JP5620636B2 - Antibacterial agent containing novel heterocyclic compound or salt thereof - Google Patents

Description

  The present invention relates to an antibacterial agent comprising a novel compound or a salt thereof having strong antibacterial activity against gram positive bacteria, gram negative bacteria and / or resistant bacteria.

In the medical field, various antibiotics and synthetic antibacterial agents have been used for the treatment of infectious diseases. However, in recent years, resistant bacteria such as methicillin resistant Staphylococcus aureus (MRSA), vancomycin resistant enterococci (VRE) and penicillin resistant pneumococci (PRSP) have emerged. Treatment of patients infected with such resistant bacteria is an important issue. In addition, multidrug-resistant bacteria that have acquired resistance to multiple drugs have emerged. Infectious diseases caused by multidrug-resistant bacteria are a major problem worldwide as an intractable disease.
The appearance of antibiotics effective against these resistant bacteria is strongly desired. For example, International Publication No. 99/07682 (Patent Document 1) discloses a quinolone compound effective for MRSA. Further, as compounds having an action mechanism different from that of existing drugs, compounds described in International Publication No. 2004/002490 pamphlet (Patent Document 2) and International Publication No. 2004/002992 pamphlet (Patent Document 3) are known. ing.

WO99 / 07682 pamphlet International Publication No. 2004/002490 Pamphlet International Publication No. 2004/002992 Pamphlet

  Development of a drug having high antibacterial activity against Gram-positive bacteria, Gram-negative bacteria and resistant bacteria and having high safety is desired. Among other things, Staphylococcus, Streptococcus, Enterococcus, Escherichia coli, Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Acne, Neisseria perfringens, Fraziris, Bacillus gingivalis, Prevotella intermedia, Fusobacterium nucleatum, Legionella pneumophila There is also a strong demand for antibacterial agents against bacterial species selected from pneumonia mycoplasma and the like.

「式中、Ｒ^１は、置換されていてもよいＣ_２−Ｃ_１２アルキル、アリールまたは複素環式基を；Ｘ^１は、置換されていてもよいＣ_２−Ｃ_４アルキレン基を；Ｘ^２は、一般式ＮＲ^２「式中、Ｒ^２は、水素原子、置換されていてもよい低級アルキル基またはイミノ保護基を意味する。」で表される基または結合手を；Ｘ^３は、一般式ＮＲ^３またはＣＲ^４Ｒ^５ＮＲ^３「式中、Ｒ^３は、水素原子、置換されていてもよい低級アルキル基またはイミノ保護基を；Ｒ^４およびＲ^５は、同一または異なって、水素原子、置換されていてもよい低級アルキル基またはＲ^４およびＲ^５が一緒になってオキソ基を意味する。」で表される基または結合手を；Ｘ^４は、置換されていてもよい低級アルキレン、低級アルケニレンもしくは低級アルキニレン基または結合手を；Ｘ^５は、酸素原子、硫黄原子、スルフィニル基、スルホニル基、一般式ＮＲ^６「式中、Ｒ^６は、水素原子、置換されていてもよい低級アルキル、低級アルケニルもしくは低級アルキニル基またはイミノ保護基を意味する。」で表される基または結合手を；Ｙ^１は、置換されていてもよい２価の脂環式炭化水素残基または置換されていてもよい２価の脂環式環状アミン残基を；Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、同一または異なって、窒素原子または一般式ＣＲ^７「式中、Ｒ^７は、水素原子、ハロゲン原子、ヒドロキシル基、シアノ基、ニトロ基、ホルミル基、保護または置換されていてもよいアミノ基、置換されていてもよい低級アルキル、シクロアルキル、アリール、低級アルコキシ、シクロアルキルオキシ、アルアルキルオキシ、アルカノイル、ウレイドもしくは単環の複素環式基または一般式Ｑ^１ＣＯＮＲ^８Ｒ^９、Ｑ^１ＣＯ_２Ｒ^１０もしくはＱ^１ＣＮ「式中、Ｒ^８およびＲ^９は、同一または異なって、水素原子、置換されていてもよい低級アルキル、シクロアルキル、アルアルキル、アリール、低級アルコキシ、アルカンスルホニルもしくは単環の複素環式基またはＲ^８およびＲ^９が、それらが結合する窒素原子と一緒になって置換されていてもよい環状アミノ基を；Ｒ^１０は、水素原子またはカルボキシル保護基を；Ｑ^１は、置換されていてもよい低級アルキレンもしくは低級アルケニレン基または結合手を意味する。」で表される基を意味する。」で表される基を；但し、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６の少なくとも一つは、窒素原子を意味する。」で表される化合物またはその塩を含有する抗菌剤が、ブドウ球菌属、レンサ球菌属、腸球菌属、大腸菌、インフルエンザ菌、モラクセラ・カタラーリス、淋菌、アクネ菌、ウエルシュ菌、フラジリス菌、ジンジバリス菌、プレボテラ・インタメディア、フソバクテリウム・ヌクレアタム、レジオネラ・ニューモフィラおよび肺炎マイコプラズマなどから選ばれる菌種が関与する感染症などの疾患の治療および／または予防に有用であることを見出し、本発明を完成した。 Under such circumstances, the present inventors have conducted extensive studies, and as a result, the general formula [1]

“Wherein R ¹ represents an optionally substituted C ₂ -C ₁₂ alkyl, aryl or heterocyclic group; X ¹ represents an optionally substituted C ₂ -C ₄ alkylene group; X ² Represents a group or a bond represented by the general formula NR ² , wherein R ² represents a hydrogen atom, an optionally substituted lower alkyl group or an imino protecting group; and X ³ represents a general formula Formula NR ³ or CR ⁴ R ⁵ NR ³ wherein R ³ is a hydrogen atom, an optionally substituted lower alkyl group or an imino protecting group; R ⁴ and R ⁵ are the same or different and are each a hydrogen atom , An optionally substituted lower alkyl group or a group or bond represented by R ⁴ and R ^{5 taken} together means an oxo group; and X ⁴ is an optionally substituted lower alkylene. , Lower alkenylene or lower alkyl Len group or a bond; X ⁵ is an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, the general formula NR ⁶ "formula, R ⁶ is a hydrogen atom, an optionally substituted lower alkyl, lower alkenyl or A lower alkynyl group or an imino protecting group means a group or a bond represented by: Y ¹ is an optionally substituted divalent alicyclic hydrocarbon residue or an optionally substituted 2 A divalent alicyclic amine residue; Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ may be the same or different and are each a nitrogen atom or a general formula CR ^{7 wherein} R ⁷ is Hydrogen atom, halogen atom, hydroxyl group, cyano group, nitro group, formyl group, amino group which may be protected or substituted, lower alkyl which may be substituted, cycloalkyl, aryl, lower alkoxy, cycl A roalkyloxy, aralkyloxy, alkanoyl, ureido or monocyclic heterocyclic group or a general formula Q ¹ CONR ⁸ R ⁹ , Q ¹ CO ₂ R ¹⁰ or Q ¹ CN wherein R ⁸ and R ⁹ are The same or different, a hydrogen atom, an optionally substituted lower alkyl, cycloalkyl, aralkyl, aryl, lower alkoxy, alkanesulfonyl or monocyclic heterocyclic group or R ⁸ and R ⁹ are attached A cyclic amino group which may be substituted together with a nitrogen atom; R ¹⁰ is a hydrogen atom or a carboxyl protecting group; Q ¹ is an optionally substituted lower alkylene or lower alkenylene group or a bond. means. Is a group represented by. Wherein at least one of Z ³ , Z ⁴ , Z ⁵ and Z ⁶ represents a nitrogen atom. Is a staphylococcus, streptococcus, enterococcus, Escherichia coli, Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Acne fungus, Clostridium perfringens, Fraziris, Bacillus gingivalis The present invention was found to be useful for the treatment and / or prevention of diseases such as infections involving bacterial species selected from Prevotella intermedia, Fusobacterium nucleatum, Legionella pneumophila and Mycoplasma pneumonia .

  Antibacterial agents containing the compound of the general formula [1] or a salt thereof are Staphylococcus, Streptococcus, Enterococcus, Escherichia coli, Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Acne fungus, Clostridium perfringens, Fraziris, and Gingivalis It is useful as an antibacterial agent against bacterial species selected from fungi, Prevotella intermedia, Fusobacterium nucleatum, Legionella pneumophila and Mycoplasma pneumoniae.

Hereinafter, the present invention will be described in detail.
In the present specification, unless otherwise specified, a halogen atom is a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; an alkyl group is, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, A linear or branched C _1-12 alkyl group such as isobutyl, tert-butyl, pentyl, hexyl and octyl; a C ₂ -C ₁₂ alkyl group is, for example, ethyl, propyl, isopropyl, butyl, linear or branched C _2-12 alkyl groups such as sec-butyl, isobutyl, tert-butyl, pentyl, hexyl and octyl; lower alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, Butyl, sec-butyl, isobutyl, tert-butyl, pentyl and iso Pentyl and linear or branched C _1-6 alkyl group such as; the alkenyl group, for example, vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, straight, such as heptenyl and octenyl A chain or branched C _2-12 alkenyl group; a lower alkenyl group is, for example, linear or branched, such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl and hexenyl the lower alkynyl group, for example, ethynyl, 2-propynyl and 2-butynyl linear or branched _{C 2-6} alkynyl group such as, _{C 2-6} alkenyl group of;

The cycloalkyl group is, for example, a C _3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; the aryl group is, for example, a group such as phenyl, naphthyl, anthracenyl, and phenanthrenyl; Represents, for example, an ar C _1-6 alkyl group such as benzyl, diphenylmethyl, trityl, phenethyl and naphthylmethyl;

The lower alkoxy group is, for example, linear or branched C _1-6 such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and isopentyloxy. An alkyloxy group; a cycloalkyloxy group means a C _3-8 cycloalkyloxy group such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy; an aralkyloxy group means, for example, benzyloxy and phenethyloxy Al _{C 1-6} alkyl group and the like; and alkoxyalkyl groups such as a _{C 1-6} alkyloxy _{C 1-6} alkyl group such as methoxymethyl and 1-ethoxyethyl; an aralkyloxyalkyl And, for example, Al _{C 1-6} alkyloxy _{C 1-6} alkyl group such as benzyloxymethyl and phenethyl oxymethyl;

The lower alkylene group is, for example, a C _1-6 alkylene group such as methylene, ethylene, propylene, butylene, and hexylene; and the C ₂ -C ₄ alkylene group is, for example, C _2-4 such as ethylene, propylene, and butylene. An alkylene group; a C ₁ -C ₃ alkylene group, for example, a C _1-3 alkylene group such as methylene, ethylene and propylene; and a lower alkenylene group, for example, C ₂ such as vinylene, propenylene, butenylene and pentenylene. _{A -6} alkenylene group; a lower alkynylene group is, for example, a C _2-6 alkynylene group such as ethynylene, propynylene, butynylene and pentynylene;

An alkanoyl group is, for example, a linear or branched C _2-12 alkanoyl group such as acetyl, propionyl, butyryl, isovaleryl and pivaloyl; an acyl group is, for example, formyl group, acetyl, propionyl, butyryl Linear or branched C _2-12 alkanoyl groups such as isovaleryl and pivaloyl, al C _1-6 alkylcarbonyl groups such as benzylcarbonyl, cyclic hydrocarbon carbonyl groups such as benzoyl and naphthoyl, nicotinoyl, thenoyl Heterocyclic carbonyl groups such as pyrrolidinocarbonyl and furoyl, succinyl group, glutaryl group, maleoyl group, phthaloyl group and amino acids (for example, glycine, alanine, valine, leucine, isoleucine, serine, N-terminal derived from onine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine, tyrosine, tryptophan, proline, and hydroxyproline). A linear or branched α-aminoalkanoyl group which may be

Examples of the acylalkyl group include groups such as acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methoxybenzoylmethyl and 1-benzoylethyl; examples of the acyloxy group include acetyloxy And linear or branched C _2-6 alkanoyloxy groups such as propionyloxy and aroyloxy groups such as benzoyloxy; acyloxyalkyl groups include, for example, acetoxymethyl, propionyloxymethyl and pivaloyloxymethyl Groups such as;

The alkyloxycarbonyl group is, for example, linear or branched such as methoxycarbonyl, ethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 2-ethylhexyloxycarbonyl, tert-butoxycarbonyl and tert-pentyloxycarbonyl. A branched C _1-12 alkyloxycarbonyl group; an aralkyloxycarbonyl group is, for example, an al C _1-6 alkyloxycarbonyl group such as benzyloxycarbonyl and phenethyloxycarbonyl groups; an aryloxycarbonyl group; For example, a group such as phenyloxycarbonyl;

An alkylthio group is, for example, a C _1-6 alkylthio group such as methylthio, ethylthio and propylthio; an arylthio group is, for example, a group such as phenylthio; an alkylthioalkyl group is, for example, methylthiomethyl, ethylthiomethyl and A C _1-6 alkylthio C _1-6 alkyl group such as propylthiomethyl; an arylthioalkyl group is a group such as (phenylthio) methyl and 2- (p-nitrophenylthio) ethyl; an alkanesulfonyl group Is, for example, a C _1-6 alkanesulfonyl group such as methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, and propanesulfonyl; an arylsulfonyl group is, for example, benzenesulfonyl, toluenesulfonyl, and naphthalene Groups such as Nsulfonyl;

The arylsulfonylalkyl group is, for example, a group such as p-toluenesulfonylethyl; the alkanesulfonyloxy group is, for example, a C _1-6 alkanesulfonyloxy group such as methanesulfonyloxy, trifluoromethanesulfonyloxy and ethanesulfonyloxy. An arylsulfonyloxy group includes, for example, groups such as benzenesulfonyloxy and toluenesulfonyloxy;

The lower alkylamino group includes, for example, mono C _1-6 alkylamino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino and pentylamino; cyclopropylamino, cyclobutylamino and C _3-6 cycloalkylamino groups such as cyclopentylamino; and diC _1-6 alkylamino groups such as dimethylamino, diethylamino, dipropylamino and dibutylamino; cyclic amino groups include, for example, piperazinyl, piperidinyl, morpholino A group such as pyrrolidinyl; an oxygen-containing heterocyclic group such as 2-tetrahydropyranyl and 2-tetrahydrofuranyl; and a sulfur-containing heterocyclic group such as tetrahydrothiopyranyl Group

The oxygen-containing heterocyclic alkyl group is, for example, a group such as 5-methyl-2-oxo-2H-1,3-dioxol-4-ylmethyl; the nitrogen-containing heterocyclic alkyl group is, for example, phthalimidomethyl And a group such as succinimidomethyl; a heterocyclic oxycarbonyl group includes, for example, groups such as 2-furfuryloxycarbonyl and 8-quinolyloxycarbonyl;

Examples of the cycloalkylidene group include groups such as cyclopentylidene and cyclohexylidene; examples of the alkylidene group include groups such as benzylidene and naphthylmethylene; and examples of the dialkylaminoalkylidene group include N, N- Groups such as dimethylaminomethylene and N, N-diethylaminomethylene; nitrogen-containing heterocyclic alkylidene groups include, for example, groups such as 3-hydroxy-4-pyridylmethylene;

A diarylphosphoryl group is a group such as diphenylphosphoryl; a dialalkylphosphoryl group is a group such as dibenzylphosphoryl; a substituted silyl group is a group such as trimethylsilyl, triethylsilyl, and tributylsilyl. An alkylsilylalkyl group is, for example, a group such as 2- (trimethylsilyl) ethyl;

Monocyclic heterocyclic groups include, for example, furyl, furfuryl, thienyl, 2-tenyl, 2-pyrrolyl, imidazolyl, 3-pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, furazonyl, pyrrolidinyl, imidazolidinyl, pyridyl, A group such as pyrimidinyl, pyridazinyl, pyrazyl, piperazinyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 2-piperazinyl, 2-morpholinyl, 2-thiomorpholinyl and pyranyl; Benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, 1H-indazolyl, pre Ru, coumarinyl, chromenyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, quinuclidinyl, 1,3-benzodioxanyl, 1,4-benzodioxanyl, benzomorpholinyl, benzo Morpholonyl, 2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-yl, 3,4-dihydro-2H-pyrido (4,3-b) (1,4) oxazine -7-yl, 3-oxo-3,4-dihydro-2H-pyrido (3,2-b) (1,4) oxazin-6-yl, 3-oxo-3,4-dihydro-2H-pyrido ( 3,2-b) (1,4) thiazin-6-yl, 3-oxo-3,4-dihydro-2H-benzothiazin-6-yl, 3,4-dihydro 2H-pyrano (2,3-c) pyridin-6-yl, 3,4-dihydro-2H- (1,4) dioxepino (2,3-c) pyridin-8-yl, (1,3) dioxolo ( 4,5-c) pyridin-6-yl, 6-oxide-2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-yl, 7-oxo-5,6,7, Groups such as 8-tetrahydro-1,8-naphthyridin-2-yl and 5,6,7,8-tetrahydroquinoxalin-2-yl; tricyclic heterocyclic groups include, for example, thianthrene-2- Yl, xanthen-2-yl, phenoxathiin-2-yl, 4aH-carbazol-2-yl, carbazol-2-yl, phenanthridin-3-yl, acridine-2-yl, perimidin-2-yl, phenanthroline- 3-Ile, Fu Groups such as phenazin-1-yl, phenothiazin-2-yl, phenoxazin-2-yl and 2,3-dihydro-5-oxo- (1H, 5H) -benzo (IJ) quinolin-6-yl; Examples of the cyclic group include groups such as the above monocyclic heterocyclic group, bicyclic heterocyclic group, and tricyclic heterocyclic group;

Protected carbonyl groups include, for example, (hydroxy) (methoxy) methylene, (hydroxy) (ethoxy) methylene, (hydroxy) (propoxy) methylene, (hydroxy) (isopropoxy) methylene, (hydroxy) (butoxy) Methylene, (hydroxy) (pentyloxy) methylene, (hydroxy) (hexyloxy) methylene, (hydroxy) (heptyloxy) methylene, (hydroxy) (octyloxy) methylene, (hydroxy) (1,1-dimethylpropoxy) methylene Dimethoxymethylene, diethoxymethylene, dipropoxymethylene, diisopropoxymethylene, dibutoxymethylene, bis (benzyloxy) methylene, 1,3-dioxolan-2-ylidene and 1,3-dioxane-2-ylidene Groups formed from carbonyl groups and alcohols such as bis (methylthio) methylene, bis (ethylthio) methylene, bis (benzylthio) methylene, 1,3-dithiolane-2-ylidene and 1,3-dithian-2-ylidene Groups formed from carbonyl groups and thiols and groups such as oxazoline-2-ylidene, imidazolidin-2-ylidene and thiazolidine-2-ylidene;

Examples of the divalent alicyclic hydrocarbon residue include 1,2-cyclobutylene, 1,3-cyclobutylene, 1,2-cyclopentylene, 1,3-cyclopentylene, 1,2-cyclohexene. C _3-8 cycloalkylene residues such as silene, 1,3-cyclohexylene, 1,4-cyclohexylene and bicyclo (3.2.1) octylene, bicyclo (2.2.0) hexylene and bicyclo (5. 2.0) a bridged C _3-8 cycloalkylene residue such as nonylene; a divalent 4, 5 or 6-membered alicyclic hydrocarbon residue is, for example, 1,2-cyclobutylene, 1,3-cyclobutylene, 1,2-cyclopentylene, 1,3-cyclopentylene, 1,2-cyclohexylene, 1,3-cyclohexylene, _{C 4-6,} such as 1,4-cyclohexylene Shi Roarukiren residues and bicyclo (the 3.2.1) octylene and bicyclo (2.2.0) _{C 4-6} cycloalkylene residue which is cross-linked, such as hexylene;

Examples of the divalent alicyclic cyclic amine residue include 4-membered alicyclic cyclic amine residues such as azetidine-1,2-diyl and azetidine-1,3-diyl, pyrrolidine-1,2-diyl And monocyclic 5-membered alicyclic amine residues such as pyrrolidine-1,3-diyl, 3-azabicyclo (3.1.0) hexane-3,5-diyl, 3-azabicyclo (3.1. 0) Hexane-3,6-diyl, 8-azabicyclo (3.2.1) octane-3,8-diyl, octahydrocyclopenta (c) pyrrole-2,4-diyl, octahydrocyclopenta (c) Crosslinked 5 such as pyrrole-2,5-diyl, octahydropyrrolo (3,4-c) pyrrole-2,4-diyl and octahydropyrrolo (3,4-c) pyrrole-2,5-diyl. Membered cycloaliphatic ring Min residue, piperidine-1,3-diyl, piperidine-1,4-diyl, piperazine-1,3-diyl, piperazine-1,4-diyl, morpholine-2,4-diyl and thiomorpholine-2,4 A monocyclic 6-membered cycloaliphatic cyclic amine residue such as diyl, 3-azabicyclo (4.1.0) heptane-3,6-diyl and hexahydroimidazo (1,5-a) pyrazine-2, Bridged 6-membered cycloaliphatic cyclic amine residues such as 7-diyl and groups such as homopiperazine-1,4-diyl;

Examples of the divalent 5-membered alicyclic cyclic amine residue include monocyclic 5-membered alicyclic cyclic amine residues such as pyrrolidine-1,2-diyl and pyrrolidine-1,3-diyl, and 3 -Azabicyclo (3.1.0) hexane-3,5-diyl, 3-azabicyclo (3.1.0) hexane-3,6-diyl, 8-azabicyclo (3.2.1) octane-3,8 -Diyl, octahydrocyclopenta (c) pyrrole-2,4-diyl, octahydrocyclopenta (c) pyrrole-2,5-diyl, octahydropyrrolo (3,4-c) pyrrole-2,4-diyl And a bridged 5-membered alicyclic amine residue such as octahydropyrrolo (3,4-c) pyrrole-2,5-diyl; and a divalent 6-membered alicyclic amine residue For example, piperidine-1,3 Monocyclic six-membered rings such as diyl, piperidine-1,4-diyl, piperazine-1,3-diyl, piperazine-1,4-diyl, morpholine-2,4-diyl and thiomorpholine-2,4-diyl Alicyclic cyclic amine residues and bridged 6 such as 3-azabicyclo (4.1.0) heptane-3,6-diyl and hexahydroimidazo (1,5-a) pyrazine-2,7-diyl It means a membered cycloaliphatic cyclic amine residue.

  The imino protecting group includes all groups that can be used as usual imino protecting groups. W. Greene et al., Protective Groups in Organic Synthesis, 3rd edition, pages 494-653, 1999, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, for example, acyl group, alkyloxycarbonyl group, aralkyloxycarbonyl group, aryloxycarbonyl group, aralkyl group, alkoxyalkyl group, aralkyloxyalkyl group, arylthio group, alkanesulfonyl group, arylsulfonyl group , A diarylphosphoryl group, a dialalkylphosphoryl group, an oxygen-containing heterocyclic alkyl group and a substituted silyl group.

  Amino protecting groups include all groups that can be used as conventional amino protecting groups. W. Greene et al., Protective Groups in Organic Synthesis, 3rd edition, pages 494-653, 1999, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, for example, acyl group, alkyloxycarbonyl group, aralkyloxycarbonyl group, aryloxycarbonyl group, aralkyl group, alkoxyalkyl group, aralkyloxyalkyl group, arylthio group, alkanesulfonyl group, arylsulfonyl group A dialkylaminoalkylidene group, an alkylidene group, a nitrogen-containing heterocyclic alkylidene group, a cycloalkylidene group, a diarylphosphoryl group, a dialalkylphosphoryl group, an oxygen-containing heterocyclic alkyl group and a substituted silyl group.

  Hydroxyl protecting groups include all groups that can be used as conventional hydroxyl protecting groups. W. Greene et al., Protective Groups in Organic Synthesis, 3rd edition, pp. 17-245, 1999, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, for example, acyl group, alkyloxycarbonyl group, aralkyloxycarbonyl group, heterocyclic oxycarbonyl group, alkyl group, alkenyl group, aralkyl group, oxygen-containing heterocyclic group, sulfur-containing heterocyclic group , Alkoxyalkyl groups, aralkyloxyalkyl groups, alkanesulfonyl groups, arylsulfonyl groups, substituted silyl groups, and the like.

  The carboxyl protecting group includes all groups that can be used as usual carboxyl protecting groups. W. Greene et al., Protective Groups in Organic Synthesis, 3rd edition, pages 369-453, 1999, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, for example, alkyl group, aryl group, aralkyl group, acylalkyl group, arylthioalkyl group, arylsulfonylalkyl group, oxygen-containing heterocyclic group, alkylsilylalkyl group, acyloxyalkyl group, nitrogen-containing complex Examples include cyclic alkyl groups, cycloalkyl groups, alkoxyalkyl groups, aralkyloxyalkyl groups, alkylthioalkyl groups, alkenyl groups, and substituted silyl groups.

  Examples of the leaving group include a halogen atom, an alkanesulfonyloxy group, an arylsulfonyloxy group, and an acyloxy group.

Examples of the salt of the compound represented by the general formula [1] include salts of known basic groups such as amino groups or acidic groups such as phenolic hydroxyl groups or carboxyl groups.
Salts in basic groups include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; salts with organic carboxylic acids such as tartaric acid, formic acid, acetic acid, citric acid, trichloroacetic acid and trifluoroacetic acid; And salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.
Examples of the salt in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Salts with nitrogenous organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine and N, N′-dibenzylethylenediamine Can be mentioned.
Furthermore, among the above salts, preferred salts of the compound of the general formula [1] include pharmacologically acceptable salts.

Examples of the substituent for the C ₂ -C ₁₂ alkyl group, aryl group and heterocyclic group of R ¹ include a halogen atom, an optionally protected hydroxyl and carboxyl group, a lower alkyl optionally substituted with a halogen atom, From lower alkenyl, lower alkynyl and lower alkoxy groups, hydroxyimino groups, acyl groups, protected amino groups, amino groups, lower alkylamino groups, alkylthio groups, aryl groups, monocyclic heterocyclic groups and oxo groups One or more groups selected may be mentioned. Preferred substituents include halogen atoms, optionally protected hydroxyl and carboxyl groups, optionally substituted lower alkyl, lower alkenyl and lower alkoxy groups, lower alkylamino groups, aryl groups, monocyclic Examples thereof include one or more groups selected from a heterocyclic group and an oxo group. More preferred substituents include a halogen atom, hydroxyl group, carboxyl group, methyl group, ethyl group, tert-butyl group, trifluoromethyl group, vinyl group, methoxy group, ethoxy group, trifluoromethoxy group, dimethylamino group, One or more groups selected from a phenyl group, a thienyl group, a pyrrolidinyl group, and an oxo group may be mentioned. More preferred substituents include one or more groups selected from a halogen atom, a methyl group, an ethyl group, a thienyl group, and an oxo group.

Examples of the substituent for the lower alkyl group of R ² , R ³ , R ⁴ and R ⁵ and the lower alkyl group, lower alkenyl group and lower alkynyl group of R ⁶ include a halogen atom, an optionally protected hydroxyl and carboxyl group, Lower alkyl, lower alkenyl, lower alkynyl and lower alkoxy groups which may be substituted with halogen atoms, lower alkyl, lower alkenyl and lower alkynyl groups, aryl groups which may be substituted with aryl groups, and monocyclic heterocyclic groups One or more groups selected from groups and the like can be mentioned. Preferred substituents are one selected from a halogen atom, a hydroxyl and carboxyl group which may be protected, a lower alkyl group which may be substituted with a halogen atom, and a lower alkynyl group which may be substituted with an aryl group. The above groups are mentioned. More preferable substituents include one or more groups selected from a halogen atom, a hydroxyl group, a carboxyl group, a methyl group, an ethyl group, a trifluoromethyl group, a 2-phenylethynyl group, and an oxo group. More preferred substituents include a carboxyl group and a 2-phenylethynyl group.

The lower alkyl group for R ^7, cycloalkyl group, aryl group, lower alkoxy group, cycloalkyloxy group, aralkyloxy group, alkanoyl group, a heterocyclic group ureido group and monocyclic, lower alkyl group and a lower of R ^7a Alkoxy group, lower alkyl group and lower alkoxy group of R ^7b , lower alkyl group of R ^7c , cycloalkyl group, aryl group, lower alkoxy group, cycloalkyloxy group, aralkyloxy group, alkanoyl group, ureido group and monocycle Heterocyclic groups of R ^7d , lower alkyl groups and lower alkoxy groups of R ^7d and lower alkyl groups of R ⁸ and R ⁹ , cycloalkyl groups, aralkyl groups, aryl groups, lower alkoxy groups, alkanesulfonyl groups and monocyclic heterocycles Cyclic group substituents include halogen atoms, protected One or more selected from a hydroxyl and carboxyl group, a lower alkyl, lower alkenyl, lower alkynyl and lower alkoxy group optionally substituted with a halogen atom, a hydroxyimino group, an aryl group and a monocyclic heterocyclic group The group of is mentioned. Preferred substituents include one or more selected from a halogen atom, an optionally protected hydroxyl and carboxyl group, a lower alkyl and lower alkoxy group optionally substituted with a halogen atom, and a monocyclic heterocyclic group. Groups. More preferable substituents include one or more groups selected from a halogen atom, a hydroxyl group, a carboxyl group, a methyl group, and a methoxy group.

The substituent for the amino group of R ⁷ is selected from lower alkyl, lower alkenyl, lower alkynyl and lower alkoxy groups optionally substituted with a halogen atom, acyl groups, aryl groups, and monocyclic heterocyclic groups. One or more groups may be mentioned. Preferred substituents include one or more groups selected from lower alkyl and lower alkenyl groups, acyl groups and aryl groups which may be substituted with a halogen atom. More preferable substituents include one or more groups selected from a methyl group, an ethyl group, a trifluoromethyl group, a vinyl group, a formyl group, an acetyl group, a benzoyl group, and a phenyl group. More preferred substituents include one or more groups selected from a methyl group, an ethyl group, an acetyl group, and a phenyl group.

Examples of the substituent of the cyclic amino group formed by combining R ⁸ and R ⁹ with the nitrogen atom to which they are bonded include a halogen atom, an optionally protected hydroxyl and carboxyl group, and a halogen atom. Lower alkyl, lower alkenyl, lower alkynyl and lower alkoxy groups, hydroxyimino group, acyl group, amino group, lower alkylamino group, alkylthio group, aryl group, monocyclic ring optionally substituted with aralkyl group One or more groups selected from a heterocyclic group and an oxo group can be mentioned. Preferred substituents include halogen atoms, optionally protected hydroxyl and carboxyl groups, lower alkyl optionally substituted with halogen atoms, lower alkenyl and lower alkoxy groups, alkanoyl groups, lower alkylamino groups, alkylthio groups, Examples thereof include one or more groups selected from an aryl group, a monocyclic heterocyclic group which may be substituted with an aralkyl group, and an oxo group. More preferred substituents include one or more groups selected from a halogen atom, hydroxyl group, carboxyl group, methyl group, ethyl group, methoxy group, ethoxy group, dimethylamino group, phenyl group and oxo group.

Examples of the substituent for the lower alkylene group and lower alkenylene group of Q ¹ include an oxo group, an optionally protected hydroxyl and carboxyl group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, and an aryl group. One or more groups selected may be mentioned. Preferred substituents include one or more groups selected from oxo groups, optionally protected hydroxyl and carboxyl groups, lower alkyl groups, lower alkoxy groups and aryl groups. More preferred substituents include one or more groups selected from an oxo group, a hydroxyl group, a carboxyl group, a methyl group, a methoxy group, and a phenyl group.

_C 2 -C ₄ substituents alkylene group X ^1, _C ¹ -C ₃ lower alkylene group of the alkylene group and ^{X 4} of ^{X 1a,} as the substituent of the lower alkenylene group and lower alkynylene group, an oxo group, a protected One or more groups selected from a hydroxyl and carboxyl group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, an aryl group, and the like, which may be included. Preferred substituents include one or more groups selected from oxo groups and lower alkyl groups. More preferred substituents include one or more groups selected from an oxo group and a methyl group.

The substituent of the divalent alicyclic hydrocarbon residue and divalent alicyclic cyclic amine residue of Y ¹ is substituted with a halogen atom, an optionally protected hydroxyl and carboxyl group, or a halogen atom. Lower alkyl, lower alkenyl, lower alkynyl and lower alkoxy groups, hydroxyimino group, acyl group, amino group, lower alkylamino group, alkylthio group, aryl group, monocyclic ring optionally substituted with aralkyl group One or more groups selected from a heterocyclic group and an oxo group can be mentioned. Preferred substituents include halogen atoms, optionally protected hydroxyl and carboxyl groups, lower alkyl optionally substituted with halogen atoms, lower alkenyl and lower alkoxy groups, alkanoyl groups, lower alkylamino groups, alkylthio groups, Examples thereof include one or more groups selected from an aryl group, a monocyclic heterocyclic group which may be substituted with an aralkyl group, and an oxo group. More preferred substituents include one or more groups selected from a halogen atom, hydroxyl group, carboxyl group, methyl group, ethyl group, methoxy group, ethoxy group, dimethylamino group, phenyl group and oxo group.

  In the compound of the general formula [1] of the present invention, preferred compounds include the following compounds.

A compound in which R ¹ is an optionally substituted aryl or heterocyclic group is preferable, and 3-fluoro-4-methylphenyl, 3-fluoro-4- (trifluoromethyl) phenyl, 3-fluoro-4- Methylpyridyl, 5-fluoro-6-methylpyridyl, 4-ethylphenyl, naphthyl, benzo (b) thiophen-2-yl, benzo (b) thiophen-5-yl, benzo (b) thiophen-6-yl, 5 -(Thiophen-2-yl) isoxazol-2-yl, 2,3-dihydro-1,4-benzodithiin-6-yl, 2,3-dihydrobenzo (1,4) dioxin-6-yl, 2, 3-dihydro (1,4) dioxino (2,3-c) pyridin-7-yl, 3-oxo-3,4-dihydro-2H-pyrido (3,2-b) (1,4) oxadi N-6-yl, 7-chloro-3-oxo-3,4-dihydro-2H-pyrido (3,2-b) (1,4) thiazin-6-yl, 3-oxo-3,4-dihydro More preferred is a compound that is -2H-pyrido (3,2-b) (1,4) thiazin-6-yl or 3-oxo-3,4-dihydro-2H-benzothiazin-6-yl. Dihydrobenzo (1,4) dioxin-6-yl, 2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-yl or 3,4-dihydro-2H-pyrano (2,3 -C) A compound that is pyridin-6-yl is more preferable, and a compound that is 2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-yl is still more preferable.

A compound in which X ¹ is an optionally substituted ethylene group is preferred, and a compound in which X ¹ is an ethylene group is more preferred.
A compound in which X ² is NH or a bond is preferable, and a compound in which X ² is a bond is more preferable.
A compound in which X ³ is NH, CH ₂ NH or a bond is preferred, a compound in which NH or a bond is preferred is more preferred, and a compound in which NH is NH is more preferred.
Yes.
A compound in which X ⁴ is an optionally substituted lower alkylene group or a bond is preferable, a compound in which a lower alkylene group is more preferable, and a compound in which a methylene group is more preferable.
A compound in which X ⁵ is an oxygen atom, a sulfur atom, NH or a bond is preferable, and a compound in which a bond is a bond is more preferable.

Y ¹ is an optionally substituted divalent 4, 5 or 6 membered alicyclic hydrocarbon residue or an optionally substituted divalent 5 or 6 membered alicyclic cyclic amine residue. A certain compound is preferable, and a compound which is a divalent 6-membered alicyclic hydrocarbon residue which may be substituted or a divalent 6-membered alicyclic amine residue which may be substituted is more preferable. may cyclohexylene substituted, more preferably a compound piperazine-diyl or piperidine-diyl group, a piperidine-1,4-diyl group (the nitrogen atom of 1-position binds to X ^2.), compound is Even more preferred.

Z ¹ has the general formula CR ⁷ "wherein, ^{R 7} is the. Having the same meaning as" compounds wherein preferably, in the general formula ^{CR 7a "formula, R 7a} represents a hydrogen atom, a halogen atom, a hydroxyl And a lower alkyl or lower alkoxy group which may be substituted ”is more preferable, and a compound which is CH is more preferable.
Z ² has the general formula CR ⁷ "wherein, ^{R 7} is. To have the same meaning as defined above" is preferred, compound of the general formula ^{CR 7a "wherein, R 7a} has the same meaning as defined above Is more preferable, and a compound that is CH is more preferable.
A compound in which Z ³ is a nitrogen atom or a group represented by the general formula CR ^7a "wherein R ^7a has the same meaning as described above" is preferable, and a compound in which Z ³ is a nitrogen atom or CH is more preferable. More preferred are compounds that are nitrogen atoms.
A compound in which Z ⁴ is a nitrogen atom or a group represented by the general formula CR ^7a "wherein R ^7a has the same meaning as described above" is preferable, and a compound in which Z ⁴ is a nitrogen atom or CH is more preferable. More preferred is a compound that is CH.
Z ⁵ has the general formula CR ⁷ "wherein, ^{R 7} is the. Having the same meaning as" compounds wherein preferably, in the general formula ^{CR 7b "formula, R 7b} is a hydrogen atom, a halogen atom, a substituted A lower alkyl or lower alkoxy group which may be substituted ”is more preferred, and a compound of the general formula CR ^7d “ wherein R ^7d is a halogen atom, an optionally substituted lower alkyl or lower alkoxy group. Is more preferable than the compound having the general formula CR ^7e , wherein R ^7e represents a halogen atom, a lower alkyl group or a lower alkoxy group.
A compound in which Z ⁶ is a nitrogen atom or a group represented by the general formula CR ^7a “wherein R ^7a has the same meaning as described above” is preferable, and a compound in which Z ⁶ is a nitrogen atom or CH is more preferable.

The most preferred compounds of the general formula [1] of the present invention include the following compounds.
7-chloro-1- (2- (4-((2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -1 , 5-Naphthyridin-2 (1H) -one, 1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) piperidine- 1-yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one, 1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3- c) Pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one and 5- (2- (4-((2,3- Dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl Amino) piperidin-1-yl) ethyl) -3-methoxypyrido (2,3-b) pyrazin -6 (5H) - one.

Next, the manufacturing method of the compound used for this invention is demonstrated.
The compound of the general formula [1] is produced by a combination of methods known per se, and can be produced, for example, by the production method shown below.

「式中、Ｙ^１ａは、環内の一つの窒素原子が隣接基に結合し、環内の他の原子がＸ^３に結合する置換されていてもよい２価の脂環式環状アミン残基を；Ｒ^１、Ｘ^１ａ、Ｘ^３、Ｘ^４、Ｘ^５、Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、前記と同様の意味を有する。」 [Production Method 1]

“In the formula, Y ^1a is an optionally substituted divalent alicyclic cyclic amine residue in which one nitrogen atom in the ring is bonded to the adjacent group and the other atom in the ring is bonded to X ^3. R ¹ , X ^1a , X ³ , X ⁴ , X ⁵ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ have the same meanings as described above.

Examples of the compound of the general formula [4a] include 4-((1-phenylethyl) amino) piperidine and tert-butyl = (3-aminobenzyl) (4-piperidinyl) carbamate, phenyl-N- (4-piperidinyl) Carboxamide and the like are known.
The compound of the general formula [1a] can be produced by reacting the compound of the general formula [2a] with the compound of the general formula [4a] in the presence of a reducing agent.
This reaction is described in WO 02/50061, WO 02/56882 and Jerry March, Advanced Organic Chemistry 4th edition, pages 898-900. 1992, John Wiley & Sons, INC. And Richard C. Larock, Comprehensive Organic Transformations 421- 425 pages, 1989, VCH Publishers, INC., Etc., or a method similar thereto may be used.

  The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; methylene chloride, chloroform and dichloroethane Halogenated hydrocarbons such as; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and ethylene glycol monomethyl ether; dimethyl sulfoxide, etc. Sulfoxides; esters such as ethyl acetate; N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl Such as amides and water, such as 2-pyrrolidone and the like, it may be used which are mixed.

Examples of the reducing agent used in this reaction include lithium aluminum hydride, sodium triacetoxyborohydride, hydrogenated complex compounds such as sodium cyanoborohydride and sodium borohydride, borane, sodium and sodium amalgam. Can be mentioned. Further, electrolytic reduction using copper or platinum as a cathode; catalytic reduction using Raney nickel, platinum oxide or palladium black, reduction using “zinc-acid”, or the like can also be used.
In this reaction, the amount of the compound of the general formula [4a] and the reducing agent used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [2a].
This reaction may be carried out at −30 to 150 ° C., preferably at 0 to 100 ° C. for 10 minutes to 120 hours.

「式中、Ｘ^２ａは、一般式ＮＲ^２ａ「式中、Ｒ^２ａは、水素原子または置換されていてもよい低級アルキル基を意味する。」で表される基を；Ｒ^１、Ｘ^１ａ、Ｘ^３、Ｘ^４、Ｘ^５、Ｙ^１、Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、前記と同様の意味を有する。」 [Production Method 2]

In the formula, X ^2a represents a group represented by the general formula NR ^2a , wherein R ^2a represents a hydrogen atom or an optionally substituted lower alkyl group; R ¹ , X ^1a , X ³ , X ⁴ , X ⁵ , Y ¹ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ have the same meaning as described above. "

As compounds of the general formula [4b], for example, 4-amino-1- (1-oxo-2-phenylethyl) piperidine and 4-amino-1- (2-phenylethyl) piperidine are known.
The compound of the general formula [1b] can be produced by reacting the compound of the general formula [2a] with the compound of the general formula [4b] in the presence of a reducing agent. This reaction may be performed according to Production Method 1.

「式中、Ｙ^１ｂは、環内の一つの窒素原子が隣接基に結合し、環内の他の原子がＸ^２に結合する置換されていてもよい２価の脂環式環状アミン残基を；Ｒ^１、Ｘ^１、Ｘ^２、Ｘ^４、Ｘ^５、Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、前記と同様の意味を有する。」 [Production Method 3]

^Wherein Y ^1b is an ^optionally substituted divalent alicyclic cyclic amine residue in which one nitrogen atom in the ring is bonded to an adjacent group and the other atom in the ring is bonded to X ² R ¹ , X ¹ , X ² , X ⁴ , X ⁵ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ have the same meaning as described above.

As a compound of general formula [6], for example, 1,4-benzodioxan-6-carbaldehyde and (2,3-dihydro-1,4-benzodioxin-6-yl) acetaldehyde are known.
The compound of the general formula [1c] can be produced by reacting the compound of the general formula [5] with the compound of the general formula [6] in the presence of a reducing agent. This reaction may be performed according to Production Method 1.

「式中、Ｘ^３ａは、一般式ＮＲ^３ａまたはＣＲ^４Ｒ^５ＮＲ^３ａ「式中、Ｒ^３ａは、水素原子または置換されていてもよい低級アルキル基を；Ｒ^４およびＲ^５は、前記と同様の意味を有する。」で表される基を；Ｒ^１、Ｘ^１、Ｘ^２、Ｘ^４、Ｘ^５、Ｙ^１、Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、前記と同様の意味を有する。」 [Production Method 4]

“Wherein X ^3a is a general formula NR ^3a or CR ⁴ R ⁵ NR ^3a ” wherein R ^3a is a hydrogen atom or an optionally substituted lower alkyl group; R ⁴ and R ⁵ are as defined above Having the same meaning. ”Represents a group represented by: R ¹ , X ¹ , X ² , X ⁴ , X ⁵ , Y ¹ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ are , Have the same meaning as above. "

  The compound of the general formula [1d] can be produced by reacting the compound of the general formula [7] with the compound of the general formula [6] in the presence of a reducing agent. This reaction may be carried out according to production method 1.

