-6 alkoxy group, A C _1-6 alkoxycarbonyl group, a C _2-6 alkanoyl group or an aryl group,
W represents R ⁹ -X ^1- , R ⁹ -X ² -Y ¹ -X ^1- , R ⁹ -X ⁴ -Y ¹ -X ² -Y ³ -X ^3- , Q-X ¹ -Y ^2-. X ³ - or ^{Q-X 1 -Y 1 -X 2} -Y 3 -X 3 - indicates,
Y ² represents —O—, —NR ¹⁰ —, —CO—, —NR ¹⁰ CO—, —CONR ¹⁰ —, —S (O) _n —, —OCO—, —COO—, —NR ¹⁰ SO ₂ —. ^{_{, -SO 2 NR 10 -, -}} OCOO -, - OCONR 10 -, - NR 10 CONR 11 - or denotes a valence bond,
Y ¹ and Y ³ are the same or different and are —O—, —NR ¹⁰ —, —CO—, —NR ¹⁰ CO—, —CONR ¹⁰ —, —S (O) _n —, —OCO—, —COO. _{^{-, - NR 10 SO 2 -}} , - SO 2 NR 10 -, - OCOO -, - OCONR 10 - or ^-NR 10 CONR ¹¹ - indicates,
n represents 0, 1 or 2,
X ¹ and X ³ are the same or different and each represents a C _1-10 alkylene group, a C _2-10 alkenylene group, a C _2-10 alkynylene group (the C _1-10 alkylene group, a C _2-10 alkenylene group and a C _{2). The -10} alkynylene group may be substituted with the same or different 1 to 4 substituents selected from the following substituent group R ^d ) or a bond;
X ² and X ⁴ are the same or different and each represents a C _1-10 alkylene group, a C _2-10 alkenylene group or a C _2-10 alkynylene group (the C _1-10 alkylene group, C _2-10 alkenylene group and C _{2 The -10} alkynylene group may be substituted with the same or different 1 to 4 substituents selected from the following substituent group R ^d );
Q is a C _3-8 cycloalkyl group, aryl group or heterocyclic group (the C _3-8 cycloalkyl group, aryl group and heterocyclic group are the same or different 1 selected from the following substituent group R ^d) Which may be substituted with four substituents),
R ⁹ is a hydrogen atom, a halogen atom, a hydroxy group that may be protected, a mercapto group, a cyano group, a nitro group, an amino group that may be protected, a formyl group that may be protected, or a carboxy group that may be protected , Carbamoyl group, sulfo group, ureido group, guanidide group, R ¹⁰ —O—NR ¹¹ —CO—, R ¹¹ —ON═CR ¹² —, R ¹¹ —ON═CR ¹² —NH—, R ¹¹ —O—NR ¹¹ −, N≡C—NR ¹¹ —, a phosphate group or a group selected from the following formula [2]:

In formula [2],
R ²¹ represents a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with the same or different 1 to 2 substituents selected from the following substituent group R ^p ). ,
R ²² and R ²³ are the same or different and are each a hydrogen atom or a C _1-6 alkyl group (the C _1-6 alkyl group is the same or different 1 to 2 substituents selected from the following substituent group R ^p ) Which may be substituted with a group)
Or R ²² and R ²³ together with the nitrogen atom to which they are bonded are a 4- to 7-membered nitrogen-containing saturated heterocyclic ring (the 4- to 7-membered nitrogen-containing saturated heterocyclic ring is represented by the following substituent group R may be substituted with the same or different 1 to 2 substituents selected from ^p .