「式中、Ｌ^１は、脱離基を；Ｒ^１、Ｘ^１、Ｘ^２、Ｘ^４、Ｘ^５、Ｙ^１ｂ、Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、前記と同様の意味を有する。」 [Production Method 5]

“Wherein L ¹ represents a leaving group; R ¹ , X ¹ , X ² , X ⁴ , X ⁵ , Y ^1b , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ are It has the same meaning as above. "

Examples of the compound of the general formula [8] include 2- (3-oxo-3,4-dihydro-2H-benzothiazin-6-yl) ethyl methanesulfonate, 2- (benzo [1,3] dioxol-5 -Yl) ethyl methanesulfonate, 2-((2-bromoethyl) thio) thiophene, 2-bromo-N- (pyridin-2-yl) acetamide and the like are known.
The compound of general formula [1e] can be produced by reacting the compound of general formula [5] with the compound of general formula [8] in the presence or absence of a base. This reaction may be performed by the method described in US Pat. No. 6,603,005 or the like, or a method analogous thereto.

The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; methylene chloride, chloroform and dichloroethane Halogenated hydrocarbons such as; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and ethylene glycol monomethyl ether; dimethyl sulfoxide, etc. Sulfoxides; ketones such as acetone and 2-butanone; esters such as ethyl acetate; N, N-dimethylformamide; , N- such amides as well as water, such as dimethylacetamide and 1-methyl-2-pyrrolidone, and the like, may be used which are mixed.
Examples of the base used in this reaction include organic bases such as pyridine, dimethylaminopyridine and triethylamine; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium carbonate and sodium carbonate, and the like. Can be mentioned.
In this reaction, the amount of the compound of the general formula [8] and the base used as required may be 1 to 20 moles compared to the compound of the general formula [5].
This reaction may be carried out at 0 to 200 ° C., preferably 0 to 150 ° C., for 30 minutes to 48 hours.

「式中、Ｒ^１、Ｌ^１、Ｘ^１、Ｘ^２、Ｘ^３ａ、Ｘ^４、Ｘ^５、Ｙ^１、Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、前記と同様の意味を有する。」 [Production Method 6]

In the formula, R ¹ , L ¹ , X ¹ , X ² , X ^3a , X ⁴ , X ⁵ , Y ¹ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ are the same as above. Has the meaning. "

  The compound of the general formula [1f] can be produced by reacting the compound of the general formula [7] with the compound of the general formula [8] in the presence or absence of a base. This reaction may be performed according to the production method 5.

「式中、Ｌ^２は、脱離基を；Ｒ^１、Ｘ^１、Ｘ^２、Ｘ^３、Ｘ^４、Ｘ^５、Ｙ^１、Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、前記と同様の意味を有する。」 [Production Method 7]

"Wherein L ² represents a leaving group; R ¹ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , Y ¹ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ has the same meaning as above. "

Examples of the compound of the general formula [9] include 2- (4- (phenylacetyl) piperazin-1-yl) ethyl chloride and 2-chloro-1- (4-phenethylpiperazin-1-yl) ethanone. It has been.
The compound of the general formula [1] can be produced by reacting the compound of the general formula [3a] with the compound of the general formula [9] in the presence or absence of a base.
The solvent used in this reaction may be any solvent that does not adversely influence the reaction. For example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and ethylene glycol monomethyl ether Examples include ethers; sulfoxides such as dimethyl sulfoxide; esters such as ethyl acetate and water. These may be used as a mixture.

In this reaction, optionally used bases include, for example, organic bases such as pyridine, dimethylaminopyridine and triethylamine; sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, sodium carbonate and carbonate. Examples thereof include inorganic bases such as cesium.
In this reaction, the amount of the base and the compound of the general formula [9] used as desired may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [3a]. .
This reaction may be carried out at −30 to 150 ° C., preferably at 0 to 100 ° C. for 30 minutes to 48 hours.

The compounds of the general formulas [1], [1a], [1b], [1c], [1d], [1e] and [1f] obtained by the production methods 1 to 7 or their salts are, for example, condensed, By subjecting to a reaction known per se such as addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis, or by appropriately combining these reactions, other compounds of the general formula [1] or their Can be derivatized into salt.
Moreover, in the compound in the above production method, when there are isomers (for example, optical isomers, geometric isomers, tautomers, etc.), these isomers can also be used, and solvates. Hydrates and crystals of various shapes can also be used.

  The compound of the general formula [2] of the present invention is produced by combining methods known per se, and can be produced, for example, by the production method shown below.

「式中、Ｙ^２ａは、保護されているカルボニル基を；Ｌ^３は、脱離基を；Ｘ^１ａ、Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、前記と同様の意味を有する。」 [Production Method 8]

“Wherein Y ^2a represents a protected carbonyl group; L ³ represents a leaving group; X ^1a , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ are the same as above. Has the meaning. "

  Examples of the compound of the general formula [10] include 2- (2-bromomethyl) -1,3-dioxolane, 2- (2-bromoethyl) -1,3-dioxolane and 2- (2-bromoethyl) -1, 3-dioxane and the like are known.

(8-1) The compound of the general formula [2b] can be produced by reacting the compound of the general formula [3a] with the compound of the general formula [10] in the presence or absence of a base. This reaction may be performed according to the production method 7.

(8-2) The compound of the general formula [2a] can be produced by deprotecting the compound of the general formula [2b]. This reaction is described, for example, by Protective Groups in Organic Synthesis, 3rd edition, pages 293-368, 1999, John Wiley & Sons, INC.), Etc., or a method similar thereto.

「式中、Ｒ^１６は、塩素原子、臭素原子、ヨウ素原子または置換されていてもよいアルカンスルホニルオキシ基を；Ｒ^１７は、カルボキシル保護基を；Ｘ^１ａ、Ｙ^２ａ、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、前記と同様の意味を有する。」 [Production Method 9]

“Wherein R ¹⁶ represents a chlorine atom, a bromine atom, an iodine atom or an optionally substituted alkanesulfonyloxy group; R ¹⁷ represents a carboxyl protecting group; X ^1a , Y ^2a , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ have the same meaning as above.

Examples of the compound of the general formula [11] include 2-chloro-N- (2,2-dimethoxyethyl) pyridin-3-amine.
Examples of the compound of the general formula [12] include methyl acrylate, ethyl acrylate, tert-butyl acrylate, and the like.

  (9-1) The compound of the general formula [13] is obtained by converting the compound of the general formula [11] into the general formula [11] in the presence of a catalyst, in the presence or absence of a base, and in the presence or absence of a ligand. 12] and can be produced by reacting with the compound. This reaction is described in, for example, Y. et al., Organic Synthesis Opened by Transition Metals, 19-22, 1997, Maruzen and Chem. Pharm. Bull., 33, 4764-4768. And the method described in 1985 or the like, or a method analogous thereto.

  The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; N, N-dimethylformamide Amides such as N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; Aromatic hydrocarbons such as benzene, toluene and xylene; Dioxane, Tetrahydrofuran , Ethers such as anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and ethylene glycol monomethyl ether; sulfoxy such as dimethyl sulfoxide S; ketones such as acetone and 2-butanone; esters such as ethyl acetate; and nitriles and water, such as acetonitrile and the like, may be used which are mixed. In addition, this reaction may be performed without a solvent.

Examples of the catalyst used in this reaction include tetrakis (triphenylphosphine) palladium (0), palladium (II) acetate, palladium (II) chloride, bis (tri-tert-butylphosphine) palladium (0) and tris. (Dibenzylideneacetone) dipalladium (0) and the like.
In this reaction, the base used as desired includes, for example, organic bases such as pyridine, dimethylaminopyridine, triethylamine, N, N-dimethylbenzylamine, sodium acetate and potassium acetate; sodium hydroxide, potassium hydroxide, carbonate Examples thereof include inorganic bases such as sodium hydrogen, potassium carbonate and sodium carbonate.
The ligands optionally used in this reaction include trialkylphosphines such as trimethylphosphine and tri-tert-butylphosphine; tricycloalkylphosphines such as tricyclohexylphosphine; triarylphosphine such as triphenylphosphine and tritolylphosphine. Reel phosphines; trialkyl phosphites such as trimethyl phosphite, triethyl phosphite and tributyl phosphite; tricycloalkyl phosphites such as tricyclohexyl phosphite; triaryl phosphites such as triphenyl phosphite; Imidazolium salts such as 3-bis (2,4,6-trimethylphenyl) imidazolium chloride; acetylacetone and octafluoroacetylacetate Diketones such as trimethylamine, triethylamine, tripropylamine and triisopropylamine; and 1,1'-bis (diphenylphosphino) ferrocene, 2,2'-bis (diphenylphosphino) -1,1 '-Binaphthyl, 2-dicyclohexylphosphino-2', 6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl, 2- (di-tert-butylphosphino)- Examples thereof include 2 ′, 4 ′, 6′-triisopropylbiphenyl and 2- (di-tert-butylphosphino) biphenyl, and these may be used in combination.
In this reaction, the amount of the compound of the general formula [12] used may be 1 to 10 times mol, preferably 1 to 5 times mol, of the compound of the general formula [11].
In this reaction, the amount of the catalyst used may be 0.001 to 10 times mol, preferably 0.01 to 2 times mol for the compound of the general formula [11].
In this reaction, the amount of the base used as desired may be 1 to 10 times mol, preferably 1 to 5 times mol, of the compound of the general formula [11].
In this reaction, the amount of the ligand used as desired may be 0.00001 to 1 times mol, preferably 0.001 to 0.1 times mol, of the compound of the general formula [11].
This reaction may be carried out at −30 to 200 ° C., preferably at 0 to 100 ° C., for 30 minutes to 48 hours.

  (9-2) The compound of the general formula [2c] can be produced by ring-closing the compound of the general formula [13] in the presence or absence of a base. This reaction may be carried out by a method described in Chem. Pharm. Bull., Vol. 33, 4764-4768, 1985, or a method analogous thereto.

  The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; N, N-dimethylformamide Amides such as N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and Ethers such as ethylene glycol monomethyl ether; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and 2-butanone; esters such as ethyl acetate Include such nitriles and water, such as acetonitrile, it may be used which are mixed.

In this reaction, optionally used bases include, for example, organic bases such as pyridine, dimethylaminopyridine and triethylamine; sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate and Examples thereof include inorganic bases such as sodium carbonate.
In this reaction, the amount of the base used as desired may be 1 to 20 times mol of the compound of the general formula [13].
This reaction may be carried out at 0 to 200 ° C., preferably 0 to 150 ° C., for 30 minutes to 48 hours.

  (9-3) The compound of the general formula [2d] can be produced by deprotecting the compound of the general formula [2c]. This reaction may be performed according to the production method 8-2.

「式中、Ｒ^７ｆは、水素原子または置換されていてもよい低級アルキル、シクロアルキルもしくはアリール基を；Ｒ^１８は、水素原子またはカルボキシル保護基を；Ｘ^１ａ、Ｙ^２ａ、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、前記と同様の意味を有する。」 [Production method 10]

“Wherein R ^7f represents a hydrogen atom or an optionally substituted lower alkyl, cycloalkyl or aryl group; R ¹⁸ represents a hydrogen atom or a carboxyl protecting group; X ^1a , Y ^2a , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ have the same meaning as above.

  Examples of the compound of the general formula [15] include ethyl glyoxylate. In this reaction, a hydrate (hemiacetal) of the compound of the general formula [15] may be used. Examples of the hydrate (hemiacetal) of the compound of the general formula [15] include ethyl = glyoxylate = hemiacetal.

  (10-1) The compound of the general formula [2e] can be produced by reacting the compound of the general formula [14] with the compound of the general formula [15]. This reaction may be performed by, for example, the method described in Journal of Chemical Society (J. Chem. Soc.), Pp. 5156-5166, 1963, or the like.

  (10-2) The compound of the general formula [2f] can be produced by deprotecting the compound of the general formula [2e]. This reaction may be performed according to the production method 8-2.

  The compound of the general formula [3] of the present invention is produced by combining methods known per se, and can be produced, for example, by the production method shown below.

「式中、Ｒ^７ｃ、Ｒ^１６、Ｒ^１７およびＺ^６ａは、前記と同様の意味を有する。」 [Production Method 11]

“Wherein R ^7c , R ¹⁶ , R ¹⁷ and Z ^6a have the same meaning as described above.”

  Examples of the compound of the general formula [16] include 3-amino-2-chloro-5-methoxypyridine and 3-amino-2-chloro-5-methoxypyrazine.

  (11-1) The compound of the general formula [17] is produced by reacting the compound of the general formula [16] with the compound of the general formula [12] in the presence of a catalyst, in the presence or absence of a base. be able to. This reaction may be performed according to the production method 9-1.

  (11-2) The compound of the general formula [3b] can be produced by ring-closing the compound of the general formula [17] in the presence or absence of a base. This reaction may be performed according to production method 9-2.

「式中、Ｒ^７ｃ、Ｒ^１８およびＺ^６ａは、前記と同様の意味を有する。」 [Production method 12]

“Wherein R ^7c , R ¹⁸ and Z ^6a have the same meaning as described above.”

  The compound of the general formula [3c] can be produced by reacting the compound of the general formula [18] with the compound of the general formula [15a]. This reaction may be performed according to the production method 10-1.

「式中、Ｚ^２ａ、Ｚ^６ａおよびＲ^７ｃは、前記と同様の意味を有する。」 [Production method 13]

“Wherein Z ^2a , Z ^6a and R ^7c have the same meaning as described above.”

(13-1) The compound of the general formula [33] can be produced by oxidizing the compound of the general formula [32].
This reaction may be carried out according to the method described in Heterocycles, Vol. 32, pp. 159-1586, 1991 and Heterocycles, Vol. 34, pp. 1055-1063, 1992 or the like What is necessary is just to carry out by the method according to it.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. Examples thereof include halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene. Sulphoxides such as dimethyl sulphoxide, water and the like may be mentioned, and these may be used as a mixture.
Examples of the oxidizing agent used in this reaction include m-chloroperbenzoic acid and peracetic acid.
In this reaction, the amount of the oxidizing agent used may be 1 to 10 moles compared to the compound of the general formula [32].
This reaction may be carried out at 0 to 200 ° C., preferably 0 to 50 ° C., for 30 minutes to 48 hours.

(13-2) The compound of general formula [3] can be produced by reacting the compound of general formula [33] with sulfonyl chlorides and then hydrating.
This reaction may be carried out according to the method described in Heterocycles, Vol. 32, pp. 159-1586, 1991 and Heterocycles, Vol. 34, pp. 1055-1063, 1992 or the like What is necessary is just to carry out by the method according to it.
The solvent used with water in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aromatic carbonization such as benzene, toluene and xylene. Examples thereof include hydrogens; sulfoxides such as dimethyl sulfoxide; nitriles such as acetonitrile. These may be used as a mixture.
Examples of sulfonyl chlorides used in this reaction include p-toluenesulfonyl chloride and benzenesulfonyl chloride.
In this reaction, the amount of sulfonyl chloride used may be 1 to 10 times mol of the compound of the general formula [33].
This reaction may be carried out at 0 to 200 ° C., preferably 0 to 50 ° C., for 30 minutes to 48 hours.

  The compound of the general formula [1] of the present invention can also be produced by the production method shown below.

「式中、Ｙ^１ｃは、環内または置換基の一つの炭素原子がオキソ基で置換されている、置換されていてもよい２価の脂環式炭化水素残基、または、環内または置換基の一つの炭素原子がオキソ基で置換されている、置換されていてもよい２価の脂環式環状アミン残基を；Ｒ^１、Ｘ^１、Ｘ^２、Ｘ^３ａ、Ｘ^４、Ｘ^５、Ｙ^１、Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、前記と同様の意味を有する。」 [Production Method 14]

"In the formula, Y ^1c is an optionally substituted divalent alicyclic hydrocarbon residue in which one carbon atom of the substituent is substituted with an oxo group, or in the ring or substituted. An optionally substituted divalent alicyclic amine residue in which one carbon atom of the group is substituted with an oxo group; R ¹ , X ¹ , X ² , X ^3a , X ⁴ , X ⁵ , Y ¹ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ have the same meaning as described above.

As a compound of the general formula [6a], for example, 1- (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-yl) methanamine and the like are known.
The compound of the general formula [1f] can be produced by reacting the compound of the general formula [5b] with the compound of the general formula [6a] in the presence of a reducing agent. This reaction may be performed according to Production Method 1.

  Next, the compounds of general formula [1], the compounds of general formula [2] and the compounds of general formula [5], [7] and [14] which are raw materials for the production of the compound of general formula [3] The manufacturing method of will be described. These compounds are produced by combining methods known per se, and can be produced, for example, by the production methods shown below.

「式中、Ｒ^１６、Ｒ^１７、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、前記と同様の意味を有する。」 [Production method A]

“Wherein R ¹⁶ , R ¹⁷ , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ have the same meaning as described above.

  Examples of the compound of the general formula [16a] include 3-amino-2-chloro-5-methoxypyridine and 3-amino-2-chloro-5-methoxypyrazine.

  (A-1) The compound of the general formula [17a] is produced by reacting the compound of the general formula [16a] with the compound of the general formula [12] in the presence of a catalyst, in the presence or absence of a base. be able to. This reaction may be performed according to the production method 9-1.

  (A-2) The compound of the general formula [3d] can be produced by ring-closing the compound of the general formula [17a] in the presence or absence of a base. This reaction may be performed according to production method 9-2.

「式中、Ｒ^７ｆ、Ｒ^１８、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、前記と同様の意味を有する。」 [Production method B]

“Wherein R ^7f , R ¹⁸ , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ have the same meaning as described above.

  The compound of the general formula [3e] can be produced by reacting the compound of the general formula [18a] with the compound of the general formula [15]. This reaction may be performed according to the production method 10-1.

「式中、Ｒ^１９は、イミノ保護基を；Ｌ^４は、脱離基を；Ｘ^１、Ｘ^２、Ｙ^１ｂ、Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、前記と同様の意味を有する。」 [Production Method C]

“Wherein R ¹⁹ is an imino protecting group; L ⁴ is a leaving group; X ¹ , X ² , Y ^1b , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ are It has the same meaning as above. "

  As a compound of general formula [19], for example, 1-tert-butyl = 4-ethyl = 4- (2- (methanesulfonyloxy) ethyl) -1,4-piperidinedicarboxylate is known.

(C-1) The compound of the general formula [20] can be produced by reacting the compound of the general formula [3a] with the compound of the general formula [19] in the presence or absence of a base. This reaction may be performed according to the production method 7.

(C-2) The compound of the general formula [5] can be produced by deprotecting the compound of the general formula [20]. This reaction is described, for example, in Protective Groups in Organic Synthesis, 3rd edition, pages 494-653, 1999, John Wiley & Sons, INC.), Etc., or a method similar thereto.

「式中、Ｒ^２０は、イミノ保護基を；Ｌ^５は、脱離基を；Ｘ^１、Ｘ^２、Ｘ^３ａ、Ｙ^１、Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、前記と同様の意味を有する。」 [Production Method D]

“Wherein R ²⁰ is an imino protecting group; L ⁵ is a leaving group; X ¹ , X ² , X ^3a , Y ¹ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ has the same meaning as above. "

  Examples of the compound of the general formula [21] include tert-butyl = ((1- (2-chloroacetyl) -4- (3- (trifluoromethyl) phenyl) -4-piperidyl) methyl) (methyl) carbamate It has been known.

(D-1) The compound of the general formula [22] can be produced by reacting the compound of the general formula [3a] with the compound of the general formula [21] in the presence or absence of a base. This reaction may be performed according to the production method 7.

(D-2) The compound of the general formula [7] can be produced by deprotecting the compound of the general formula [22]. This reaction may be performed according to the production method C-2.

「式中、Ｒ^２１は、イミノ保護基を；Ｙ^１ｃは、環内の二つの窒素原子がそれぞれ互いの隣接基と結合する置換されていてもよい２価の脂環式環状アミン残基を；Ｘ^１ａ、Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、前記と同様の意味を有する。」 [Production Method E]

“Wherein R ²¹ represents an imino protecting group; Y ^1c represents an ^optionally substituted divalent alicyclic cyclic amine residue in which two nitrogen atoms in the ring are respectively bonded to adjacent groups. X ^1a , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ have the same meaning as described above.

  Examples of the compound of the general formula [23] include 1- (tert-butoxycarbonyl) piperazine and methyl = 4- (tert-butoxycarbonyl) piperazine-2-carboxylate.

(E-1) The compound of general formula [20a] can be produced by reacting the compound of general formula [2a] with the compound of general formula [23] in the presence of a reducing agent. This reaction may be carried out according to production method 1.

(E-2) The compound of the general formula [5a] can be produced by deprotecting the compound of the general formula [20a]. This reaction may be performed according to the production method C-2.

「式中、Ｒ^２２は、イミノ保護基を；Ｘ^１ａ、Ｘ^３ａ、Ｙ^１ａ、Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、前記と同様の意味を有する。」 [Production Method F]

“Wherein R ²² represents an imino protecting group; X ^1a , X ^3a , Y ^1a , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ have the same meaning as described above.

  Examples of the compound of the general formula [24] include 4-((benzyloxycarbonyl) amino) -4-methylpiperidine.

(F-1) The compound of the general formula [22a] can be produced by reacting the compound of the general formula [2a] with the compound of the general formula [24] in the presence of a reducing agent. This reaction may be carried out according to production method 1.

(F-2) The compound of the general formula [7a] can be produced by deprotecting the compound of the general formula [22a]. This reaction may be performed according to the production method C-2.

「式中、Ｒ^２３は、イミノ保護基を；Ｒ^１、Ｘ^４、Ｘ^５およびＹ^１ｃは、前記と同様の意味を有する。」 [Production method G]

“Wherein R ²³ represents an imino protecting group; R ¹ , X ⁴ , X ⁵ and Y ^1c have the same meaning as described above.

(G-1) The compound of general formula [26] can be produced by reacting the compound of general formula [25] with the compound of general formula [6] in the presence of a reducing agent. This reaction may be carried out according to production method 1.

(G-2) The compound of the general formula [4c] can be produced by deprotecting the compound of the general formula [26]. This reaction may be performed according to the production method C-2.

「式中、Ｒ^２４は、イミノ保護基を；Ｒ^１、Ｘ^３ａ、Ｘ^４、Ｘ^５およびＹ^１ａは、前記と同様の意味を有する。」 [Production Method H]

“Wherein R ²⁴ represents an imino protecting group; R ¹ , X ^3a , X ⁴ , X ⁵ and Y ^1a have the same meaning as described above.

(H-1) The compound of the general formula [28] can be produced by reacting the compound of the general formula [27] with the compound of the general formula [6] in the presence of a reducing agent. This reaction may be carried out according to production method 1.

(H-2) The compound of the general formula [4d] can be produced by deprotecting the compound of the general formula [28]. This reaction may be performed according to the production method C-2.

「式中、Ｙ^２ａ、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、前記と同様の意味を有する。」 [Production Method I]

“Wherein Y ^2a , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ have the same meaning as described above.

Examples of the compound of the general formula [29] include 3-nitropyridin-2-amine and 3-amino-2-nitropyridine.
Examples of the compound of the general formula [30] include 2,2-dimethoxyacetaldehyde and 2,2-diethoxyacetaldehyde.

(I-1) The compound of general formula [31] can be produced by reacting the compound of general formula [29] with the compound of general formula [30] in the presence of a reducing agent. This reaction may be carried out according to production method 1.

(I-2) The compound of the general formula [14a] can be produced by reducing the compound of the general formula [31]. This reaction is described in Richard C. Larock, Comprehensive Organic Transformations, pages 411-415, 1989, VCH Publishers, INC. ) Etc., or a method according to it.

「式中、Ｘ^１ｂは、置換されていてもよいメチレンもしくはエチレン基または結合手を；Ｒ^１７、Ｘ^１ａ、Ｙ^２ａ、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、前記と同様の意味を有する。」 [Production Method J]

“Wherein, X ^1b represents an optionally substituted methylene or ethylene group or a bond; R ¹⁷ , X ^1a , Y ^2a , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ have the same meanings as described above. Have. "

  The compound of the general formula [13] can be produced by reacting the compound of the general formula [17a] with the compound of the general formula [30b] in the presence of a reducing agent. This reaction may be carried out according to production method 1.

「式中、Ｙ^１ｄは、環内もしくは置換基の一つの炭素原子が保護されたカルボニル基である、置換されていてもよい２価の脂環式炭化水素残基、または、環内もしくは置換基の一つの炭素原子が保護されたカルボニル基である、置換されていてもよい２価の脂環式環状アミン残基を；Ｒ^１７、Ｘ^１、Ｘ^１ａ、Ｘ^２、Ｙ^１ｃ、Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、前記と同様の意味を有する。」 [Production method K]

“In the formula, Y ^1d is an optionally substituted divalent alicyclic hydrocarbon residue in which one carbon atom in the ring or a substituent is protected carbonyl group, or in the ring or a substituent An optionally substituted divalent alicyclic amine residue in which one carbon atom of the group is a protected carbonyl group; R ¹⁷ , X ¹ , X ^1a , X ² , Y ^1c , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ have the same meaning as described above.

(K-1) The compound of the general formula [13b] can be produced by reacting the compound of the general formula [17b] with the compound of the general formula [30a] in the presence of a reducing agent. This reaction may be carried out according to production method 1.

(K-2) The compound of the general formula [5c] can be produced by ring-closing the compound of the general formula [13b] in the presence or absence of a base. This reaction may be performed according to production method 9-2.

(K-3) The compound of the general formula [5b] can be produced by deprotecting the compound of the general formula [5c] in the presence or absence of a base. This reaction may be performed according to the production method 8-2.

The compounds obtained by production methods 1 to 14 and production methods A to K are subjected to reactions known per se such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis, for example. Alternatively, other compounds can be induced by appropriately combining these reactions.
When imino, amino, hydroxyl and carboxyl groups are present in the compounds obtained by Production Methods 1 to 14 and Production Methods A to K and intermediates thereof, the reaction can be carried out by appropriately combining those protecting groups. .
In production methods 1 to 14 and production methods A to K, when a compound having a carbonyl group is used in the reaction, a compound in which the carbonyl group is protected can be used instead of the compound having a carbonyl group.

  When the compound of the general formula [1] is used as a medicine, formulation adjuvants such as excipients, carriers and diluents usually used for formulation may be appropriately mixed. These are tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powder formulations, suppositories, eye drops, nasal drops, ear drops, It can be administered orally or parenterally in the form of a patch, ointment or injection. In addition, the administration method, the dosage, and the number of administrations can be appropriately selected according to the age, weight and symptoms of the patient. In general, for adults, oral administration or parenteral administration (for example, injection, infusion, administration to the rectal site, etc.), 0.01 to 1000 mg / kg can be divided into 1 to several times a day. Good.

Antibacterial agents of the present invention include grapes such as Staphylococcus epidermidis, rot staphylococci, Staphylococcus aureus, methicillin resistant Staphylococcus aureus (MRSA), vancomycin resistant Staphylococcus aureus, quinolone resistant Staphylococcus aureus and multidrug resistant Staphylococcus aureus. Streptococcus; green streptococci, group A β-hemolytic streptococci, group B β-hemolytic streptococci, pneumococci, penicillin-resistant pneumococci and multidrug-resistant pneumococci; Enterococcus faecalis, Enterococcus faecium, Enterococcus, such as vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium; Escherichia coli; Haemophilus influenzae; Moraxella catarrhalis; Neisseria gonorrhoeae; Acne; Clostridium perfringens; Fraziris: Bacillus gingivalis; Prebotella intermedia; It has an excellent antibacterial action against bacterial species such as S. nucleatum; Legionella pneumophila and Mycoplasma pneumonia.
The antibacterial agent of the present invention has a further excellent antibacterial action against bacterial species such as Staphylococcus, Streptococcus, Enterococcus, Haemophilus influenzae, Moraxella catarrhalis, Legionella pneumophila or Mycoplasma pneumoniae, More excellent antibacterial action against bacterial species such as Genus or Enterococcus.
The antibacterial agent of the present invention exhibits a particularly excellent antibacterial effect for pneumococci, penicillin-resistant pneumococci, multi-drug resistant pneumococci, enterococcus faecalis, enterococcus faecium, vancomycin-resistant enterococcus faecalis or vancomycin-resistant enterococcus faecium, It exhibits the most excellent antibacterial action for resistant bacteria such as penicillin-resistant pneumococci, multidrug-resistant pneumococci, vancomycin-resistant Enterococcus faecalis or vancomycin-resistant Enterococcus faecium.

The compounds described in the present invention exhibit excellent safety. Safety is assessed by various tests, including, for example, cytotoxicity tests, selectivity tests for human and bacterial DNA gyrase, selectivity tests for human and bacterial topoisomerase IV, hERG tests, repeated dose toxicity It can be evaluated by various safety tests selected from a test, cytochrome P450 (CYP) activity inhibition test, metabolism-dependent inhibition test, in vivo mouse micronucleus test, in vivo rat liver UDS test, etc. it can.
The compounds of the present invention exhibit excellent metabolic stability. Metabolic stability is evaluated by various tests, and can be evaluated by various stability tests selected from, for example, a human liver microsome metabolic stability test and a human S9 stability test.

Furthermore, antibacterial activity and safety of the compound represented by the general formula [1] against various bacterial species will be described in the following test examples.
In each test example, each abbreviation has the following meaning.
DMSO: Dimethyl sulfoxide
MHA: Mueller-Hinton agar
BHIA: Brain Heart Infusion Agar
BHIB: Brain Heart Infusion Medium
CAMHB: Cation-adjusted Mueller-Hinton broth
Modified GAMB: Modified gum medium Modified GAMA: Modified gum agar The MIC in the susceptibility test was the lowest test substance concentration at which no bacterial growth was observed macroscopically.

Test Example 1 Staphylococcus aureus susceptibility test A test substance was dissolved in DMSO, and antibacterial activity (MIC) was measured by a micro liquid dilution method recommended by the Japanese Society of Chemotherapy.
The bacterium used was Staphylococcus aureus (S. aureus FDA209P (sensitive) and F-3095 (multidrug resistant)). MHA was suspended in sterilized physiological saline so as to be equivalent to 0.5 McFarland. This suspension was diluted 10 times to obtain an inoculum solution. CAMHB (100 μL / well) containing the test substance was inoculated with about 0.005 mL of the inoculum and cultured at 35 ° C. overnight. The results are shown in Table 1.

Test Example 2 Staphylococcus aureus Infection Experiment As mice, ICR male SPF mice (4 weeks old: 5 mice per group) were used. The inoculum was prepared by suspending Staphylococcus aureus Smith (S. aureus Smith) cultured overnight on a MHA plate at 37 ° C in a sterile physiological saline solution to prepare a bacterial solution of about 4 x 10 ⁸ CFU / mL. Prepared by diluting 10-fold with 5.6% mucin / phosphate buffer. Infection was caused by inoculating 0.5 mL (about 2 × 10 ⁷ CFU / mouse) of the inoculum into the abdominal cavity of mice. The test substance was dissolved in 10% hydroxypropyl-β-cyclodextrin and 0.05 mol / L hydrochloric acid, and 3 mg / kg was subcutaneously administered once 1 hour after infection. The number of surviving animals was recorded 5 days after infection.
As a result, all of the control groups not administered with the test substance died, but all of the administration groups of Example Nos. 2, 4, 68, 77, 93, 103, 119B, 140, 149 and 151 survived. Similarly, the compound of Example 85 was administered at 1 mg / kg. As a result, 4 out of 5 cases survived.

Test Example 3 VRE sensitivity test 1
The test substance was dissolved in sterilized distilled water or DMSO, and antibacterial activity (MIC) was measured according to the micro liquid dilution method recommended by the Japanese Society of Chemotherapy.
The bacterium used was Enterococcus faecalis D-2648. The cells cultured overnight on the MHA plate were suspended in sterilized physiological saline so as to be equivalent to 0.5 McFarland. This suspension was diluted 10 times to obtain an inoculum solution. CAMHB (100 μL / well) containing the test substance was inoculated with about 0.005 mL of the inoculum and cultured at 35 ° C. overnight.
As a result, the MICs of the compounds of Example Nos. 2, 4, 77 and 85 were 0.125, 0.25, 0.25 and 0.25 μg / mL, respectively.

Test Example 4 VRE sensitivity test 2
The test substance was dissolved in sterilized distilled water or DMSO, and antibacterial activity (MIC) was measured according to the micro liquid dilution method recommended by the Japanese Society of Chemotherapy.
The bacterium used was Enterococcus faecium EF-211. The cells cultured overnight on the MHA plate were suspended in sterilized physiological saline so as to be equivalent to 0.5 McFarland. This suspension was diluted 10 times to obtain an inoculum solution. CAMHB (100 μL / well) containing the test substance was inoculated with about 0.005 mL of the inoculum and cultured at 35 ° C. overnight.
As a result, the MICs of the compounds of Examples 2 and 4 were 0.125 and 0.25 μg / mL, respectively.

Test Example 5 Moraxella catarrhalsis susceptibility test The test substance was dissolved in sterilized distilled water or DMSO, and antibacterial activity (MIC) was measured according to a micro liquid dilution method recommended by the Japanese Society of Chemotherapy.
As the bacterium, Moraxella catarrhalis ATCC25238 was used. Bacteria cultured overnight on MHA plates supplemented with sheep defibrinated blood were suspended in sterile physiological saline so as to be equivalent to 0.5 McFarland. This suspension was diluted 10 times to obtain an inoculum solution. About 0.005 mL of the inoculum was inoculated into CAMHB (100 μL / well) to which horse hemolyzed blood containing the test substance was added, and cultured overnight at 35 ° C.
As a result, the MICs of the compounds of Example Nos. 2 and 4 were 0.0625 and 0.0625 μg / mL, respectively.

Test Example 6 Pneumococcal Susceptibility Test The test substance was dissolved in sterilized distilled water or DMSO, and antibacterial activity (MIC) was measured according to a micro liquid dilution method recommended by the Japanese Chemotherapy Society.
As the bacterium, Streptococcus pneumoniae IID553 was used. Bacteria cultured overnight on MHA plates supplemented with sheep defibrinated blood were suspended in sterile physiological saline so as to be equivalent to 0.5 McFarland. This suspension was diluted 10 times to obtain an inoculum solution. About 0.005 mL of the inoculum was inoculated into CAMHB (100 μL / well) to which horse hemolyzed blood containing the test substance was added, and cultured overnight at 35 ° C.
As a result, the MICs of the compounds of Examples 2, 4, 77, and 85 were 0.0313, 0.0625, 0.0625, and 0.0313 μg / mL, respectively.

Test Example 7 PRSP Susceptibility Test The test substance was dissolved in sterilized distilled water or DMSO, and antibacterial activity (MIC) was measured according to a micro liquid dilution method recommended by the Japanese Society of Chemotherapy.
Penicillin resistant Streptococcus pneumoniae (Streptococcus pneumoniae D-1687) was used as the bacterium. Bacteria cultured overnight on MHA plates supplemented with sheep defibrinated blood were suspended in sterile physiological saline so as to be equivalent to 0.5 McFarland. This suspension was diluted 10 times to obtain an inoculum solution. About 0.005 mL of the inoculum was inoculated into CAMHB (100 μL / well) to which horse hemolyzed blood containing the test substance was added, and cultured overnight at 35 ° C.
As a result, the MICs of the compounds of Examples 2, 4, 77, and 85 were 0.0313, 0.0625, 0.0313, and 0.0313 μg / mL, respectively.

Test Example 8 Haemophilus influenzae susceptibility test (1) A test substance was dissolved in sterilized distilled water or DMSO, and antibacterial activity (MIC) was measured according to a micro liquid dilution method recommended by the Japanese Chemotherapy Society.
As the bacterium, Haemophilus influenzae ATCC49247 was used. The cells cultured overnight on the MHA plate to which enrichment was added were suspended in sterile physiological saline so as to be equivalent to 0.5 McFarland. This suspension was diluted 10 times to obtain an inoculum solution. About 0.005 mL of the inoculum was inoculated into HTM (100 μL / well) containing the test substance and cultured at 35 ° C. overnight.
As a result, the MICs of the compounds of Examples 2 and 4 were 0.5 and 0.5 μg / mL, respectively.
(2) The test substance was dissolved in DMSO, and antibacterial activity (MIC) was measured according to the micro liquid dilution method recommended by the Japanese Society of Chemotherapy.
As the bacterium, Haemophilus influenzae ATCC49766 was used. The cells cultured overnight on the MHA plate to which enrichment was added were suspended in sterile physiological saline so as to be equivalent to 0.5 McFarland. This suspension was diluted 10 times to obtain an inoculum solution. About 0.005 mL of the inoculum was inoculated into HTM (100 μL / well) containing the test substance and cultured at 35 ° C. overnight.
As a result, the MICs of the compounds of Examples 77 and 85 were 0.5 and 0.25 μg / mL, respectively.

Test Example 9 Neisseria gonorrhoeae susceptibility test The test substance was dissolved in sterilized distilled water or DMSO, and antibacterial activity (MIC) was measured according to a micro liquid dilution method recommended by the Japanese Society of Chemotherapy.
As a bacterium, Neisseria gonorrhoeae ATCC19424 was used. The cells cultured overnight on a chocolate BHIA plate were suspended in sterile physiological saline so as to be equivalent to 0.5 McFarland. This suspension was diluted 10 times to obtain an inoculum solution. About 0.005 mL of the inoculum was inoculated into cation-adjusted BHIB medium (100 μL / well) supplemented with horse hemolyzed blood containing the test substance, and cultured overnight at 35 ° C. in a CO ₂ incubator.
As a result, the MICs of the compounds of Examples 2 and 4 were 0.0625 and 0.0625 μg / mL, respectively.

Test Example 10 Acne Bacterial Susceptibility Test The test substance was dissolved in sterilized distilled water or DMSO, and antibacterial activity (MIC) was measured according to a micro liquid dilution method recommended by the Japanese Society of Chemotherapy.
Bacteria used were Acne bacteria (Propionibacterium acnes JCM6425). The cells cultured overnight on the modified GAMA plate were suspended in sterilized physiological saline so as to correspond to 0.5 McFarland. This suspension was diluted 10 times to obtain an inoculum solution. Modified GAMB (100 μL / well) containing the test substance was inoculated with about 0.005 mL of the inoculum and cultured at 35 ° C. for 2 days using an anaerobic jar.
As a result, the MICs of the compounds of Examples 2 and 4 were 0.0078 μg / mL or less and 0.0156 μg / mL, respectively.

Test Example 11 Clostridium perfringens susceptibility test The test substance was dissolved in sterilized distilled water or DMSO, and antibacterial activity (MIC) was measured according to a micro liquid dilution method recommended by the Japanese Society of Chemotherapy.
As bacteria, Clostridium perfringens ATCC13124 was used. The cells cultured overnight on the modified GAMA plate were suspended in sterilized physiological saline so as to correspond to 0.5 McFarland. This suspension was diluted 10 times to obtain an inoculum solution. Modified GAMB (100 μL / well) containing the test substance was inoculated with about 0.005 mL of the inoculum and cultured at 35 ° C. for 2 days using an anaerobic jar.
As a result, the MICs of the compounds of Examples 2 and 4 were 0.125 and 0.125 μg / mL, respectively.

Test Example 12 Fragilis Susceptibility Test The test substance was dissolved in sterilized distilled water or DMSO, and antibacterial activity (MIC) was measured according to a micro liquid dilution method recommended by the Japanese Chemotherapy Society.
The bacterium used was Bacteroides fragilis ATCC25285. The cells cultured overnight on the modified GAMA plate were suspended in sterilized physiological saline so as to correspond to 0.5 McFarland. This suspension was diluted 10 times to obtain an inoculum solution. Modified GAMB (100 μL / well) containing the test substance was inoculated with about 0.005 mL of the inoculum and cultured at 35 ° C. for 2 days using an anaerobic jar.
As a result, the MICs of the compounds of Examples 2 and 4 were 0.0078 μg / mL or less and 0.0313 μg / mL, respectively.

Test Example 13 Susceptibility test for Gingivalis The test substance was dissolved in sterilized distilled water or DMSO, and antibacterial activity (MIC) was measured according to a micro liquid dilution method recommended by the Japanese Chemotherapy Society.
As the bacterium, Gingivalis bacterium (Porphyromonas gingivalis JCM8525) was used. The cells cultured overnight on the modified GAMA plate were suspended in sterilized physiological saline so as to correspond to 0.5 McFarland. This suspension was diluted 10 times to obtain an inoculum solution. A modified GAMB (100 μL / well) containing a test substance was inoculated with about 0.005 mL of the inoculum and cultured at 35 ° C. for 2 days using an anaerobic jar.
As a result, the MICs of the compounds of Examples 2 and 4 were 0.5 and 0.5 μg / mL, respectively.

Test Example 14 Prevotella intermedia susceptibility test The test substance was dissolved in sterilized distilled water or DMSO, and antibacterial activity (MIC) was measured according to a micro liquid dilution method recommended by the Japanese Society of Chemotherapy.
As bacteria, Prevotella intermadia JCM7365 was used. The cells cultured overnight on the modified GAMA plate were suspended in sterile physiological saline so as to be equivalent to 0.5 McFarland. This suspension was diluted 10 times to obtain an inoculum solution. Modified GAMB (100 μL / well) containing the test substance was inoculated with about 0.005 mL of the inoculum and cultured at 35 ° C. for 2 days using an anaerobic jar.
As a result, the MICs of the compounds of Examples 2 and 4 were 0.0078 μg / mL or less and 0.0156 μg / mL, respectively.

Test Example 15 Fusobacterium nucleatum sensitivity test The test substance was dissolved in sterilized distilled water or DMSO, and antibacterial activity (MIC) was measured according to a micro liquid dilution method recommended by the Japanese Society of Chemotherapy.
As the bacterium, Fusobacterium nucleatum JCM8532 was used. The cells cultured overnight on the modified GAMA plate were suspended in sterilized physiological saline so as to correspond to 0.5 McFarland. This suspension was diluted 10 times to obtain an inoculum solution. Modified GAMB (100 μL / well) containing the test substance was inoculated with about 0.005 mL of the inoculum and cultured at 35 ° C. for 2 days using an anaerobic jar.
As a result, the MICs of the compounds of Examples 2 and 4 were 0.0156 and 0.125 μg / mL, respectively.

Test Example 16 Legionella Susceptibility Test (1) The test substance was dissolved in sterilized distilled water and antibacterial activity (MIC) was measured.
As the bacterium, Legionella pneumophilia ATCC33152 was used. The cells cultured overnight on a Legionella agarbase plate to which enrichment was added were suspended in sterile physiological saline so as to be equivalent to 0.5 McFarland. This suspension was diluted 10 times to obtain an inoculum solution. BSYE broth (100 μL / well) to which enrichment containing the test substance was added was inoculated with about 0.005 mL of the inoculum and cultured at 35 ° C. for 3 days.
As a result, the MIC of the compound of Example 4 was 0.25 μg / mL.
(2) The test substance was dissolved in DMSO, and antibacterial activity (MIC) was measured according to the micro liquid dilution method recommended by the Japanese Society of Chemotherapy.
As the bacterium, Legionella pneumophilia ATCC33153 was used. The cells cultured overnight on a Legionella agarbase plate to which enrichment was added were suspended in sterile physiological saline so as to be equivalent to 0.5 McFarland. This suspension was diluted 10 times to obtain an inoculum solution. BSYE broth (100 μL / well) to which enrichment containing the test substance was added was inoculated with about 0.005 mL of the inoculum and cultured at 35 ° C. for 3 days.
As a result, the MIC of the compound of Example 2 was 0.0625 μg / mL.

Test Example 17 Pneumonia Mycoplasma Susceptibility Test The test substance is dissolved in sterilized distilled water or DMSO, and "Mycoplasma and its experimental method" (Satoshi Susui, Takamasa Shimizu, Takashi Yamamoto, 1st edition, Modern Publishing Co., Ltd., 1988) On July 1, antibacterial activity (MIC) was measured according to p.441-448).
As a bacterium, Mycoplasma pneumoniae ATCC15531 was used. Cells cultured for 9 days at 37 ° C. in a CO ₂ incubator using PPLO Broth supplemented with supplements were used as a preculture solution. This preculture was used as an inoculum. About 0.005 mL of the inoculum was inoculated into PPLO Broth (100 μL / well) supplemented with a test substance-containing supplement, and cultured at 37 ° C. for 5 days in a CO ₂ incubator.
As a result, the MICs of the compounds of Examples 2 and 4 were 0.0313 and 0.125 μg / mL, respectively.

Test Example 18 Cytotoxicity Test A test substance was dissolved in dimethyl sulfoxide, adjusted to various concentrations using E'MEM supplemented with 10% FBS, and then dispensed in 0.1 mL to each well of a 96-well microplate. The Vero cell suspension was prepared to 3 × 10 ⁴ cells / mL with E′MEM supplemented with 10% FBS, 0.1 mL was seeded in each well, and cultured at 37 ° C. with 5% CO ₂ for 3 days. 1 mg / mL 2,3-bis- (2-methoxy-4-nitro-5-sulfophenyl) -5-[(phenylamino) carbonyl] -2H-tetrazolium = inner salt = monosodium salt (XTT) at the end of the culture E′MEM supplemented with 25 μM phenazine = methosulphate (PMS) was prepared, and 50 μL was added to each well. About 2 hours later, the absorbance at 450 nm was measured using a microplate reader.
The absorbance ratio of the test substance-free control and each well was calculated, and the concentration of the compound that inhibits cell growth by 50% (CC ₅₀ ; μg / mL) was calculated.
As a result, the CC ₅₀ values of the compounds of Example Nos. 2, 4, 8, 10, 30, 33, 35, 55, 68, 77, 79, 80, 85, 90, 93, 95, 96 and 103 are all 51.2. It was more than μg / mL.

From the above test examples, the compounds described in the present invention exhibited excellent antibacterial activity against various bacterial species and had excellent safety.
Next, the present invention will be described with reference examples and examples, but the present invention is not limited thereto.

Unless otherwise specified, the carrier in silica gel column chromatography is Fuji Silysia Chemical Ltd., B.I. W. Silica gel, BW-127ZH; the carrier in basic silica gel column chromatography is Fuji Silysia Chemical Co., Ltd., silica gel, FL100D; the carrier in reverse phase silica gel column chromatography is YMC, Inc., ODS-AM120-S50.
Flash column chromatography was performed by Yamazen Corporation, medium pressure liquid chromatograph, YFLC-Wprep2XY. N. Unless otherwise specified, the silica gel column is Yamazen Corporation, High Flash Column, W001, W002, W003 or W004; the basic silica gel column is Yamazen Corporation, High Flash Column, W091, W092 or W093.
The mixing ratio in the eluent is a volume ratio.

In each example, each abbreviation has the following meaning.
Ac; acetyl, Boc: tert-butoxycarbonyl, Bu; butyl, Et: ethyl, Me: methyl, MOM; methoxymethyl, Tf; trifluoromethylsulfonyl, THP; tetrahydro-2H-pyran-2-yl, Z; benzyl Oxycarbonyl,
DMSO-d ₆ : heavy dimethyl sulfoxide

２−クロロ−５−メトキシピリジン−３−アミン1.0gにエチル＝アクリラート0.82mL、トリエチルアミン4.2mLおよびビス（トリ−ｔｅｒｔ−ブチルホスフィン）パラジウム（０）0.16gを加え、封管中、外温150〜160℃で6時間攪拌した。反応混合物を室温まで冷却し、減圧下で溶媒を留去した。得られた残留物をフラッシュ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＝１００：０−９０：１０］で精製し、淡褐色固体のエチル＝（２Ｅ）−３−（３−アミノ−５−メトキシピリジン−２−イル）アクリラート0.41gおよび７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン0.25gを得た。
エチル＝（２Ｅ）−３−（３−アミノ−５−メトキシピリジン−２−イル）アクリラート
¹H-NMR(CDCl₃)δ値：1.32(3H,t,J=7.2Hz),3.83(3H,s),3.96-4.04(2H,m),4.25(2H,q,J=7.2Hz),6.46(1H,d,J=2.7Hz),6.78(1H,d,J=15.1Hz),7.74(1H,d,J=15.1Hz),7.83(1H,d,J=2.7Hz)
７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン
¹H-NMR(DMSO-d₆)δ値：3.88(3H,s),6.54(1H,d,J=9.8Hz),7.13(1H,d,J=2.6Hz),7.86(1H,d,J=9.8Hz),8.21(1H,d,J=2.6Hz),11.78(1H,s) Reference example 1

To 1.0 g of 2-chloro-5-methoxypyridin-3-amine, 0.82 mL of ethyl acrylate, 4.2 mL of triethylamine and 0.16 g of bis (tri-tert-butylphosphine) palladium (0) were added, and the outside temperature was 150 in the sealed tube. Stir at ~ 160 ° C for 6 hours. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash silica gel column chromatography [gradient elution of chloroform: methanol = 100: 0-90: 10], and light brown solid ethyl = (2E) -3- (3-amino-5- 0.41 g of methoxypyridin-2-yl) acrylate and 0.25 g of 7-methoxy-1,5-naphthyridin-2 (1H) -one were obtained.
Ethyl = (2E) -3- (3-amino-5-methoxypyridin-2-yl) acrylate
¹ H-NMR (CDCl ₃ ) δ value: 1.32 (3H, t, J = 7.2 Hz), 3.83 (3H, s), 3.96-4.04 (2H, m), 4.25 (2H, q, J = 7.2 Hz) , 6.46 (1H, d, J = 2.7Hz), 6.78 (1H, d, J = 15.1Hz), 7.74 (1H, d, J = 15.1Hz), 7.83 (1H, d, J = 2.7Hz)
7-Methoxy-1,5-naphthyridin-2 (1H) -one
¹ H-NMR (DMSO-d ₆ ) δ values: 3.88 (3H, s), 6.54 (1H, d, J = 9.8 Hz), 7.13 (1H, d, J = 2.6 Hz), 7.86 (1H, d, J = 9.8Hz), 8.21 (1H, d, J = 2.6Hz), 11.78 (1H, s)

エチル＝（２Ｅ）−３−（３−アミノ−５−メトキシピリジン−２−イル）アクリラート0.51gのメタノール6mL溶液に室温で28％ナトリウムメトキシド／メタノール溶液0.53gを加え、加熱還流下、2時間20分間攪拌した。28％ナトリウムメトキシド／メタノール溶液0.53gを加え、加熱還流下、1時間45分間攪拌した。さらに28％ナトリウムメトキシド／メタノール溶液0.53gを加え、加熱還流下、1時間15分間攪拌した。反応混合物を室温まで冷却した後、減圧下で溶媒を留去し、得られた残留物に酢酸エチルおよび水を加え、1mol/L塩酸でpH7.2に調整した。減圧下で溶媒を留去し、固形物を濾取し、水およびジエチルエーテルで洗浄し、淡褐色固体の７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン0.25gを得た。 Reference example 2

Ethyl (2E) -3- (3-amino-5-methoxypyridin-2-yl) acrylate 0.51 g of methanol 6 mL solution was added with 28% sodium methoxide / methanol solution 0.53 g at room temperature. Stir for 20 minutes. 0.53 g of 28% sodium methoxide / methanol solution was added, and the mixture was stirred for 1 hour and 45 minutes under reflux. Furthermore, 0.53 g of 28% sodium methoxide / methanol solution was added, and the mixture was stirred for 1 hour and 15 minutes under reflux. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure, ethyl acetate and water were added to the resulting residue, and the pH was adjusted to 7.2 with 1 mol / L hydrochloric acid. The solvent was distilled off under reduced pressure, and the solid was collected by filtration and washed with water and diethyl ether to obtain 0.25 g of 7-methoxy-1,5-naphthyridin-2 (1H) -one as a light brown solid.

７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン0.23gのＮ，Ｎ−ジメチルホルムアミド3mL懸濁液に室温で60％水素化ナトリウム79mgを加え、50℃まで昇温し、15分間攪拌した。２−ブロモメチル−１，３−ジオキソラン0.41mLを加え、反応混合物を90〜100℃まで昇温し、3時間攪拌した。反応混合物を室温まで冷却し、水および酢酸エチルを加えた。有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をフラッシュ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＝１００：０−３３：６７］から［クロロホルム：メタノールの勾配溶離＝１００：０−９０：１０］で精製し、淡褐色固体の１−（１，３−ジオキソラン−２−イルメチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン0.11gを得た。
¹H-NMR(CDCl₃)δ値：3.83-4.07(4H,m),3.97(3H,s),4.50(2H,d,J=4.1Hz),5.20(1H,t,J=4.1Hz),6.77(1H,d,J=9.8Hz),7.40(1H,d,J=2.4Hz),7.86(1H,d,J=9.8Hz),8.28(1H,d,J=2.4Hz) Reference example 3

7-methoxy-1,5-naphthyridin-2 (1H) -one 0.23 g of N, N-dimethylformamide 3 mL suspension was added with 60% sodium hydride 79 mg at room temperature, and the temperature was raised to 50 ° C. for 15 minutes. Stir. 2-Bromomethyl-1,3-dioxolane (0.41 mL) was added, and the reaction mixture was heated to 90-100 ° C. and stirred for 3 hours. The reaction mixture was cooled to room temperature and water and ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash silica gel column chromatography [gradient elution of hexane: ethyl acetate = 100: 0-33: 67] to [gradient elution of chloroform: methanol = 100: 0-90: 10]. 0.11 g of 1- (1,3-dioxolan-2-ylmethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one as a brown solid was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.83 to 4.07 (4H, m), 3.97 (3H, s), 4.50 (2H, d, J = 4.1Hz), 5.20 (1H, t, J = 4.1Hz) , 6.77 (1H, d, J = 9.8Hz), 7.40 (1H, d, J = 2.4Hz), 7.86 (1H, d, J = 9.8Hz), 8.28 (1H, d, J = 2.4Hz)

１−（１，３−ジオキソラン−２−イルメチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン0.11gに80％トリフルオロ酢酸水溶液6.0mLを加え、60〜70℃で1時間攪拌した。80％トリフルオロ酢酸水溶液4.0mLを加え、60〜70℃で1時間攪拌した。反応混合物を室温まで冷却し、減圧下で溶媒を留去した。得られた残留物に酢酸エチルおよび水を加え、1mol/L水酸化ナトリウム水溶液でpH7.0に調整した。有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、淡褐色泡状物の（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド0.11gを得た。
¹H-NMR(DMSO-d₆)δ値：3.92(3H,s),5.28(2H,s),6.70(1H,d,J=9.6Hz),7.36(1H,d,J=2.4Hz),7.94(1H,d,J=9.6Hz),8.29(1H,d,J=2.4Hz),9.68(1H,s) Reference example 4

To 0.11 g of 1- (1,3-dioxolan-2-ylmethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one, 6.0 mL of an 80% aqueous trifluoroacetic acid solution was added, and the mixture was heated at 60 to 70 ° C. Stir for hours. An 80% aqueous trifluoroacetic acid solution (4.0 mL) was added, and the mixture was stirred at 60 to 70 ° C. for 1 hour. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. Ethyl acetate and water were added to the obtained residue, and the pH was adjusted to 7.0 with a 1 mol / L aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give (7-methoxy-2-oxo-1,5-naphthyridine-1 (2H)- Yl) 0.11 g of acetaldehyde was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.92 (3H, s), 5.28 (2H, s), 6.70 (1H, d, J = 9.6 Hz), 7.36 (1H, d, J = 2.4 Hz) , 7.94 (1H, d, J = 9.6Hz), 8.29 (1H, d, J = 2.4Hz), 9.68 (1H, s)

２−ブロモ−５−フルオロピリジン−３−アミン0.99gにエチル＝アクリラート0.67mL、トリエチルアミン3.5mLおよびビス（トリ−ｔｅｒｔ−ブチルホスフィン）パラジウム（０）0.13gを加え、封管中、外温145〜150℃で5時間攪拌した。反応混合物を室温まで冷却し、減圧下で溶媒を留去した。得られた残留物をフラッシュ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＝１００：０−９０：１０］で精製し、淡褐色固体のエチル＝（２Ｅ）−３−（３−アミノ−５−フルオロピリジン−２−イル）アクリラート0.37gおよび７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン0.15gを得た。
エチル＝（２Ｅ）−３−（３−アミノ−５−フルオロピリジン−２−イル）アクリラート
¹H-NMR(CDCl₃)δ値：1.33(3H,t,J=7.1Hz),4.02-4.12(2H,broad),4.27(2H,q,J=7.1Hz),6.71(1H,dd,J=9.8,2.4Hz),6.85(1H,d,J=15.1Hz),7.71(1H,d,J=15.1Hz),7.94(1H,d,J=2.4Hz)
７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン
¹H-NMR(DMSO-d₆)δ値：6.72(1H,dd,J=9.8,1.7Hz),7.47(1H,dd,J=9.6,2.5Hz),7.94(1H,d,J=9.8Hz),8.50(1H,d,J=2.5Hz),11.99(1H,s) Reference Example 5

To 0.99 g of 2-bromo-5-fluoropyridin-3-amine, 0.67 mL of ethyl acrylate, 3.5 mL of triethylamine and 0.13 g of bis (tri-tert-butylphosphine) palladium (0) were added. Stir at ˜150 ° C. for 5 hours. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash silica gel column chromatography [gradient elution of chloroform: methanol = 100: 0-90: 10], and light brown solid ethyl = (2E) -3- (3-amino-5- 0.37 g of fluoropyridin-2-yl) acrylate and 0.15 g of 7-fluoro-1,5-naphthyridin-2 (1H) -one were obtained.
Ethyl = (2E) -3- (3-amino-5-fluoropyridin-2-yl) acrylate
¹ H-NMR (CDCl ₃ ) δ value: 1.33 (3H, t, J = 7.1 Hz), 4.02-4.12 (2H, broad), 4.27 (2H, q, J = 7.1 Hz), 6.71 (1H, dd, J = 9.8,2.4Hz), 6.85 (1H, d, J = 15.1Hz), 7.71 (1H, d, J = 15.1Hz), 7.94 (1H, d, J = 2.4Hz)
7-Fluoro-1,5-naphthyridine-2 (1H) -one
¹ H-NMR (DMSO-d ₆ ) δ value: 6.72 (1H, dd, J = 9.8,1.7 Hz), 7.47 (1H, dd, J = 9.6,2.5 Hz), 7.94 (1H, d, J = 9.8 Hz), 8.50 (1H, d, J = 2.5Hz), 11.99 (1H, s)

エチル＝（２Ｅ）−３−（３−アミノ−５−フルオロピリジン−２−イル）アクリラート0.36gのメタノール3mL溶液に室温で28％ナトリウムメトキシド／メタノール溶液0.37gを加え、加熱還流下、2時間40分間攪拌した。28％ナトリウムメトキシド／メタノール溶液72mgを加え、加熱還流下、1時間攪拌した。反応混合物を室温まで冷却した後、減圧下で溶媒を留去し得られた残留物に酢酸エチルおよび水を加え、1mol/L塩酸でpH6.7に調整した。減圧下で溶媒を留去し、固形物を濾取し、水およびジエチルエーテルで洗浄し、淡褐色固体の７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン0.17gを得た。
¹H-NMR(DMSO-d₆)δ値：6.72(1H,d,J=9.8Hz),7.47(1H,dd,J=9.6,2.4Hz),7.94(1H,d,J=9.8Hz),8.50(1H,d,J=2.4Hz),11.99(1H,brs) Reference Example 6

To a solution of ethyl (2E) -3- (3-amino-5-fluoropyridin-2-yl) acrylate 0.33 g in 3 mL of methanol was added 0.37 g of a 28% sodium methoxide / methanol solution at room temperature. Stir for 40 minutes. A 28% sodium methoxide / methanol solution (72 mg) was added, and the mixture was stirred for 1 hour with heating under reflux. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, ethyl acetate and water were added to the resulting residue, and the pH was adjusted to 6.7 with 1 mol / L hydrochloric acid. The solvent was distilled off under reduced pressure, and the solid substance was collected by filtration and washed with water and diethyl ether to obtain 0.17 g of 7-fluoro-1,5-naphthyridin-2 (1H) -one as a light brown solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 6.72 (1H, d, J = 9.8Hz), 7.47 (1H, dd, J = 9.6,2.4Hz), 7.94 (1H, d, J = 9.8Hz) , 8.50 (1H, d, J = 2.4Hz), 11.99 (1H, brs)

７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン0.32gのＮ，Ｎ−ジメチルホルムアミド3mL懸濁液に室温で60％水素化ナトリウム0.12gを加え、50〜60℃で1時間攪拌した。２−ブロモメチル−１，３−ジオキソラン0.60mLを加え、85〜95℃まで昇温し、4時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび水を加え、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にクロロホルムを加え、固形物を濾去し、フラッシュ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＝１００：０−３０：７０］で精製し、淡黄色固体の１−（１，３−ジオキソラン−２−イルメチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン0.23gを得た。
¹H-NMR(CDCl₃)δ値：3.84-3.93(2H,m),3.96-4.05(2H,m),4.45(2H,d,J=4.2Hz),5.19(1H,t,J=4.2Hz),6.88(1H,d,J=9.8Hz),7.69(1H,dd,J=10.5,2.4Hz),7.90(1H,d,J=9.8Hz),8.41(1H,d,J=2.4Hz) Reference Example 7

7-Fluoro-1,5-naphthyridin-2 (1H) -one 0.12 g of 60% sodium hydride was added to a suspension of 0.32 g of N, N-dimethylformamide in 3 mL at room temperature, and the mixture was stirred at 50 to 60 ° C. for 1 hour. did. 0.60 mL of 2-bromomethyl-1,3-dioxolane was added, the temperature was raised to 85 to 95 ° C., and the mixture was stirred for 4 hours. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Chloroform was added to the obtained residue, the solid was filtered off, and purified by flash silica gel column chromatography [gradient elution of hexane: ethyl acetate = 100: 0-30: 70] to give 1- ( 0.23 g of 1,3-dioxolan-2-ylmethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.84 to 3.93 (2H, m), 3.96 to 4.05 (2H, m), 4.45 (2H, d, J = 4.2 Hz), 5.19 (1H, t, J = 4.2 Hz), 6.88 (1H, d, J = 9.8Hz), 7.69 (1H, dd, J = 10.5, 2.4Hz), 7.90 (1H, d, J = 9.8Hz), 8.41 (1H, d, J = 2.4) Hz)

１−（１，３−ジオキソラン−２−イルメチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン0.21gに80％トリフルオロ酢酸水溶液3mLを加え、室温で20分間、次いで50〜60℃で1時間攪拌した。80％トリフルオロ酢酸水溶液3mLを加え、80〜90℃で1時間45分間攪拌した後、さらに80％トリフルオロ酢酸水溶液3mLを加え、同温度で1時間攪拌した。反応混合物を室温まで冷却した後、減圧下で溶媒を留去した。得られた残留物にクロロホルムおよび水を加え、20％水酸化ナトリウム水溶液でpH7.4に調整した。有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、黄色油状物の（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド0.20gを得た。
¹H-NMR(CDCl₃)δ値：5.12(2H,s),6.93(1H,d,J=9.9Hz),7.04(1H,dd,J=9.6,2.3Hz),7.98(1H,d,J=9.9Hz),8.46(1H,d,J=2.3Hz),9.77(1H,s) Reference Example 8

To 0.21 g of 1- (1,3-dioxolan-2-ylmethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one was added 3 mL of 80% aqueous trifluoroacetic acid solution at room temperature for 20 minutes, then 50 Stir at ~ 60 ° C for 1 hour. After adding 3 mL of 80% aqueous trifluoroacetic acid and stirring at 80 to 90 ° C. for 1 hour and 45 minutes, 3 mL of 80% aqueous trifluoroacetic acid was further added and stirred at the same temperature for 1 hour. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. Chloroform and water were added to the obtained residue, and the pH was adjusted to 7.4 with a 20% aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give (7-fluoro-2-oxo-1,5-naphthyridin-1 (2H) -yl) as a yellow oil. 0.20 g of acetaldehyde was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 5.12 (2H, s), 6.93 (1H, d, J = 9.9 Hz), 7.04 (1H, dd, J = 9.6, 2.3 Hz), 7.98 (1H, d, J = 9.9Hz), 8.46 (1H, d, J = 2.3Hz), 9.77 (1H, s)

参考例２１と同様の手法により、１−ベンジル−２−メチルピペリジン−４−オン0.24gおよび１−（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イル）メタンアミン0.20gから（Ａ）無色油状物の１−ベンジル−Ｎ−（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）−２−メチルピペリジン−４−アミン0.22gおよび（Ｂ）無色油状物の１−ベンジル−Ｎ−（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）−２−メチルピペリジン−４−アミン0.13gを得た。
（Ａ）¹H-NMR(CDCl₃)δ値：1.07(3H,d,J=6.6Hz),1.40-1.85(4H,m),2.40-2.60(2H,m),2.80-3.00(2H,m),3.42(1H,d,J=13.7Hz),3.69-3.82(3H,m),4.24-4.35(4H,m),6.83(1H,s),7.18-7.36(5H,m),8.10(1H,s)
（Ｂ）¹H-NMR(CDCl₃)δ値：1.19-1.40(2H,m),1.22(3H,d,J=6.1Hz),1.76-1.84(1H,m),1.86-1.97(2H,m),2.20-2.30(1H,m),2.40-2.55(1H,m),2.75-2.85(1H,m),3.14(1H,d,J=13.5Hz),3.78(2H,s),4.07(1H,d,J=13.5Hz),4.24-4.34(4H,m),6.81(1H,s),7.20-7.40(5H,m),8.09(1H,s) Reference Example 9

In the same manner as in Reference Example 21, 1-benzyl-2-methylpiperidin-4-one 0.24 g and 1- (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-yl ) From 0.20 g of methanamine to (A) 1-benzyl-N- (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) -2-methylpiperidine-4 as a colorless oil 0.22 g of amine and (B) 1-benzyl-N- (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) -2-methylpiperidine-4 as a colorless oil -0.13 g of amine was obtained.
(A) ¹ H-NMR (CDCl ₃ ) δ value: 1.07 (3H, d, J = 6.6 Hz), 1.40-1.85 (4H, m), 2.40-2.60 (2H, m), 2.80-3.00 (2H, m), 3.42 (1H, d, J = 13.7Hz), 3.69-3.82 (3H, m), 4.24-4.35 (4H, m), 6.83 (1H, s), 7.18-7.36 (5H, m), 8.10 (1H, s)
(B) ¹ H-NMR (CDCl ₃ ) δ value: 1.19-1.40 (2H, m), 1.22 (3H, d, J = 6.1 Hz), 1.76-1.84 (1H, m), 1.86-1.97 (2H, m), 2.20-2.30 (1H, m), 2.40-2.55 (1H, m), 2.75-2.85 (1H, m), 3.14 (1H, d, J = 13.5Hz), 3.78 (2H, s), 4.07 (1H, d, J = 13.5Hz), 4.24-4.34 (4H, m), 6.81 (1H, s), 7.20-7.40 (5H, m), 8.09 (1H, s)

参考例６１と同様の手法により、１−ベンジル−Ｎ−（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）−２−メチルピペリジン−４−アミンからｔｅｒｔ−ブチル＝（１−ベンジル−２−メチルピペリジン−４−イル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.00-1.13(3H,m),1.35-1.65(12H,s),1.78-1.92(1H,m),2.48-2.60(2H,m),3.09-3.20(1H,m),3.48(1H,d,J=13.5Hz),3.59(1H,d,J=13.5Hz),4.20-4.66(7H,m),6.73(1H,s),7.20-7.30(5H,m),8.05(1H,s) Reference Example 10

In the same manner as in Reference Example 61, from 1-benzyl-N- (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) -2-methylpiperidin-4-amine tert-Butyl = (1-benzyl-2-methylpiperidin-4-yl) (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.00-1.13 (3H, m), 1.35-1.65 (12H, s), 1.78-1.92 (1H, m), 2.48-2.60 (2H, m), 3.09-3.20 (1H, m), 3.48 (1H, d, J = 13.5Hz), 3.59 (1H, d, J = 13.5Hz), 4.20-4.66 (7H, m), 6.73 (1H, s), 7.20-7.30 ( 5H, m), 8.05 (1H, s)

１，７−ナフチリジン−２（１Ｈ）−オン6.0gのＮ，Ｎ−ジメチルホルムアミド60mL懸濁液に室温で60％水素化ナトリウム2.5gを加え、50〜60℃で1時間攪拌した。２−ブロモメチル−１，３−ジオキソラン6.4mLを加え、反応混合物を90〜95℃まで昇温し、2時間30分間攪拌した。さらに95〜100℃に昇温し、4時間攪拌した。60％水素化ナトリウム0.82gおよび２−ブロモメチル−１，３−ジオキソラン2.1mLを加え、同温度でさらに2時間攪拌した。60％水素化ナトリウム0.49gおよび２−ブロモメチル−１，３−ジオキソラン1.3mLを加え、90〜100℃で2時間攪拌した。さらに60％水素化ナトリウム0.49gおよび２−ブロモメチル−１，３−ジオキソラン1.3mLを加え、同温度で4時間攪拌した。反応混合物を5℃まで冷却した後、酢酸エチルおよび氷水に加え、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をフラッシュ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＝１００：０−０：１００］続いて［クロロホルム：メタノールの勾配溶離＝１００：０−９０：１０］で精製し、褐色固体の１−（１，３−ジオキソラン−２−イルメチル）−１，７−ナフチリジン−２（１Ｈ）−オン3.1gを得た。
¹H-NMR(CDCl₃)δ値：3.85-3.94(2H,m),3.99-4.08(2H,m),4.58(2H,d,J=4.5Hz),5.29(1H,t,J=4.5Hz),6.91(1H,d,J=9.4Hz),7.41(1H,d,J=5.1Hz),7.67(1H,d,J=9.4Hz),8.45(1H,d,J=5.1Hz),9.05(1H,s) Reference Example 11

To a suspension of 6.0 g of N, N-dimethylformamide in 6.0 g of 1,7-naphthyridin-2 (1H) -one was added 2.5 g of 60% sodium hydride at room temperature, and the mixture was stirred at 50 to 60 ° C. for 1 hour. 6.4 mL of 2-bromomethyl-1,3-dioxolane was added and the reaction mixture was warmed to 90-95 ° C. and stirred for 2 hours 30 minutes. The temperature was further raised to 95 to 100 ° C., and the mixture was stirred for 4 hours. 0.82 g of 60% sodium hydride and 2.1 mL of 2-bromomethyl-1,3-dioxolane were added, and the mixture was further stirred at the same temperature for 2 hours. 0.49 g of 60% sodium hydride and 1.3 mL of 2-bromomethyl-1,3-dioxolane were added, and the mixture was stirred at 90 to 100 ° C. for 2 hours. Further, 0.49 g of 60% sodium hydride and 1.3 mL of 2-bromomethyl-1,3-dioxolane were added, and the mixture was stirred at the same temperature for 4 hours. The reaction mixture was cooled to 5 ° C., added to ethyl acetate and ice water, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by flash silica gel column chromatography [hexane: ethyl acetate gradient elution = 100: 0-0: 100] followed by [chloroform: methanol gradient elution = 100: 0-90: 10] A brown solid of 1- (1,3-dioxolan-2-ylmethyl) -1,7-naphthyridin-2 (1H) -one (3.1 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.85-3.94 (2H, m), 3.99-4.08 (2H, m), 4.58 (2H, d, J = 4.5Hz), 5.29 (1H, t, J = 4.5 Hz), 6.91 (1H, d, J = 9.4Hz), 7.41 (1H, d, J = 5.1Hz), 7.67 (1H, d, J = 9.4Hz), 8.45 (1H, d, J = 5.1Hz) , 9.05 (1H, s)

（１）１−（１，３−ジオキソラン−２−イルメチル）−１，７−ナフチリジン−２（１Ｈ）−オン3.1gに80％トリフルオロ酢酸水溶液30mLを加え、70〜80℃で2時間攪拌した。反応混合物を室温まで冷却した後、80％トリフルオロ酢酸水溶液30mLを加え、70〜80℃で3時間30分間、75〜85℃に昇温して2時間攪拌した。さらに80％トリフルオロ酢酸水溶液30mLを加え、80〜90℃で2時間30分間攪拌した。反応混合物を室温まで冷却した後、一晩放置した。減圧下で溶媒を留去し、得られた残留物にクロロホルムおよび水を加え、20％水酸化ナトリウム水溶液でpH10.4に調整した。塩化ナトリウムを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、黄色油状物の（２−オキソ−１，７−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド2.5gを得た。
（２）（２−オキソ−１，７−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド2.5gのジクロロメタン25mL溶液にｔｅｒｔ−ブチル＝（ピペリジン−４−イル）カルバマート2.6gおよび酢酸0.76mL、水素化トリアセトキシホウ素ナトリウム4.2gを加え、室温で4時間攪拌した後、一晩放置した。クロロホルムを加え、飽和炭酸水素ナトリウム水溶液および20％水酸化ナトリウム水溶液でpH9.1に調整した。有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジエチルエーテルを加え、固形物を濾取し、微黄色固体のｔｅｒｔ−ブチル＝（１−（２−（２−オキソ−１，７−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート2.8gを得た。
¹H-NMR(CDCl₃)δ値：1.35-1.51(2H,m),1.44(9H,s),1.89-1.98(2H,m),2.23-2.32(2H,m),2.67-2.74(2H,m),2.90-2.98(2H,m),3.41-3.55(1H,m),4.37-4.50(3H,m),6.89(1H,d,J=9.5Hz),7.42(1H,d,J=5.0Hz),7.65(1H,d,J=9.5Hz),8.45(1H,d,J=5.0Hz),8.89(1H,s) Reference Example 12

(1) 30 mL of 80% aqueous trifluoroacetic acid solution was added to 3.1 g of 1- (1,3-dioxolan-2-ylmethyl) -1,7-naphthyridin-2 (1H) -one, and the mixture was stirred at 70 to 80 ° C. for 2 hours. did. After cooling the reaction mixture to room temperature, 30 mL of an 80% aqueous trifluoroacetic acid solution was added, and the mixture was heated to 70 to 80 ° C. for 3 hours and 30 minutes, then to 75 to 85 ° C. and stirred for 2 hours. Furthermore, 30 mL of 80% trifluoroacetic acid aqueous solution was added, and the mixture was stirred at 80 to 90 ° C. for 2 hours 30 minutes. The reaction mixture was cooled to room temperature and then left overnight. The solvent was distilled off under reduced pressure, chloroform and water were added to the obtained residue, and the pH was adjusted to 10.4 with a 20% aqueous sodium hydroxide solution. Sodium chloride was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 2.5 g of (2-oxo-1,7-naphthyridin-1 (2H) -yl) acetaldehyde as a yellow oil was obtained. Obtained.
(2) (2-Oxo-1,7-naphthyridin-1 (2H) -yl) acetaldehyde 2.5 g in dichloromethane 25 mL solution tert-butyl = (piperidin-4-yl) carbamate 2.6 g and acetic acid 0.76 mL, hydrogenated After adding 4.2 g of sodium triacetoxyborohydride and stirring at room temperature for 4 hours, it was left overnight. Chloroform was added, and the pH was adjusted to 9.1 with a saturated aqueous sodium hydrogen carbonate solution and a 20% aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the obtained residue, and the solid substance was collected by filtration, and a slightly yellow solid tert-butyl = (1- (2- (2-oxo-1,7-naphthyridin-1 (2H) -yl) 2.8 g of ethyl) piperidin-4-yl) carbamate were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.35-1.51 (2H, m), 1.44 (9H, s), 1.89-1.98 (2H, m), 2.23-2.32 (2H, m), 2.67-2.74 (2H , m), 2.90-2.98 (2H, m), 3.41-3.55 (1H, m), 4.37-4.50 (3H, m), 6.89 (1H, d, J = 9.5Hz), 7.42 (1H, d, J = 5.0Hz), 7.65 (1H, d, J = 9.5Hz), 8.45 (1H, d, J = 5.0Hz), 8.89 (1H, s)

ｔｅｒｔ−ブチル＝（１−（２−（２−オキソ−１，７−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート2.8gのエタノール20mL溶液に室温で6.2mol/L塩化水素／エタノール溶液60mLを加え、2時間攪拌した。さらに6.2mol/L塩化水素／エタノール溶液60mLを加え、4時間攪拌した後、4日間放置した。減圧下で溶媒を留去し、得られた残留物にジエチルエーテルを加え、固形物を濾取し、黄色固体の１−（２−（４−アミノピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オン塩酸塩2.8gを得た。
¹H-NMR(D₂O)δ値：1.94-2.09(2H,m),2.36-2.45(2H,m),3.23-3.37(2H,m),3.54-3.70(3H,m),3.92-4.03(2H,m),4.81-4.87(2H,m),7.25(1H,d,J=9.6Hz),8.20(1H,d,J=9.6Hz),8.27(1H,d,J=5.9Hz),8.64(1H,d,J=5.9Hz),9.18(1H,s) Reference Example 13

tert-butyl = (1- (2- (2-oxo-1,7-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate 2.8 g in a 20 mL ethanol solution at room temperature is 6.2 mol / L 60 mL of a hydrogen chloride / ethanol solution was added and stirred for 2 hours. Further, 60 mL of a 6.2 mol / L hydrogen chloride / ethanol solution was added, stirred for 4 hours, and then allowed to stand for 4 days. The solvent was distilled off under reduced pressure, diethyl ether was added to the obtained residue, the solid was collected by filtration, and 1- (2- (4-aminopiperidin-1-yl) ethyl) -1, 2.8 g of 7-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.94.2.99 (2H, m), 2.36-2.45 (2H, m), 3.23-3.37 (2H, m), 3.54-3.70 (3H, m), 3.92 4.03 (2H, m), 4.81-4.87 (2H, m), 7.25 (1H, d, J = 9.6Hz), 8.20 (1H, d, J = 9.6Hz), 8.27 (1H, d, J = 5.9Hz) ), 8.64 (1H, d, J = 5.9Hz), 9.18 (1H, s)

１−（１，３−ジオキソラン−２−イル）メタンアミン1.1gのＮ，Ｎ−ジメチルホルムアミド10mL溶液に室温でトリエチルアミン1.6mLおよび２−クロロ−６−メトキシ−３−ニトロピリジン2.0gを加え、55〜65℃で1時間攪拌した。反応混合物を室温まで冷却し、酢酸エチルおよび水を加え、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で順次洗浄した。無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、黄色固体のＮ−（１，３−ジオキソラン−２−イルメチル）−６−メトキシ−３−ニトロピリジン−２−アミン2.7gを得た。
¹H-NMR(CDCl₃)δ値：3.90(2H,dd,J=5.6,3.5Hz),3.92-3.99(2H,m),3.97(3H,s),4.01-4.10(2H,m),5.17(1H,t,J=3.5Hz),6.07(1H,d,J=9.1Hz),8.31(1H,d,J=9.1Hz),8.76-8.85(1H,broad) Reference Example 14

To a solution of 1.1 g of 1- (1,3-dioxolan-2-yl) methanamine in 10 mL of N, N-dimethylformamide was added 1.6 mL of triethylamine and 2.0 g of 2-chloro-6-methoxy-3-nitropyridine at room temperature. Stir at ~ 65 ° C for 1 hour. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined and washed sequentially with water and saturated aqueous sodium chloride solution. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.7 g of N- (1,3-dioxolan-2-ylmethyl) -6-methoxy-3-nitropyridin-2-amine as a yellow solid. .
¹ H-NMR (CDCl ₃ ) δ value: 3.90 (2H, dd, J = 5.6, 3.5 Hz), 3.92-3.99 (2H, m), 3.97 (3H, s), 4.01-4.10 (2H, m), 5.17 (1H, t, J = 3.5Hz), 6.07 (1H, d, J = 9.1Hz), 8.31 (1H, d, J = 9.1Hz), 8.76-8.85 (1H, broad)

Ｎ−（１，３−ジオキソラン−２−イルメチル）−６−メトキシ−３−ニトロピリジン−２−アミン2.7gのエタノール30mL溶液に室温で10％パラジウム−炭素0.81gを加え、水素雰囲気下、40℃で2時間30分間攪拌した。反応混合物を室温まで冷却し、不溶物を濾去し、濾滓をジエチルエーテルで洗浄した。減圧下で溶媒を留去し、紫色固体の３−アミノ−２−（１，３−ジオキソラン−２−イルメチル）アミノ−６−メトキシピリジン2.4gを得た。
¹H-NMR(CDCl₃)δ値：2.30-2.80(2H,broad),3.62-3.76(2H,m),3.84(3H,s),3.86-4.08(4H,m),4.30-5.10(1H,broad),5.15(1H,t,J=4.4Hz),5.93(1H,d,J=7.8Hz),6.91(1H,d,J=7.8Hz) Reference Example 15

To a solution of N- (1,3-dioxolan-2-ylmethyl) -6-methoxy-3-nitropyridin-2-amine (2.7 g) in ethanol (30 mL) was added 10% palladium-carbon (0.81 g) at room temperature. The mixture was stirred at ° C for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, the insoluble material was filtered off, and the filter cake was washed with diethyl ether. The solvent was distilled off under reduced pressure to obtain 2.4 g of purple solid 3-amino-2- (1,3-dioxolan-2-ylmethyl) amino-6-methoxypyridine.
¹ H-NMR (CDCl ₃ ) δ value: 2.30-2.80 (2H, broad), 3.62-3.76 (2H, m), 3.84 (3H, s), 3.86-4.08 (4H, m), 4.30-5.10 (1H , broad), 5.15 (1H, t, J = 4.4Hz), 5.93 (1H, d, J = 7.8Hz), 6.91 (1H, d, J = 7.8Hz)

３−アミノ−２−（１，３−ジオキソラン−２−イルメチル）アミノ−６−メトキシピリジン0.20gのジオキサン2mL溶液にエチル＝オキソアセタートの45-50％トルエン溶液0.22gを加え、室温で2時間攪拌した後、一晩放置した。60％水素化ナトリウム36mgを加え、室温で30分間攪拌した。反応混合物に水および酢酸エチルを加えた。有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をフラッシュ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＝１００：０−５０：５０］で精製し、淡褐色固体の４−（１，３−ジオキソラン−２−イルメチル）−６−メトキシピリド（２，３−ｂ）ピラジン−３（４Ｈ）−オン36mgを得た。
¹H-NMR(CDCl₃)δ値：3.87-3.96(2H,m),4.04(3H,s),4.06-4.15(2H,m),4.60(2H,d,J=5.1Hz),5.57(1H,t,J=5.1Hz),6.73(1H,d,J=8.8Hz),8.01(1H,d,J=8.8Hz),8.18(1H,s) Reference Example 16

To 0.22 g of 3-amino-2- (1,3-dioxolan-2-ylmethyl) amino-6-methoxypyridine in 2 mL of dioxane was added 0.22 g of a 45-50% toluene solution of ethyl oxoacetate and stirred at room temperature for 2 hours. And then left overnight. 36 mg of 60% sodium hydride was added and stirred at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash silica gel column chromatography [hexane: ethyl acetate gradient elution = 100: 0-50: 50] to give 4- (1,3-dioxolan-2-ylmethyl)-as a light brown solid. 36 mg of 6-methoxypyrido (2,3-b) pyrazin-3 (4H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.87-3.96 (2H, m), 4.04 (3H, s), 4.06-4.15 (2H, m), 4.60 (2H, d, J = 5.1 Hz), 5.57 ( 1H, t, J = 5.1Hz), 6.73 (1H, d, J = 8.8Hz), 8.01 (1H, d, J = 8.8Hz), 8.18 (1H, s)

４−（１，３−ジオキソラン−２−イルメチル）−６−メトキシピリド（２，３−ｂ）ピラジン−３（４Ｈ）−オン0.21gに80％トリフルオロ酢酸水溶液10mLを加え、室温で5時間攪拌した後、一晩放置した。減圧下で溶媒を留去し、残渣に酢酸エチルおよび水を加え、1mol/L水酸化ナトリウム水溶液でpH7.0に調整した。有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、淡褐色泡状物の（６−メトキシ−３−オキソピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）アセトアルデヒド0.18gを得た。
¹H-NMR(CDCl₃)δ値：3.94(3H,s),5.22(2H,s),6.76(1H,d,J=8.8Hz),8.07(1H,d,J=8.8Hz),8.24(1H,s),9.70(1H,s) Reference Example 17

To 0.21 g of 4- (1,3-dioxolan-2-ylmethyl) -6-methoxypyrido (2,3-b) pyrazin-3 (4H) -one, add 10 mL of 80% aqueous trifluoroacetic acid and stir at room temperature for 5 hours. And then left overnight. The solvent was distilled off under reduced pressure, ethyl acetate and water were added to the residue, and the pH was adjusted to 7.0 with a 1 mol / L aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and a light brown foam (6-methoxy-3-oxopyrido (2,3-b) pyrazine-4 (3H 0.18 g of) -yl) acetaldehyde was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.94 (3H, s), 5.22 (2H, s), 6.76 (1H, d, J = 8.8Hz), 8.07 (1H, d, J = 8.8Hz), 8.24 (1H, s), 9.70 (1H, s)

１，８−ナフチリジン−２（１Ｈ）−オン1.2gのＮ，Ｎ−ジメチルホルムアミド溶液18mLに60％水素化ナトリウム0.36gを加え、50〜60℃で7分間攪拌した。２−ブロモメチル−１，３−ジオキソラン0.94mLを加え、95〜105℃で3時間攪拌した。反応混合物を室温まで冷却後、水および酢酸エチルを加え、有機層を分取した。水層を酢酸エチルおよびクロロホルムで、抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［溶離液；ヘキサン：酢酸エチル＝１：１］で精製し、白色固体の１−（１，３−ジオキソラン−２−イルメチル）−１，８−ナフチリジン−２（１Ｈ）−オン1.2gを得た。
¹H-NMR(CDCl₃)δ値：3.83-3.93(2H,m),3.95-4.17(2H,m),4.72(1H,d,J=5.1Hz),5.56(1H,t,J=5.1Hz),6.72(1H,d,J=9.5Hz),7.17(1H,dd,J=7.6,4.7Hz),7.64(1H,d,J=9.5Hz),7.86(1H,dd,J=7.6,1.8Hz),8.57(1H,dd,J=4.7,1.8Hz) Reference Example 18