R ^p represents a carboxy group, a phosphoric acid group, a phosphonic acid group or a group represented by the following formula [3],

In formula [3],
R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with a carboxy group, a phosphate group, or a phosphonic acid group). Show
Or R ²⁴ and R ²⁵ together with the nitrogen atom to which they are attached may form a 4 to 7 membered nitrogen-containing saturated heterocycle;
R ²⁶ represents a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with a carboxy group, a phosphate group, a phosphonic acid group, or an anion thereof);
R ²⁷ and R ²⁸ are the same or different and each represents a C _1-6 alkyl group,
Or R ²⁷ and R ²⁸ together with the quaternized nitrogen atom to which they are attached may form a 4 to 7 membered nitrogen-containing saturated heterocycle;
R ¹⁰ and R ¹¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, an aryl group or a heterocyclic group (the C _1-6 alkyl group, C _3-8 cyclo group). An alkyl group, an aryl group and a heterocyclic group may be substituted with the same or different 1 to 4 substituents selected from the following substituent group R ^d ):
R ¹² represents a hydrogen atom, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, an amino group or a C _1-6 alkylamino group,
Substituent group R ^d is a halogen atom, hydroxy group, cyano group, nitro group, amino group (the amino group may be substituted with a C _2-6 alkanoyl group or 1 or 2 C _1-6 alkyl groups). Carboxy group, carbamoyl group, ureido group, guanidide group, C _1-6 alkyl group, C _1-6 hydroxyalkyl group, C _1-6 haloalkyl group, C _3-8 cycloalkyl group, C _1-6. An alkoxy group, a C _3-8 cycloalkoxy group, a C _1-6 alkoxycarbonyl group, a C _1-6 alkoxycarbonylamino group, a C _2-6 alkanoyl group, a C _1-6 alkylsulfonyl group, a C _1-6 alkylthio group, An aryl group or a heterocyclic group (the aryl group and heterocyclic group are “halogen atom, hydroxy group, cyano group, nitro group, amino group and carboxy group” More may be substituted the same or different 1 to 4 substituents selected.) Shows a. )
Or a pharmaceutically acceptable salt thereof. General formula [1]
(Where
V ² is, ^{C-R 2} or ^N + -O ^- indicates,
V ³ is, ^{C-R 3} or ^N + -O ^- indicates,
V ⁴ represents C—R ⁴ or N ⁺ —O ⁻ .
V ⁵ represents C—R ⁵ or N ⁺ —O ⁻ .
Provided that any one of V ² , V ³ , V ⁴ and V ⁵ is N ⁺ -O ⁻ .
R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same or different and are a hydrogen atom, halogen atom, hydroxy group, cyano group, carboxy group, carbamoyl group, C _1-6 alkyl group, C _3-8. Cycloalkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 alkoxy group, C _3-8 cycloalkoxy group, aryloxy group, C _1-6 alkylthio group, C _1-6 alkoxycarbonyl Group, aryl group, heterocyclic group (the C _1-6 alkyl group, C _3-8 cycloalkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 alkoxy group, C _3-8 cycloalkoxy group, an aryloxy group, C _1-6 alkylthio group, C _1-6 alkoxycarbonyl group, aryl group and heterocyclic group are the same or selected from substituent group R ^a below May be substituted with 1 to 4 different substituents), -NR ⁶ R ⁷ or -CONR ⁶ R ⁷ ,
The substituent group R ^a is a halogen atom, a hydroxy group, a carboxy group, an amino group (the amino group may be substituted with 1 or 2 C _1-6 alkyl groups), a C _1-6 alkyl group. , C _3-8 cycloalkyl group, C _1-6 alkoxy group, aryl group or heterocyclic group,
R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-6 alkanoyl group, a C _1-6 alkylsulfonyl group, an aryl group or a heterocyclic ring. Group (the C _1-6 alkyl group, C _3-8 cycloalkyl group, C _2-6 alkanoyl group, C _1-6 alkylsulfonyl group, aryl group and heterocyclic group are “halogen atom, hydroxy group, amino group, And may be substituted with the same or different 1 to 4 substituents selected from “group, carboxy group and C _1-6 alkyl group”.