To 18 mL of N, N-dimethylformamide solution of 1.2 g of 1,8-naphthyridin-2 (1H) -one, 0.36 g of 60% sodium hydride was added and stirred at 50 to 60 ° C. for 7 minutes. 2-Bromomethyl-1,3-dioxolane (0.94 mL) was added, and the mixture was stirred at 95 to 105 ° C. for 3 hours. The reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and chloroform. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 1: 1] to give 1- (1,3-dioxolan-2-ylmethyl) -1,8-naphthyridine- as a white solid. 1.2 g of 2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.83-3.93 (2H, m), 3.95-4.17 (2H, m), 4.72 (1H, d, J = 5.1Hz), 5.56 (1H, t, J = 5.1 Hz), 6.72 (1H, d, J = 9.5Hz), 7.17 (1H, dd, J = 7.6, 4.7Hz), 7.64 (1H, d, J = 9.5Hz), 7.86 (1H, dd, J = 7.6 , 1.8Hz), 8.57 (1H, dd, J = 4.7,1.8Hz)

１−（１，３−ジオキソラン−２−イルメチル）−１，８−ナフチリジン−２（１Ｈ）−オン1.1gに90％トリフルオロ酢酸水溶液11mLを加え、室温で2時間攪拌した。次いで、水1.1mLを加え、13時間、さらに水1.1mLを加え、3時間30分間、50〜70℃で1時間30分間攪拌した。減圧下で溶媒を留去し、得られた残留物に飽和炭酸水素ナトリウム水溶液、水およびクロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、黄色固体の（２−オキソ−１，８−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド0.75gを得た。
¹H-NMR(CDCl₃)δ値：5.36(2H,s),6.80(1H,d,J=9.5Hz),7.20(1H,dd,J=7.6,4.8Hz),7.72(1H,d,J=9.5Hz),7.91(1H,dd,J=7.6,1.8Hz),8.51(1H,dd,J=4.8,1.8Hz),9.72(1H,s) Reference Example 19

To 1.1 g of 1- (1,3-dioxolan-2-ylmethyl) -1,8-naphthyridin-2 (1H) -one was added 11 mL of 90% aqueous trifluoroacetic acid solution, and the mixture was stirred at room temperature for 2 hours. Subsequently, 1.1 mL of water was added, and further 1.1 mL of water was added for 13 hours, followed by stirring for 3 hours 30 minutes at 50 to 70 ° C. for 1 hour 30 minutes. The solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate solution, water and chloroform were added to the resulting residue, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give (2-oxo-1,8-naphthyridine-1 (2H) as a yellow solid. -Ill) 0.75 g of acetaldehyde was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 5.36 (2H, s), 6.80 (1H, d, J = 9.5 Hz), 7.20 (1H, dd, J = 7.6, 4.8 Hz), 7.72 (1H, d, J = 9.5Hz), 7.91 (1H, dd, J = 7.6,1.8Hz), 8.51 (1H, dd, J = 4.8,1.8Hz), 9.72 (1H, s)

１，６−ナフチリジン−２（１Ｈ）−オン1.0gのＮ，Ｎ−ジメチルホルムアミド10mL溶液に60％水素化ナトリウム0.30gを加え、50〜60℃で1時間攪拌し、２−ブロモメチル−１，３−ジオキソラン0.78mLを加え、反応混合物を90〜100℃で30分間攪拌した。さらに60％水素化ナトリウム0.30gおよび２−ブロモメチル−１，３−ジオキソラン0.78mLを加え、90〜108℃で5時間30分間攪拌した。室温まで冷却後、水およびクロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。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［溶離液；クロロホルム：メタノール＝１００：１］で精製し、黄色固体の１−（１，３−ジオキソラン−２−イルメチル）−１，６−ナフチリジン−２（１Ｈ）−オン0.60gを得た。
¹H-NMR(CDCl₃)δ値：3.84-3.94(2H,m),3.98-4.07(2H,m),4.48(2H,d,J=4.3Hz),5.23(1H,t,J=4.3Hz),6.75(1H,d,J=9.5Hz),7.47(1H,d,J=6.2Hz),7.78(1H,d,J=9.5Hz),8.58(1H,d,J=6.2Hz),8.76(1H,s) Reference Example 20

To a solution of 1.0 g of 1,6-naphthyridin-2 (1H) -one in 10 mL of N, N-dimethylformamide was added 0.30 g of 60% sodium hydride, and the mixture was stirred at 50 to 60 ° C. for 1 hour to give 2-bromomethyl-1, 0.78 mL of 3-dioxolane was added and the reaction mixture was stirred at 90-100 ° C. for 30 minutes. Further, 0.30 g of 60% sodium hydride and 0.78 mL of 2-bromomethyl-1,3-dioxolane were added, and the mixture was stirred at 90 to 108 ° C. for 5 hours and 30 minutes. After cooling to room temperature, water and chloroform were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 100: 1] to give 1- (1,3-dioxolan-2-ylmethyl) -1,6-naphthyridine-2 as a yellow solid. 0.60 g of (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.84-3.94 (2H, m), 3.98-4.07 (2H, m), 4.48 (2H, d, J = 4.3Hz), 5.23 (1H, t, J = 4.3 Hz), 6.75 (1H, d, J = 9.5Hz), 7.47 (1H, d, J = 6.2Hz), 7.78 (1H, d, J = 9.5Hz), 8.58 (1H, d, J = 6.2Hz) , 8.76 (1H, s)

（２−オキソ−１，8−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド0.29gの塩化メチレン溶液10mLにｔｅｒｔ−ブチル＝（ピペリジン−４−イル）カルバマート0.30gおよび酢酸87μLを加え、10分間攪拌した後、反応混合物に水素化トリアセトキシホウ素ナトリウム0.48gを加え、室温で4時間攪拌した。水、飽和炭酸水素ナトリウム水溶液およびクロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、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［溶離液；クロロホルム：メタノール＝１００：１］で精製し、淡褐色油状物のｔｅｒｔ−ブチル＝（１−（２−（２−オキソ−１，８−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.27gを得た。
¹H-NMR(CDCl₃)δ値：1.36-1.51(11H,m),1.88-1.96(2H,m),2.19-2.28(2H,m),2.66-2.72(2H,m),2.98-3.06(2H,m),3.41-3.56(1H,m),4.50-4.60(1H,m),4.65-4.70(2H,m),6.74(1H,d,J=9.5Hz),7.17(1H,dd,J=7.7,4.8Hz),7.63(1H,d,J=9.5Hz),7.86(1H,dd,J=7.7,1.8Hz),8.58(1H,dd,J=4.8,1.8Hz) Reference Example 21

To 10 mL of methylene chloride solution of 0.29 g of (2-oxo-1,8-naphthyridin-1 (2H) -yl) acetaldehyde was added 0.30 g of tert-butyl = (piperidin-4-yl) carbamate and 87 μL of acetic acid, and the mixture was stirred for 10 minutes. After that, 0.48 g of sodium triacetoxyborohydride was added to the reaction mixture and stirred at room temperature for 4 hours. Water, saturated aqueous sodium hydrogen carbonate solution and chloroform were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography [eluent; chloroform: methanol = 100: 1] and tert-butyl = (1- (2- (2-oxo-1,8-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate as a light brown oil 0.27 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.36-1.51 (11H, m), 1.88-1.96 (2H, m), 2.19-2.28 (2H, m), 2.66-2.72 (2H, m), 2.98-3.06 (2H, m), 3.41-3.56 (1H, m), 4.50-4.60 (1H, m), 4.65-4.70 (2H, m), 6.74 (1H, d, J = 9.5Hz), 7.17 (1H, dd , J = 7.7,4.8Hz), 7.63 (1H, d, J = 9.5Hz), 7.86 (1H, dd, J = 7.7,1.8Hz), 8.58 (1H, dd, J = 4.8,1.8Hz)

ｔｅｒｔ−ブチル＝（１−（２−（２−オキソ−１，８−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.26gのジクロロメタン溶液4mLにトリフルオロ酢酸2mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物に水およびジエチルエーテルを加え、水層を分取し、ジエチルエーテルで洗浄後、20％水酸化ナトリウム水溶液を加え、pH13〜14に調整した。ジクロロメタンおよび塩化ナトリウムを加え、有機層を分取し、水層を塩析しながら、クロロホルムで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、黄色油状物の１−（２−（４−アミノピペリジン−１−イル）エチル）−１，８−ナフチリジン−２（１Ｈ）−オン0.15gを得た。
¹H-NMR(CDCl₃)δ値：1.31-1.43(2H,m),1.77-1.91(4H,m),2.13-2.22(2H,m),2.62-2.73(3H,m),3.03-3.10(2H,m),4.66-4.72(2H,m),6.74(1H,d,J=9.4Hz),7.17(1H,dd,J=7.6,4.6Hz),7.63(1H,d,J=9.4Hz),7.86(1H,dd,J=7.6,1.9Hz),8.59(1H,dd,J=4.6,1.9Hz) Reference Example 22

tert-Butyl = (1- (2- (2-oxo-1,8-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate 0.26 g of dichloromethane solution 4 mL was added with 2 mL of trifluoroacetic acid. And stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, water and diethyl ether were added to the resulting residue, the aqueous layer was separated, washed with diethyl ether, and then adjusted to pH 13-14 by adding 20% aqueous sodium hydroxide solution. . Dichloromethane and sodium chloride were added, the organic layer was separated, and the aqueous layer was extracted with chloroform while salting out. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 1- (2- (4-aminopiperidin-1-yl) ethyl) -1,8- 0.15 g of naphthyridine-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.31-1.43 (2H, m), 1.77-1.91 (4H, m), 2.13-2.22 (2H, m), 2.62-2.73 (3H, m), 3.03-3.10 (2H, m), 4.66-4.72 (2H, m), 6.74 (1H, d, J = 9.4Hz), 7.17 (1H, dd, J = 7.6,4.6Hz), 7.63 (1H, d, J = 9.4 Hz), 7.86 (1H, dd, J = 7.6,1.9Hz), 8.59 (1H, dd, J = 4.6,1.9Hz)

１，５−ナフチリジン−２（１Ｈ）−オン1.2gのＮ，Ｎ−ジメチルホルムアミド24mL溶液に45℃で60％水素化ナトリウム0.82gを加え、同温度で20分間攪拌した後、55〜80℃で30分間攪拌した。60℃で２−ブロモメチル−１，３−ジオキソラン1.3mLを加えた後、反応混合物を4時間かけて、100℃まで昇温し、炭酸カリウム2.3gを加え、同温度で3時間攪拌した。一晩放置後、２−ブロモメチル−１，３−ジオキソラン0.85mLおよび60％水素化ナトリウム0.33gを加え、70〜75℃で1時間30分間攪拌した。反応混合物を室温まで冷却後、水、塩化ナトリウムおよびクロロホルムを加え、有機層を分取した。水層をクロロホルムで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［溶離液；クロロホルム：メタノール＝４９：１］で精製し、淡黄色固体の１−（１，３−ジオキソラン−２−イルメチル）−１，５−ナフチリジン−２（１Ｈ）−オン1.1gを得た。
¹H-NMR(CDCl₃)δ値：3.82-3.94(2H,m),3.96-4.05(2H,m),4.52(2H,d,J=4.2Hz),5.22(1H,t,J=4.2Hz),6.94(1H,d,J=9.8Hz),7.45(1H,dd,J=8.6,4.5Hz),7.90-7.98(2H,m),8.54(1H,dd,J=4.5,1.2Hz) Reference Example 23

To a solution of 1.2 g of 1,5-naphthyridin-2 (1H) -one in 24 mL of N, N-dimethylformamide was added 0.82 g of 60% sodium hydride at 45 ° C., and the mixture was stirred at the same temperature for 20 minutes. For 30 minutes. After adding 1.3 mL of 2-bromomethyl-1,3-dioxolane at 60 ° C., the reaction mixture was heated to 100 ° C. over 4 hours, added with 2.3 g of potassium carbonate, and stirred at the same temperature for 3 hours. After standing overnight, 0.85 mL of 2-bromomethyl-1,3-dioxolane and 0.33 g of 60% sodium hydride were added, and the mixture was stirred at 70 to 75 ° C. for 1 hour and 30 minutes. After cooling the reaction mixture to room temperature, water, sodium chloride and chloroform were added, and the organic layer was separated. The aqueous layer was extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 49: 1] to give 1- (1,3-dioxolan-2-ylmethyl) -1,5-naphthyridine- as a pale yellow solid. 1.1 g of 2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.82 to 3.94 (2H, m), 3.96 to 4.05 (2H, m), 4.52 (2H, d, J = 4.2 Hz), 5.22 (1H, t, J = 4.2 Hz), 6.94 (1H, d, J = 9.8Hz), 7.45 (1H, dd, J = 8.6,4.5Hz), 7.90-7.98 (2H, m), 8.54 (1H, dd, J = 4.5,1.2Hz) )

１−（１，３−ジオキソラン−２−イルメチル）−１，５−ナフチリジン−２（１Ｈ）−オン1.0gに80％トリフルオロ酢酸水溶液5mLを加え、60〜70℃で30分間攪拌した後、70〜90℃で、4時間攪拌した。さらに、80％トリフルオロ酢酸水溶液5mLを加え、2時間攪拌した。減圧下で溶媒を留去し、得られた残留物に飽和炭酸水素ナトリウム水溶液、塩化ナトリウムおよびクロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、橙色油状物の（２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド0.73gを得た。
¹H-NMR(CDCl₃)δ値：5.15(2H,s),6.99(1H,d,J=10.0Hz),7.43-7.49(1H,m),7.96-8.03(2H,m),8.56-8.62(1H,m),9.76(1H,s) Reference Example 24

To 1.0 g of 1- (1,3-dioxolan-2-ylmethyl) -1,5-naphthyridin-2 (1H) -one was added 5 mL of an 80% aqueous trifluoroacetic acid solution and stirred at 60 to 70 ° C. for 30 minutes. The mixture was stirred at 70 to 90 ° C. for 4 hours. Further, 5 mL of an 80% aqueous trifluoroacetic acid solution was added and stirred for 2 hours. The solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate solution, sodium chloride and chloroform were added to the resulting residue, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 0.73 g of (2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde as an orange oil was obtained. Obtained.
¹ H-NMR (CDCl ₃ ) δ value: 5.15 (2H, s), 6.99 (1H, d, J = 10.0 Hz), 7.43-7.49 (1H, m), 7.96-8.03 (2H, m), 8.56- 8.62 (1H, m), 9.76 (1H, s)

ｔｅｒｔ−ブチル＝（１−ベンジル−２−メチルピペリジン−４−イル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）カルバマート0.24gのメタノール3mL溶液に酢酸90μLおよび20％水酸化パラジウム0.32gを加えた。反応混合物を水素雰囲気下、4時間30分間攪拌した。不溶物を濾去し、減圧下で溶媒を留去し、黄色泡状物のｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（２−メチルピペリジン−４−イル）カルバマート0.16gを得た。
¹H-NMR(CDCl₃)δ値：1.36-1.45(9H,m),1.50(3H,d,J=6.8Hz),1.67-1.75(1H,m),1.86-1.95(1H,m),2.03-2.14(1H,m),2.18-2.30(1H,m),3.04-3.17(1H,m),3.26-3.35(1H,m),3.83-3.93(1H,m),4.27-4.51(7H,m),6.71-6.83(1H,m),8.08(1H,s),9.40-9.60(1H,m) Reference Example 25

tert-butyl = (1-benzyl-2-methylpiperidin-4-yl) (2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) carbamate 0.24 g in 3 mL of methanol 90 μL of acetic acid and 0.32 g of 20% palladium hydroxide were added. The reaction mixture was stirred under a hydrogen atmosphere for 4 hours 30 minutes. The insoluble material was removed by filtration, the solvent was distilled off under reduced pressure, and yellow foam tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) 0.16 g of (2-methylpiperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.36-1.45 (9H, m), 1.50 (3H, d, J = 6.8 Hz), 1.67-1.75 (1H, m), 1.86-1.95 (1H, m), 2.03-2.14 (1H, m), 2.18-2.30 (1H, m), 3.04-3.17 (1H, m), 3.26-3.35 (1H, m), 3.83-3.93 (1H, m), 4.27-4.51 (7H , m), 6.71-6.83 (1H, m), 8.08 (1H, s), 9.40-9.60 (1H, m)

（１）参考例６１と同様の手法により、１−ベンジル−Ｎ−（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）−２−メチルピペリジン−４−アミンからｔｅｒｔ−ブチル＝（１−ベンジル−２−メチルピペリジン−４−イル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）カルバマートを得た。
（２）参考例２５と同様の手法により、ｔｅｒｔ−ブチル＝（１−ベンジル−２−メチルピペリジン−４−イル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）カルバマートからｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（２−メチルピペリジン−４−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.27-1.57(14H,m),1.82-2.00(2H,m),2.83-2.97(1H,m),3.14-3.27(1H,m),3.40-3.53(1H,m),4.26-4.61(7H,m),6.62-7.02(1H,m),8.05-8.13(1H,m),9.84-10.06(1H,m) Reference Example 26

(1) In the same manner as in Reference Example 61, 1-benzyl-N- (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) -2-methylpiperidine-4 Tert-butyl = (1-benzyl-2-methylpiperidin-4-yl) (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) carbamate was obtained from the amine. .
(2) In the same manner as in Reference Example 25, tert-butyl = (1-benzyl-2-methylpiperidin-4-yl) (2,3-dihydro (1,4) dioxyno (2,3-c) pyridine Tert-Butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (2-methylpiperidin-4-yl) carbamate was obtained from -7-ylmethyl) carbamate. .
¹ H-NMR (CDCl ₃ ) δ value: 1.27-1.57 (14H, m), 1.82-2.00 (2H, m), 2.83-2.97 (1H, m), 3.14-3.27 (1H, m), 3.40-3.53 (1H, m), 4.26-4.61 (7H, m), 6.62-7.02 (1H, m), 8.05-8.13 (1H, m), 9.84-10.06 (1H, m)

参考例３と同様の手法により、ピリド（３，４−ｂ）ピラジン−２（１Ｈ）−オンおよび２−ブロモメチル−１，３−ジオキソランから１−（１，３−ジオキソラン−２−イルメチル）ピリド（３，４−ｂ）ピラジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：3.84-4.02(4H,m),4.44(2H,d,J=4.0Hz),5.24(1H,t,J=4.0Hz),7.43(1H,d,J=6.0Hz),8.33(1H,s),8.63(1H,d,J=6.0Hz),9.07(1H,s) Reference Example 27

In the same manner as in Reference Example 3, pyrido (3,4-b) pyrazin-2 (1H) -one and 2-bromomethyl-1,3-dioxolane were converted to 1- (1,3-dioxolan-2-ylmethyl) pyrido. (3,4-b) pyrazin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.84-4.02 (4H, m), 4.44 (2H, d, J = 4.0Hz), 5.24 (1H, t, J = 4.0Hz), 7.43 (1H, d, J = 6.0Hz), 8.33 (1H, s), 8.63 (1H, d, J = 6.0Hz), 9.07 (1H, s)

７−クロロ−１，８−ナフチリジン−２（１Ｈ）−オン3.2gのＮ，Ｎ−ジメチルホルムアミド32mL溶液に炭酸カリウム3.7gを加え、50〜60℃で23分間攪拌した後、２−ブロモメチル−１，３−ジオキソラン2.2mLを加え、60〜78℃で25分間攪拌した。Ｎ，Ｎ−ジメチルホルムアミド16mLおよび２−ブロモメチル−１，３−ジオキソラン1.1mLを加え、90〜95℃で2時間15分間攪拌した後、炭酸カリウム3.7gを加え、20分間攪拌した。反応混合物を室温まで冷却後、水および酢酸エチルを加え、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、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［溶離液；ヘキサン：酢酸エチル＝１：１］で精製し、黄色固体の７−クロロ−１−（１，３−ジオキソラン−２−イルメチル）−１，８−ナフチリジン−２（１Ｈ）−オン3.6gを得た。
¹H-NMR(CDCl₃)δ値：3.86-3.96(2H,m),4.10-4.20(2H,m),4.63(2H,t,J=5.4Hz),5.60(1H,t,J=5.4Hz),6.75(1H,d,J=9.6Hz),7.17(1H,d,J=8.0Hz),7.62(1H,d,J=9.6Hz),7.79(1H,d,J=8.0Hz) Reference Example 28

To a solution of 3.2 g of 7-chloro-1,8-naphthyridin-2 (1H) -one in 32 g of N, N-dimethylformamide was added 3.7 g of potassium carbonate, and the mixture was stirred at 50-60 ° C. for 23 minutes. 1,3-Dioxolane (2.2 mL) was added, and the mixture was stirred at 60 to 78 ° C for 25 minutes. N, N-dimethylformamide (16 mL) and 2-bromomethyl-1,3-dioxolane (1.1 mL) were added, and the mixture was stirred at 90 to 95 ° C. for 2 hours and 15 minutes. Then, potassium carbonate (3.7 g) was added, and the mixture was stirred for 20 minutes. The reaction mixture was cooled to room temperature, water and ethyl acetate were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 1: 1]. Then, 3.6 g of 7-chloro-1- (1,3-dioxolan-2-ylmethyl) -1,8-naphthyridin-2 (1H) -one as a yellow solid was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.86-3.96 (2H, m), 4.10-4.20 (2H, m), 4.63 (2H, t, J = 5.4Hz), 5.60 (1H, t, J = 5.4 Hz), 6.75 (1H, d, J = 9.6Hz), 7.17 (1H, d, J = 8.0Hz), 7.62 (1H, d, J = 9.6Hz), 7.79 (1H, d, J = 8.0Hz)

７−クロロ−１−（１，３−ジオキソラン−２−イルメチル）−１，８−ナフチリジン−２（１Ｈ）−オン2.5gのメタノール30mL溶液に28％ナトリウムメトキシド／メタノール溶液5.4gを加え、加熱還流下、3時間40分間攪拌した。反応混合物を室温まで冷却後、水を加え、減圧下で溶媒を留去した。得られた残留物に水、飽和塩化アンモニウム水溶液およびクロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、黄色油状物の１−（１，３−ジオキソラン−２−イルメチル）−７−メトキシ−１，８−ナフチリジン−２（１Ｈ）−オン2.9gを得た。
¹H-NMR(CDCl₃)δ値：3.84-3.94(2H,m),4.00(3H,s),4.05-4.15(2H,m),4.65(2H,d,J=5.1Hz),5.56(1H,t,J=5.1Hz),6.55(1H,d,J=9.3Hz),6.57(1H,d,J=8.6Hz),7.55(1H,d,J=9.3Hz),7.69(1H,d,J=8.6Hz) Reference Example 29

To a 30 mL solution of 7-chloro-1- (1,3-dioxolan-2-ylmethyl) -1,8-naphthyridin-2 (1H) -one in 30 mL of methanol was added 5.4 g of a 28% sodium methoxide / methanol solution. The mixture was stirred for 3 hours and 40 minutes with heating under reflux. The reaction mixture was cooled to room temperature, water was added, and the solvent was evaporated under reduced pressure. Water, saturated aqueous ammonium chloride solution and chloroform were added to the obtained residue, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 1- (1,3-dioxolan-2-ylmethyl)- 2.9 g of 7-methoxy-1,8-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.84-3.94 (2H, m), 4.00 (3H, s), 4.05-4.15 (2H, m), 4.65 (2H, d, J = 5.1 Hz), 5.56 ( 1H, t, J = 5.1Hz), 6.55 (1H, d, J = 9.3Hz), 6.57 (1H, d, J = 8.6Hz), 7.55 (1H, d, J = 9.3Hz), 7.69 (1H, d, J = 8.6Hz)

１−（１，３−ジオキソラン−２−イルメチル）−７−メトキシ−１，８−ナフチリジン−２（１Ｈ）−オン2.8gに80％トリフルオロ酢酸水溶液20mLを加え、60〜72℃で3時間20分間、80〜85℃で2時間20分間攪拌した後、水4mLを加え、さらに4時間攪拌した。反応混合物を室温まで冷却後、一晩放置し、減圧下で溶媒を留去した。得られた残留物に飽和炭酸水素ナトリウム水溶液およびクロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、黄色固体の（７−メトキシ−２−オキソ−１，８−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド1.8gを得た。
¹H-NMR(CDCl₃)δ値：3.92(3H,s),5.23(2H,d,J=0.7Hz),6.63-6.67(2H,m),7.66(1H,d,J=9.5Hz),7.78(1H,d,J=8.3Hz),9.65-9.67(1H,m) Reference Example 30

To 2.8 g of 1- (1,3-dioxolan-2-ylmethyl) -7-methoxy-1,8-naphthyridin-2 (1H) -one, 20 mL of 80% aqueous trifluoroacetic acid solution was added and the mixture was heated at 60 to 72 ° C. for 3 hours After stirring for 20 minutes at 80 to 85 ° C. for 2 hours and 20 minutes, 4 mL of water was added, and the mixture was further stirred for 4 hours. The reaction mixture was cooled to room temperature and allowed to stand overnight, and the solvent was distilled off under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the obtained residue, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give (7-methoxy-2-oxo-1,8-naphthyridin-1 (2H) -yl) acetaldehyde as a yellow solid. 1.8 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.92 (3H, s), 5.23 (2H, d, J = 0.7Hz), 6.63-6.67 (2H, m), 7.66 (1H, d, J = 9.5Hz) , 7.78 (1H, d, J = 8.3Hz), 9.65-9.67 (1H, m)

（７−メトキシ−２−オキソ−１，８−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド1.6gのジクロロメタン70mL溶液にｔｅｒｔ−ブチル＝（ピペリジン−４−イル）カルバマート1.5gおよび酢酸0.42mLを加え、20分間攪拌した後、反応混合物に水素化トリアセトキシホウ素ナトリウム2.3gを加え、室温で2時間10分間攪拌した。水、飽和炭酸水素ナトリウム水溶液およびクロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、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［溶離液；クロロホルム：メタノール＝５０：１］で精製し、白色泡状物のｔｅｒｔ−ブチル＝（１−（２−（７−メトキシ−２−オキソ−１，８−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート2.8gを得た。
¹H-NMR(CDCl₃)δ値：1.38-1.51(11H,m),1.88-1.98(2H,m),2.22-2.31(2H,m),2.69-2.75(2H,m),2.98-3.06(2H,m),3.41-3.52(1H,m),4.01(3H,s),4.38-4.47(1H,m),4.61-4.66(2H,m),6.57(1H,d,J=9.3Hz),6.61(1H,d,J=8.5Hz),7.56(1H,d,J=9.3Hz),7.72(1H,d,J=8.5Hz) Reference Example 31

To a solution of 1.6 g of (7-methoxy-2-oxo-1,8-naphthyridin-1 (2H) -yl) acetaldehyde in 70 mL of dichloromethane was added 1.5 g of tert-butyl = (piperidin-4-yl) carbamate and 0.42 mL of acetic acid. After stirring for 20 minutes, 2.3 g of sodium triacetoxyborohydride was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours and 10 minutes. Water, saturated aqueous sodium hydrogen carbonate solution and chloroform were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography [eluent; chloroform: methanol = 50: 1] and white foam tert-butyl = (1- (2- (7-methoxy-2-oxo-1,8-naphthyridin-1 (2H) -yl) ethyl) piperidine-4 Yl) carbamate 2.8 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.38-1.51 (11H, m), 1.88-1.98 (2H, m), 2.22-2.31 (2H, m), 2.69-2.75 (2H, m), 2.98-3.06 (2H, m), 3.41-3.52 (1H, m), 4.01 (3H, s), 4.38-4.47 (1H, m), 4.61-4.66 (2H, m), 6.57 (1H, d, J = 9.3Hz ), 6.61 (1H, d, J = 8.5Hz), 7.56 (1H, d, J = 9.3Hz), 7.72 (1H, d, J = 8.5Hz)

ｔｅｒｔ−ブチル＝（１−（２−（７−メトキシ−２−オキソ−１，８−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート2.8gに4mol/L塩化水素／酢酸エチル溶液50mLを加え、室温で29時間攪拌した。減圧下で溶媒を留去し、得られた固形物に酢酸エチルを加え、結晶を濾取し、酢酸エチルで洗浄し、淡黄色固体の１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，８−ナフチリジン−２（１Ｈ）−オン塩酸塩2.3gを得た。
¹H-NMR(D₂O)δ値：1.90-2.05(2H,m),2.34-2.43(2H,m),3.17-3.30(2H,m),3.55-3.67(3H,m),3.93-4.02(2H,m),4.04(3H,s),4.88-4.94(2H,m),6.62(1H,d,J=9.5Hz),6.83(1H,d,J=8.5Hz),7.93(1H,d,J=9.5Hz),8.01(1H,d,J=8.5Hz) Reference Example 32

tert-butyl = (1- (2- (7-methoxy-2-oxo-1,8-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate (2.8 g) 50 mL of an ethyl acetate solution was added, and the mixture was stirred at room temperature for 29 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the resulting solid, the crystals were collected by filtration, washed with ethyl acetate, and 1- (2- (4-aminopiperidin-1-yl) as a pale yellow solid. ) Ethyl) -7-methoxy-1,8-naphthyridin-2 (1H) -one hydrochloride 2.3 g was obtained.
¹ H-NMR (D ₂ O) δ value: 1.90-2.05 (2H, m), 2.34-2.43 (2H, m), 3.17-3.30 (2H, m), 3.55-3.67 (3H, m), 3.93 4.02 (2H, m), 4.04 (3H, s), 4.88-4.94 (2H, m), 6.62 (1H, d, J = 9.5Hz), 6.83 (1H, d, J = 8.5Hz), 7.93 (1H , d, J = 9.5Hz), 8.01 (1H, d, J = 8.5Hz)

参考例１４と同様の手法により、２−ブロモ−３−ニトロピリジンおよび１−（１，３−ジオキソラン−２−イル）メタンアミンからＮ−（１，３−ジオキソラン−２−イルメチル）−３−ニトロピリジン−２−アミンを得た。
¹H-NMR(CDCl₃)δ値：3.90-4.10(6H,m),5.17(1H,t,J=3.4Hz),6.64-6.69(1H,m),8.36-8.44(3H,m) Reference Example 33

In the same manner as in Reference Example 14, from 2-bromo-3-nitropyridine and 1- (1,3-dioxolan-2-yl) methanamine to N- (1,3-dioxolan-2-ylmethyl) -3-nitro Pyridin-2-amine was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.90-4.10 (6H, m), 5.17 (1H, t, J = 3.4Hz), 6.64-6.69 (1H, m), 8.36-8.44 (3H, m)

参考例１５と同様の手法により、Ｎ−（１，３−ジオキソラン−２−イルメチル）−３−ニトロピリジン−２−アミンから３−アミノ−２−（１，３−ジオキソラン−２−イルメチル）アミノピリジンを得た。
¹H-NMR(CDCl₃)δ値：3.20-3.60(2H,broad),3.70-3.74(2H,m),3.87-4.08(4H,m),4.76-4.88(1H,broad),5.16(1H,t,J=4.1Hz),6.55(1H,dd,J=7.4,5.2Hz),6.86(1H,dd,J=7.4,1.3Hz),7.70(1H,dd,J=5.2,1.3Hz) Reference Example 34

In the same manner as in Reference Example 15, N- (1,3-dioxolan-2-ylmethyl) -3-nitropyridin-2-amine was converted to 3-amino-2- (1,3-dioxolan-2-ylmethyl) amino. Pyridine was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.20-3.60 (2H, broad), 3.70-3.74 (2H, m), 3.87-4.08 (4H, m), 4.76-4.88 (1H, broad), 5.16 (1H , t, J = 4.1Hz), 6.55 (1H, dd, J = 7.4,5.2Hz), 6.86 (1H, dd, J = 7.4,1.3Hz), 7.70 (1H, dd, J = 5.2,1.3Hz)

３−アミノ−２−（１，３−ジオキソラン−２−イルメチル）アミノピリジン0.20gのエタノール2mL溶液にエチル＝オキソアセタートの45-50％トルエン溶液0.25gを加え、加熱還流下、1時間30分間攪拌した。反応混合物を室温まで冷却し、水および酢酸エチルを加えた。有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をフラッシュ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＝１００：０−９０：１０］で精製し、淡褐色固体の４−（１，３−ジオキソラン−２−イルメチル）ピリド（２，３−ｂ）ピラジン−３（４Ｈ）−オン0.16gを得た。
¹H-NMR(CDCl₃)δ値：3.85-3.95(2H,m),4.06-4.16(2H,m),4.66(2H,d,J=5.2Hz),5.56(1H,t,J=5.2Hz),7.33(1H,dd,J=7.9,4.7Hz),8.17(1H,dd,J=7.9,1.7Hz),8.35(1H,s),8.60(1H,dd,J=4.7,1.7Hz) Reference Example 35

To a solution of 0.20 g of 3-amino-2- (1,3-dioxolan-2-ylmethyl) aminopyridine in 2 mL of ethanol was added 0.25 g of a 45-50% toluene solution of ethyl oxoacetate, and the mixture was stirred for 1 hour and 30 minutes while heating under reflux. did. The reaction mixture was cooled to room temperature and water and ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash silica gel column chromatography [gradient elution of chloroform: methanol = 100: 0-90: 10], and 4- (1,3-dioxolan-2-ylmethyl) pyrido (light brown solid) 2,3-b) pyrazin-3 (4H) -one 0.16 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.85-3.95 (2H, m), 4.06-4.16 (2H, m), 4.66 (2H, d, J = 5.2Hz), 5.56 (1H, t, J = 5.2 Hz), 7.33 (1H, dd, J = 7.9,4.7Hz), 8.17 (1H, dd, J = 7.9,1.7Hz), 8.35 (1H, s), 8.60 (1H, dd, J = 4.7,1.7Hz) )

参考例４と同様の手法により、４−（１，３−ジオキソラン−２−イルメチル）ピリド（２，３−ｂ）ピラジン−３（４Ｈ）−オンから（３−オキソピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）アセトアルデヒドを得た。
¹H-NMR(CDCl₃)δ値：5.33(2H,s),7.35(1H,dd,J=7.9,4.7Hz),8.22(1H,dd,J=7.9,1.7Hz),8.40(1H,s),8.52(1H,dd,J=4.7,1.7Hz),9.75(1H,s) Reference Example 36

In the same manner as in Reference Example 4, from 4- (1,3-dioxolan-2-ylmethyl) pyrido (2,3-b) pyrazin-3 (4H) -one to (3-oxopyrido (2,3-b) Pyrazin-4 (3H) -yl) acetaldehyde was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 5.33 (2H, s), 7.35 (1H, dd, J = 7.9, 4.7 Hz), 8.22 (1H, dd, J = 7.9, 1.7 Hz), 8.40 (1H, s), 8.52 (1H, dd, J = 4.7,1.7Hz), 9.75 (1H, s)

参考例４２と同様の手法により、（２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒドおよびｔｅｒｔ−ブチル＝（ピペリジン−４−イル）カルバマートからｔｅｒｔ−ブチル＝（１−（２−（２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートを得た。
¹H-NMR(CDCl₃,D₂O)δ値：1.24-1.46(11H,m),1.90-1.98(2H,m),2.21-2.30(2H,m),2.62-2.68(2H,m),2.88-2.97(2H,m),4.35-4.55(3H,m),6.92(1H,d,J=9.7Hz),7.47(1H,dd,J=8.5,4.5Hz),7.74-7.78(1H,m),7.92(1H,d,J=9.7Hz),8.55(1H,dd,J=4.5,1.1Hz) Reference Example 37

In the same manner as in Reference Example 42, (2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde and tert-butyl = (piperidin-4-yl) carbamate were converted into tert-butyl = (1- ( 2- (2-Oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ , D ₂ O) δ value: 1.24-1.46 (11H, m), 1.90-1.98 (2H, m), 2.21-2.30 (2H, m), 2.62-2.68 (2H, m) , 2.88-2.97 (2H, m), 4.35-4.55 (3H, m), 6.92 (1H, d, J = 9.7Hz), 7.47 (1H, dd, J = 8.5,4.5Hz), 7.74-7.78 (1H , m), 7.92 (1H, d, J = 9.7Hz), 8.55 (1H, dd, J = 4.5,1.1Hz)

参考例１３と同様の手法により、ｔｅｒｔ−ブチル＝（１−（２−（２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートから１−（２−（４−アミノピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：1.80-2.10(2H,m),2.26-2.48(2H,m),3.10-3.40(2H,m),3.53-3.70(3H,m),3.90-4.10(2H,m),4.84-4.90(2H,m),7.31(1H,d,J=10.0Hz),8.21(1H,dd,J=9.0,5.5Hz),8.26(1H,d,J=10.0Hz),8.72(1H,d,J=9.0Hz),8.81(1H,d,J=5.5Hz) Reference Example 38

In the same manner as in Reference Example 13, tert-butyl = (1- (2- (2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate was converted to 1- ( 2- (4-Aminopiperidin-1-yl) ethyl) -1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.80-2.10 (2H, m), 2.26-2.48 (2H, m), 3.10-3.40 (2H, m), 3.53-3.70 (3H, m), 3.90- 4.10 (2H, m), 4.84-4.90 (2H, m), 7.31 (1H, d, J = 10.0Hz), 8.21 (1H, dd, J = 9.0,5.5Hz), 8.26 (1H, d, J = 10.0Hz), 8.72 (1H, d, J = 9.0Hz), 8.81 (1H, d, J = 5.5Hz)

ピリジン−２，３−ジアミン3.8gのジオキサン100mL懸濁液に、エチル＝オキソアセタートの45-50％トルエン溶液7.1gを加え、室温で1時間攪拌した後、加熱還流下、1時間攪拌した。反応混合物を氷浴で冷却し、ジエチルエーテルを加えた。固形物を濾取し、淡褐色固体のピリド（２，３−ｂ）ピラジン−２（１Ｈ）−オン3.9gを得た。
¹H-NMR(DMSO-d₆)δ値：7.58(1H,dd,J=8.2,4.5Hz),7.73(1H,dd,J=8.2,1.6Hz),8.37(1H,s),8.53(1H,dd,J=4.5,1.6Hz) Reference Example 39

To a suspension of 3.8 g of pyridine-2,3-diamine in 100 mL of dioxane was added 7.1 g of a 45-50% toluene solution of ethyl oxoacetate, and the mixture was stirred at room temperature for 1 hour and then stirred for 1 hour under heating and reflux. The reaction mixture was cooled in an ice bath and diethyl ether was added. The solid was collected by filtration to obtain 3.9 g of pyrido (2,3-b) pyrazin-2 (1H) -one as a light brown solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.58 (1H, dd, J = 8.2, 4.5 Hz), 7.73 (1H, dd, J = 8.2, 1.6 Hz), 8.37 (1H, s), 8.53 ( (1H, dd, J = 4.5,1.6Hz)

参考例３と同様の手法により、ピリド（２，３−ｂ）ピラジン−２（１Ｈ）−オンおよび２−ブロモメチル−１，３−ジオキソランから１−（１，３−ジオキソラン−２−イルメチル）ピリド（２，３−ｂ）ピラジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：3.83-4.00(4H,m),4.49(2H,d,J=4.0Hz),5.23(1H,t,J=4.0Hz),7.52(1H,dd,J=8.5,4.4Hz),7.99(1H,dd,J=8.5,1.5Hz),8.56(1H,s),8.66(1H,dd,J=4.4,1.5Hz) Reference Example 40

In the same manner as in Reference Example 3, pyrido (2,3-b) pyrazin-2 (1H) -one and 2-bromomethyl-1,3-dioxolane were converted to 1- (1,3-dioxolan-2-ylmethyl) pyrido. (2,3-b) pyrazin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ values: 3.83 to 4.00 (4H, m), 4.49 (2H, d, J = 4.0 Hz), 5.23 (1H, t, J = 4.0 Hz), 7.52 (1H, dd, J = 8.5, 4.4Hz), 7.99 (1H, dd, J = 8.5, 1.5Hz), 8.56 (1H, s), 8.66 (1H, dd, J = 4.4, 1.5Hz)

参考例３と同様の手法により、ピリド（３，４−ｂ）ピラジン−３（４Ｈ）−オンおよび２−ブロモメチル−１，３−ジオキソランから４−（１，３−ジオキソラン−２−イルメチル）ピリド（３，４−ｂ）ピラジン−３（４Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：3.85-4.05(4H,m),4.53(2H,d,J=4.2Hz),5.29(1H,t,J=4.2Hz),7.73(1H,d,J=5.2Hz),8.49(1H,s),8.59(1H,d,J=5.2Hz),9.05(1H,s) Reference Example 41

In the same manner as in Reference Example 3, pyrido (3,4-b) pyrazin-3 (4H) -one and 2-bromomethyl-1,3-dioxolane were converted to 4- (1,3-dioxolan-2-ylmethyl) pyrido. (3,4-b) pyrazin-3 (4H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.85-4.05 (4H, m), 4.53 (2H, d, J = 4.2 Hz), 5.29 (1H, t, J = 4.2 Hz), 7.73 (1H, d, J = 5.2Hz), 8.49 (1H, s), 8.59 (1H, d, J = 5.2Hz), 9.05 (1H, s)

（６−メトキシ−３−オキソピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）アセトアルデヒド0.18gのジクロロメタン4mL溶液に、ｔｅｒｔ−ブチル＝（ピペリジン−４−イル）カルバマート0.16g、酢酸47μLおよび水素化トリアセトキシホウ素ナトリウム0.26gを加え、室温で3時間攪拌した。反応混合物にクロロホルムおよび飽和炭酸水素ナトリウム水溶液を加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジエチルエーテル、メタノールおよびヘキサンを加え、固形物を濾取し、淡褐色固体のｔｅｒｔ−ブチル＝（１−（２−（６−メトキシ−３−オキソピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.23gを得た。
¹H-NMR(CDCl₃)δ値：1.25-1.47(2H,m),1.44(9H,s),1.86-1.95(2H,m),2.18-2.28(2H,m),2.70-2.77(2H,m),2.93-3.02(2H,m),3.38-3.52(1H,broad),4.02(3H,s),4.35-4.44(1H,m),4.53-4.59(2H,m),6.73(1H,d,J=8.8Hz),8.01(1H,d,J=8.8Hz),8.15(1H,s) Reference Example 42

(6-Methoxy-3-oxopyrido (2,3-b) pyrazin-4 (3H) -yl) acetaldehyde 0.18 g in dichloromethane 4 mL solution, tert-butyl = (piperidin-4-yl) carbamate 0.16 g, acetic acid 47 μL Then, 0.26 g of sodium triacetoxyborohydride was added and stirred at room temperature for 3 hours. Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diethyl ether, methanol and hexane were added to the obtained residue, and the solid substance was collected by filtration, and tert-butyl = (1- (2- (6-methoxy-3-oxopyrido (2,3-b 0.23 g of pyrazin-4 (3H) -yl) ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.25-1.47 (2H, m), 1.44 (9H, s), 1.86-1.95 (2H, m), 2.18-2.28 (2H, m), 2.70-2.77 (2H , m), 2.93-3.02 (2H, m), 3.38-3.52 (1H, broad), 4.02 (3H, s), 4.35-4.44 (1H, m), 4.53-4.59 (2H, m), 6.73 (1H , d, J = 8.8Hz), 8.01 (1H, d, J = 8.8Hz), 8.15 (1H, s)

ｔｅｒｔ−ブチル＝（１−（２−（６−メトキシ−３−オキソピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.23gの酢酸エチル3mL懸濁液に、室温で4.0mol/L塩化水素／酢酸エチル溶液4.0mLを加えた。同温度で5時間攪拌した後、一晩放置した。減圧下で溶媒を留去し、得られた残留物にジエチルエーテルを加え、固形物を濾取し、淡褐色固体の４−（２−（４−アミノピペリジン−１−イル）エチル）−６−メトキシピリド（２，３−ｂ）ピラジン−３（４Ｈ）−オン塩酸塩0.23gを得た。
¹H-NMR(D₂O)δ値：1.88-2.03(2H,m),2.32-2.43(2H,m),3.18-3.32(2H,m),3.52-3.74(3H,m),3.91-4.04(2H,m),4.07(3H,s),4.87-4.93(2H,m),6.98(1H,d,J=8.9Hz),8.17(1H,d,J=8.9Hz),8.18(1H,s) Reference Example 43

tert-butyl = (1- (2- (6-methoxy-3-oxopyrido (2,3-b) pyrazin-4 (3H) -yl) ethyl) piperidin-4-yl) carbamate 0.23 g of ethyl acetate 3 mL To the suspension, 4.0 mL of 4.0 mol / L hydrogen chloride / ethyl acetate solution was added at room temperature. The mixture was stirred at the same temperature for 5 hours and then left overnight. The solvent was distilled off under reduced pressure, diethyl ether was added to the obtained residue, and the solid was collected by filtration to give 4- (2- (4-aminopiperidin-1-yl) ethyl) -6 as a light brown solid. 0.23 g of -methoxypyrido (2,3-b) pyrazin-3 (4H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.88-2.03 (2H, m), 2.32-2.43 (2H, m), 3.18-3.32 (2H, m), 3.52-3.74 (3H, m), 3.91 4.04 (2H, m), 4.07 (3H, s), 4.87-4.93 (2H, m), 6.98 (1H, d, J = 8.9Hz), 8.17 (1H, d, J = 8.9Hz), 8.18 (1H , s)

参考例１と同様の手法により、２−クロロ−５−メチルピリジン−３−アミンおよびエチル＝アクリラートから７−メチル−１，５−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(DMSO-d₆)δ値：2.39(3H,s),6.66(1H,d,J=9.8Hz),7.43-7.47(1H,m),7.89(1H,d,J=9.8Hz),8.32-8.34(1H,m),11.81-11.85(1H,broad) Reference Example 44

In the same manner as in Reference Example 1, 7-methyl-1,5-naphthyridin-2 (1H) -one was obtained from 2-chloro-5-methylpyridin-3-amine and ethyl acrylate.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.39 (3H, s), 6.66 (1H, d, J = 9.8 Hz), 7.43-7.47 (1H, m), 7.89 (1H, d, J = 9.8 Hz), 8.32-8.34 (1H, m), 11.81-11.85 (1H, broad)

参考例３と同様の手法により、７−メチル−１，５−ナフチリジン−２（１Ｈ）−オンおよび２−ブロモメチル−１，３−ジオキソランから１−（１，３−ジオキソラン−２−イルメチル）−７−メチル−１，５−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：2.50(3H,s),3.84-3.93(2H,m),3.97-4.07(2H,m),4.50(2H,d,J=4.2Hz),5.22(1H,t,J=4.2Hz),6.87(1H,d,J=9.8Hz),7.69-7.73(1H,m),7.89(1H,d,J=9.8Hz),8.38(1H,d,J=1.5Hz) Reference Example 45

In the same manner as in Reference Example 3, from 7-methyl-1,5-naphthyridin-2 (1H) -one and 2-bromomethyl-1,3-dioxolane to 1- (1,3-dioxolan-2-ylmethyl)- 7-methyl-1,5-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.50 (3H, s), 3.84 to 3.93 (2H, m), 3.97-4.07 (2H, m), 4.50 (2H, d, J = 4.2Hz), 5.22 ( 1H, t, J = 4.2Hz), 6.87 (1H, d, J = 9.8Hz), 7.69-7.73 (1H, m), 7.89 (1H, d, J = 9.8Hz), 8.38 (1H, d, J = 1.5Hz)

参考例４と同様の手法により、１−（１，３−ジオキソラン−２−イルメチル）−７−メチル−１，５−ナフチリジン−２（１Ｈ）−オンから（７−メチル−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒドを得た。
¹H-NMR(DMSO-d₆)δ値：2.41(3H,s),5.25(2H,s),6.83(1H,d,J=9.8Hz),7.73-7.78(1H,m),7.97(1H,d,J=9.8Hz),8.38-8.42(1H,m),9.70(1H,s) Reference Example 46

In the same manner as in Reference Example 4, from 1- (1,3-dioxolan-2-ylmethyl) -7-methyl-1,5-naphthyridin-2 (1H) -one to (7-methyl-2-oxo-1 , 5-Naphthyridin-1 (2H) -yl) acetaldehyde was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.41 (3H, s), 5.25 (2H, s), 6.83 (1H, d, J = 9.8 Hz), 7.73-7.78 (1H, m), 7.97 ( 1H, d, J = 9.8Hz), 8.38-8.42 (1H, m), 9.70 (1H, s)

参考例３９と同様の手法により、５−ブロモピリジン−２，３−ジアミンおよびエチル＝オキソアセタートから７−ブロモピリド（２，３−ｂ）ピラジン−２（１Ｈ）−オンを得た。
¹H-NMR(DMSO-d₆)δ値：7.86(1H,d,J=2.2Hz),8.39(1H,s),8.60(1H,d,J=2.2Hz),12.56-12.64(1H,broad) Reference Example 47

In the same manner as in Reference Example 39, 7-bromopyrido (2,3-b) pyrazin-2 (1H) -one was obtained from 5-bromopyridine-2,3-diamine and ethyl oxoacetate.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.86 (1H, d, J = 2.2 Hz), 8.39 (1H, s), 8.60 (1H, d, J = 2.2 Hz), 12.56-12.64 (1H, broad)

７−ブロモピリド（２，３−ｂ）ピラジン−２（１Ｈ）−オン4.0gのＮ，Ｎ−ジメチルホルムアミド40mL懸濁液に、室温で28％ナトリウムメトキシド／メタノール溶液8.2gおよび臭化銅（I）0.25gを加え、窒素雰囲気下、80〜90℃で3時間攪拌した。反応混合物を55℃まで冷却し、２−ブロモメチル−１，３−ジオキソラン2.8mLを加え、窒素雰囲気下、80〜90℃で1時間30分間攪拌した。反応混合物を室温まで冷却した後、一晩放置した。さらに80〜90℃で1時間攪拌した後、90〜100℃で1時間30分間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび水を加えた。不溶物を濾去し、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をフラッシュ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、得られた橙色油状物に酢酸エチルを加え、固形物を濾取し、橙色固体の１−（１，３−ジオキソラン−２−イルメチル）−７−メトキシピリド（２，３−ｂ）ピラジン−２（１Ｈ）−オン0.12gを得た。
¹H-NMR(CDCl₃)δ値：3.84-3.93(2H,m),3.93-4.02(2H,m),3.99(3H,s),4.47(2H,d,J=3.8Hz),5.21(1H,t,J=3.8Hz),7.39(1H,d,J=2.7Hz),8.36(1H,d,J=2.7Hz),8.38(1H,s) Reference Example 48

A suspension of 4.0 g of 7-bromopyrido (2,3-b) pyrazin-2 (1H) -one in 40 mL of N, N-dimethylformamide at room temperature with 8.2 g of 28% sodium methoxide / methanol solution and copper bromide ( I) 0.25g was added and it stirred at 80-90 degreeC under nitrogen atmosphere for 3 hours. The reaction mixture was cooled to 55 ° C, 2.8 mL of 2-bromomethyl-1,3-dioxolane was added, and the mixture was stirred at 80 to 90 ° C for 1 hour and 30 minutes under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and then left overnight. Furthermore, after stirring at 80-90 degreeC for 1 hour, it stirred at 90-100 degreeC for 1 hour 30 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added. Insolubles were removed by filtration, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash silica gel column chromatography [gradient elution of chloroform: methanol = 100: 0-95: 5], ethyl acetate was added to the obtained orange oil, and the solid was collected by filtration. 0.12 g of 1- (1,3-dioxolan-2-ylmethyl) -7-methoxypyrido (2,3-b) pyrazin-2 (1H) -one as an orange solid was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.84-3.93 (2H, m), 3.93-4.02 (2H, m), 3.99 (3H, s), 4.47 (2H, d, J = 3.8Hz), 5.21 ( 1H, t, J = 3.8Hz), 7.39 (1H, d, J = 2.7Hz), 8.36 (1H, d, J = 2.7Hz), 8.38 (1H, s)

参考例４と同様の手法により、１−（１，３−ジオキソラン−２−イルメチル）−７−メトキシピリド（２，３−ｂ）ピラジン−２（１Ｈ）−オンから（７−メトキシ−２−オキソピリド（２，３−ｂ）ピラジン−１（２Ｈ）−イル）アセトアルデヒドを得た。
¹H-NMR(DMSO-d₆)δ値：3.94(3H,s),5.31(2H,s),7.48(1H,d,J=2.7Hz),8.32(1H,s),8.33(1H,d,J=2.7Hz),9.68(1H,s) Reference Example 49

In the same manner as in Reference Example 4, from 1- (1,3-dioxolan-2-ylmethyl) -7-methoxypyrido (2,3-b) pyrazin-2 (1H) -one to (7-methoxy-2-oxopyrido (2,3-b) pyrazin-1 (2H) -yl) acetaldehyde was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.94 (3H, s), 5.31 (2H, s), 7.48 (1H, d, J = 2.7 Hz), 8.32 (1H, s), 8.33 (1H, d, J = 2.7Hz), 9.68 (1H, s)

２，６−ジクロロ−３−ニトロピリジン0.50gのアセトニトリル5mL溶液に、炭酸カリウム0.43gを加え、氷冷下で２−アミノメチル−１，３−ジオキソラン0.24mLのアセトニトリル3mL溶液を加え、氷冷下で2時間攪拌した。さらに２−アミノメチル−１，３−ジオキソラン80μLを加え、氷冷下で2時間攪拌した。氷冷下で水および酢酸エチルを加え、有機層を分取し、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝２０：１］で精製し、黄色固体の６−クロロ−Ｎ−（１，３−ジオキソラン−２−イルメチル）−３−ニトロピリジン−２−アミン0.44gを得た。
¹H-NMR(CDCl₃)δ値：3.90-4.00(2H,m),4.00-4.12(2H,m),5.16(1H,t,J=3.3Hz),6.63(1H,d,J=8.7Hz),8.35(1H,d,J=8.7Hz),8.40-8.60(1H,broad) Reference Example 50

To a solution of 0.50 g of 2,6-dichloro-3-nitropyridine in 5 mL of acetonitrile is added 0.43 g of potassium carbonate. Under ice cooling, 0.24 mL of 2-aminomethyl-1,3-dioxolane is added in 3 mL of acetonitrile, and ice-cooled. Stir for 2 hours under. Further, 80 μL of 2-aminomethyl-1,3-dioxolane was added and stirred for 2 hours under ice cooling. Water and ethyl acetate were added under ice cooling, and the organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography [eluent: hexane: ethyl acetate = 20: 1] to give 6-chloro-N- (1,3-dioxolan-2-ylmethyl)-as a yellow solid. 0.44 g of 3-nitropyridin-2-amine was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.90-4.00 (2H, m), 4.00-4.12 (2H, m), 5.16 (1H, t, J = 3.3 Hz), 6.63 (1H, d, J = 8.7 Hz), 8.35 (1H, d, J = 8.7Hz), 8.40-8.60 (1H, broad)

鉄粉13gのエタノール650mLおよび水350mLの懸濁液に塩化ナトリウム14gを加え、加熱還流下で20分間攪拌した。65℃で６−クロロ−Ｎ−（１，３−ジオキソラン−２−イルメチル）−３−ニトロピリジン−２−アミン10gを加え、加熱還流下で30分間攪拌した。不溶物を濾去し、減圧下で300mLまで溶媒を留去し、酢酸エチルを加え、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー［溶離液；酢酸エチル］で精製し、淡紫色固体の３−アミノ−６−クロロ−２−（１，３−ジオキソラン−２−イルメチル）アミノピリジン6.5gを得た。
¹H-NMR(CDCl₃)δ値：3.15(2H,s),3.68(2H,dd,J=6.0,4.2Hz),3.88-3.98(2H,m),3.98-4.06(2H,m),4.50-4.60(1H,m),5.14(1H,t,J=4.2Hz),6.51(1H,d,J=7.7Hz),6.80(1H,d,J=7.7Hz) Reference Example 51

14 g of sodium chloride was added to a suspension of iron powder 13 g of ethanol 650 mL and water 350 mL, and stirred for 20 minutes under heating and reflux. At 65 ° C., 10 g of 6-chloro-N- (1,3-dioxolan-2-ylmethyl) -3-nitropyridin-2-amine was added, and the mixture was stirred for 30 minutes with heating under reflux. The insoluble material was removed by filtration, the solvent was distilled off to 300 mL under reduced pressure, ethyl acetate was added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography [eluent: ethyl acetate] to give 3-amino-6-chloro-2- (1,3-dioxolan-2-ylmethyl) aminopyridine as a pale purple solid. 6.5 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.15 (2H, s), 3.68 (2H, dd, J = 6.0, 4.2 Hz), 3.88-3.98 (2H, m), 3.98-4.06 (2H, m), 4.50-4.60 (1H, m), 5.14 (1H, t, J = 4.2Hz), 6.51 (1H, d, J = 7.7Hz), 6.80 (1H, d, J = 7.7Hz)

参考例１６と同様の手法により、３−アミノ−６−クロロ−２−（１，３−ジオキソラン−２−イルメチル）アミノピリジンおよびエチル＝オキソアセタートから６−クロロ−４−（１，３−ジオキソラン−２−イルメチル）ピリド（２，３−ｂ）ピラジン−３（４Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：3.87-3.96(2H,m),4.08-4.18(2H,m),4.56(2H,d,J=5.4Hz),5.58(1H,t,J=5.4Hz),7.30(1H,d,J=8.3Hz),8.10(1H,d,J=8.3Hz),8.32(1H,s) Reference Example 52

In the same manner as in Reference Example 16, from 3-amino-6-chloro-2- (1,3-dioxolan-2-ylmethyl) aminopyridine and ethyl oxoacetate to 6-chloro-4- (1,3-dioxolane- 2-ylmethyl) pyrido (2,3-b) pyrazin-3 (4H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.87-3.96 (2H, m), 4.08-4.18 (2H, m), 4.56 (2H, d, J = 5.4Hz), 5.58 (1H, t, J = 5.4 Hz), 7.30 (1H, d, J = 8.3Hz), 8.10 (1H, d, J = 8.3Hz), 8.32 (1H, s)

６−クロロ−４−（１，３−ジオキソラン−２−イルメチル）ピリド（２，３−ｂ）ピラジン−３（４Ｈ）−オン0.10gのＮ，Ｎ−ジメチルホルムアミド3mL溶液に、フッ化セシウム0.57gを加え、90〜100℃で1時間10分間攪拌した。さらにフッ化セシウム0.57gを加え、90〜100℃で1時間30分間攪拌した。酢酸エチルおよび水を加え、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、希塩酸および飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［溶離液；クロロホルム：メタノール＝５０：１］で精製し、淡黄色固体の４−（１，３−ジオキソラン−２−イルメチル）−６−フルオロピリド（２，３−ｂ）ピラジン−３（４Ｈ）−オン60mgを得た。
¹H-NMR(CDCl₃)δ値：3.86-3.96(2H,m),4.06-4.16(2H,m),4.53(2H,d,J=5.4Hz),5.54(1H,t,J=5.4Hz),6.91(1H,dd,J=8.4,2.4Hz),8.25(1H,dd,J=8.4,7.3Hz),8.30(1H,s) Reference Example 53

6-Chloro-4- (1,3-dioxolan-2-ylmethyl) pyrido (2,3-b) pyrazin-3 (4H) -one In a solution of 0.10 g of N, N-dimethylformamide in 3 mL of cesium fluoride 0.57 g was added and it stirred at 90-100 degreeC for 1 hour and 10 minutes. Further, 0.57 g of cesium fluoride was added and stirred at 90 to 100 ° C. for 1 hour and 30 minutes. Ethyl acetate and water were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with dilute hydrochloric acid and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 50: 1] to give 4- (1,3-dioxolan-2-ylmethyl) -6-fluoropyrido (2,2) as a pale yellow solid. 3-b) 60 mg of pyrazin-3 (4H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.86-3.96 (2H, m), 4.06-4.16 (2H, m), 4.53 (2H, d, J = 5.4Hz), 5.54 (1H, t, J = 5.4 Hz), 6.91 (1H, dd, J = 8.4,2.4Hz), 8.25 (1H, dd, J = 8.4,7.3Hz), 8.30 (1H, s)

参考例４と同様の手法により、４−（１，３−ジオキソラン−２−イルメチル）−６−フルオロピリド（２，３−ｂ）ピラジン−３（４Ｈ）−オンから（６−フルオロ−３−オキソピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）アセトアルデヒドを得た。
¹H-NMR(CDCl₃)δ値：5.27(2H,s),6.93(1H,dd,J=8.5,2.4Hz),8.30(1H,dd,J=8.5,7.1Hz),8.34(1H,s),9.75(1H,s) Reference Example 54

In the same manner as in Reference Example 4, 4- (1,3-dioxolan-2-ylmethyl) -6-fluoropyrido (2,3-b) pyrazin-3 (4H) -one was converted to (6-fluoro-3-oxopyrido (2,3-b) pyrazin-4 (3H) -yl) acetaldehyde was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 5.27 (2H, s), 6.93 (1H, dd, J = 8.5, 2.4 Hz), 8.30 (1H, dd, J = 8.5, 7.1 Hz), 8.34 (1H, s), 9.75 (1H, s)

参考例４と同様の手法により、６−クロロ−４−（１，３−ジオキソラン−２−イルメチル）ピリド（２，３−ｂ）ピラジン−３（４Ｈ）−オンから（６−クロロ−３−オキソピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）アセトアルデヒドを得た。
¹H-NMR(CDCl₃)δ値：5.31(2H,s),7.32(1H,d,J=8.3Hz),8.15(1H,d,J=8.3Hz),8.36(1H,s),9.76(1H,s) Reference Example 55

In the same manner as in Reference Example 4, from 6-chloro-4- (1,3-dioxolan-2-ylmethyl) pyrido (2,3-b) pyrazin-3 (4H) -one to (6-chloro-3- Oxopyrido (2,3-b) pyrazin-4 (3H) -yl) acetaldehyde was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 5.31 (2H, s), 7.32 (1H, d, J = 8.3 Hz), 8.15 (1H, d, J = 8.3 Hz), 8.36 (1H, s), 9.76 (1H, s)

６−クロロ−４−（１，３−ジオキソラン−２−イルメチル）ピリド（２，３−ｂ）ピラジン−３（４Ｈ）−オン0.30gおよび１，２，４−トリアゾール78mgのＮ，Ｎ−ジメチルホルムアミド9mL溶液に60％水素化ナトリウム48mgを加え、40〜50℃で1時間30分間攪拌した。さらに１，２，４−トリアゾール78mgおよび60％水素化ナトリウム48mgを加え、40〜50℃で1時間30分間攪拌し、60〜70℃で20分間攪拌した。反応混合物を酢酸エチルおよび水の混合液に加え、2.0mol/L塩酸で中和し、不溶物を濾去した。有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。残留物をフラッシュ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＝８０：２０−３０：７０］で精製し、ジイソプロピルエーテルで洗浄し、淡赤色固体の４−（１，３−ジオキソラン−２−イルメチル）−６−（１Ｈ−１，２，４−トリアゾル−１−イル）ピリド（２，３−ｂ）ピラジン−３（４Ｈ）−オン77mgを得た。
¹H-NMR(CDCl₃)δ値：3.86-3.96(2H,m),4.04-4.14(2H,m),4.67(2H,d,J=4.9Hz),5.47(1H,t,J=4.9Hz),7.93(1H,d,J=8.5Hz),8.16(1H,s),8.34-8.37(2H,m),9.19(1H,s) Reference Example 56

0.30 g of 6-chloro-4- (1,3-dioxolan-2-ylmethyl) pyrido (2,3-b) pyrazin-3 (4H) -one and 78 mg of 1,2,4-triazole N, N-dimethyl 48 mg of 60% sodium hydride was added to 9 mL of formamide, and the mixture was stirred at 40-50 ° C. for 1 hour 30 minutes. Furthermore, 78 mg of 1,2,4-triazole and 48 mg of 60% sodium hydride were added, and the mixture was stirred at 40 to 50 ° C. for 1 hour and 30 minutes and then at 60 to 70 ° C. for 20 minutes. The reaction mixture was added to a mixture of ethyl acetate and water, neutralized with 2.0 mol / L hydrochloric acid, and insolubles were removed by filtration. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by flash silica gel column chromatography [gradient elution of hexane: ethyl acetate = 80: 20-30: 70], washed with diisopropyl ether and washed with 4- (1,3-dioxolane-2- 77 mg of (Ilmethyl) -6- (1H-1,2,4-triazol-1-yl) pyrido (2,3-b) pyrazin-3 (4H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.86-3.96 (2H, m), 4.04-4.14 (2H, m), 4.67 (2H, d, J = 4.9 Hz), 5.47 (1H, t, J = 4.9 Hz), 7.93 (1H, d, J = 8.5Hz), 8.16 (1H, s), 8.34-8.37 (2H, m), 9.19 (1H, s)

シュウ酸モノエチルエステル1.0gのジクロロメタン14mL溶液に、５，６，７，８−テトラヒドロキノキサリン0.47g、濃硫酸91μL、過硫酸ナトリウム1.7gおよび硝酸銀60mgの水14mL懸濁液を加え、1時間30分間加熱還流した。さらに反応混合物に過硫酸ナトリウム1.7g、硝酸銀60mgを加え、1時間50分間加熱還流した。反応混合物にクロロホルムを加え、飽和炭酸水素ナトリウム水溶液でpH7.5に調整し、不溶物を濾去し、有機層を分取した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をフラッシュ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＝９０：１０−６７：３３］で精製し、黄色油状物のエチル＝５，６，７，８−テトラヒドロキノキサリン−２−カルボキシラート0.16gを得た。
¹H-NMR(CDCl₃)δ値：1.44(3H,t,J=7.1Hz),1.92-2.00(4H,m),3.00-3.10(4H,m),4.50(2H,q,J=7.1Hz),9.02(1H,s) Reference Example 57

To a solution of 1.0 g of oxalic acid monoethyl ester in 14 mL of dichloromethane was added a suspension of 0.47 g of 5,6,7,8-tetrahydroquinoxaline, 91 μL of concentrated sulfuric acid, 1.7 g of sodium persulfate, and 60 mg of silver nitrate in 14 mL of water. Heated to reflux for minutes. Furthermore, 1.7 g of sodium persulfate and 60 mg of silver nitrate were added to the reaction mixture, and the mixture was heated to reflux for 1 hour and 50 minutes. Chloroform was added to the reaction mixture, the pH was adjusted to 7.5 with a saturated aqueous sodium hydrogen carbonate solution, the insoluble material was removed by filtration, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash silica gel column chromatography [gradient elution of hexane: ethyl acetate = 90: 10-67: 33], ethyl of yellow oil = 5,6,7,8-tetrahydroquinoxaline-2 -0.16 g of carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.44 (3H, t, J = 7.1 Hz), 1.92-2.00 (4H, m), 3.00-3.10 (4H, m), 4.50 (2H, q, J = 7.1) Hz), 9.02 (1H, s)

エチル＝５，６，７，８−テトラヒドロキノキサリン−２−カルボキシラート0.16gのテトラヒドロフラン1.5mL溶液に、氷冷下、水素化アルミニウムリチウム29mgを加え、45分間攪拌し、さらに水素化アルミニウムリチウム29mgを加え、30分間攪拌した。酢酸エチルおよび水を加え、不溶物を濾去し、濾液に塩化ナトリウムを加え、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、褐色固体の（５，６，７，８−テトラヒドロキノキサリン−２−イル）メタノール0.10gを得た。
¹H-NMR(CDCl₃)δ値：1.89-1.98(4H,m),2.92-3.01(4H,m),4.76(2H,s),8.33(1H,s) Reference Example 58

To a 1.5 mL tetrahydrofuran solution of 0.16 g of ethyl = 5,6,7,8-tetrahydroquinoxaline-2-carboxylate, 29 mg of lithium aluminum hydride was added under ice-cooling, stirred for 45 minutes, and further 29 mg of lithium aluminum hydride was added. Added and stirred for 30 minutes. Ethyl acetate and water were added, insolubles were removed by filtration, sodium chloride was added to the filtrate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, evaporated under reduced pressure to give (5,6,7,8-tetrahydroquinoxalin-2-yl as a brown solid). ) 0.10 g of methanol was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.89-1.98 (4H, m), 2.92-3.01 (4H, m), 4.76 (2H, s), 8.33 (1H, s)

参考例６７と同様の手法により、（５，６，７，８−テトラヒドロキノキサリン−２−イル）メタノールから５，６，７，８−テトラヒドロキノキサリン−２−カルバルデヒドを得た。
¹H-NMR(CDCl₃)δ値：1.96-2.01(4H,m),3.03-3.10(4H,m),8.91(1H,s),10.09(1H,s) Reference Example 59

In the same manner as in Reference Example 67, 5,6,7,8-tetrahydroquinoxaline-2-carbaldehyde was obtained from (5,6,7,8-tetrahydroquinoxalin-2-yl) methanol.
¹ H-NMR (CDCl ₃ ) δ value: 1.96-2.01 (4H, m), 3.03-3.10 (4H, m), 8.91 (1H, s), 10.09 (1H, s)

１−（トリフルオロアセチル）ピペリジン−４−アミン塩酸塩1.0gのジクロロメタン20mL懸濁液に、２，３−ジヒドロ−１，４−ベンゾジオキシン−６−カルバルデヒド0.71gおよび酢酸0.25mLを加え、室温で2時間攪拌した。反応混合物に水素化トリアセトキシホウ素ナトリウム1.37gを加え、同温度で30分間攪拌した。減圧下で溶媒を留去した後、水および酢酸エチルを加え、1mol/L塩酸でpH1.5に調整した。水層を分取し、酢酸エチルで洗浄し、酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液でpH7.8に調整した。有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、無色油状物のＮ−（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）−１−（トリフルオロアセチル）ピペリジン−４−アミン1.4gを得た。
¹H-NMR(CDCl₃)δ値：1.35-1.50(2H,m),1.90-2.00(2H,m),2.80-2.88(1H,m),3.02-3.12(1H,m),3.18-3.28(1H,m),3.71(2H,s),3.90-4.00(1H,m),4.25(4H,s),4.25-4.32(1H,m),6.75-6.83(3H,m) Reference Example 60

To a 20 mL suspension of 1- (trifluoroacetyl) piperidin-4-amine hydrochloride 1.0 g in dichloromethane is added 0.71 g 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde and 0.25 mL acetic acid, Stir at room temperature for 2 hours. To the reaction mixture, 1.37 g of sodium triacetoxyborohydride was added and stirred at the same temperature for 30 minutes. After evaporating the solvent under reduced pressure, water and ethyl acetate were added, and the pH was adjusted to 1.5 with 1 mol / L hydrochloric acid. The aqueous layer was separated, washed with ethyl acetate, ethyl acetate was added, and the pH was adjusted to 7.8 with saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give N- (2,3-dihydro-1,4-benzoate as a colorless oil. 1.4 g of dioxin-6-ylmethyl) -1- (trifluoroacetyl) piperidin-4-amine was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.35-1.50 (2H, m), 1.90-2.00 (2H, m), 2.80-2.88 (1H, m), 3.02-3.12 (1H, m), 3.18-3.28 (1H, m), 3.71 (2H, s), 3.90-4.00 (1H, m), 4.25 (4H, s), 4.25-4.32 (1H, m), 6.75-6.83 (3H, m)

Ｎ−（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）−１−（トリフルオロアセチル）ピペリジン−４−アミン1.4gのジクロロメタン20mL溶液に、ジ−ｔｅｒｔ−ブチル＝ジカルボナート0.88gを加え、室温で30分間攪拌した。トリエチルアミン0.28mLを加え、同温度で10分間攪拌した後、ジ−ｔｅｒｔ−ブチル＝ジカルボナート0.44gを追加し、10分間攪拌した。40℃で30分間攪拌した後、減圧下で溶媒を留去し、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［溶離液；ヘキサン：酢酸エチル＝１：１］で精製し、白色泡状物のｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（１−（トリフルオロアセチル）ピペリジン−４−イル）カルバマート1.4gを得た。
¹H-NMR(CDCl₃)δ値：1.44(9H,s),1.60-1.82(4H,m),2.60-2.80(1H,m),3.00-3.20(1H,m),3.95-4.05(1H,m),4.15-4.40(3H,m),4.25(4H,s),4.50-4.65(1H,m),6.60-6.75(2H,m),6.70-6.73(1H,m),6.79(1H,d,J=8.3Hz) Reference Example 61

N- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -1- (trifluoroacetyl) piperidin-4-amine (1.4 g) in dichloromethane (20 mL) was added di-tert-butyl dicarbonate (0.88 g). And stirred at room temperature for 30 minutes. After adding 0.28 mL of triethylamine and stirring for 10 minutes at the same temperature, 0.44 g of di-tert-butyl = dicarbonate was added and stirred for 10 minutes. After stirring at 40 ° C. for 30 minutes, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 1: 1] to give a white foam. 1.4 g of tert-butyl = (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (1- (trifluoroacetyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.44 (9H, s), 1.60-1.82 (4H, m), 2.60-2.80 (1H, m), 3.00-3.20 (1H, m), 3.95-4.05 (1H , m), 4.15-4.40 (3H, m), 4.25 (4H, s), 4.50-4.65 (1H, m), 6.60-6.75 (2H, m), 6.70-6.73 (1H, m), 6.79 (1H , d, J = 8.3Hz)

ｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（1-（トリフルオロアセチル）ピペリジン−４−イル）カルバマート1.4gのメタノール20mL溶液に、水5mLおよび炭酸カリウム0.53gを加え、室温で1時間15分間攪拌した。減圧下で溶媒を留去し、酢酸エチルおよび水を加えた。有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、淡黄色油状物のｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（ピペリジン−４−イル）カルバマート1.0gを得た。
¹H-NMR(CDCl₃)δ値：1.42(9H,s),1.35-1.70(4H,m),2.55-2.70(2H,m),3.05-3.15(2H,m),4.15-4.35(3H,m),4.24(4H,s),6.66-6.71(1H,m),6.73-6.75(1H,m),6.78(1H,d,J=8.3Hz) Reference Example 62

tert-butyl = (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (1- (trifluoroacetyl) piperidin-4-yl) carbamate 1.4 g in methanol 20 mL solution, water 5 mL and potassium carbonate 0.53 g was added and stirred at room temperature for 1 hour and 15 minutes. The solvent was distilled off under reduced pressure, and ethyl acetate and water were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and tert-butyl = (2,3-dihydro 1.0 g of -1,4-benzodioxin-6-ylmethyl) (piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.42 (9H, s), 1.35-1.70 (4H, m), 2.55-2.70 (2H, m), 3.05-3.15 (2H, m), 4.15-4.35 (3H , m), 4.24 (4H, s), 6.66-6.71 (1H, m), 6.73-6.75 (1H, m), 6.78 (1H, d, J = 8.3Hz)

参考例６０と同様の手法により、１−（トリフルオロアセチル）ピペリジン−４−アミン塩酸塩および２，３−ジヒドロ−１，４−ジオキシノ（２，３−ｃ）ピリジン−７−カルバルデヒドからＮ−（２，３−ジヒドロ−１，４−ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）−１−（トリフルオロアセチル）ピペリジン−４−アミンを得た。
¹H-NMR(CDCl₃)δ値：1.39-1.51(2H,m),1.93-2.01(2H,m),2.79-2.88(1H,m),3.02-3.10(1H,m),3.19-3.27(1H,m),3.80(2H,s),3.90-3.99(1H,m),4.25-4.35(5H,m),6.80(1H,s),8.11(1H,s) Reference Example 63

In the same manner as in Reference Example 60, 1- (trifluoroacetyl) piperidin-4-amine hydrochloride and 2,3-dihydro-1,4-dioxyno (2,3-c) pyridine-7-carbaldehyde were converted to N -(2,3-Dihydro-1,4-dioxyno (2,3-c) pyridin-7-ylmethyl) -1- (trifluoroacetyl) piperidin-4-amine was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.39-1.51 (2H, m), 1.93-2.01 (2H, m), 2.79-2.88 (1H, m), 3.02-3.10 (1H, m), 3.19-3.27 (1H, m), 3.80 (2H, s), 3.90-3.99 (1H, m), 4.25-4.35 (5H, m), 6.80 (1H, s), 8.11 (1H, s)

参考例６１と同様の手法により、Ｎ−（２，３−ジヒドロ−１，４−ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）−１−（トリフルオロアセチル）ピペリジン−４−アミンからｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（トリフルオロアセチル）ピペリジン−４−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.43(9H,s),1.37-1.84(4H,m),2.60-2.80(1H,m),3.00-3.20(1H,m),3.98-4.06(1H,m),4.25-4.41(7H,m),4.54-4.62(1H,m),6.74(1H,s),8.05(1H,s) Reference Example 64

In the same manner as in Reference Example 61, N- (2,3-dihydro-1,4-dioxyno (2,3-c) pyridin-7-ylmethyl) -1- (trifluoroacetyl) piperidin-4-amine tert-Butyl = (2,3-dihydro-1,4-dioxyno (2,3-c) pyridin-7-ylmethyl) (1- (trifluoroacetyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.43 (9H, s), 1.37-1.84 (4H, m), 2.60-2.80 (1H, m), 3.00-3.20 (1H, m), 3.98-4.06 (1H , m), 4.25-4.41 (7H, m), 4.54-4.62 (1H, m), 6.74 (1H, s), 8.05 (1H, s)

参考例６２と同様の手法により、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（トリフルオロアセチル）ピペリジン−４−イル）カルバマートからｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（ピペリジン−４−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.39(9H,s),1.34-1.71(4H,m),2.52-2.70(2H,m),3.04-3.11(2H,m),4.11-4.48(7H,m),6.75(1H,s),8.05(1H,s) Reference Example 65

In the same manner as in Reference Example 62, tert-butyl = (2,3-dihydro-1,4-dioxyno (2,3-c) pyridin-7-ylmethyl) (1- (trifluoroacetyl) piperidine-4- Yl) carbamate gave tert-butyl = (2,3-dihydro-1,4-dioxyno (2,3-c) pyridin-7-ylmethyl) (piperidin-4-yl) carbamate.
¹ H-NMR (CDCl ₃ ) δ value: 1.39 (9H, s), 1.34-1.71 (4H, m), 2.52-2.70 (2H, m), 3.04-3.11 (2H, m), 4.11-4.48 (7H , m), 6.75 (1H, s), 8.05 (1H, s)

５−ヒドロキシ−２−（ヒドロキシメチル）−１，４−ジヒドロピリジン−４−オン二ナトリウム塩0.11kgのジメチルスルホキシド溶液600mLに、炭酸カリウム0.25kgおよび１−ブロモ−３−クロロプロパン81mLを加え、80〜90℃で3時間20分間、90〜100℃で45分間、さらに80〜95℃で5時間攪拌した。反応混合物を室温まで冷却後、水およびクロロホルムを加え、不溶物を濾去した。有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、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［溶離液；クロロホルム：メタノール＝１０：１］で精製し、褐色油状物の（３，４−ジヒドロ−２Ｈ−（１，４）ジオキセピノ（２，３−ｃ）ピリジン−８−イル）メタノール31gを得た。
¹H-NMR(CDCl₃)δ値：2.23-2.30(2H,m),4.24-4.28(2H,m),4.33-4.37(2H,m),4.63(2H,s),6.82(1H,s),8.19(1H,s) Reference Example 66

To 600 mL of a dimethyl sulfoxide solution of 0.11 kg of 5-hydroxy-2- (hydroxymethyl) -1,4-dihydropyridin-4-one disodium salt, 0.25 kg of potassium carbonate and 81 mL of 1-bromo-3-chloropropane were added, and The mixture was stirred at 90 ° C for 3 hours and 20 minutes, at 90 to 100 ° C for 45 minutes, and further at 80 to 95 ° C for 5 hours. The reaction mixture was cooled to room temperature, water and chloroform were added, and the insoluble material was removed by filtration. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent; chloroform: methanol = 10: 1] 31 g of (3,4-dihydro-2H- (1,4) dioxepino (2,3-c) pyridin-8-yl) methanol as a brown oil was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.23-2.30 (2H, m), 4.24-4.28 (2H, m), 4.33-4.37 (2H, m), 4.63 (2H, s), 6.82 (1H, s ), 8.19 (1H, s)

（３，４−ジヒドロ−２Ｈ−（１，４）ジオキセピノ（２，３−ｃ）ピリジン−８−イル）メタノール13gのクロロホルム溶液250mLに二酸化マンガン13gを加え、室温で30分間攪拌した。さらに、二酸化マンガン20gを分割して加えた後、室温で20分間、60〜70℃で1時間30分間攪拌した。反応混合物を室温まで冷却後、不溶物を濾去し、減圧下で溶媒を留去した。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［溶離液；ヘキサン：酢酸エチル＝１：１］で精製し、淡黄白色固体の３，４−ジヒドロ−２Ｈ−（１，４）ジオキセピノ（２，３−ｃ）ピリジン−８−カルバルデヒド2.2gを得た。
¹H-NMR(CDCl₃)δ値：2.28-2.35(2H,m),4.36-4.43(4H,m),7.53(1H,s),8.36(1H,s),9.94(1H,s) Reference Example 67

13 g of manganese dioxide was added to 250 ml of a chloroform solution of 13 g of (3,4-dihydro-2H- (1,4) dioxepino (2,3-c) pyridin-8-yl) methanol, and the mixture was stirred at room temperature for 30 minutes. Further, 20 g of manganese dioxide was added in portions, followed by stirring at room temperature for 20 minutes and at 60 to 70 ° C. for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 1: 1] to give 3,4-dihydro-2H- (1,4) dioxepino (2,3) as a pale yellowish white solid. -C) 2.2 g of pyridine-8-carbaldehyde was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.28-2.35 (2H, m), 4.36-4.43 (4H, m), 7.53 (1H, s), 8.36 (1H, s), 9.94 (1H, s)

参考例６０と同様の手法により、１−（トリフルオロアセチル）ピペリジン−４−アミン塩酸塩および３，４−ジヒドロ−２Ｈ−（１，４）ジオキセピノ（２，３−ｃ）ピリジン−８−カルバルデヒドからＮ−（３，４−ジヒドロ−２Ｈ−（１，４）ジオキセピノ（２，３−ｃ）ピリジン−８−イルメチル）−１−（トリフルオロアセチル）ピペリジン−４−アミンを得た。
¹H-NMR(CDCl₃)δ値：1.39-1.52(2H,m),1.93-2.01(2H,m),2.12-2.30(2H,m),2.80-2.88(1H,m),3.01-3.11(1H,m),3.18-3.28(1H,m),3.81(2H,s),3.90-3.99(1H,m),4.21-4.38(5H,m),6.85(1H,s),8.18(1H,s) Reference Example 68

In the same manner as in Reference Example 60, 1- (trifluoroacetyl) piperidin-4-amine hydrochloride and 3,4-dihydro-2H- (1,4) dioxepino (2,3-c) pyridine-8-carba N- (3,4-dihydro-2H- (1,4) dioxepino (2,3-c) pyridin-8-ylmethyl) -1- (trifluoroacetyl) piperidin-4-amine was obtained from aldehyde.
¹ H-NMR (CDCl ₃ ) δ value: 1.39-1.52 (2H, m), 1.93-2.01 (2H, m), 2.12-2.30 (2H, m), 2.80-2.88 (1H, m), 3.01-3.11 (1H, m), 3.18-3.28 (1H, m), 3.81 (2H, s), 3.90-3.99 (1H, m), 4.21-4.38 (5H, m), 6.85 (1H, s), 8.18 (1H , s)

参考例６１と同様の手法により、Ｎ−（３，４−ジヒドロ−２Ｈ−（１，４）ジオキセピノ(２，３−ｃ)ピリジン−８−イルメチル）−１−（トリフルオロアセチル）ピペリジン−４−アミンからｔｅｒｔ−ブチル＝（３，４−ジヒドロ−２Ｈ−（１，４）ジオキセピノ(２，３−ｃ)ピリジン−８−イルメチル）（１−（トリフルオロアセチル）ピペリジン−４−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.41(9H,s),1.55-1.90(4H,m),2.20-2.30(2H,m),2.65-2.80(1H,m),3.04-3.21(1H,m),3.70-4.50(8H,m),4.55-4.64(1H,m),6.78(1H,s),8.13(1H,s) Reference Example 69

In the same manner as in Reference Example 61, N- (3,4-dihydro-2H- (1,4) dioxepino (2,3-c) pyridin-8-ylmethyl) -1- (trifluoroacetyl) piperidine-4 -Amine to tert-butyl = (3,4-dihydro-2H- (1,4) dioxepino (2,3-c) pyridin-8-ylmethyl) (1- (trifluoroacetyl) piperidin-4-yl) carbamate Got.
¹ H-NMR (CDCl ₃ ) δ value: 1.41 (9H, s), 1.55-1.90 (4H, m), 2.20-2.30 (2H, m), 2.65-2.80 (1H, m), 3.04-3.21 (1H , m), 3.70-4.50 (8H, m), 4.55-4.64 (1H, m), 6.78 (1H, s), 8.13 (1H, s)

参考例６２と同様の手法により、ｔｅｒｔ−ブチル＝（３，４−ジヒドロ−２Ｈ−（１，４）ジオキセピノ（２，３−ｃ）ピリジン−８−イルメチル）（１−（トリフルオロアセチル）ピペリジン−４−イル）カルバマートからｔｅｒｔ−ブチル＝（３，４−ジヒドロ−２Ｈ−（１，４）ジオキセピノ（２，３−ｃ）ピリジン−８−イルメチル）（ピペリジン−４−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.40-1.72(13H,m),2.17-2.28(2H,m),2.50-2.70(2H,m),3.01-3.11(2H,m),4.10-4.50(7H,m),6.79(1H,s),8.13(1H,s) Reference Example 70

In the same manner as in Reference Example 62, tert-butyl = (3,4-dihydro-2H- (1,4) dioxepino (2,3-c) pyridin-8-ylmethyl) (1- (trifluoroacetyl) piperidine -4-yl) carbamate gave tert-butyl = (3,4-dihydro-2H- (1,4) dioxepino (2,3-c) pyridin-8-ylmethyl) (piperidin-4-yl) carbamate .
¹ H-NMR (CDCl ₃ ) δ value: 1.40-1.72 (13H, m), 2.17-2.28 (2H, m), 2.50-2.70 (2H, m), 3.01-3.11 (2H, m), 4.10-4.50 (7H, m), 6.79 (1H, s), 8.13 (1H, s)