R ⁶ and R ⁷ are formed together with a nitrogen atom to be bonded, and form a saturated or unsaturated 5- or 6-membered ring that may further contain one or more nitrogen atoms, oxygen atoms, or sulfur atoms. You can,
A ¹ represents a divalent aryl group, a divalent monocyclic heterocyclic group (the divalent aryl group and divalent monocyclic heterocyclic group are the same or selected from the following substituent group R ^b , or May be substituted with 1 to 4 different substituents) or -C≡C-
The substituent group R ^b is a halogen atom, a hydroxy group, an amino group (the amino group may be substituted with a C _2-6 alkanoyl group or 1 or 2 C _1-6 alkyl groups), a carboxy group. , Carbamoyl group, C _1-6 alkyl group, C _3-8 cycloalkyl group, C _2-6 alkenyl group or C _1-6 alkoxy group (the C _1-6 alkyl group, C _3-8 cycloalkyl group, C _{The 2-6} alkenyl group and the C _1-6 alkoxy group are the same or different selected from “halogen atom, hydroxy group, amino group, carboxy group, C _1-6 alkylaminocarbonyl group and C _1-6 alkoxycarbonyl group”. And optionally substituted with 1 to 4 substituents)
L is —C≡C—, —C≡C—C≡C—, —O—, —S—, —NR ⁸ —, —CONR ⁸ —, —NR ⁸ CO—, a divalent heterocyclic group, _{^{- (CH 2) m -NR 8}} -, - (CH 2) m -O -, - NR 8 - (CH 2) m -, - O- (CH 2) m -, - ON = CH-, C 2 _{-4 represents an} alkylene group or a bond,
R ⁸ represents a hydrogen atom, a C _1-6 alkyl group, a C _3-8 cycloalkyl group or an aryl group,
m represents 1, 2 or 3,
A ² represents a divalent aryl group, a divalent heterocyclic group, a divalent partially saturated condensed polycyclic hydrocarbon ring group, a C _3-8 cycloalkylene group, a C _1-4 alkylene group or C _2-4 alkenylene group (the divalent aryl group, divalent heterocyclic group, divalent partially saturated condensed polycyclic hydrocarbon ring group, C _3-8 cycloalkylene group, C _{1- 4} alkylene group and C _2-4 alkenylene group may be substituted with the same or different 1 to 4 substituents selected from the following substituent group R ^c ):
The substituent group R ^c is a halogen atom, a hydroxy group that may be protected, a mercapto group, a cyano group, a nitro group, an amino group that may be protected, a formyl group that may be protected, or a carboxy group that may be protected. Carbamoyl group, sulfo group, ureido group, guanidide group, C _1-6 alkyl group, C _3-8 cycloalkyl group, C _1-6 haloalkyl group, C _1-6 hydroxyalkyl group, C _1-6 alkoxy group, A C _1-6 alkoxycarbonyl group, a C _2-6 alkanoyl group or an aryl group,
W represents R ⁹ -X ^1- , R ⁹ -X ² -Y ¹ -X ^1- , R ⁹ -X ⁴ -Y ¹ -X ² -Y ³ -X ^3- , Q-X ¹ -Y ^2-. X ³ - or ^{Q-X 1 -Y 1 -X 2} -Y 3 -X 3 - indicates,
Y ² represents —O—, —NR ¹⁰ —, —CO—, —NR ¹⁰ CO—, —CONR ¹⁰ —, —S (O) _n —, —OCO—, —COO—, —NR ¹⁰ SO ₂ —. ^{_{, -SO 2 NR 10 -, -}} OCOO -, - OCONR 10 -, - NR 10 CONR 11 - or denotes a valence bond,
Y ¹ and Y ³ are the same or different and are —O—, —NR ¹⁰ —, —CO—, —NR ¹⁰ CO—, —CONR ¹⁰ —, —S (O) _n —, —OCO—, —COO. _{^{-, - NR 10 SO 2 -}} , - SO 2 NR 10 -, - OCOO -, - OCONR 10 - or ^-NR 10 CONR ¹¹ - indicates,
n represents 0, 1 or 2,
X ¹ and X ³ are the same or different and each represents a C _1-10 alkylene group, a C _2-10 alkenylene group, a C _2-10 alkynylene group (the C _1-10 alkylene group, a C _2-10 alkenylene group and a C _{2). The -10} alkynylene group may be substituted with the same or different 1 to 4 substituents selected from the following substituent group R ^d ) or a bond;
X ² and X ⁴ are the same or different and each represents a C _1-10 alkylene group, a C _2-10 alkenylene group or a C _2-10 alkynylene group (the C _1-10 alkylene group, C _2-10 alkenylene group and C _{2 The -10} alkynylene group may be substituted with the same or different 1 to 4 substituents selected from the following substituent group R ^d );
Q is a C _3-8 cycloalkyl group, aryl group or heterocyclic group (the C _3-8 cycloalkyl group, aryl group and heterocyclic group are the same or different 1 selected from the following substituent group R ^d) Which may be substituted with four substituents),
R ⁹ is a hydrogen atom, a halogen atom, a hydroxy group that may be protected, a mercapto group, a cyano group, a nitro group, an amino group that may be protected, a formyl group that may be protected, or a carboxy group that may be protected , Carbamoyl group, sulfo group, ureido group, guanidide group, R ¹⁰ —O—NR ¹¹ —CO—, R ¹¹ —ON═CR ¹² —, R ¹¹ —ON═CR ¹² —NH—, R ¹¹ —O—NR ¹¹ − or N≡C—NR ¹¹ —
R ¹⁰ and R ¹¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, an aryl group or a heterocyclic group (the C _1-6 alkyl group, C _3-8 cyclo group). An alkyl group, an aryl group and a heterocyclic group may be substituted with the same or different 1 to 4 substituents selected from the following substituent group R ^d ):
R ¹² represents a hydrogen atom, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, an amino group or a C _1-6 alkylamino group,
Substituent group R ^d is a halogen atom, hydroxy group, cyano group, nitro group, amino group (the amino group may be substituted with a C _2-6 alkanoyl group or 1 or 2 C _1-6 alkyl groups). Carboxy group, carbamoyl group, ureido group, guanidide group, C _1-6 alkyl group, C _1-6 hydroxyalkyl group, C _1-6 haloalkyl group, C _3-8 cycloalkyl group, C _1-6. An alkoxy group, a C _3-8 cycloalkoxy group, a C _1-6 alkoxycarbonyl group, a C _1-6 alkoxycarbonylamino group, a C _2-6 alkanoyl group, a C _1-6 alkylsulfonyl group, a C _1-6 alkylthio group, An aryl group and a heterocyclic group (the aryl group and heterocyclic group are represented by “halogen atom, hydroxy group, cyano group, nitro group, amino group and carboxy group”; More may be substituted the same or different 1 to 4 substituents selected.) Shows a. )
The compound of Claim 1 represented by these, or its pharmaceutically acceptable salt. V ² is C—R ² ,
V ³ is N ⁺ —O ⁻ ,
V ⁴ is ^{C-R 4,}
V ⁵ is C—R ⁵ ;
The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof. A ¹ is a phenylene group (the phenylene group may be substituted with the same or different 1 to 4 substituents selected from “halogen atom, hydroxy group, amino group and C _1-6 alkyl group”). Yes,
L is —C≡C— or a bond,
A ² is a divalent aryl group (the divalent aryl group is substituted with the same or different 1 to 4 substituents selected from “halogen atom, hydroxy group, amino group and C _1-6 alkyl group”). A divalent monocyclic aromatic heterocyclic group, a divalent monocyclic saturated heterocyclic group, a divalent partially saturated monocyclic aromatic heterocyclic group (the divalent The monocyclic aromatic heterocyclic group, the divalent monocyclic saturated heterocyclic group and the divalent partially saturated monocyclic aromatic heterocyclic group are arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom. 1 to 3 atoms selected from the above as ring-constituting atoms and substituted with the same or different 1 to 4 substituents selected from “halogen atom, hydroxy group, amino group and C _1-6 alkyl group” A divalent fused cyclic aromatic heterocyclic group or a divalent partially saturated monocyclic ring. A condensed cyclic heterocyclic group (the condensed cyclic heterocyclic group having a divalent fused cyclic aromatic heterocyclic group and a divalent partially saturated monocycle includes a nitrogen atom, an oxygen atom and a sulfur atom) wherein 1 to 4 atoms selected arbitrarily from a ring-constituting atom, at least one of the rings constituting the condensed ring is a benzene ring or a pyridine ring, "halogen atom, hydroxy group, amino group and C _1- Which may be substituted with the same or different 1 to 4 substituents selected from “ ₆ alkyl groups”.
The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof. A ² is a phenylene group or a pyridinediyl group (the phenylene group and pyridinediyl group may be substituted with 1 to 4 halogen atoms).
The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof. R ¹ is a hydrogen atom, a halogen atom, an amino group, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _1-6 alkoxy group, a C _3-8 cycloalkoxy group, a C _1-6 alkylthio group or C _{A 1-6} alkylamino group,
R ² , R ³ , R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a halogen atom, a hydroxy group, an amino group, a C _1-6 alkyl group, a C _1-6 alkoxy group or a C _1-6 alkylamino group. (The C _1-6 alkyl group, C _1-6 alkoxy group and C _1-6 alkylamino group are “halogen atom, hydroxy group and amino group (the amino group is one or two C _1-6 alkyl And may be substituted with the same or different 1 to 4 substituents selected from “).