参考例１と同様の手法により、２，５−ジクロロピリジン−３−アミンおよびエチル＝アクリラートからエチル＝（２Ｅ）−３−（３−アミノ−５−クロロピリジン−２−イル）アクリラートおよびエチル＝（２Ｅ）−３−（６−オキソ−５，６−ジヒドロ−１，５−ナフチリジン−３−イル）アクリラートを得た。
エチル＝（２Ｅ）−３−（３−アミノ−５−クロロピリジン−２−イル）アクリラート
¹H-NMR(CDCl₃)δ値：1.33(3H,t,J=7.1Hz),4.04(2H,s),4.27(2H,q,J=7.1Hz),6.91(1H,d,J=15.2Hz),7.01(1H,d,J=2.0Hz),7.71(1H,d,J=15.2Hz),8.00(1H,d,J=2.0Hz)
エチル＝（２Ｅ）−３−（６−オキソ−５，６−ジヒドロ−１，５−ナフチリジン−３−イル）アクリラート
¹H-NMR(DMSO-d₆)δ値：1.28(3H,t,J=7.1Hz),4.22(2H,q,J=7.1Hz),6.77(1H,d,J=16.0Hz),6.78(1H,d,J=9.5Hz),7.75(1H,d,J=16.0Hz),7.80-7.84(1H,m),7.94(1H,d,J=9.5Hz),8.82-8.87(1H,m),11.98(1H,ｓ) Reference Example 71

In the same manner as in Reference Example 1, 2,5-dichloropyridin-3-amine and ethyl acrylate to ethyl (2E) -3- (3-amino-5-chloropyridin-2-yl) acrylate and ethyl = (2E) -3- (6-Oxo-5,6-dihydro-1,5-naphthyridin-3-yl) acrylate was obtained.
Ethyl = (2E) -3- (3-amino-5-chloropyridin-2-yl) acrylate
¹ H-NMR (CDCl ₃ ) δ value: 1.33 (3H, t, J = 7.1 Hz), 4.04 (2H, s), 4.27 (2H, q, J = 7.1 Hz), 6.91 (1H, d, J = 15.2Hz), 7.01 (1H, d, J = 2.0Hz), 7.71 (1H, d, J = 15.2Hz), 8.00 (1H, d, J = 2.0Hz)
Ethyl = (2E) -3- (6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl) acrylate
¹ H-NMR (DMSO-d ₆ ) δ value: 1.28 (3H, t, J = 7.1 Hz), 4.22 (2H, q, J = 7.1 Hz), 6.77 (1H, d, J = 16.0 Hz), 6.78 (1H, d, J = 9.5Hz), 7.75 (1H, d, J = 16.0Hz), 7.80-7.84 (1H, m), 7.94 (1H, d, J = 9.5Hz), 8.82-8.87 (1H, m), 11.98 (1H, s)

参考例３と同様の手法により、エチル＝（２Ｅ）−３−（６−オキソ−５，６−ジヒドロ−１，５−ナフチリジン−３−イル）アクリラートおよび２−ブロモメチル−１，３−ジオキソランからエチル＝（２Ｅ）−３−（５−（１，３−ジオキソラン−２−イルメチル）−６−オキソ−５，６−ジヒドロ−１，５−ナフチリジン−３−イル）アクリラートを得た。
¹H-NMR(CDCl₃)δ値：1.38(3H,t,J=7.1Hz),3.84-3.93(2H,m),3.96-4.06(2H,m),4.32(2H,q,J=7.1Hz),4.53(2H,d,J=4.1Hz),5.20(1H,t,J=4.1Hz),6.63(1H,d,J=16.1Hz),6.96(1H,d,J=9.8Hz),7.77(1H,d,J=16.1Hz),7.91(1H,d,J=9.8Hz),8.03-8.06(1H,m),8.68(1H,d,J=1.7Hz) Reference Example 72

In the same manner as in Reference Example 3, from ethyl = (2E) -3- (6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl) acrylate and 2-bromomethyl-1,3-dioxolane Ethyl = (2E) -3- (5- (1,3-dioxolan-2-ylmethyl) -6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl) acrylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.38 (3H, t, J = 7.1 Hz), 3.84 to 3.93 (2H, m), 3.96 to 4.06 (2H, m), 4.32 (2H, q, J = 7.1) Hz), 4.53 (2H, d, J = 4.1Hz), 5.20 (1H, t, J = 4.1Hz), 6.63 (1H, d, J = 16.1Hz), 6.96 (1H, d, J = 9.8Hz) , 7.77 (1H, d, J = 16.1Hz), 7.91 (1H, d, J = 9.8Hz), 8.03-8.06 (1H, m), 8.68 (1H, d, J = 1.7Hz)

参考例４と同様の手法により、エチル＝（２Ｅ）−３−（５−（１，３−ジオキソラン−２−イルメチル）−６−オキソ−５，６−ジヒドロ−１，５−ナフチリジン−３−イル）アクリラートからエチル＝（２Ｅ）−３−（６−オキソ−５−（２−オキソエチル）−５，６−ジヒドロ−１，５−ナフチリジン−３−イル）アクリラートを得た。
¹H-NMR(CDCl₃)δ値：1.36(3H,t,J=7.2Hz),4.30(2H,q,J=7.2Hz),5.19(2H,s),6.59(1H,d,J=16.1Hz),7.00(1H,d,J=9.8Hz),7.34-7.38(1H,m),7.71(1H,d,J=16.1Hz),7.99(1H,d,J=9.8Hz),8.72(1H,d,J=1.5Hz),9.79(1H,s) Reference Example 73

In the same manner as in Reference Example 4, ethyl = (2E) -3- (5- (1,3-dioxolan-2-ylmethyl) -6-oxo-5,6-dihydro-1,5-naphthyridine-3- Yl) acrylate gave ethyl = (2E) -3- (6-oxo-5- (2-oxoethyl) -5,6-dihydro-1,5-naphthyridin-3-yl) acrylate.
¹ H-NMR (CDCl ₃ ) δ value: 1.36 (3H, t, J = 7.2 Hz), 4.30 (2H, q, J = 7.2 Hz), 5.19 (2H, s), 6.59 (1H, d, J = 16.1Hz), 7.00 (1H, d, J = 9.8Hz), 7.34-7.38 (1H, m), 7.71 (1H, d, J = 16.1Hz), 7.99 (1H, d, J = 9.8Hz), 8.72 (1H, d, J = 1.5Hz), 9.79 (1H, s)

参考例２と同様の手法により、エチル＝（２Ｅ）−３−（３−アミノ−５−クロロピリジン−２−イル）アクリラートから７−クロロ−１，５−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(DMSO-d₆)δ値：6.77(1H,d,J=9.8Hz),7.70-7.73(1H,m),7.94(1H,d,J=9.8Hz),8.49(1H,d,J=2.2Hz),11.95-12.05(1H,broad) Reference Example 74

In the same manner as in Reference Example 2, ethyl 7-chloro-1,5-naphthyridin-2 (1H) -one was converted from ethyl = (2E) -3- (3-amino-5-chloropyridin-2-yl) acrylate. Obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 6.77 (1H, d, J = 9.8 Hz), 7.70-7.73 (1H, m), 7.94 (1H, d, J = 9.8 Hz), 8.49 (1H, d, J = 2.2Hz), 11.95-12.05 (1H, broad)

参考例３と同様の手法により、７−クロロ−１，５−ナフチリジン−２（１Ｈ）−オンおよび２−ブロモメチル−１，３−ジオキソランから７−クロロ−１−（１，３−ジオキソラン−２−イルメチル）−１，５−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：3.84-4.06(4H,m),4.46(2H,d,J=4.2Hz),5.20(1H,t,J=4.2Hz),6.92(1H,d,J=9.8Hz),7.89(1H,d,J=9.8Hz),7.96(1H,d,J=2.0Hz),8.46(1H,d,J=2.0Hz) Reference Example 75

In the same manner as in Reference Example 3, 7-chloro-1,5-naphthyridin-2 (1H) -one and 2-bromomethyl-1,3-dioxolane were converted to 7-chloro-1- (1,3-dioxolane-2. -Ilmethyl) -1,5-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.84-4.06 (4H, m), 4.46 (2H, d, J = 4.2Hz), 5.20 (1H, t, J = 4.2Hz), 6.92 (1H, d, J = 9.8Hz), 7.89 (1H, d, J = 9.8Hz), 7.96 (1H, d, J = 2.0Hz), 8.46 (1H, d, J = 2.0Hz)

参考例４と同様の手法により、７−クロロ−１−（１，３−ジオキソラン−２−イルメチル）−１，５−ナフチリジン−２（１Ｈ）−オンから（７−クロロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒドを得た。
¹H-NMR(CDCl₃)δ値：5.13(2H,s),6.96(1H,d,J=9.9Hz),7.31-7.33(1H,m),7.96(1H,d,J=9.9Hz),8.51(1H,d,J=2.0Hz),9.78(1H,s) Reference Example 76

In the same manner as in Reference Example 4, from 7-chloro-1- (1,3-dioxolan-2-ylmethyl) -1,5-naphthyridin-2 (1H) -one to (7-chloro-2-oxo-1 , 5-Naphthyridin-1 (2H) -yl) acetaldehyde was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 5.13 (2H, s), 6.96 (1H, d, J = 9.9Hz), 7.31-7.33 (1H, m), 7.96 (1H, d, J = 9.9Hz) , 8.51 (1H, d, J = 2.0Hz), 9.78 (1H, s)

（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド0.16gのジクロロメタン2mL溶液に、ｔｅｒｔ−ブチル＝（ピペリジン−４−イル）カルバマート0.14g、酢酸41μLおよび水素化トリアセトキシホウ素ナトリウム0.23gを加え、室温で1時間30分間攪拌した。クロロホルムおよび飽和炭酸水素ナトリウム水溶液を加え、pH8.5に調整し、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝19：1］で精製し、黄色油状物のｔｅｒｔ−ブチル＝（１−（２−（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.23gを得た。
¹H-NMR(CDCl₃)δ値：1.36-1.48(2H,m),1.45(9H,s),1.91-1.99(2H,m),2.22-2.31(2H,m),2.61-2.68(2H,m),2.90-2.97(2H,m),3.42-3.54(1H,m),3.98(3H,s),4.32-4.47(3H,m),6.74(1H,d,J=9.8Hz),7.18(1H,d,J=2.3Hz),7.84(1H,d,J=9.8Hz),8.28(1H,d,J=2.3Hz) Reference Example 77

To a solution of 0.17 g of (7-methoxy-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde in 2 mL of dichloromethane, 0.14 g of tert-butyl = (piperidin-4-yl) carbamate, 41 μL of acetic acid and hydrogen 0.23 g of sodium triacetoxyborohydride was added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to adjust to pH 8.5, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography [eluent: chloroform: methanol = 19: 1], and tert-butyl = (1- (2- (7-methoxy-2-oxo 0.23 g of -1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.36-1.48 (2H, m), 1.45 (9H, s), 1.91-1.99 (2H, m), 2.22-2.31 (2H, m), 2.61-2.68 (2H , m), 2.90-2.97 (2H, m), 3.42-3.54 (1H, m), 3.98 (3H, s), 4.32-4.47 (3H, m), 6.74 (1H, d, J = 9.8Hz), 7.18 (1H, d, J = 2.3Hz), 7.84 (1H, d, J = 9.8Hz), 8.28 (1H, d, J = 2.3Hz)

ｔｅｒｔ−ブチル＝（１−（２−（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.23gのエタノール5mL溶液に、室温で6.0mol/L塩化水素／エタノール溶液5mLを加え、1時間攪拌した。減圧下で溶媒を留去し、得られた残留物にジエチルエーテルを加え、固形物を濾取し、淡黄色固体の１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.22gを得た。
¹H-NMR(D₂O)δ値：1.93-2.07(2H,m),2.34-2.44(2H,m),3.20-3.33(2H,m),3.57-3.67(3H,m),3.90-4.01(2H,m),4.05(3H,s),4.73-4.85(2H,m),6.89(1H,d,J=9.8Hz),7.50(1H,d,J=2.3Hz),8.06(1H,d,J=9.8Hz),8.42(1H,d,J=2.3Hz) Reference Example 78

tert-Butyl = (1- (2- (7-methoxy-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate 0.23 g in a 5 mL ethanol solution at room temperature Then, 5 mL of 6.0 mol / L hydrogen chloride / ethanol solution was added and stirred for 1 hour. The solvent was distilled off under reduced pressure, diethyl ether was added to the obtained residue, and the solid was collected by filtration to give 1- (2- (4-aminopiperidin-1-yl) ethyl) -7 as a pale yellow solid. 0.22 g of -methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.93-2.07 (2H, m), 2.34-2.44 (2H, m), 3.20-3.33 (2H, m), 3.57-3.67 (3H, m), 3.90- 4.01 (2H, m), 4.05 (3H, s), 4.73-4.85 (2H, m), 6.89 (1H, d, J = 9.8Hz), 7.50 (1H, d, J = 2.3Hz), 8.06 (1H , d, J = 9.8Hz), 8.42 (1H, d, J = 2.3Hz)

１，８−ナフチリジン−２（１Ｈ）−オン0.15gのＮ，Ｎ−ジメチルホルムアミド2mL溶液に、60％水素化ナトリウム45mgを加え、50〜65℃で1時間攪拌した。１−ｔｅｒｔ−ブチル＝４−エチル＝４−（３−（（メチルスルホニル）オキシ）プロピル）ピペリジン−１，４−ジカルボキシラート0.44gのＮ，Ｎ−ジメチルホルムアミド溶液1.2mLを加え、反応混合物を80〜90℃で1時間30分間攪拌し、室温まで冷却後、水および酢酸エチルを加え、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、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［溶離液；ヘキサン：酢酸エチル＝３：２］で精製し、無色油状物の１−ｔｅｒｔ−ブチル＝４−エチル＝４−（３−（２−オキソ−１，８−ナフチリジン−１（２Ｈ）−イル）プロピル）ピペリジン−１，４−ジカルボキシラート0.29gを得た。
¹H-NMR(CDCl₃)δ値：1.22(3H,t,J=7.1Hz),1.32-1.41(2H,m),1.44(9H,s),1.65-1.72(4H,m),2.05-2.11(2H,m),2.80-3.00(2H,m),3.75-4.00(2H,m),4.13(2H,q,J=7.1Hz),4.43-4.48(2H,m),6.72(1H,d,J=9.5Hz),7.18(1H,dd,J=7.7,4.7Hz),7.65(1H,d,J=9.5Hz),7.88(1H,dd,J=7.7,1.8Hz),8.57(1H,dd,J=4.7,1.8Hz) Reference Example 79

To a solution of 0.18 g of 1,8-naphthyridin-2 (1H) -one in 2 mL of N, N-dimethylformamide was added 45 mg of 60% sodium hydride, and the mixture was stirred at 50 to 65 ° C. for 1 hour. 1-tert-butyl = 4-ethyl = 4- (3-((methylsulfonyl) oxy) propyl) piperidine-1,4-dicarboxylate (0.44 g) in N, N-dimethylformamide solution (1.2 mL) was added, and the reaction mixture was added. The mixture was stirred at 80 to 90 ° C. for 1 hour and 30 minutes, cooled to room temperature, water and ethyl acetate were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography [eluent: hexane: ethyl acetate. = 3: 2], 1-tert-butyl = 4-ethyl = 4- (3- (2-oxo-1,8-naphthyridin-1 (2H) -yl) propyl) piperidine- 0.29 g of 1,4-dicarboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.22 (3H, t, J = 7.1 Hz), 1.32-1.41 (2H, m), 1.44 (9H, s), 1.65-1.72 (4H, m), 2.05- 2.11 (2H, m), 2.80-3.00 (2H, m), 3.75-4.00 (2H, m), 4.13 (2H, q, J = 7.1Hz), 4.43-4.48 (2H, m), 6.72 (1H, d, J = 9.5Hz), 7.18 (1H, dd, J = 7.7,4.7Hz), 7.65 (1H, d, J = 9.5Hz), 7.88 (1H, dd, J = 7.7,1.8Hz), 8.57 ( (1H, dd, J = 4.7,1.8Hz)

１−ｔｅｒｔ−ブチル＝４−エチル＝（４−（３−（２−オキソー１，８−ナフチリジン−１（２Ｈ）−イル）プロピル）ピペリジン−１，４−ジカルボキシラート0.53gのクロロホルム6mL溶液にトリフルオロ酢酸25mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物に飽和炭酸水素ナトリウム水溶液を加え、中和後、クロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、無色油状物のエチル＝４−（３−（２−オキソ−１，８−ナフチリジン−１（２Ｈ）−イル）プロピル）ピペリジン−４−カルボキシラート0.47gを得た。
¹H-NMR(CDCl₃)δ値：1.22(3H,t,J=7.1Hz),1.45-1.54(2H,m),1.64-1.71(4H,m),2.12-2.20(2H,m),2.67-2.78(2H,m),3.02-3.08(2H,m),4.14(2H,q,J=7.1Hz),4.41-4.47(3H,m),6.73(1H,d,J=9.5Hz),7.17(1H,dd,J=7.6,4.7Hz),7.64(1H,d,J=9.5Hz),7.87(1H,dd,J=7.6,1.7Hz),8.57(1H,dd,J=4.7,1.7Hz) Reference Example 80

1-tert-butyl = 4-ethyl = (4- (3- (2-oxo-1,8-naphthyridin-1 (2H) -yl) propyl) piperidine-1,4-dicarboxylate 0.53 g in 6 mL chloroform 25 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours, the solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, neutralized, and chloroform was added to separate the organic layer. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a colorless oily ethyl = 4. 0.47 g of-(3- (2-oxo-1,8-naphthyridin-1 (2H) -yl) propyl) piperidine-4-carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.22 (3H, t, J = 7.1 Hz), 1.45-1.54 (2H, m), 1.64-1.71 (4H, m), 2.12-2.20 (2H, m), 2.67-2.78 (2H, m), 3.02-3.08 (2H, m), 4.14 (2H, q, J = 7.1Hz), 4.41-4.47 (3H, m), 6.73 (1H, d, J = 9.5Hz) , 7.17 (1H, dd, J = 7.6,4.7Hz), 7.64 (1H, d, J = 9.5Hz), 7.87 (1H, dd, J = 7.6,1.7Hz), 8.57 (1H, dd, J = 4.7 , 1.7Hz)

参考例７９と同様の手法により、１，７−ナフチリジン−２（１Ｈ）−オンおよび１−ｔｅｒｔ−ブチル＝４−エチル＝４−（３−（（メタンスルホニル）オキシ）プロピル）ピペリジン−１，４−ジカルボキシラートから1−ｔｅｒｔ−ブチル＝４−エチル＝４−（３−（２−オキソ−１，７−ナフチリジン−１（２Ｈ）−イル）プロピル）ピペリジン−１，４−ジカルボキシラートを得た。
¹H-NMR(CDCl₃)δ値：1.20-1.74(9H,m),1.44(9H,s),2.05-2.13(2H,m),2.74-2.95(2H,m),3.77-3.95(2H,m),4.14(2H,q,J=7.1Hz),4.26-4.31(2H,m),6.89(1H,d,J=9.5Hz),7.43(1H,d,J=5.1Hz),7.65(1H,d,J=9.5Hz),8.45(1H,d,J=5.1Hz),8.74(1H,s) Reference Example 81

In the same manner as in Reference Example 79, 1,7-naphthyridin-2 (1H) -one and 1-tert-butyl = 4-ethyl = 4- (3-((methanesulfonyl) oxy) propyl) piperidine-1, 4-dicarboxylate to 1-tert-butyl = 4-ethyl = 4- (3- (2-oxo-1,7-naphthyridin-1 (2H) -yl) propyl) piperidine-1,4-dicarboxylate Got.
¹ H-NMR (CDCl ₃ ) δ value: 1.20-1.74 (9H, m), 1.44 (9H, s), 2.05-2.13 (2H, m), 2.74-2.95 (2H, m), 3.77-3.95 (2H , m), 4.14 (2H, q, J = 7.1Hz), 4.26-4.31 (2H, m), 6.89 (1H, d, J = 9.5Hz), 7.43 (1H, d, J = 5.1Hz), 7.65 (1H, d, J = 9.5Hz), 8.45 (1H, d, J = 5.1Hz), 8.74 (1H, s)

１−ｔｅｒｔ−ブチル＝４−エチル＝４−（３−（２−オキソ−１，７−ナフチリジン−１（２Ｈ）−イル）プロピル）ピペリジン−１，４−ジカルボキシラート0.50gのエタノール3mL溶液に4.0mol/L塩化水素／酢酸エチル溶液3.0mLを加え、室温で1時間攪拌した。4.0mol/L塩化水素／酢酸エチル溶液2.0mLを加え、室温で1時間攪拌した。固形物を濾取し、淡黄色固体のエチル＝４−（３−（２−オキソ−１，７−ナフチリジン−１（２Ｈ）−イル）プロピル）ピペリジン−４−カルボキシラート塩酸塩0.29gを得た。
¹H-NMR(DMSO-d₆)δ値：1.11(3H,t,J=7.1Hz),1.48-1.58(2H,m),1.62-1.72(4H,m),2.03-2.11(2H,m),2.70-2.82(2H,m),3.14-3.25(2H,m),4.07(2H,q,J=7.1Hz),4.24-4.30(2H,m),7.03(1H,d,J=9.5Hz),8.02(1H,d,J=5.4Hz),8.09(1H,d,J=9.5Hz),8.54(1H,d,J=5.4Hz),8.88-9.07(2H,m),9.17(1H,s) Reference Example 82

1-tert-butyl = 4-ethyl = 4- (3- (2-oxo-1,7-naphthyridin-1 (2H) -yl) propyl) piperidine-1,4-dicarboxylate 0.50 g in 3 mL of ethanol To the solution, 3.0 mL of 4.0 mol / L hydrogen chloride / ethyl acetate solution was added and stirred at room temperature for 1 hour. A 2.0 mol / L hydrogen chloride / ethyl acetate solution (2.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. The solid was collected by filtration to obtain 0.29 g of ethyl 4- (3- (2-oxo-1,7-naphthyridin-1 (2H) -yl) propyl) piperidine-4-carboxylate hydrochloride as a pale yellow solid. It was.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.11 (3H, t, J = 7.1 Hz), 1.48-1.58 (2H, m), 1.62-1.72 (4H, m), 2.03-2.11 (2H, m ), 2.70-2.82 (2H, m), 3.14-3.25 (2H, m), 4.07 (2H, q, J = 7.1Hz), 4.24-4.30 (2H, m), 7.03 (1H, d, J = 9.5 Hz), 8.02 (1H, d, J = 5.4Hz), 8.09 (1H, d, J = 9.5Hz), 8.54 (1H, d, J = 5.4Hz), 8.88-9.07 (2H, m), 9.17 ( 1H, s)

ジイソプロピルアミン1.2mLのテトラヒドロフラン20mL溶液に、−78℃で1.6mol/Lブチルリチウム／ヘキサン溶液5.8mLを滴下し、同温度で1時間攪拌した。１−ｔｅｒｔ−ブチル＝４−エチル＝ピペリジン−１，４−ジカルボキシラート2.0gのテトラヒドロフラン2mL溶液を滴下し、1時間攪拌した。ベンジル＝３−ブロモプロピル＝エーテル1.7mLを加え、反応混合物を室温まで昇温し、10時間攪拌した。水を加え、6mol/L塩酸でpH2.0に調整した。有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、無色油状物の１−ｔｅｒｔ−ブチル＝４−エチル＝４−（３−（ベンジルオキシ）プロピル）ピペリジン−１，４−ジカルボキシラート2.0gを得た。
¹H-NMR(CDCl₃)δ値：1.25(3H,t,J=7.2Hz),1.25-1.45(2H,m),1.45(9H,s),1.50-1.65(4H,m),2.05-2.15(2H,m),2.75-3.00(2H,m),3.42(2H,t,J=6.1Hz),3.75-3.95(2H,m),4.16(2H,q,J=7.2Hz),4.47(2H,s),7.26-7.37(5H,m) Reference Example 83

To a 20 mL tetrahydrofuran solution of 1.2 mL diisopropylamine, 5.8 mL of a 1.6 mol / L butyllithium / hexane solution was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 1 hour. A solution of 1-tert-butyl = 4-ethyl = piperidine-1,4-dicarboxylate (2.0 g) in tetrahydrofuran (2 mL) was added dropwise and stirred for 1 hour. 1.7 mL of benzyl = 3-bromopropyl = ether was added, and the reaction mixture was warmed to room temperature and stirred for 10 hours. Water was added and the pH was adjusted to 2.0 with 6 mol / L hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate = 10: 1], and colorless oily 1-tert-butyl = 4-ethyl = 4- (3- (benzyloxy) 2.0 g of propyl) piperidine-1,4-dicarboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.25 (3H, t, J = 7.2 Hz), 1.25-1.45 (2H, m), 1.45 (9H, s), 1.50-1.65 (4H, m), 2.05- 2.15 (2H, m), 2.75-3.00 (2H, m), 3.42 (2H, t, J = 6.1Hz), 3.75-3.95 (2H, m), 4.16 (2H, q, J = 7.2Hz), 4.47 (2H, s), 7.26-7.37 (5H, m)

１−ｔｅｒｔ−ブチル＝４−エチル＝４−（３−（ベンジルオキシ）プロピル）ピペリジン−１，４−ジカルボキシラート2.0gのエタノール20mL溶液に、10％パラジウム炭素0.30gのエタノール2mL懸濁液を加え、水素雰囲気下、4時間攪拌した。不溶物を濾去し、減圧下で溶媒を留去し、無色油状物の１−ｔｅｒｔ−ブチル＝４−エチル＝４−（３−ヒドロキシプロピル）ピペリジン−１，４−ジカルボキシラート1.7gを得た。
¹H-NMR(CDCl₃)δ値：1.27(3H,t,J=7.2Hz),1.23-1.62(6H,m),1.45(9H,s),2.05-2.15(2H,m),2.80-2.95(2H,m),3.58-3.63(2H,m),3.75-3.95(2H,m),4.18(2H,q,J=7.2Hz) Reference Example 84

1-tert-butyl = 4-ethyl = 4- (3- (benzyloxy) propyl) piperidine-1,4-dicarboxylate (2.0 g) in ethanol (20 mL) and 10% palladium carbon (0.30 g) in ethanol (2 mL) And stirred for 4 hours under hydrogen atmosphere. Insoluble matter was removed by filtration, the solvent was distilled off under reduced pressure, and 1.7 g of colorless oily 1-tert-butyl = 4-ethyl = 4- (3-hydroxypropyl) piperidine-1,4-dicarboxylate was obtained. Obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.27 (3H, t, J = 7.2 Hz), 1.23-1.62 (6H, m), 1.45 (9H, s), 2.05-2.15 (2H, m), 2.80- 2.95 (2H, m), 3.58-3.63 (2H, m), 3.75-3.95 (2H, m), 4.18 (2H, q, J = 7.2Hz)

１−ｔｅｒｔ−ブチル＝４−エチル＝４−（３−ヒドロキシプロピル）ピペリジン−１，４−ジカルボキシラート1.7gのテトラヒドロフラン20mL溶液に、5℃でトリエチルアミン0.82mLおよびメタンスルホニルクロリド0.58mLを加え、室温で1時間攪拌した。酢酸エチルおよび水を加えた。有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、無色油状物の１−ｔｅｒｔ−ブチル＝４−エチル＝４−（３−（（メタンスルホニル）オキシ）プロピル）ピペリジン−１，４−ジカルボキシラート1.9gを得た。
¹H-NMR(CDCl₃)δ値：1.25-1.75(6H,m),1.28(3H,t,J=7.2Hz),1.45(9H,s),2.05-2.15(2H,m),2.80-2.95(2H,m),3.00(3H,s),3.80-3.95(2H,m),4.19(2H,q,J=7.2Hz),4.15-4.22(2H,m) Reference Example 85

To a 20 mL tetrahydrofuran solution of 1.7 g of 1-tert-butyl = 4-ethyl = 4- (3-hydroxypropyl) piperidine-1,4-dicarboxylate, 0.85 mL of triethylamine and 0.58 mL of methanesulfonyl chloride were added at 5 ° C. Stir at room temperature for 1 hour. Ethyl acetate and water were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 1-tert-butyl = 4-ethyl = 4- (3 -((Methanesulfonyl) oxy) propyl) piperidine-1,4-dicarboxylate (1.9 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.25-1.75 (6H, m), 1.28 (3H, t, J = 7.2 Hz), 1.45 (9H, s), 2.05-2.15 (2H, m), 2.80- 2.95 (2H, m), 3.00 (3H, s), 3.80-3.95 (2H, m), 4.19 (2H, q, J = 7.2Hz), 4.15-4.22 (2H, m)

１−（１，３−ジオキソラン−２−イルメチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン4.60gを80％トリフルオロ酢酸184mLに溶解し、室温にて11時間、60℃にて3.5時間攪拌した。反応混合物にクロロホルムを加え、氷冷下10％水酸化ナトリウム水溶液でアルカリ性とした。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、黄色固体の（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒドを得た。
得られた（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒドをクロロホルム58mLに溶解し、ｔｅｒｔ−ブチル＝（ピペリジン−４−イル）カルバマート2.67gおよび酢酸0.80gを加え、室温で1.5時間攪拌した。反応混合物に水素化トリアセトキシホウ素ナトリウム4.23gを加え、15時間攪拌した。飽和炭酸水素ナトリウム水溶液を加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［シリカゲル；関東化学株式会社、シリカゲル６０Ｎ、溶離液；クロロホルム：メタノール＝１０：１］で精製し、白色固体のｔｅｒｔ−ブチル＝（１−（２−（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート4.36gを得た。
¹H-NMR(CDCl₃)δ値：1.38-1.44(2H,m),1.45(9H,s),1.90-2.00(2H,m),2.21-2.30(2H,m),2.59-2.70(2H,m),2.87-2.99(2H,m),3.43-3.54(1H,m),3.98(3H,s),4.29-4.38(2H,m),4.40-4.49(1H,m),6.74(1H,d,J=9.6Hz),7.16-7.19(1H,m),7.84(1H,d,J=9.6Hz),8.28(1H,d,J=2.3Hz) Reference Example 86

1.60 g of 1- (1,3-dioxolan-2-ylmethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one was dissolved in 184 mL of 80% trifluoroacetic acid, and 11 hours at room temperature for 60 hours. Stir at 3.5C for 3.5 hours. Chloroform was added to the reaction mixture, and the mixture was made alkaline with 10% aqueous sodium hydroxide under ice cooling. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give (7-methoxy-2-oxo-1,5-naphthyridine-1 as a yellow solid). (2H) -yl) acetaldehyde was obtained.
The obtained (7-methoxy-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde was dissolved in 58 mL of chloroform, and 2.67 g of tert-butyl = (piperidin-4-yl) carbamate and 0.80 of acetic acid were dissolved. g was added and stirred at room temperature for 1.5 hours. To the reaction mixture, 4.23 g of sodium triacetoxyborohydride was added and stirred for 15 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60N, eluent: chloroform: methanol = 10: 1], and white solid tert-butyl = (1- (2- ( 7.36 g of 7-methoxy-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.38-1.44 (2H, m), 1.45 (9H, s), 1.90-2.00 (2H, m), 2.21-2.30 (2H, m), 2.59-2.70 (2H , m), 2.87-2.99 (2H, m), 3.43-3.54 (1H, m), 3.98 (3H, s), 4.29-4.38 (2H, m), 4.40-4.49 (1H, m), 6.74 (1H , d, J = 9.6Hz), 7.16-7.19 (1H, m), 7.84 (1H, d, J = 9.6Hz), 8.28 (1H, d, J = 2.3Hz)

ｔｅｒｔ−ブチル＝（１−（２−（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート4.36gのクロロホルム50mL溶液にトリフルオロ酢酸10mLを加え、室温で1時間攪拌した。反応混合物を減圧下で溶媒留去し、飽和炭酸水素ナトリウム水溶液でアルカリ性とした後、減圧下で溶媒を留去して、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［シリカゲル；富士シリシア化学株式会社、Chromatorex-NH、溶離液；クロロホルム：メタノール＝１０：１］で精製し、黄色油状の１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン2.16gを得た。
¹H-NMR(CDCl₃)δ値：1.39(4H,m),1.81-1.86(2H,m),2.17-2.24(2H,m),2.63-2.73(3H,m),2.95-3.00(2H,m),3.98(3H,s),4.34-4.39(2H,m),6.75(1H,d,J=9.6Hz),7.23(1H,d,J=2.3Hz),7.84(1H,d,J=9.6Hz),8.28(1H,d,J=2.3Hz) Reference Example 87

tert-Butyl = (1- (2- (7-methoxy-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate in a solution of 4.36 g of chloroform in 50 mL of chloroform Acetic acid (10 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure, made alkaline with saturated aqueous sodium hydrogen carbonate solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [silica gel; Fuji Silysia Chemical Ltd. Chromatorex-NH, eluent; chloroform: methanol = 10: 1] and purified as a yellow oil 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridine 2.16 g of -2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.39 (4H, m), 1.81-1.86 (2H, m), 2.17-2.24 (2H, m), 2.63-2.73 (3H, m), 2.95-3.00 (2H , m), 3.98 (3H, s), 4.34-4.39 (2H, m), 6.75 (1H, d, J = 9.6Hz), 7.23 (1H, d, J = 2.3Hz), 7.84 (1H, d, J = 9.6Hz), 8.28 (1H, d, J = 2.3Hz)

３−ブロモ−１，５−ナフチリジン5.00gをクロロホルム50mLに溶解し、ｍ−クロロ過安息香酸6.40gを加え、室温で1.5時間攪拌した。反応混合物に5％チオ硫酸ナトリウム水溶液、クロロホルムを加え、有機層を分取し、5％水酸化ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［シリカゲル；富士シリシア化学株式会社、Chromatorex-NH、溶離液；酢酸エチル：ヘキサン＝１：１］で精製し、淡黄色固体の３−ブロモ−１，５−ナフチリジン−５−オキシド1.95gを得た。
¹H-NMR(CDCl₃)δ値：7.55(1H,dd,J=8.7,6.0Hz),7.99(1H,d,J=8.7Hz),8.55(1H,d,J=6.0Hz),9.04(1H,d,J=2.3Hz),9.23(1H,d,J=2.3Hz) Reference Example 88

5.00 g of 3-bromo-1,5-naphthyridine was dissolved in 50 mL of chloroform, 6.40 g of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added 5% aqueous sodium thiosulfate and chloroform, and the organic layer was separated, washed successively with 5% aqueous sodium hydroxide and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Left. The obtained residue was purified by silica gel column chromatography [silica gel; Fuji Silysia Chemical Co., Ltd., Chromatorex-NH, eluent; ethyl acetate: hexane = 1: 1] to give 3-bromo-1,5 as a pale yellow solid. -1.95 g of naphthyridine-5-oxide was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 7.55 (1H, dd, J = 8.7, 6.0 Hz), 7.99 (1H, d, J = 8.7 Hz), 8.55 (1H, d, J = 6.0 Hz), 9.04 (1H, d, J = 2.3Hz), 9.23 (1H, d, J = 2.3Hz)

３−ブロモ−１，５−ナフチリジン−５−オキシド0.50gのクロロホルム10mL溶液に、ｐ−トルエンスルホニルクロリド0.51g、炭酸カリウム1.04gおよび水3mLを加え、室温で一晩攪拌した。水およびクロロホルムを加え、固形物を濾取し、白色固体の７−ブロモ−１，５−ナフチリジン−２（１Ｈ）−オン0.39gを得た。
¹H-NMR(DMSO-d₆)δ値：6.77(1H,d,J=9.6Hz),7.85-7.87(1H,m),7.90(1H,d,J=9.6Hz),8.53(1H,d,J=1.8Hz),11.69-12.50(1H,m) Reference Example 89

To a 10 mL chloroform solution of 0.50 g of 3-bromo-1,5-naphthyridine-5-oxide was added 0.51 g of p-toluenesulfonyl chloride, 1.04 g of potassium carbonate and 3 mL of water, and the mixture was stirred overnight at room temperature. Water and chloroform were added, and the solid was collected by filtration to obtain 0.39 g of 7-bromo-1,5-naphthyridin-2 (1H) -one as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 6.77 (1H, d, J = 9.6 Hz), 7.85-7.87 (1H, m), 7.90 (1H, d, J = 9.6 Hz), 8.53 (1H, d, J = 1.8Hz), 11.69-12.50 (1H, m)

７−ブロモ−１，５−ナフチリジン−２（１Ｈ）−オン770mgをＮ，Ｎ−ジメチルホルムアミド5mLに溶解し、60％水素化ナトリウム278mgを加え、室温で1時間攪拌した。２−ブロモメチル−１，３−ジオキソラン1.1mLを加え、110℃で4日間攪拌した。反応混合物を室温まで冷却後、酢酸エチルおよび1mol/L塩酸を加えた。有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［シリカゲル；関東化学株式会社、シリカゲル６０、溶離液；酢酸エチル：ヘキサン＝２：１］で精製し、淡黄色固体の７−ブロモ−１−（１，３−ジオキソラン−２−イルメチル）−１，５−ナフチリジン−２（１Ｈ）−オン467mgを得た。
¹H-NMR(CDCl₃)δ値：3.87-3.91(2H,m),4.00-4.03(2H,m),4.46(2H,d,J=4.1Hz),5.20(1H,t,J=4.1Hz),6.94(1H,d,J=9.6Hz),7.86-7.89(1H,m),8.11(1H,d,J=1.8Hz),8.56(1H,d,J=1.8Hz) Reference Example 90

770 mg of 7-bromo-1,5-naphthyridin-2 (1H) -one was dissolved in 5 mL of N, N-dimethylformamide, 278 mg of 60% sodium hydride was added, and the mixture was stirred at room temperature for 1 hour. 2-Bromomethyl-1,3-dioxolane (1.1 mL) was added, and the mixture was stirred at 110 ° C. for 4 days. After the reaction mixture was cooled to room temperature, ethyl acetate and 1 mol / L hydrochloric acid were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent; ethyl acetate: hexane = 2: 1] to give 7-bromo-1- (1, 467 mg of 3-dioxolan-2-ylmethyl) -1,5-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.87-3.91 (2H, m), 4.00-4.03 (2H, m), 4.46 (2H, d, J = 4.1Hz), 5.20 (1H, t, J = 4.1 Hz), 6.94 (1H, d, J = 9.6Hz), 7.86-7.89 (1H, m), 8.11 (1H, d, J = 1.8Hz), 8.56 (1H, d, J = 1.8Hz)

７−ブロモ−１−（１，３−ジオキソラン−２−イルメチル）−１，５−ナフチリジン−２（１Ｈ）−オン358mgおよびシアン化銅183mgを１−メチル−２−ピロリジノン10mLに懸濁し、70分間加熱還流した。反応混合物を室温まで冷却後、酢酸エチルを加え、水およ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させ、減圧下で溶媒を留去し、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［シリカゲル；関東化学株式会社、シリカゲル６０、溶離液；酢酸エチル：ヘキサン＝１：１］で精製し、黄色固体の７−シアノ−１−（１，３−ジオキソラン−２−イルメチル）−１，５−ナフチリジン−２（１Ｈ）−オンを145mg得た。
¹H-NMR(CDCl₃)δ値：3.87-3.90(2H,m),3.98-4.02(2H,m),4.49(2H,d,J=4.1Hz),5.17(1H,t,J=4.1Hz),7.06(1H,d,J=9.6Hz),7.95(1H,d,J=9.6Hz),8.23-8.24(1H,m),8.72(1H,d,J=1.8Hz) Reference Example 91

7-Bromo-1- (1,3-dioxolan-2-ylmethyl) -1,5-naphthyridin-2 (1H) -one (358 mg) and copper cyanide (183 mg) were suspended in 10 mL of 1-methyl-2-pyrrolidinone, 70 Heated to reflux for minutes. The reaction mixture was cooled to room temperature, ethyl acetate was added, and the mixture was washed successively with water and saturated brine. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent; ethyl acetate: hexane = 1: 1]. Purification gave 145 mg of 7-cyano-1- (1,3-dioxolan-2-ylmethyl) -1,5-naphthyridin-2 (1H) -one as a yellow solid.
¹ H-NMR (CDCl ₃ ) δ value: 3.87-3.90 (2H, m), 3.98-4.02 (2H, m), 4.49 (2H, d, J = 4.1 Hz), 5.17 (1H, t, J = 4.1 Hz), 7.06 (1H, d, J = 9.6Hz), 7.95 (1H, d, J = 9.6Hz), 8.23-8.24 (1H, m), 8.72 (1H, d, J = 1.8Hz)

７−シアノ−１−（１，３−ジオキソラン−２−イルメチル）−１，５−ナフチリジン−２（１Ｈ）−オン215mgを90％トリフルオロ酢酸5mLに溶解し、60℃で7時間攪拌した。反応混合物を室温まで冷却後、10％水酸化ナトリウム水溶液でアルカリ性とした後、減圧下で溶媒を留去し、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［シリカゲル；関東化学株式会社、シリカゲル６０、溶離液；酢酸エチル：ヘキサン＝１：１］で精製し、水で洗浄して淡黄色固体の（７−シアノ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド90mgを得た。
¹H-NMR(CDCl₃)δ値：5.19(2H,s),7.09-7.11(1H,m),7.52-7.53(1H,m),8.02(1H,d,J=9.6Hz),8.76(1H,d,J=1.4Hz),9.83(1H,s) Reference Example 92

215 mg of 7-cyano-1- (1,3-dioxolan-2-ylmethyl) -1,5-naphthyridin-2 (1H) -one was dissolved in 5 mL of 90% trifluoroacetic acid and stirred at 60 ° C. for 7 hours. The reaction mixture was cooled to room temperature, made alkaline with 10% aqueous sodium hydroxide solution, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, Eluent; ethyl acetate: hexane = 1: 1] and washed with water to give 90 mg of (7-cyano-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde as a pale yellow solid. Obtained.
¹ H-NMR (CDCl ₃ ) δ value: 5.19 (2H, s), 7.09-7.11 (1H, m), 7.52-7.53 (1H, m), 8.02 (1H, d, J = 9.6 Hz), 8.76 ( 1H, d, J = 1.4Hz), 9.83 (1H, s)

（７−シアノ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド83mgおよびｔｅｒｔ−ブチル＝ピペリジン−４−イル−カルバマート80mgのクロロホルム10mL溶液に酢酸24μLを加え、室温で1.5時間攪拌した。反応混合物に水素化トリアセトキシホウ素ナトリウム136mgを加え、1.5時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、減圧下で溶媒を留去した。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［シリカゲル；富士シリシア社、Chromatorex-NH、溶離液；酢酸エチル：ヘキサン＝１：１］で精製し、褐色固体のｔｅｒｔ−ブチル＝（１−（２−（７−シアノ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート76mgを得た。
¹H-NMR(CDCl₃)δ値：1.33-1.39(2H,m),1.44(9H,s),1.92-1.97(2H,m),2.22-2.28(2H,m),2.64-2.68(2H,m),2.85-2.90(2H,m),3.46-3.51(1H,m),4.30-4.35(2H,m),4.41-4.45(1H,m),7.05(1H,d,J=9.6Hz),7.94(1H,d,J=9.6Hz),8.12-8.15(1H,m),8.72(1H,d,J=1.4Hz) Reference Example 93