6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof. W is ^{R 9 -X 1 -, R 9} -X 2 -Y 1 -X 1 -, R 9 -X 4 -Y 1 -X 2 -Y 3 -X 3 -, Q-X 1 -Y 2 -X ³ - or ^{Q-X 1 -Y 1 -X 2} -Y 3 -X 3 - is and,
Y ² is —O—, —NR ¹⁰ —, —CO—, —NR ¹⁰ CO—, —CONR ¹⁰ —, —S (O) _n —, —OCO— or a bond;
Y ¹ and Y ³ are the same or different and are —O—, —NR ¹⁰ —, —CO—, —NR ¹⁰ CO—, —CONR ¹⁰ —, —S (O) _n — or —OCO—,
X ¹ and X ³ are the same or different, and a C _1-6 alkylene group (the C _1-6 alkylene group is substituted with 1 to 4 substituents which are the same or different selected from the substituent group R ^d below) Or a bond,
X ² and X ⁴ are the same or different, and a C _1-6 alkylene group (the C _1-6 alkylene group is substituted with the same or different 1 to 4 substituents selected from the following substituent group R ^d ) May be)
Q is a C _3-8 cycloalkyl group, aryl group or heterocyclic group (the C _3-8 cycloalkyl group, aryl group and heterocyclic group are the same or different 1 to 4 selected from the following substituent group R ^d) May be substituted with one substituent),
R ⁹ is a hydrogen atom, a halogen atom, a hydroxy group that may be protected, a cyano group, a nitro group, an amino group that may be protected, a carboxy group that may be protected, or R ¹⁰ —O—NR ¹¹ —CO—. Yes,
R ¹⁰ and R ¹¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a C _3-8 cycloalkyl group (the C _1-6 alkyl group and the C _3-8 cycloalkyl group are each a “halogen atom, Which may be substituted with the same or different 1 to 4 substituents selected from “hydroxy group, cyano group, nitro group, amino group and C _1-6 alkylamino group”.
Substituent group R ^d is a halogen atom, a hydroxy group, a cyano group, an amino group (the amino group may be substituted with 1 or 2 C _1-6 alkyl groups), a C _1-6 alkyl group, A C _1-6 hydroxyalkyl group, a C _1-6 haloalkyl group, a C _3-8 cycloalkyl group, a C _1-6 alkoxy group or a C _2-6 alkanoyl group,
The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof. W is ^{R 9 -X 1 -, R 9} -X 2 -Y 1 -X 1 -, R 9 -X 4 -Y 1 -X 2 -Y 3 -X 3 -, Q-X 1 -Y 2 -X ³ - or ^{Q-X 1 -Y 1 -X 2} -Y 3 -X 3 - is and,
Y ² is —O—, —NR ¹⁰ —, —OCO— or a bond,
Y ¹ and Y ³ are the same or different and are —O—, —NR ¹⁰ — or —OCO—,
X ¹ and X ³ are the same or different, and a C _1-6 alkylene group (the C _1-6 alkylene group is substituted with the same or different 1 to 4 substituents selected from the following substituent group R ^d ) Or a bond.
X ² and X ⁴ are the same or different, and a C _1-6 alkylene group (the C _1-6 alkylene group is substituted with the same or different 1 to 4 substituents selected from the following substituent group R ^d ) May be)
Q is a C _3-8 cycloalkyl group (the C _3-8 cycloalkyl group may be substituted with the same or different 1 to 4 substituents selected from the following substituent group R ^d ), tetrahydro Pyranyl group or formula [4]

A 4- to 7-membered nitrogen-containing saturated heterocycle represented by:
q is 0, 1, 2, 3 or 4;
Substituent group R ^d is a halogen atom, a hydroxy group, a cyano group, an amino group (the amino group may be substituted with 1 or 2 C _1-6 alkyl groups) or a C _1-6 hydroxyalkyl group. And
R ⁹ is a hydrogen atom, a halogen atom, a hydroxy group or a cyano group,
R ¹⁰ is a hydrogen atom, a C _1-6 alkyl group or a C _3-8 cycloalkyl group (the C _1-6 alkyl group and the C _3-8 cycloalkyl group are selected from “halogen atom, hydroxy group and cyano group”) And may be substituted with 1 to 4 substituents that are the same or different.
The compound according to claim 7 or a pharmaceutically acceptable salt thereof. R ⁹ is a phosphate group or a group selected from the formula [2].
The compound according to claim 1 or any one of claims 3 to 6, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising the compound of claim 1 to 9 or a pharmaceutically acceptable salt thereof. An LpxC inhibitor comprising the compound of claim 1 to 9 or a pharmaceutically acceptable salt thereof. An antibacterial agent comprising the compound of claim 1 to 9 or a pharmaceutically acceptable salt thereof.