To a solution of 83 mg of (7-cyano-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde and 80 mg of tert-butyl = piperidin-4-yl-carbamate in 10 mL of chloroform was added 24 μL of acetic acid, and 1.5 mL at room temperature. Stir for hours. To the reaction mixture, 136 mg of sodium triacetoxyborohydride was added and stirred for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Fuji Silysia, Chromatorex-NH, eluent; ethyl acetate: hexane = 1: 1], and tert-butyl = (1- (2- 76 mg of (7-cyano-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.33-1.39 (2H, m), 1.44 (9H, s), 1.92-1.97 (2H, m), 2.22-2.28 (2H, m), 2.64-2.68 (2H , m), 2.85-2.90 (2H, m), 3.46-3.51 (1H, m), 4.30-4.35 (2H, m), 4.41-4.45 (1H, m), 7.05 (1H, d, J = 9.6Hz ), 7.94 (1H, d, J = 9.6Hz), 8.12-8.15 (1H, m), 8.72 (1H, d, J = 1.4Hz)

３−クロロ−６−メトキシピラジン−２−アミン3.15gのトリエチルアミン20mL溶液にエチル＝アクリラート2.6mLおよびビス（トリ−ｔｅｒｔ−ブチルホスフィン）パラジウム（０）0.50gを加え、封管中、外温120〜130℃で2時間攪拌した。さらに、トリエチルアミン5mLを加え、同温度で4時間50分間攪拌した。反応混合物を室温まで冷却し、一晩放置後、エチル＝アクリラート0.5mLおよびビス（トリ−ｔｅｒｔ−ブチルホスフィン）パラジウム（０）0.25gを加え、封管中、外温115〜125℃で9時間20分間攪拌した。反応混合物を室温まで冷却後、水および酢酸エチルを加え、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、黄色固体のエチル＝（２Ｅ）−３−（３−アミノ−５−メトキシピラジン−２−イル）アクリラート2.55gを得た。
¹H-NMR(CDCl₃)δ値：1.32(3H,t,J=7.1Hz),3.91(3H,s),4.26(2H,q,J=7.1Hz),4.72(2H,s),6.73(1H,d,J=15.1Hz),7.61-7.68(2H,m) Reference Example 94

Ethyl acrylate 2.6 mL and bis (tri-tert-butylphosphine) palladium (0) 0.50 g were added to a solution of 3-chloro-6-methoxypyrazin-2-amine (3.15 g) in 20 mL of triethylamine, and the external temperature was 120 in the sealed tube. Stir at ~ 130 ° C for 2 hours. Further, 5 mL of triethylamine was added, and the mixture was stirred at the same temperature for 4 hours and 50 minutes. The reaction mixture was cooled to room temperature and allowed to stand overnight, after which 0.5 mL of ethyl acrylate and 0.25 g of bis (tri-tert-butylphosphine) palladium (0) were added, and the outer temperature was 115 to 125 ° C. for 9 hours in a sealed tube. Stir for 20 minutes. The reaction mixture was cooled to room temperature, water and ethyl acetate were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 4: 1], and yellow solid ethyl = (2E) -3- (3-amino-5-methoxypyrazine-2- Yl) 2.55 g of acrylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.32 (3H, t, J = 7.1 Hz), 3.91 (3H, s), 4.26 (2H, q, J = 7.1 Hz), 4.72 (2H, s), 6.73 (1H, d, J = 15.1Hz), 7.61-7.68 (2H, m)

エチル＝（２Ｅ）−３−（３−アミノ−５−メトキシピラジン−２−イル）アクリラ−ト0.85gのエタノール40mL溶液に28％ナトリウムメトキシド／メタノール溶液2.20gを加え、加熱還流下、7時間30分間攪拌した。反応混合物を室温まで冷却後、減圧下で溶媒を留去し、得られた残留物に水、飽和塩化アンモニウム水溶液およびクロロホルムを加えた。有機層を分取し、水層に塩化ナトリウムを加え、クロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジエチルエーテルを加え、固形物を濾取し、ジエチルエーテルで洗浄し、淡黄色固体の３−メトキシピリド（２，３−ｂ）ピラジン−６（５Ｈ）−オン0.64gを得た。
¹H-NMR(CDCl₃)δ値：4.06(3H,s),6.72(1H,d,J=9.8Hz),7.92(1H,d,J=9.8Hz),8.13(1H,s),9.68(1H,s) Reference Example 95

Ethyl (2E) -3- (3-amino-5-methoxypyrazin-2-yl) acrylate (0.85 g) in ethanol (40 mL) was added with 28% sodium methoxide / methanol solution (2.20 g). Stir for 30 minutes. The reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and water, a saturated aqueous ammonium chloride solution and chloroform were added to the obtained residue. The organic layer was separated, sodium chloride was added to the aqueous layer, and the mixture was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the obtained residue, and the solid was collected by filtration and washed with diethyl ether to obtain 0.64 g of 3-methoxypyrido (2,3-b) pyrazin-6 (5H) -one as a pale yellow solid. It was.
¹ H-NMR (CDCl ₃ ) δ value: 4.06 (3H, s), 6.72 (1H, d, J = 9.8 Hz), 7.92 (1H, d, J = 9.8 Hz), 8.13 (1H, s), 9.68 (1H, s)

３−メトキシピリド（２，３−ｂ）ピラジン−６（５Ｈ）−オン0.30gのＮ，Ｎ−ジメチルホルムアミド6mL溶液に、炭酸カリウム0.35gを加え、65〜75℃で10分間攪拌した。２−ブロモメチル−１，３−ジオキソラン0.21mLを加え、95〜100℃で1時間30分間攪拌した。さらに２−ブロモメチル−１，３−ジオキソラン0.05mLおよび炭酸カリウム120mgを加え、95〜100℃で2時間15分間攪拌した。反応混合物を室温まで冷却後、水および酢酸エチルを加え、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［溶離液；ヘキサン：酢酸エチル＝２：１］で精製し、黄色固体の５−（１，３−ジオキソラン−２−イルメチル）−３−メトキシピリド（２，３−ｂ）ピラジン−６（５Ｈ）−オン0.13gを得た。
¹H-NMR(CDCl₃)δ値：3.88-3.92(2H,m),4.06-4.12(5H,m),4.63(2H,d,J=5.1Hz),5.51(1H,t,J=5.1Hz),6.78(1H,d,J=9.8Hz),7.85(1H,d,J=9.8Hz),8.12(1H,s) Reference Example 96

To a solution of 0.30 g of 3-methoxypyrido (2,3-b) pyrazin-6 (5H) -one in 6 mL of N, N-dimethylformamide was added 0.35 g of potassium carbonate, and the mixture was stirred at 65 to 75 ° C. for 10 minutes. 2-Bromomethyl-1,3-dioxolane (0.21 mL) was added, and the mixture was stirred at 95-100 ° C. for 1 hr 30 min. Further, 0.05 mL of 2-bromomethyl-1,3-dioxolane and 120 mg of potassium carbonate were added, and the mixture was stirred at 95 to 100 ° C. for 2 hours and 15 minutes. The reaction mixture was cooled to room temperature, water and ethyl acetate were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 2: 1] to give yellow solid 5- (1,3-dioxolan-2-ylmethyl) -3-methoxypyrido (2, 3-b) 0.13 g of pyrazin-6 (5H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.88-3.92 (2H, m), 4.06-4.12 (5H, m), 4.63 (2H, d, J = 5.1Hz), 5.51 (1H, t, J = 5.1 Hz), 6.78 (1H, d, J = 9.8Hz), 7.85 (1H, d, J = 9.8Hz), 8.12 (1H, s)

５−（１，３−ジオキソラン−２−イルメチル）−３−メトキシピリド（２，３−ｂ）ピラジン−６（５Ｈ）−オン0.12gに90％トリフルオロ酢酸水溶液5mLを加え、室温で3時間30分間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液およびクロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、淡黄色固体の（３−メトキシ−６−オキソピリド（２，３−ｂ）ピラジン−５（６Ｈ）−イル）アセトアルデヒド0.12gを得た。
¹H-NMR(CDCl₃)δ値：3.99(3H,s),5.24(2H,s),6.82(1H,d,J=9.8Hz),7.94(1H,d,J=9.8Hz),8.15(1H,s),9.71(1H,s) Reference Example 97

To 0.12 g of 5- (1,3-dioxolan-2-ylmethyl) -3-methoxypyrido (2,3-b) pyrazin-6 (5H) -one, 5 mL of 90% aqueous trifluoroacetic acid solution was added, and the mixture was stirred for 3 hours at room temperature. Stir for minutes. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give (3-methoxy-6-oxopyrido (2,3-b ) 0.12 g of pyrazine-5 (6H) -yl) acetaldehyde was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.99 (3H, s), 5.24 (2H, s), 6.82 (1H, d, J = 9.8Hz), 7.94 (1H, d, J = 9.8Hz), 8.15 (1H, s), 9.71 (1H, s)

参考例６０と同様の手法により、１−（４−ベンジルモルホリン−２−イル）メタンアミンおよび２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−カルバルデヒドから１−（４−ベンジルモルホリン−２−イル）−Ｎ−（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）メタンアミンを得た。
参考例６１と同様の手法により、１−（４−ベンジルモルホリン−２−イル）−Ｎ−（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）メタンアミンからｔｅｒｔ−ブチル＝（（４−ベンジルモルホリン−２−イル）メチル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.34-1.49(9H,m),1.81-1.93(1H,m),2.09-2.18(1H,m),2.56-2.66(1H,m),2.70-2.77(1H,m),3.20-3.85(7H,m),4.23-4.35(4H,m),4.37-4.64(2H,m),6.68-6.74(1H,m),7.20-7.36(5H,m),8.07(1H,s) Reference Example 98

In the same manner as in Reference Example 60, 1- (4-benzylmorpholin-2-yl) methanamine and 2,3-dihydro (1,4) dioxyno (2,3-c) pyridine-7-carbaldehyde (4-Benzylmorpholin-2-yl) -N- (2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) methanamine was obtained.
In the same manner as in Reference Example 61, 1- (4-benzylmorpholin-2-yl) -N- (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) methanamine From tert-butyl = ((4-benzylmorpholin-2-yl) methyl) (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) carbamate.
¹ H-NMR (CDCl ₃ ) δ value: 1.34-1.49 (9H, m), 1.81-1.93 (1H, m), 2.09-2.18 (1H, m), 2.56-2.66 (1H, m), 2.70-2.77 (1H, m), 3.20-3.85 (7H, m), 4.23-4.35 (4H, m), 4.37-4.64 (2H, m), 6.68-6.74 (1H, m), 7.20-7.36 (5H, m) , 8.07 (1H, s)

参考例２５と同様の手法により、ｔｅｒｔ−ブチル＝（（４−ベンジルモルホリン−２−イル）メチル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）カルバマートからｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（モルホリン−２−イルメチル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.35-1.57(9H,m),2.75-3.10(2H,m),3.25-3.56(4H,m),3.93-4.19(3H,m),4.25-4.44(4H,m),4.46-4.67(2H,m),6.70-6.92(1H,m),8.10-8.19(1H,m),9.80-10.4(1H,broad) Reference Example 99

In the same manner as in Reference Example 25, tert-butyl = ((4-benzylmorpholin-2-yl) methyl) (2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl ) -Carbamate gave tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (morpholin-2-ylmethyl) carbamate.
¹ H-NMR (CDCl ₃ ) δ value: 1.35-1.57 (9H, m), 2.75-3.10 (2H, m), 3.25-3.56 (4H, m), 3.93-4.19 (3H, m), 4.25-4.44 (4H, m), 4.46-4.67 (2H, m), 6.70-6.92 (1H, m), 8.10-8.19 (1H, m), 9.80-10.4 (1H, broad)

２，６−ジクロロ−３−フルオロ−５−（（メトキシメトキシ）メチル）ピリジン0.62gのＮ，Ｎ−ジメチルホルムアミド18mL溶液にトリエチルアミン0.54mL、ギ酸0.15mLおよびテトラキス（トリフェニルホスフィン）パラジウム（０）0.15gを加え、窒素雰囲気下、90〜100℃で4時間30分間攪拌した。水および酢酸エチルを加え、不溶物を濾去し、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［溶離液；ヘキサン：酢酸エチル＝８：１］で精製し、無色油状物の２−クロロ−５−フルオロ−３−（（メトキシメトキシ）メチル）ピリジン0.39gを得た。
¹H-NMR(CDCl₃)δ値：3.43(3H,s),4.65(2H,d,J=0.8Hz),4.80(2H,s),7.66(1H,dd,J=8.4,3.0Hz),8.18(1H,d,J=3.0Hz) Reference Example 100

To a solution of 0.62 g of 2,6-dichloro-3-fluoro-5-((methoxymethoxy) methyl) pyridine in 18 mL of N, N-dimethylformamide, 0.54 mL of triethylamine, 0.15 mL of formic acid and tetrakis (triphenylphosphine) palladium (0) 0.15g was added and it stirred at 90-100 degreeC for 4 hours and 30 minutes by nitrogen atmosphere. Water and ethyl acetate were added, the insoluble material was removed by filtration, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 8: 1] to give colorless oily 2-chloro-5-fluoro-3-((methoxymethoxy) methyl) pyridine 0.39. g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.43 (3H, s), 4.65 (2H, d, J = 0.8 Hz), 4.80 (2H, s), 7.66 (1H, dd, J = 8.4, 3.0 Hz) , 8.18 (1H, d, J = 3.0Hz)

２−クロロ−５−フルオロ−３−（（メトキシメトキシ）メチル）ピリジン0.10gのジオキサン3mL溶液に炭酸カリウム0.20g、トリメチルボロキシン68μLおよびテトラキス（トリフェニルホスフィン）パラジウム（０）56mgを加え、窒素雰囲気下、加熱還流下で2時間攪拌した。炭酸カリウム0.20g、トリメチルボロキシン68μLおよびテトラキス（トリフェニルホスフィン）パラジウム（０）56mgを加え、窒素雰囲気下、加熱還流下で2時間攪拌した。炭酸カリウム0.20g、トリメチルボロキシン68μLおよびテトラキス（トリフェニルホスフィン）パラジウム（０）56mgを加え、窒素雰囲気下、加熱還流下で1時間攪拌した。不溶物を濾去し、減圧下で溶媒を留去した。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［溶離液；クロロホルム：メタノール＝１００：１］で精製し、無色油状物93mgを得た。塩基性シリカゲルカラムクロマトグラフィー［溶離液；クロロホルム］で精製し、無色油状物の５−フルオロ−３−（（メトキシメトキシ）メチル）−２−メチルピリジン64mgを得た。
¹H-NMR(CDCl₃)δ値：2.49(3H,s),3.42(3H,s),4.58(2H,s),4.76(2H,s),7.47(1H,dd,J=9.2,2.7Hz),8.27(1H,d,J=2.7Hz) Reference Example 101

To a solution of 0.10 g of 2-chloro-5-fluoro-3-((methoxymethoxy) methyl) pyridine in 3 mL of dioxane was added 0.20 g of potassium carbonate, 68 μL of trimethylboroxine and 56 mg of tetrakis (triphenylphosphine) palladium (0), and nitrogen was added. The mixture was stirred for 2 hours under heating and refluxing. 0.20 g of potassium carbonate, 68 μL of trimethylboroxine and 56 mg of tetrakis (triphenylphosphine) palladium (0) were added, and the mixture was stirred for 2 hours under heating and reflux in a nitrogen atmosphere. 0.20 g of potassium carbonate, 68 μL of trimethylboroxine and 56 mg of tetrakis (triphenylphosphine) palladium (0) were added, and the mixture was stirred for 1 hour under heating and refluxing in a nitrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 100: 1] to obtain 93 mg of a colorless oil. Purification by basic silica gel column chromatography [eluent: chloroform] gave 64 mg of 5-fluoro-3-((methoxymethoxy) methyl) -2-methylpyridine as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ value: 2.49 (3H, s), 3.42 (3H, s), 4.58 (2H, s), 4.76 (2H, s), 7.47 (1H, dd, J = 9.2,2.7 Hz), 8.27 (1H, d, J = 2.7Hz)

５−フルオロ−３−（（メトキシメトキシ）メチル）−２−メチルピリジン0.49gのジオキサン20mL溶液に6.0mol/L塩酸10mLを加え、30〜40℃で1時間攪拌した。水および酢酸エチルを加え、20％水酸化ナトリウム水溶液および飽和炭酸水素ナトリウム水溶液でpH5.5に調整した。有機層を分取し、水層を酢酸エチルで2回抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、淡黄色油状物の（５−フルオロ−２−メチルピリジン−３−イル）メタノール0.41gを得た。
¹H-NMR(CDCl₃)δ値：2.40(1H,t,J=5.2Hz),2.46(3H,s),4.72(2H,d,J=5.2Hz),7.53(1H,dd,J=9.1,2.6Hz),8.24(1H,d,J=2.6Hz) Reference Example 102

To 20 mL of dioxane in 0.49 g of 5-fluoro-3-((methoxymethoxy) methyl) -2-methylpyridine was added 10 mL of 6.0 mol / L hydrochloric acid, and the mixture was stirred at 30 to 40 ° C. for 1 hour. Water and ethyl acetate were added, and the pH was adjusted to 5.5 with 20% aqueous sodium hydroxide solution and saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layer and the extract were combined, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give (5-fluoro-2-methylpyridine-3) as a pale yellow oil. -Yl) 0.41 g of methanol was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.40 (1H, t, J = 5.2 Hz), 2.46 (3H, s), 4.72 (2H, d, J = 5.2 Hz), 7.53 (1H, dd, J = 9.1, 2.6Hz), 8.24 (1H, d, J = 2.6Hz)

（５−フルオロ−２−メチルピリジン−３−イル）メタノール32mgのジクロロメタン2mL溶液にモレキュラーシーブス３Ａ80mgおよび４−メチルモルホリン＝Ｎ−オキシド40mgを加え、室温下30分間攪拌した。過ルテニウム酸テトラプロピルアンモニウム6.0mgを加え、室温下1時間30分間攪拌した。不溶物を濾去し、減圧下で溶媒を留去した。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［溶離液；クロロホルム：メタノール＝１００：１］で精製し、無色油状物の５−フルオロ−２−メチルニコチンアルデヒド20mgを得た。
¹H-NMR(CDCl₃)δ値：2.87(3H,d,J=1.0Hz),7.81(1H,dd,J=8.0,3.0Hz),8.56(1H,d,J=3.0Hz),10.33(1H,d,J=2.2Hz) Reference Example 103

To a solution of 32 mg of (5-fluoro-2-methylpyridin-3-yl) methanol in 2 mL of dichloromethane were added 80 mg of molecular sieves 3A and 40 mg of 4-methylmorpholine = N-oxide, and the mixture was stirred at room temperature for 30 minutes. 6.0 mg of tetrapropylammonium perruthenate was added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 100: 1] to obtain 20 mg of colorless oily 5-fluoro-2-methylnicotinaldehyde.
¹ H-NMR (CDCl ₃ ) δ value: 2.87 (3H, d, J = 1.0 Hz), 7.81 (1H, dd, J = 8.0, 3.0 Hz), 8.56 (1H, d, J = 3.0 Hz), 10.33 (1H, d, J = 2.2Hz)

水素化ナトリウム77mgのＮ，Ｎ−ジメチルホルムアミド2mL懸濁液にイミダゾール0.13gを加えて、室温で10分間攪拌した。反応混合物に７−ブロモ−１−（（１，３−ジオキソラン−２−イル）メチル）−１，５−ナフチリジン−２（１Ｈ）−オン0.20gを分割で添加した後、酸化第二銅18mgを加えた。反応混合物135〜140℃で30分間攪拌した。室温まで冷却し、反応混合物にクロロホルムおよび水を加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジエチルエーテル：酢酸エチル（３：１）の混合溶媒を加え、固形物を濾取し、黄色固体の１−（（１，３−ジオキソラン−２−イル）メチル）−７−（１Ｈ−イミダゾール−１−イル）−１，５−ナフチリジン−２（１Ｈ）−オン0.12gを得た。
¹H-NMR(CDCl₃)δ値：3.86-4.20(4H,m),4.55(2H,d,J=4.0Hz),5.18(1H,t,J=4.0Hz),6.97(1H,d,J=9.9Hz),7.32(1H,s),7.40(1H,s),7.95(1H,d,J=9.9Hz),7.98(1H,s),8.01(1H,d,J=2.1Hz),8.65(1H,d,J=2.1Hz) Reference Example 104

To a suspension of 77 mg of sodium hydride in 2 mL of N, N-dimethylformamide, 0.13 g of imidazole was added and stirred at room temperature for 10 minutes. After 0.20 g of 7-bromo-1-((1,3-dioxolan-2-yl) methyl) -1,5-naphthyridin-2 (1H) -one was added in portions to the reaction mixture, 18 mg of cupric oxide was added. Was added. The reaction mixture was stirred at 135-140 ° C. for 30 minutes. After cooling to room temperature, chloroform and water were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. A mixed solvent of diethyl ether: ethyl acetate (3: 1) was added to the obtained residue, and the solid was collected by filtration to give 1-((1,3-dioxolan-2-yl) methyl) -7 as a yellow solid. There was obtained 0.12 g of-(1H-imidazol-1-yl) -1,5-naphthyridin-2 (1H) -one.
¹ H-NMR (CDCl ₃ ) δ value: 3.86-4.20 (4H, m), 4.55 (2H, d, J = 4.0Hz), 5.18 (1H, t, J = 4.0Hz), 6.97 (1H, d, J = 9.9Hz), 7.32 (1H, s), 7.40 (1H, s), 7.95 (1H, d, J = 9.9Hz), 7.98 (1H, s), 8.01 (1H, d, J = 2.1Hz) , 8.65 (1H, d, J = 2.1Hz)

１−（（１，３−ジオキソラン−２−イル）メチル）−７−（１Ｈ−イミダゾール−１−イル）−１，５−ナフチリジン−２（１Ｈ）−オン0.12gに室温で80％トリフルオロ酢酸水溶液2mLを加え、50〜60℃で1時間30分間攪拌した。反応混合物を室温まで冷却後、減圧下で溶媒を留去した。得られた残留物にクロロホルムおよび水を加え、20％水酸化ナトリウム水溶液でpH7.8に調整した。有機層を分取し、水層をクロロホルムで抽出した後、さらに酢酸エチルで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、黄色固体の（７−（１Ｈ−イミダゾール−１−イル）−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド0.12gを得た。
¹H-NMR(DMSO-d₆)δ値：5.35(2H,s),6.92(1H,d,J=9.8Hz),7.20(1H,s),7.22(1H,s),8.00(1H,s),8.05(1H,d,J=9.8Hz),8.12(1H,d,J=2.2Hz),8.96(1H,d,J=2.2Hz),9.70(1H,s) Reference Example 105

1-((1,3-Dioxolan-2-yl) methyl) -7- (1H-imidazol-1-yl) -1,5-naphthyridin-2 (1H) -one at 0.12 g at room temperature with 80% trifluoro 2 mL of acetic acid aqueous solution was added, and the mixture was stirred at 50-60 ° C. for 1 hour 30 minutes. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. Chloroform and water were added to the obtained residue, and the pH was adjusted to 7.8 with a 20% aqueous sodium hydroxide solution. The organic layer was separated, the aqueous layer was extracted with chloroform, and further extracted with ethyl acetate. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give (7- (1H-imidazol-1-yl) -2-oxo-1,5-naphthyridine- 0.12 g of 1 (2H) -yl) acetaldehyde was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 5.35 (2H, s), 6.92 (1H, d, J = 9.8 Hz), 7.20 (1H, s), 7.22 (1H, s), 8.00 (1H, s), 8.05 (1H, d, J = 9.8Hz), 8.12 (1H, d, J = 2.2Hz), 8.96 (1H, d, J = 2.2Hz), 9.70 (1H, s)

参考例６０と同様の手法により、ベンジル＝（３Ｒ，４Ｒ）−４−アミノ−３−ヒドロキシピペリジン−１−カルボキシラートおよび２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−カルバルデヒドからベンジル＝（３Ｒ，４Ｒ）−４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）−３−ヒドロキシピペリジン−１−カルボキシラートを得た。
参考例６１と同様の手法により、ベンジル＝（３Ｒ，４Ｒ）−４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）−３−ヒドロキシピペリジン−１−カルボキシラートからベンジル＝（３Ｒ，４Ｒ）−４−（（ｔｅｒｔ−ブトキシカルボニル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）−３−ヒドロキシピペリジン−１−カルボキシラートを得た。
参考例２５と同様の手法により、ベンジル＝（３Ｒ，４Ｒ）−４−（（ｔｅｒｔ−ブトキシカルボニル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）−３−ヒドロキシピペリジン−１−カルボキシラートからｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（（３Ｒ，４Ｒ）−３−ヒドロキシピペリジン−４−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.28-1.57(9H,m),1.90-2.40(2H,m),2.70-3.10(2H,m),3.43-3.80(2H,m),4.00-4.35(2H,m),4.40-4.86(6H,m),7.20-7.40(1H,m),8.23-8.39(1H,m),9.10-9.90(2H,m) Reference Example 106

In the same manner as in Reference Example 60, benzyl = (3R, 4R) -4-amino-3-hydroxypiperidine-1-carboxylate and 2,3-dihydro (1,4) dioxino (2,3-c) pyridine From 7-carbaldehyde to benzyl = (3R, 4R) -4-((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) -3-hydroxypiperidine- 1-carboxylate was obtained.
In the same manner as in Reference Example 61, benzyl = (3R, 4R) -4-((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) -3- Hydroxypiperidine-1-carboxylate to benzyl = (3R, 4R) -4-((tert-butoxycarbonyl) (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) Amino) -3-hydroxypiperidine-1-carboxylate was obtained.
In the same manner as in Reference Example 25, benzyl = (3R, 4R) -4-((tert-butoxycarbonyl) (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) ) Amino) -3-hydroxypiperidine-1-carboxylate to tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) ((3R, 4R)- 3-Hydroxypiperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.28-1.57 (9H, m), 1.90-2.40 (2H, m), 2.70-3.10 (2H, m), 3.43-3.80 (2H, m), 4.00-4.35 (2H, m), 4.40-4.86 (6H, m), 7.20-7.40 (1H, m), 8.23-8.39 (1H, m), 9.10-9.90 (2H, m)

参考例４２と同様の手法により、（３−メトキシ−６−オキソピリド（２，３−ｂ）ピラジン−５（６Ｈ）−イル）アセトアルデヒドおよびｔｅｒｔ−ブチル＝ピペリジン−４−イルカルバマートからｔｅｒｔ−ブチル＝（１−（２−（３−メトキシ−６−オキソピリド（２，３−ｂ）ピラジン−５（６Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.30-1.50(11H,m),1.87-1.96(2H,m),2.18-2.30(2H,m),2.66-2.74(2H,m),2.94-3.06(2H,m),3.39-3.52(1H,m),4.06(3H,s),4.34-4.46(1H,m),4.53-4.61(2H,m),6.76(1H,d,J=9.6Hz),7.84(1H,d,J=9.6Hz),8.11(1H,s) Reference Example 107

In the same manner as in Reference Example 42, from (3-methoxy-6-oxopyrido (2,3-b) pyrazin-5 (6H) -yl) acetaldehyde and tert-butyl = piperidin-4-ylcarbamate to tert-butyl = (1- (2- (3- (Methoxy-6-oxopyrido (2,3-b) pyrazin-5 (6H) -yl) ethyl) piperidin-4-yl) carbamate) was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.30-1.50 (11H, m), 1.87-1.96 (2H, m), 2.18-2.30 (2H, m), 2.66-2.74 (2H, m), 2.94-3.06 (2H, m), 3.39-3.52 (1H, m), 4.06 (3H, s), 4.34-4.46 (1H, m), 4.53-4.61 (2H, m), 6.76 (1H, d, J = 9.6Hz ), 7.84 (1H, d, J = 9.6Hz), 8.11 (1H, s)

実施例６５と同様の手法により、ｔｅｒｔ−ブチル＝（１−（２−（３−メトキシ−６−オキソピリド（２，３−ｂ）ピラジン−５（６Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートから５−（２−（４−アミノピペリジン−１−イル）エチル）−３−メトキシピリド（２，３−ｂ）ピラジン−６（５Ｈ）−オン塩酸塩を得た。
¹H-NMR(DMSO-d₆)δ値：1.88-2.20(4H,m),3.05-3.19(2H,m),3.20-3.68(3H,m),3.71-3.82(2H,m),4.11(3H,s),4.68-4.78(2H,m),6.77(1H,d,J=9.6Hz),8.01(1H,d,J=9.6Hz),8.29(1H,s),8.30-8.38(3H,broad),10.58-10.70(1H,broad) Reference Example 108

In a similar manner as in Example 65, tert-butyl = (1- (2- (3-methoxy-6-oxopyrido (2,3-b) pyrazin-5 (6H) -yl) ethyl) piperidin-4-yl ) 5- (2- (4-Aminopiperidin-1-yl) ethyl) -3-methoxypyrido (2,3-b) pyrazin-6 (5H) -one hydrochloride was obtained from carbamate.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.88-2.20 (4H, m), 3.05-3.19 (2H, m), 3.20-3.68 (3H, m), 3.71-3.82 (2H, m), 4.11 (3H, s), 4.68-4.78 (2H, m), 6.77 (1H, d, J = 9.6Hz), 8.01 (1H, d, J = 9.6Hz), 8.29 (1H, s), 8.30-8.38 ( 3H, broad), 10.58-10.70 (1H, broad)

５−クロロ−２−メトキシピリミジン−４−アミン2.9gにエチル＝アクリラート2.35mL、トリエチルアミン18mLおよびビス（トリ−ｔｅｒｔ−ブチルホスフィン）パラジウム（０）0.46gを加え、封管中、外温115〜130℃で5時間攪拌した。さらに、トリエチルアミン5mL、ビス（トリ−ｔｅｒｔ−ブチルホスフィン）パラジウム（０）0.30gおよびエチル＝アクリラート0.5mLを加え、封管中、外温120〜130℃で6時間30分間攪拌した。反応混合物を室温まで冷却し水および酢酸エチルを加えた。有機層を分取し、水層をクロロホルムおよび酢酸エチルで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［溶離液；ヘキサン：酢酸エチル＝１：１］で精製し、黄色固体のエチル＝（２Ｅ）−３−（４−アミノ−２−メトキシピリミジン−５−イル）アクリラート0.89gを得た。
¹H-NMR(CDCl₃)δ値：1.33(3H,t,J=7.1Hz),3.95(3H,s),4.26(2H,q,J=7.1Hz),5.45(2H,s),6.28(1H,d,J=16.1Hz),7.57(1H,d,J=16.1Hz),8.29(1H,s) Reference Example 109

To 2.9 g of 5-chloro-2-methoxypyrimidin-4-amine, 2.35 mL of ethyl acrylate, 18 mL of triethylamine and 0.46 g of bis (tri-tert-butylphosphine) palladium (0) were added. Stir at 130 ° C. for 5 hours. Furthermore, 5 mL of triethylamine, 0.30 g of bis (tri-tert-butylphosphine) palladium (0) and 0.5 mL of ethyl acrylate were added, and the mixture was stirred at an external temperature of 120 to 130 ° C. for 6 hours and 30 minutes. The reaction mixture was cooled to room temperature and water and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with chloroform and ethyl acetate. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 1: 1], and yellow solid ethyl = (2E) -3- (4-amino-2-methoxypyrimidine-5- Il) 0.89 g of acrylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.33 (3H, t, J = 7.1 Hz), 3.95 (3H, s), 4.26 (2H, q, J = 7.1 Hz), 5.45 (2H, s), 6.28 (1H, d, J = 16.1Hz), 7.57 (1H, d, J = 16.1Hz), 8.29 (1H, s)

エチル＝（２Ｅ）−３−（４−アミノ−２−メトキシピリミジン−５−イル）アクリラート0.87gのメタノール50mL溶液に室温で28％ナトリウムメトキシド／メタノール溶液2.31gを加え、加熱還流下、4時間攪拌した。反応混合物を室温まで冷却した後、減圧下で溶媒を留去した。得られた残留物に飽和塩化アンモニウム水溶液およびクロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた固形物をジエチルエーテルで洗浄し、黄色固体の２−メトキシピリド（２，３−ｄ）ピリミジン−７（８Ｈ）−オン0.55gを得た。
¹H-NMR(CDCl₃)δ値：4.07(3H,s),6.56(1H,d,J=9.5Hz),7.68(1H,d,J=9.5Hz),8.68(1H,s),9.32(1H,s) Reference Example 110

Ethyl (2E) -3- (4-amino-2-methoxypyrimidin-5-yl) acrylate 0.87 g in 50 mL of methanol was added at room temperature with 2.31 g of 28% sodium methoxide / methanol solution. Stir for hours. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. A saturated aqueous ammonium chloride solution and chloroform were added to the obtained residue, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained solid was washed with diethyl ether to obtain 0.55 g of 2-methoxypyrido (2,3-d) pyrimidin-7 (8H) -one as a yellow solid.
¹ H-NMR (CDCl ₃ ) δ value: 4.07 (3H, s), 6.56 (1H, d, J = 9.5Hz), 7.68 (1H, d, J = 9.5Hz), 8.68 (1H, s), 9.32 (1H, s)

２−メトキシピリド（２，３−ｄ）ピリミジン−７（８Ｈ）−オン0.50gのＮ，Ｎ−ジメチルホルムアミド7.5mL懸濁液に室温で炭酸カリウム0.59gを加え、60〜80℃まで昇温し、1時間攪拌した。80℃で２−ブロモメチル−１，３−ジオキソラン0.35mLを加え、反応混合物を103℃まで昇温し、3時間30分間攪拌した。反応混合物を室温まで冷却し、水およびクロロホルムを加えた。有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［溶離液；クロロホルム：メタノール＝７５：１］で精製し、黄色固体の８−（１，３−ジオキソラン−２−イルメチル）−２−メトキシピリド（２，３−ｄ）ピリミジン−７（８Ｈ）−オン0.60gを得た。
¹H-NMR(CDCl₃)δ値：3.87-3.95(2H,m),4.05-4.13(2H,m),4.09(3H,s),4.59(2H,d,J=5.1Hz),5.52(1H,d,J=5.1Hz),6.60(1H,d,J=9.5Hz),7.62(1H,d,J=9.5Hz),8.65(1H,s) Reference Example 111

To a suspension of 0.50 g of 2-methoxypyrido (2,3-d) pyrimidin-7 (8H) -one in 0.5 mL of N, N-dimethylformamide was added 0.59 g of potassium carbonate at room temperature, and the temperature was raised to 60-80 ° C. And stirred for 1 hour. At 80 ° C., 0.35 mL of 2-bromomethyl-1,3-dioxolane was added, and the reaction mixture was heated to 103 ° C. and stirred for 3 hours and 30 minutes. The reaction mixture was cooled to room temperature and water and chloroform were added. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 75: 1] to give 8- (1,3-dioxolan-2-ylmethyl) -2-methoxypyrido (2,3) as a yellow solid. -D) 0.60 g of pyrimidine-7 (8H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.87-3.95 (2H, m), 4.05-4.13 (2H, m), 4.09 (3H, s), 4.59 (2H, d, J = 5.1 Hz), 5.52 ( 1H, d, J = 5.1Hz), 6.60 (1H, d, J = 9.5Hz), 7.62 (1H, d, J = 9.5Hz), 8.65 (1H, s)

８−（１，３−ジオキソラン−２−イルメチル）−２−メトキシピリド（２，３−ｄ）ピリミジン−７（８Ｈ）−オン0.20gに80％トリフルオロ酢酸水溶液5mLを加え、室温で8時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液およびクロロホルムを加えた。有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、黄色油状物の（２−メトキシ−７−オキソピリド（２，３−ｄ）ピリミジン−８（７Ｈ）−イル）アセトアルデヒド0.21gを得た。
¹H-NMR(CDCl₃)δ値：4.04(3H,s),5.25(2H,s),6.64(1H,d,J=9.5Hz),7.72(1H,d,J=9.5Hz),8.71(1H,s),9.72(1H,s) Reference Example 112

To 0.20 g of 8- (1,3-dioxolan-2-ylmethyl) -2-methoxypyrido (2,3-d) pyrimidin-7 (8H) -one, add 5 mL of 80% aqueous trifluoroacetic acid and stir at room temperature for 8 hours. did. Saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give (2-methoxy-7-oxopyrido (2,3-d ) 0.21 g of pyrimidine-8 (7H) -yl) acetaldehyde was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 4.04 (3H, s), 5.25 (2H, s), 6.64 (1H, d, J = 9.5Hz), 7.72 (1H, d, J = 9.5Hz), 8.71 (1H, s), 9.72 (1H, s)

ｔｅｒｔ−ブチル＝３−（アミノメチル）ピペリジン−１−カルボキシラート0.65gのジクロロメタン5mL溶液に（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−カルバルデヒド0.50gおよび酢酸0.17mLを加えた。続いて水素化トリアセトキシホウ素ナトリウム0.96gを加え室温で1時15分間攪拌した。反応混合物にクロロホルムを加え、飽和炭酸水素ナトリウム水溶液および20％水酸化ナトリウム水溶液でpH8.6に調整し、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、黄色油状物のｔｅｒｔ−ブチル＝３−（（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）メチル）ピペリジン−１−カルボキシラート1.3gを得た。
¹H-NMR(CDCl₃)δ値：1.12-1.92(5H,m),1.45(9H,s),2.20-2.72(3H,m),2.80-2.90(1H,m),3.78(2H,s),3.78-3.98(2H,m),4.22-4.35(4H,m),6.84(1H,s),8.10(1H,s) Reference Example 113

To a solution of tert-butyl 3- (aminomethyl) piperidine-1-carboxylate 0.65 g in dichloromethane 5 mL was added (2,3-dihydro (1,4) dioxyno (2,3-c) pyridine-7-carbaldehyde 0.50 g. Then, 0.16 mL of acetic acid was added, 0.96 g of sodium triacetoxyborohydride was added, and the mixture was stirred at room temperature for 1:15 min. The organic layer was separated, the aqueous layer was extracted with chloroform, the organic layer and the extract were combined, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The tert-butyl 3-(((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylme 1.3 g of til) amino) methyl) piperidine-1-carboxylate were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.12-1.92 (5H, m), 1.45 (9H, s), 2.20-2.72 (3H, m), 2.80-2.90 (1H, m), 3.78 (2H, s ), 3.78-3.98 (2H, m), 4.22-4.35 (4H, m), 6.84 (1H, s), 8.10 (1H, s)

ｔｅｒｔ−ブチル＝３（（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）メチル）ピペリジン−１−カルボキシラート1.3gのメタノール10mL溶液にトリフルオロ酢酸エチル0.54mLを加え、室温で2時間攪拌した後、40〜45℃で3時間攪拌した。トリフルオロ酢酸エチル0.54mLを加え、加熱還流下で3時間攪拌した。室温まで冷却後、減圧下で溶媒を留去した。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［溶離液；ヘキサン：酢酸エチル＝１：１］で精製し、無色油状物のｔｅｒｔ−ブチル＝３（（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（トリフルオロアセチル）アミノ）メチル）ピペリジン−１−カルボキシラート0.47gを得た。
¹H-NMR(CDCl₃)δ値：1.07-2.10(5H,m),1.44(9H,s),2.58-2.66(1H,m),2.70-2.79(1H,m),3.20-3.50(2H,m),3.80-4.00(2H,m),4.26-4.36(4H,m),4.58-4.68(2H,m),6.66(1H,s),8.11(1H,s) Reference Example 114

tert-Butyl = 3 (((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) methyl) piperidine-1-carboxylate in a solution of 1.3 g of methanol in 10 mL of methanol After adding 0.54 mL of ethyl fluoroacetate and stirring at room temperature for 2 hours, it stirred at 40-45 degreeC for 3 hours. Ethyl trifluoroacetate (0.54 mL) was added, and the mixture was stirred with heating under reflux for 3 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 1: 1] to give tert-butyl = 3 ((((2,3-dihydro (1,4) dioxyno) as a colorless oil. 0.47 g of (2,3-c) pyridin-7-ylmethyl) (trifluoroacetyl) amino) methyl) piperidine-1-carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.07-2.10 (5H, m), 1.44 (9H, s), 2.58-2.66 (1H, m), 2.70-2.79 (1H, m), 3.20-3.50 (2H , m), 3.80-4.00 (2H, m), 4.26-4.36 (4H, m), 4.58-4.68 (2H, m), 6.66 (1H, s), 8.11 (1H, s)

ｔｅｒｔ−ブチル＝３−（（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（トリフルオロアセチル）アミノ）メチル）ピペリジン−１−カルボキシラート0.43gのクロロホルム3mL溶液にトリフルオロ酢酸3mLを加え、室温で1時間40分間攪拌した。減圧下で溶媒を留去し、得られた残留物にクロロホルムおよび水を加え、炭酸水素ナトリウム水溶液および20％水酸化ナトリウム水溶液でpH8.0に調整した。有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、淡黄色油状物のＮ−（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）−２，２，２−トリフルオロ−Ｎ−（ピペリジン−３−イルメチル）アセトアミド0.15gを得た。
¹H-NMR(CDCl₃)δ値：1.08-1.26(1H,m),1.48-1.62(1H,m),1.68-2.15(3H,m),2.32-2.47(1H,m),2.54-2.66(1H,m),3.00-3.12(2H,m),3.22-3.30(1H,m),3.32-3.44(1H,m),4.24-4.36(4H,m),4.61(2H,s),6.67(1H,s),8.11(1H,s) Reference Example 115

tert-Butyl = 3-(((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (trifluoroacetyl) amino) methyl) piperidine-1-carboxylate 0.43 g 3 mL of chloroform was added to 3 mL of trifluoroacetic acid and stirred at room temperature for 1 hour and 40 minutes. The solvent was distilled off under reduced pressure, chloroform and water were added to the obtained residue, and the pH was adjusted to 8.0 with an aqueous sodium hydrogen carbonate solution and a 20% aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give N- (2,3-dihydro (1,1, 4) 0.15 g of dioxino (2,3-c) pyridin-7-ylmethyl) -2,2,2-trifluoro-N- (piperidin-3-ylmethyl) acetamide was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.08-1.26 (1H, m), 1.48-1.62 (1H, m), 1.68-2.15 (3H, m), 2.32-2.47 (1H, m), 2.54-2.66 (1H, m), 3.00-3.12 (2H, m), 3.22-3.30 (1H, m), 3.32-3.44 (1H, m), 4.24-4.36 (4H, m), 4.61 (2H, s), 6.67 (1H, s), 8.11 (1H, s)

メチル＝２，６−ジクロロ−５−フルオロニコチナート1.5gのメタノール12mL溶液に28％ナトリウムメトキシド/メタノール1.3gのメタノール3mL溶液を滴下し、室温で40分間攪拌した。水および酢酸エチルを加え、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、白色固体のメチル＝２−クロロ−５−フルオロ−６−メトキシニコチナート1.2gを得た。
¹H-NMR(CDCl₃)δ値：3.92(3H,s),4.09(3H,s),7.92(1H,d,J=9.8Hz) Reference Example 116

A methanol 3mL solution of 28% sodium methoxide / methanol 1.3g was added dropwise to a methanol 12mL solution of methyl = 2,6-dichloro-5-fluoronicotinate 1.5g, and the mixture was stirred at room temperature for 40 minutes. Water and ethyl acetate were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give methyl 2-chloro-5-fluoro-6-methoxy as a white solid. Nicotinate 1.2g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.92 (3H, s), 4.09 (3H, s), 7.92 (1H, d, J = 9.8 Hz)

メチル＝２−クロロ−５−フルオロ−６−メトキシニコチナート1.5gのＮ，Ｎ−ジメチルホルムアミド15mL溶液に室温でテトラキス（トリフェニルホスフィン）パラジウム（０）0.38g、トリエチルアミン1.4mLおよびギ酸0.38mLを加え、窒素雰囲気下、50〜60℃で1時間攪拌し、ついで90〜100℃で2時間20分間攪拌した。室温下でトリエチルアミン1.4mL、テトラキス（トリフェニルホスフィン）パラジウム（０）0.38gおよびギ酸0.38mLを追加し、90〜100℃で1時間攪拌した。室温まで冷却後、反応混合物に酢酸エチルおよび水を加え、2mol/L塩酸でpH4.8に調整した。有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄した。有機層にクロロホルム：メタノールの混合溶媒を加えて、不溶物を溶解させ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物に酢酸エチルを加え、固形物を濾取し、黄色固体のメチル＝５−フルオロ−６−メトキシニコチナート0.30gを得た。
¹H-NMR(CDCl₃)δ値：3.92(3H,s),4.09(3H,s),7.88(1H,dd,J=10.5,2.0Hz),8.61(1H,d,J=2.0Hz) Reference Example 117

To a solution of 1.5 g of methyl-2-chloro-5-fluoro-6-methoxynicotinate in 15 mL of N, N-dimethylformamide is added 0.38 g of tetrakis (triphenylphosphine) palladium (0), 1.4 mL of triethylamine and 0.38 mL of formic acid at room temperature. In addition, the mixture was stirred at 50 to 60 ° C. for 1 hour under a nitrogen atmosphere, and then stirred at 90 to 100 ° C. for 2 hours and 20 minutes. At room temperature, 1.4 mL of triethylamine, 0.38 g of tetrakis (triphenylphosphine) palladium (0) and 0.38 mL of formic acid were added, and the mixture was stirred at 90 to 100 ° C. for 1 hour. After cooling to room temperature, ethyl acetate and water were added to the reaction mixture, and the pH was adjusted to 4.8 with 2 mol / L hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined and washed with a saturated aqueous sodium chloride solution. A mixed solvent of chloroform: methanol was added to the organic layer to dissolve insoluble matters, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.30 g of yellow solid methyl = 5-fluoro-6-methoxynicotinate.
¹ H-NMR (CDCl ₃ ) δ value: 3.92 (3H, s), 4.09 (3H, s), 7.88 (1H, dd, J = 10.5, 2.0 Hz), 8.61 (1H, d, J = 2.0 Hz)

水素化アルミニウムリチウム0.24gのテトラヒドロフラン6mL懸濁液に氷冷下でメチル＝５−フルオロ−６−メトキシニコチナート0.58gのテトラヒドロフラン3.5mL溶液を滴下した。室温まで昇温後、30分間攪拌した。氷冷下で飽和炭酸水素ナトリウム水溶液を滴下し、10分間攪拌後、反応混合物をセライト濾過し、濾滓を酢酸エチルおよび水で洗浄した。濾液の有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、褐色油状物の（５−フルオロ−６−メトキシピリジン−３−イル）メタノール0.55gを得た。
¹H-NMR(CDCl₃)δ値：1.72(1H,t,J=5.7Hz),4.03(3H,s),4.65(2H,d,J=5.7Hz),7.40(1H,dd,J=10.7,2.0Hz),7.89(1H,d,J=2.0Hz) Reference Example 118

To a suspension of 0.24 g of lithium aluminum hydride in 6 mL of tetrahydrofuran was added dropwise a solution of 0.58 g of methyl = 5-fluoro-6-methoxynicotinate in 3.5 mL of tetrahydrofuran under ice cooling. After warming to room temperature, the mixture was stirred for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added dropwise under ice-cooling, and the mixture was stirred for 10 minutes. The reaction mixture was filtered through Celite, and the filter cake was washed with ethyl acetate and water. The organic layer of the filtrate was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and (5-fluoro-6-methoxypyridine-3- I) 0.55 g of methanol was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.72 (1H, t, J = 5.7 Hz), 4.03 (3H, s), 4.65 (2H, d, J = 5.7 Hz), 7.40 (1H, dd, J = 10.7, 2.0Hz), 7.89 (1H, d, J = 2.0Hz)

（５−フルオロ−６−メトキシピリジン−３−イル）メタノール0.54gのジクロロメタン5mL溶液に二酸化マンガン1.5gを加えた。室温で3時間攪拌後、二酸化マンガン0.89gおよびジクロロメタン4mLを加え、1時間攪拌した。さらに、二酸化マンガン1.5gおよびジクロロメタン2mLを追加し、室温で2時間30分間攪拌した。一晩放置後、不溶物を濾去し、濾滓をクロロホルムで洗浄した。減圧下で溶媒を留去し、黄色固体の５−フルオロ−６−メトキシニコチンアルデヒド0.48gを得た。
¹H-NMR(CDCl₃)δ値：4.13(3H,s),7.78(1H,dd,J=9.8,1.8Hz),8.42(1H,d,J=1.8Hz),9.97(1H,d,J=2.7Hz) Reference Example 119

1.5 g of manganese dioxide was added to a solution of 0.54 g of (5-fluoro-6-methoxypyridin-3-yl) methanol in 5 mL of dichloromethane. After stirring at room temperature for 3 hours, 0.89 g of manganese dioxide and 4 mL of dichloromethane were added and stirred for 1 hour. Further, 1.5 g of manganese dioxide and 2 mL of dichloromethane were added, and the mixture was stirred at room temperature for 2 hours and 30 minutes. After standing overnight, the insoluble material was removed by filtration, and the filter cake was washed with chloroform. The solvent was distilled off under reduced pressure to obtain 0.48 g of yellow solid 5-fluoro-6-methoxynicotinaldehyde.
¹ H-NMR (CDCl ₃ ) δ value: 4.13 (3H, s), 7.78 (1H, dd, J = 9.8, 1.8 Hz), 8.42 (1H, d, J = 1.8 Hz), 9.97 (1H, d, (J = 2.7Hz)

参考例１０１と同様の手法により、２，６−ジクロロ−３−フルオロ−５−（（メトキシメトキシ）メチル）ピリジンから３−フルオロ−５−（（メトキシメトキシ）メチル）−２，６−ジメチルピリジンを得た。
¹H-NMR(CDCl₃)δ値：2.47(3H,s),2.48(3H,d,J=2.7Hz),3.42(3H,s),4.55(2H,s),4.73(2H,s),7.35(1H,d,J=9.8Hz) Reference Example 120

In the same manner as in Reference Example 101, 2,6-dichloro-3-fluoro-5-((methoxymethoxy) methyl) pyridine was converted to 3-fluoro-5-((methoxymethoxy) methyl) -2,6-dimethylpyridine. Got.
¹ H-NMR (CDCl ₃ ) δ value: 2.47 (3H, s), 2.48 (3H, d, J = 2.7 Hz), 3.42 (3H, s), 4.55 (2H, s), 4.73 (2H, s) , 7.35 (1H, d, J = 9.8Hz)

参考例１０２と同様の手法により、３−フルオロ−５−（（メトキシメトキシ）メチル）−２，６−ジメチルピリジンから（５−フルオロ−２，６−ジメチルピリジン−３−イル）メタノールを得た。
¹H-NMR(CDCl₃)δ値：1.99-2.20(1H,broad),2.45(3H,s),2.48(3H,d,J=2.9Hz),4.68(2H,s),7.40(1H,d,J=9.8Hz) Reference Example 121

(5-Fluoro-2,6-dimethylpyridin-3-yl) methanol was obtained from 3-fluoro-5-((methoxymethoxy) methyl) -2,6-dimethylpyridine by the same method as in Reference Example 102. .
¹ H-NMR (CDCl ₃ ) δ value: 1.99-2.20 (1H, broad), 2.45 (3H, s), 2.48 (3H, d, J = 2.9 Hz), 4.68 (2H, s), 7.40 (1H, d, J = 9.8Hz)

参考例１０３と同様の手法により、（５−フルオロ−２，６−ジメチルピリジン−３−イル）メタノールから５−フルオロ−２，６−ジメチルニコチンアルデヒドを得た。
¹H-NMR(CDCl₃)δ値：2.57(3H,d,J=2.9Hz),2.82(3H,d,J=1.0Hz),7.72(1H,d,J=9.0Hz),10.28(1H,d,J=2.2Hz) Reference Example 122

In the same manner as in Reference Example 103, 5-fluoro-2,6-dimethylnicotinaldehyde was obtained from (5-fluoro-2,6-dimethylpyridin-3-yl) methanol.
¹ H-NMR (CDCl ₃ ) δ value: 2.57 (3H, d, J = 2.9 Hz), 2.82 (3H, d, J = 1.0 Hz), 7.72 (1H, d, J = 9.0 Hz), 10.28 (1H , d, J = 2.2Hz)

（３，４−ジヒドロ−２Ｈ−ピラノ（２，３−ｃ）ピリジン−６−イル）メタノール0.25gのクロロホルム7.5mL溶液に二酸化マンガン0.66gを加え、加熱還流下4時間50分間攪拌した。反応混合物を室温まで冷却後、不溶物を濾去し、減圧下で溶媒を留去し、淡黄色油状物の３，４−ジヒドロ−２Ｈ−ピラノ（２，３−ｃ）ピリジン−６−カルバルデヒド0.24gを得た。
¹H-NMR(CDCl₃)δ値：2.04-2.11(2H,m),2.85(2H,t,J=6.5Hz),4.32(2H,t,J=5.1Hz),7.72(1H,s),8.27(1H,s),9.94(1H,s) Reference Example 123

To a solution of (3,4-dihydro-2H-pyrano (2,3-c) pyridin-6-yl) methanol (0.25 g) in chloroform (7.5 mL) was added manganese dioxide (0.66 g), and the mixture was stirred with heating under reflux for 4 hours and 50 minutes. After cooling the reaction mixture to room temperature, insolubles were removed by filtration, the solvent was distilled off under reduced pressure, and 3,4-dihydro-2H-pyrano (2,3-c) pyridine-6-carba was obtained as a pale yellow oil. 0.24 g of aldehyde was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.04-2.11 (2H, m), 2.85 (2H, t, J = 6.5 Hz), 4.32 (2H, t, J = 5.1 Hz), 7.72 (1H, s) , 8.27 (1H, s), 9.94 (1H, s)

参考例６０と同様の手法により、ｔｅｒｔ−ブチル＝（３Ｓ）−３−アミノピロリジン−１−カルボキシラートおよび２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−カルバルデヒドからｔｅｒｔ−ブチル＝（３Ｓ）−３−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピロリジン−１−カルボキシラートを得た。
¹H-NMR(CDCl₃)δ値：1.43(9H,s),1.54-1.64(1H,m),2.18-2.42(2H,m),2.50-2.86(3H,m),3.62(2H,s),4.10-4.22(1H,broad),4.25-4.36(4H,m),4.86-4.94(1H,m),6.86(1H,s),8.10(1H,s) Reference Example 124

In the same manner as in Reference Example 60, tert-butyl = (3S) -3-aminopyrrolidine-1-carboxylate and 2,3-dihydro (1,4) dioxyno (2,3-c) pyridine-7-carba From aldehyde, tert-butyl = (3S) -3-((2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) amino) pyrrolidine-1-carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.43 (9H, s), 1.54-1.64 (1H, m), 2.18-2.42 (2H, m), 2.50-2.86 (3H, m), 3.62 (2H, s ), 4.10-4.22 (1H, broad), 4.25-4.36 (4H, m), 4.86-4.94 (1H, m), 6.86 (1H, s), 8.10 (1H, s)

参考例１３と同様の手法により、ｔｅｒｔ−ブチル＝（３Ｓ）−３−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピロリジン−１−カルボキシラートから（３Ｓ）−Ｎ−（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）ピロリジン−３−アミン塩酸塩を得た。
¹H-NMR(DMSO-d₆)δ値：2.03-2.14(1H,m),2.30-2.40(1H,m),3.30-3.72(4H,m),3.92-4.05(1H,m),4.32-4.43(4H,m),4.45(2H,s),7.19(1H,s),8.22(1H,s) Reference Example 125

In the same manner as in Reference Example 13, tert-butyl = (3S) -3-((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) pyrrolidine-1 (3S) -N- (2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) pyrrolidin-3-amine hydrochloride was obtained from the carboxylate.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.03-2.14 (1H, m), 2.30-2.40 (1H, m), 3.30-3.72 (4H, m), 3.92-4.05 (1H, m), 4.32 -4.43 (4H, m), 4.45 (2H, s), 7.19 (1H, s), 8.22 (1H, s)

１−（１，３−ジオキソラン−２−イルメチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン2.2gに80％トリフルオロ酢酸水溶液20mLを加え、80〜90℃で3時間攪拌した。80％トリフルオロ酢酸水溶液10mLを加え、80〜90℃で2時間攪拌した後、さらに80％トリフルオロ酢酸水溶液10mLを加え、同温度で9時間攪拌した。反応混合物を室温まで冷却した後、減圧下で溶媒を留去した。得られた残留物に2mol/L水酸化ナトリウム水溶液を加え、pH8.0に調整し、クロロホルムおよびメタノールを加えた。有機層を分取し、水層をクロロホルムおよびメタノールの混合液で2回抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジエチルエーテルおよびヘキサンを加え、固形物を濾取し、淡褐色固体の７−フルオロ−１−（２−ヒドロキシ−２−メトキシエチル）−１，５−ナフチリジン−２（１Ｈ）−オン1.5gを得た。
¹H-NMR(DMSO-d₆)δ値：3.21(3H,s),4.19-4.31(2H,m),4.72-4.79(1H,m),6.53(1H,d,J=7.1Hz),6.84(1H,d,J=9.8Hz),7.97(1H,d,J=9.8Hz),8.03(1H,dd,J=11.5,2.4Hz),8.55(1H,d,J=2.4Hz) Reference Example 126

To 2.2 g of 1- (1,3-dioxolan-2-ylmethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one was added 20 mL of an 80% aqueous trifluoroacetic acid solution, and the mixture was heated at 80 to 90 ° C. for 3 hours. Stir. 10 mL of an 80% aqueous trifluoroacetic acid solution was added and stirred at 80 to 90 ° C. for 2 hours, and then 10 mL of an 80% aqueous trifluoroacetic acid solution was further added and stirred at the same temperature for 9 hours. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. A 2 mol / L aqueous sodium hydroxide solution was added to the obtained residue to adjust to pH 8.0, and chloroform and methanol were added. The organic layer was separated, and the aqueous layer was extracted twice with a mixture of chloroform and methanol. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diethyl ether and hexane were added to the obtained residue, the solid was collected by filtration, and a light brown solid of 7-fluoro-1- (2-hydroxy-2-methoxyethyl) -1,5-naphthyridine-2 (1H ) -One 1.5 g was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.21 (3H, s), 4.19-4.31 (2H, m), 4.72-4.79 (1H, m), 6.53 (1H, d, J = 7.1 Hz), 6.84 (1H, d, J = 9.8Hz), 7.97 (1H, d, J = 9.8Hz), 8.03 (1H, dd, J = 11.5,2.4Hz), 8.55 (1H, d, J = 2.4Hz)

参考例７７と同様の手法により、７−フルオロ−１−（２−ヒドロキシ−２−メトキシエチル）−１，５−ナフチリジン−２（１Ｈ）−オンおよびｔｅｒｔ−ブチル＝（ピペリジン−４−イル）カルバマートからｔｅｒｔ−ブチル＝（１−（２−（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.32-1.49(2H,m),1.44(9H,s),1.89-1.99(2H,m),2.20-2.30(2H,m),2.61-2.68(2H,m),2.86-2.95(2H,m),3.42-3.54(1H,m),4.27-4.35(2H,m),4.38-4.47(1H,m),6.86(1H,d,J=9.8Hz),7.48-7.55(1H,m),7.89(1H,d,J=9.8Hz),8.42(1H,d,J=2.4Hz) Reference Example 127

In the same manner as in Reference Example 77, 7-fluoro-1- (2-hydroxy-2-methoxyethyl) -1,5-naphthyridin-2 (1H) -one and tert-butyl = (piperidin-4-yl) From the carbamate, tert-butyl = (1- (2- (7-fluoro-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.32-1.49 (2H, m), 1.44 (9H, s), 1.89-1.99 (2H, m), 2.20-2.30 (2H, m), 2.61-2.68 (2H , m), 2.86-2.95 (2H, m), 3.42-3.54 (1H, m), 4.27-4.35 (2H, m), 4.38-4.47 (1H, m), 6.86 (1H, d, J = 9.8Hz ), 7.48-7.55 (1H, m), 7.89 (1H, d, J = 9.8Hz), 8.42 (1H, d, J = 2.4Hz)

参考例７８と同様の手法により、ｔｅｒｔ−ブチル＝（１−（２−（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートから１−（２−（４−アミノピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：1.92-2.08(2H,m),2.34-2.45(2H,m),3.17-3.35(2H,m),3.56-3.68(3H,m),3.91-4.03(2H,m),4.71-4.78(2H,m),6.99(1H,d,J=9.9Hz),7.96(1H,dd,J=10.0,2.1Hz),8.09(1H,d,J=9.9Hz),8.57(1H,d,J=2.1Hz) Reference Example 128

In the same manner as in Reference Example 78, tert-butyl = (1- (2- (7-fluoro-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate To 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one hydrochloride.
¹ H-NMR (D ₂ O) δ value: 1.92-2.08 (2H, m), 2.34-2.45 (2H, m), 3.17-3.35 (2H, m), 3.56-3.68 (3H, m), 3.91 4.03 (2H, m), 4.71-4.78 (2H, m), 6.99 (1H, d, J = 9.9Hz), 7.96 (1H, dd, J = 10.0,2.1Hz), 8.09 (1H, d, J = 9.9Hz), 8.57 (1H, d, J = 2.1Hz)

７−ブロモ−１−（（１，３−ジオキソラン−２−イル）メチル）−１，５−ナフチリジン−２（１Ｈ）−オン0.40gのジオキサン4mL懸濁液に室温でｔｅｒｔ−ブチルカルバマート0.18g、炭酸セシウム0.59g、４，５−ビス（ジフェニルホスフィノ）−９，９−ジメチルキサンテン22mgおよびトリス（ジベンジリデンアセトン）ジパラジウム（０）18mgを加え、90〜95℃で4時間15分間攪拌した。室温まで冷却後、反応混合物にクロロホルムおよび水を加え、有機層を分取し、水および飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、得られた残留物にジエチルエーテルを加え、固形物を濾取し、淡黄色固体のｔｅｒｔ−ブチル＝（５−（１，３−ジオキソラン−２−イル）メチル−６−オキソ−５，６−ジヒドロ−１，５−ナフチリジン−３−イル）カルバマート0.29gを得た。
¹H-NMR(CDCl₃)δ値：1.55(9H,s),3.86-3.94(2H,m),4.02-4.13(2H,m),4.46(2H,d,J=4.6Hz),5.33(1H,t,J=4.6Hz),6.80(1H,d,J=9.6Hz),6.91(1H,s),7.83(1H,d,J=9.6Hz),8.29(1H,d,J=2.0Hz),8.43(1H,s) Reference Example 129

7-Bromo-1-((1,3-dioxolan-2-yl) methyl) -1,5-naphthyridin-2 (1H) -one In a suspension of 0.40 g of dioxane in 4 mL at room temperature was added tert-butyl carbamate 0.18. g, 0.59 g of cesium carbonate, 22 mg of 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene and 18 mg of tris (dibenzylideneacetone) dipalladium (0) were added and the mixture was heated at 90 to 95 ° C. for 4 hours and 15 minutes. Stir. After cooling to room temperature, chloroform and water were added to the reaction mixture, and the organic layer was separated and washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, diethyl ether was added to the obtained residue, the solid matter was collected by filtration, and tert-butyl = (5- (1,3-3- 0.29 g of dioxolan-2-yl) methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.55 (9H, s), 3.86-3.94 (2H, m), 4.02-4.13 (2H, m), 4.46 (2H, d, J = 4.6 Hz), 5.33 ( 1H, t, J = 4.6Hz), 6.80 (1H, d, J = 9.6Hz), 6.91 (1H, s), 7.83 (1H, d, J = 9.6Hz), 8.29 (1H, d, J = 2.0 Hz), 8.43 (1H, s)

ｔｅｒｔ−ブチル＝（５−（１，３−ジオキソラン−２−イル）メチル−６−オキソ−５，６−ジヒドロ−１，５−ナフチリジン−３−イル）カルバマート0.15gのＮ，Ｎ−ジメチルホルムアミド2mL溶液に60％水素化ナトリウム21mgおよびヨウ化メチル32μLを加え、室温で2時間20分間攪拌した。60％水素化ナトリウム9mgおよびヨウ化メチル13μLを追加し、室温で1時間攪拌した。反応混合物に酢酸エチルおよび水を加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をフラッシュ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＝１：１−３：７］で精製し、褐色油状物のｔｅｒｔ−ブチル＝（５−（１，３−ジオキソラン−２−イル）メチル−６−オキソ−５，６−ジヒドロ−１，５−ナフチリジン−３−イル）（メチル）カルバマート0.13gを得た。
¹H-NMR(CDCl₃)δ値：1.50(9H,s),3.38(3H,s),3.85-3.94(2H,m),3.97-4.05(2H,m),4.48(2H,d,J=4.3Hz),5.22(1H,t,J=4.3Hz),6.87(1H,d,J=9.8Hz),7.84-7.89(2H,m),8.51(1H,d,J=2.0Hz) Reference Example 130

tert-butyl = (5- (1,3-dioxolan-2-yl) methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl) carbamate 0.15 g of N, N-dimethylformamide To 2 mL solution, 21 mg of 60% sodium hydride and 32 μL of methyl iodide were added and stirred at room temperature for 2 hours and 20 minutes. 9 mg of 60% sodium hydride and 13 μL of methyl iodide were added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash silica gel column chromatography [gradient elution of hexane: ethyl acetate = 1: 1-3: 7], and tert-butyl = (5- (1,3-dioxolane- 0.13 g of 2-yl) methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl) (methyl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.50 (9H, s), 3.38 (3H, s), 3.85-3.94 (2H, m), 3.97-4.05 (2H, m), 4.48 (2H, d, J = 4.3Hz), 5.22 (1H, t, J = 4.3Hz), 6.87 (1H, d, J = 9.8Hz), 7.84-7.89 (2H, m), 8.51 (1H, d, J = 2.0Hz)

５−（ベンジルオキシ）−２−（ヒドロキシメチル）ピリジン−４（１Ｈ）−オン10gのピリジン58mL溶液に氷冷下、アセチルクロリド4.6mLを加え、60〜70℃で3時間攪拌した。減圧下で溶媒を留去し、水を加え、氷冷下攪拌した。固形物を濾取し、クロロホルムを加え、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。ジエチルエーテルを加え、固形物を濾取し、淡褐色固体の（５−（ベンジルオキシ）−４−オキソ−１，４−ジヒドロピリジン−２−イル）メチル＝アセタート9.2gを得た。
¹H-NMR(CDCl₃)δ値：2.08(3H,s),4.89(2H,s),5.00(2H,s),6.63(1H,s),7.28(5H,s),7.50(1H,s) Reference Example 131

To a 58 mL pyridine solution of 10 g of 5- (benzyloxy) -2- (hydroxymethyl) pyridin-4 (1H) -one, 4.6 mL of acetyl chloride was added under ice cooling, and the mixture was stirred at 60 to 70 ° C. for 3 hours. The solvent was distilled off under reduced pressure, water was added, and the mixture was stirred under ice cooling. The solid was collected by filtration, added with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diethyl ether was added, and the solid was collected by filtration to obtain 9.2 g of (5- (benzyloxy) -4-oxo-1,4-dihydropyridin-2-yl) methyl acetate as a light brown solid.
¹ H-NMR (CDCl ₃ ) δ value: 2.08 (3H, s), 4.89 (2H, s), 5.00 (2H, s), 6.63 (1H, s), 7.28 (5H, s), 7.50 (1H, s)

（５−（ベンジルオキシ）−４−オキソ−１，４−ジヒドロピリジン−２−イル）メチル＝アセタート6.1gのジメチルスルホキシド50mL溶液にｔｅｒｔ−ブチル＝（２−ブロモエチル）カルバマート5.0gおよび炭酸カリウム10gを加え、80〜90℃で6時間30分間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび水を加え、有機層を分取し、水洗し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をフラッシュ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＝９９：１−９８：２］で精製し、褐色油状物の（５−（ベンジルオキシ）−４−（２−（（ｔｅｒｔ−ブトキシカルボニル）アミノ）エトキシ）ピリジン−２−イル）メチル＝アセタート3.8gを得た。
¹H-NMR(CDCl₃)δ値：1.45(9H,s),2.15(3H,s),3.58(2H,q,J=5.3Hz),4.13(2H,t,J=5.3Hz),4.96(1H,s),5.10(2H,s),5.16(2H,s),6.89(1H,s),7.30-7.45(5H,m),8.16(1H,s) Reference Example 132

A solution of 6.1 g of (5- (benzyloxy) -4-oxo-1,4-dihydropyridin-2-yl) methyl acetate in 50 mL of dimethyl sulfoxide was charged with 5.0 g of tert-butyl = (2-bromoethyl) carbamate and 10 g of potassium carbonate. In addition, the mixture was stirred at 80 to 90 ° C. for 6 hours and 30 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added, the organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash silica gel column chromatography [gradient elution of chloroform: methanol = 99: 1-98: 2] to give (5- (benzyloxy) -4- (2-(( 3.8 g of tert-butoxycarbonyl) amino) ethoxy) pyridin-2-yl) methyl acetate were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.45 (9H, s), 2.15 (3H, s), 3.58 (2H, q, J = 5.3 Hz), 4.13 (2H, t, J = 5.3 Hz), 4.96 (1H, s), 5.10 (2H, s), 5.16 (2H, s), 6.89 (1H, s), 7.30-7.45 (5H, m), 8.16 (1H, s)

（５−（ベンジルオキシ）−４−（２−（（ｔｅｒｔ−ブトキシカルボニル）アミノ）エトキシ）ピリジン−２−イル）メチル＝アセタート3.8gのエタノール91mL溶液に10％パラジウムー炭素1.1gを加え、室温で水素雰囲気下、5時間攪拌した。不溶物を濾去し、減圧下で溶媒を留去した。クロロホルムおよびジエチルエーテルを加え、固形物を濾取し、淡褐色固体の（４−（２−（（ｔｅｒｔ−ブトキシカルボニル）アミノ）エトキシ）−５−ヒドロキシピリジン−２−イル）メチル＝アセタート2.1gを得た。
¹H-NMR(CDCl₃)δ値：1.45(9H,s),2.15(3H,s),3.61(2H,q,J=4.8Hz),4.21(2H,t,J=4.8Hz),5.20(2H,s),5.35(1H,s),6.94(1H,s),8.26(1H,s) Reference Example 133

To a solution of 3.8 g of (5- (benzyloxy) -4- (2-((tert-butoxycarbonyl) amino) ethoxy) pyridin-2-yl) methyl acetate in 91 mL of ethanol was added 1.1 g of 10% palladium-carbon, and room temperature. For 5 hours under hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. Chloroform and diethyl ether were added and the solid was collected by filtration to give 2.1 g of (4- (2-((tert-butoxycarbonyl) amino) ethoxy) -5-hydroxypyridin-2-yl) methyl acetate as a light brown solid. Got.
¹ H-NMR (CDCl ₃ ) δ value: 1.45 (9H, s), 2.15 (3H, s), 3.61 (2H, q, J = 4.8Hz), 4.21 (2H, t, J = 4.8Hz), 5.20 (2H, s), 5.35 (1H, s), 6.94 (1H, s), 8.26 (1H, s)

（４−（２−（（ｔｅｒｔ−ブトキシカルボニル）アミノ）エトキシ）−５−ヒドロキシピリジン−２−イル）メチル＝アセタート1.0gのジクロロメタン15mL溶液に氷冷下トリエチルアミン0.86mLおよびトリフルオロメタンスルホン酸無水物0.78mLを加え、30分間攪拌した。飽和炭酸水素ナトリウム水溶液および水を加え、有機層を分取し、飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をフラッシュ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＝６６：３４−５０：５０］で精製し、無色油状物の（４−（２−（（ｔｅｒｔ−ブトキシカルボニル）アミノ）エトキシ）−５−（（（トリフルオロメチル）スルホニル）オキシ）ピリジン−２−イル）メチル＝アセタート1.3gを得た。
¹H-NMR(CDCl₃)δ値：1.45(9H,s),2.20(3H,s),3.60(2H,q,J=5.2Hz),4.23(2H,t,J=5.2Hz),5.05(1H,s),5.18(2H,s),7.04(1H,s),8.35(1H,s) Reference Example 134

(4- (2-((tert-Butoxycarbonyl) amino) ethoxy) -5-hydroxypyridin-2-yl) methyl acetate 1.0 g in dichloromethane 15 mL solution under ice-cooling triethylamine 0.86 mL and trifluoromethanesulfonic anhydride 0.78 mL was added and stirred for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution and water were added, and the organic layer was separated and washed with a saturated aqueous sodium chloride solution. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash silica gel column chromatography [gradient elution of hexane: ethyl acetate = 66: 34-50: 50] to give (4- (2-((tert-butoxycarbonyl) amino as a colorless oil). 1.3 g of ethoxy) -5-(((trifluoromethyl) sulfonyl) oxy) pyridin-2-yl) methyl acetate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.45 (9H, s), 2.20 (3H, s), 3.60 (2H, q, J = 5.2Hz), 4.23 (2H, t, J = 5.2Hz), 5.05 (1H, s), 5.18 (2H, s), 7.04 (1H, s), 8.35 (1H, s)

（４−（２−（（ｔｅｒｔ−ブトキシカルボニル）アミノ）エトキシ）−５−（（（トリフルオロメチル）スルホニル）オキシ）ピリジン−２−イル）メチル＝アセタート1.0gのジオキサン5.0mL溶液に炭酸セシウム1.0g、トリス（ジベンジリデンアセトン）ジパラジウム（０）58mgおよび４，５−ビス（ジフェニルホスフィノ）−９，９−ジメチルキサンテン76mgを加え、加熱還流下2時間攪拌した。反応混合物に酢酸エチルを加え、不溶物を濾去し、減圧下で溶媒を留去した。得られた残留物をフラッシュ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＝６０：４０−０：１００］で精製し、褐色固体のｔｅｒｔ−ブチル＝７−（（アセトキシ）メチル）−２，３−ジヒドロ−４Ｈ−ピリド（４，３−ｂ）（１，４）オキサジン−４−カルボキシラート0.29gを得た。
¹H-NMR(CDCl₃)δ値：1.56(9H,s),2.14(3H,s),3.85-3.89(2H,m),4.29-4.32(2H,m),5.11(2H,s),6.86(1H,s),8.88(1H,s) Reference Example 135

(4- (2-((tert-butoxycarbonyl) amino) ethoxy) -5-(((trifluoromethyl) sulfonyl) oxy) pyridin-2-yl) methyl acetate in a solution of 1.0 g of dioxane in 5.0 mL of dioxane 1.0 g, 58 mg of tris (dibenzylideneacetone) dipalladium (0) and 76 mg of 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene were added, and the mixture was stirred with heating under reflux for 2 hours. Ethyl acetate was added to the reaction mixture, the insoluble material was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash silica gel column chromatography [gradient elution of hexane: ethyl acetate = 60: 40-0: 100], and tert-butyl = 7-((acetoxy) methyl) -2, brown solid 0.29 g of 3-dihydro-4H-pyrido (4,3-b) (1,4) oxazine-4-carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.56 (9H, s), 2.14 (3H, s), 3.85-3.89 (2H, m), 4.29-4.32 (2H, m), 5.11 (2H, s), 6.86 (1H, s), 8.88 (1H, s)

ｔｅｒｔ−ブチル＝７−（（アセトキシ）メチル）−２，３−ジヒドロ−４Ｈ−ピリド（４，３−ｂ）（１，４）オキサジン−４−カルボキシラート0.11gのテトラヒドロフラン1.7mLおよび水1.7mLの混合溶液に2.0mol/L水酸化ナトリウム水溶液0.36mLを加え、室温で1時間攪拌した。反応液を炭酸カリウムで飽和後、酢酸エチルを加え、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、褐色油状物のｔｅｒｔ−ブチル＝７−（ヒドロキシメチル）−２，３−ジヒドロ−４Ｈ−ピリド（４，３−ｂ）（１，４）オキサジン−４−カルボキシラート90mgを得た。
¹H-NMR(CDCl₃)δ値：1.56(9H,s),3.32-3.41(1H,m),3.86-3.89(2H,m),4.29-4.32(2H,m),4.64(2H,s),6.76(1H,s),8.82-8.89(1H,m) Reference Example 136

tert-Butyl = 7-((acetoxy) methyl) -2,3-dihydro-4H-pyrido (4,3-b) (1,4) oxazine-4-carboxylate 0.11 g of tetrahydrofuran 1.7 mL and water 1.7 mL To this mixed solution was added 0.36 mL of a 2.0 mol / L aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was saturated with potassium carbonate, ethyl acetate was added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give a brown oily substance of tert-butyl = 7- (hydroxymethyl) -2,3 -90 mg of dihydro-4H-pyrido (4,3-b) (1,4) oxazine-4-carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.56 (9H, s), 3.32-3.41 (1H, m), 3.86-3.89 (2H, m), 4.29-4.32 (2H, m), 4.64 (2H, s ), 6.76 (1H, s), 8.82-8.89 (1H, m)

参考例６７と同様の手法によりｔｅｒｔ−ブチル＝７−（ヒドロキシメチル）−２，３−ジヒドロ−４Ｈ−ピリド（４，３−ｂ）（１，４）オキサジン−４−カルボキシラートからｔｅｒｔ−ブチル＝７−ホルミル−２，３−ジヒドロ−４Ｈ−ピリド（４，３−ｂ）（１，４）オキサジン−４−カルボキシラートを得た。
¹H-NMR(CDCl₃)δ値：1.58(9H,s),3.91-3.94(2H,m),4.34-4.37(2H,m),7.48(1H,s),9.12-9.21(1H,m),9.96(1H,s) Reference Example 137

In the same manner as in Reference Example 67, tert-butyl = 7- (hydroxymethyl) -2,3-dihydro-4H-pyrido (4,3-b) (1,4) oxazine-4-carboxylate to tert-butyl = 7-formyl-2,3-dihydro-4H-pyrido (4,3-b) (1,4) oxazine-4-carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.58 (9H, s), 3.91-3.94 (2H, m), 4.34-4.37 (2H, m), 7.48 (1H, s), 9.12-9.21 (1H, m ), 9.96 (1H, s)

８−（２−ヒドロキシエチル）−１，４−ジオキサスピロ（４．５）デカン−８−オール0.30gのジクロロメタン溶液5mLに氷冷下デス−マーチン＝ペルヨージナン0.76gを加え、室温で1時間攪拌した。反応混合物に氷冷下、水を加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させた。減圧下で溶媒を留去し、クロロホルムを加え、不溶物を濾去した。得られた残留物をフラッシュ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＝３５：６５−２５：７５］で精製し、微黄色油状物の（８−ヒドロキシ−１，４−ジオキサスピロ（４．５）デカ−８−イル）アセトアルデヒド0.19gを得た。
¹H-NMR(CDCl₃)δ値：1.53-1.64(2H,m),1.68(2H,td,J=13.1,4.3Hz),1.79-1.89(2H,m),1.95(2H,dt,J=12.7,4.3Hz),2.54-2.59(1H,broad),2.65(2H,d,J=1.5Hz),3.90-4.00(4H,m),9.88(1H,t,J=1.5Hz) Reference Example 138

To a 5 mL dichloromethane solution of 0.30 g 8- (2-hydroxyethyl) -1,4-dioxaspiro (4.5) decan-8-ol, 0.76 g Dess-Martin periodinane was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. . Water was added to the reaction mixture under ice cooling, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, chloroform was added, and the insoluble material was removed by filtration. The obtained residue was purified by flash silica gel column chromatography [hexane: ethyl acetate gradient elution = 35: 65-25: 75] to give (8-hydroxy-1,4-dioxaspiro (4. 5) Deca-8-yl) acetaldehyde 0.19 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.53-1.64 (2H, m), 1.68 (2H, td, J = 13.1, 4.3 Hz), 1.79-1.89 (2H, m), 1.95 (2H, dt, J = 12.7, 4.3Hz), 2.54-2.59 (1H, broad), 2.65 (2H, d, J = 1.5Hz), 3.90-4.00 (4H, m), 9.88 (1H, t, J = 1.5Hz)

窒素気流下、２−クロロ−５−フルオロピリジン−３−アミン150gのＮ，Ｎ−ジメチルホルムアミド600mL溶液にブチル＝アクリラート190mLおよびトリエチルアミン287mLを加え、110℃で2時間攪拌した。反応混合物を58℃まで冷却し、ビス（トリ−ｔｅｒｔ−ブチルホスフィン）パラジウム（０）13.1gを加え、110〜120℃で40分間攪拌した。反応混合物を57℃まで冷却し、ビス（トリ−ｔｅｒｔ−ブチルホスフィン）パラジウム（０）13.1gを加え、110〜120℃で3間攪拌した。反応混合物を室温まで冷却し、水および酢酸エチルを加えた。不溶物を濾去し、濾液の有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にシクロヘキサンおよび酢酸エチルを加え、固形物を濾取し、淡褐色固体のブチル＝（２Ｅ）−３−（３−アミノ−５−フルオロピリジン−２−イル）アクリラート200gを得た。
¹H-NMR(CDCl₃)δ値：0.95(3H,t,J=7.3Hz),1.38-1.48(2H,m),1.64-1.72(2H,m),4.13(2H,s),4.21(2H,t,J=6.7Hz),6.71(1H,dd,J=9.8,2.3Hz),6.86(1H,d,J=15.3Hz),7.72(1H,d,J=15.3Hz),7.94(1H,d,J=2.3Hz) Reference Example 139

Under a nitrogen stream, 190 mL of butyl acrylate and 287 mL of triethylamine were added to a solution of 150 g of 2-chloro-5-fluoropyridin-3-amine in 600 mL of N, N-dimethylformamide and stirred at 110 ° C. for 2 hours. The reaction mixture was cooled to 58 ° C, 13.1 g of bis (tri-tert-butylphosphine) palladium (0) was added, and the mixture was stirred at 110 to 120 ° C for 40 minutes. The reaction mixture was cooled to 57 ° C., 13.1 g of bis (tri-tert-butylphosphine) palladium (0) was added, and the mixture was stirred at 110 to 120 ° C. for 3 hours. The reaction mixture was cooled to room temperature and water and ethyl acetate were added. Insolubles were removed by filtration, the organic layer of the filtrate was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Cyclohexane and ethyl acetate are added to the obtained residue, and the solid is collected by filtration to obtain 200 g of butyl = (2E) -3- (3-amino-5-fluoropyridin-2-yl) acrylate as a light brown solid. It was.
¹ H-NMR (CDCl ₃ ) δ value: 0.95 (3H, t, J = 7.3 Hz), 1.38-1.48 (2H, m), 1.64-1.72 (2H, m), 4.13 (2H, s), 4.21 ( 2H, t, J = 6.7Hz), 6.71 (1H, dd, J = 9.8,2.3Hz), 6.86 (1H, d, J = 15.3Hz), 7.72 (1H, d, J = 15.3Hz), 7.94 ( (1H, d, J = 2.3Hz)

ブチル＝（２Ｅ）−３−（３−アミノ−５−フルオロピリジン−２−イル）アクリラート90mgのジクロロメタン5mL溶液に（８−ヒドロキシ−１，４−ジオキサスピロ（４．５）デカ−８−イル）アセトアルデヒド90mgおよび酢酸33μLを加え、室温で4時間攪拌し、一晩放置した。反応混合物に水素化トリアセトキシホウ素ナトリウム80mgを加え、室温で1時間攪拌した。飽和炭酸水素ナトリウム水溶液およびクロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、得られた残留物をフラッシュ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＝６０：４０−５０：５０］で精製し、黄色油状物のブチル＝（２Ｅ）−３−（５−フルオロ−３−（（２−（８−ヒドロキシ−１，４−ジオキサスピロ（４．５）デカ−８−イル）エチル）アミノ）ピリジン−２−イル）アクリラート82mgを得た。
¹H-NMR(CDCl₃)δ値：0.95(3H,t,J=7.4Hz),1.38-1.48(2H,m),1.55-2.00(10H,m),3.22-3.30(2H,m),3.90-4.02(6H,m),4.20(2H,t,J=6.6Hz),5.40-5.47(1H,m),6.63(1H,dd,J=11.2,2.4Hz),6.83(1H,d,J=15.2Hz),7.71(1H,d,J=15.2Hz),7.82(1H,d,J=2.4Hz) Reference Example 140

Butyl = (2E) -3- (3-amino-5-fluoropyridin-2-yl) acrylate in a solution of 90 mg of dichloromethane in 5 mL of dichloromethane (8-hydroxy-1,4-dioxaspiro (4.5) dec-8-yl) 90 mg of acetaldehyde and 33 μL of acetic acid were added, stirred at room temperature for 4 hours, and left overnight. To the reaction mixture, 80 mg of sodium triacetoxyborohydride was added and stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to flash silica gel column chromatography [hexane: ethyl acetate gradient. Elution = 60: 40-50: 50] and butyl yellow oil (2E) -3- (5-fluoro-3-((2- (8-hydroxy-1,4-dioxaspiro (4. 5) Deca-8-yl) ethyl) amino) pyridin-2-yl) acrylate 82 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 0.95 (3H, t, J = 7.4 Hz), 1.38-1.48 (2H, m), 1.55-2.00 (10H, m), 3.22-3.30 (2H, m), 3.90-4.02 (6H, m), 4.20 (2H, t, J = 6.6Hz), 5.40-5.47 (1H, m), 6.63 (1H, dd, J = 11.2,2.4Hz), 6.83 (1H, d, J = 15.2Hz), 7.71 (1H, d, J = 15.2Hz), 7.82 (1H, d, J = 2.4Hz)

ブチル＝（２Ｅ）−３−（５−フルオロ−３−（（２−（８−ヒドロキシ−１，４−ジオキサスピロ（４．５）デカ−８−イル）エチル）アミノ）ピリジン−２−イル）アクリラート80mgのメタノール、テトラヒドロフラン（１：１）4mL混合溶液に、室温で28％ナトリウムメトキシド／メタノール溶液55mgを加え、加熱還流下、1時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび水を加え、有機層を分取した。飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し黄色油状物の１−（２−（８−ヒドロキシ−１，４−ジオキサスピロ（４．５）デカ−８−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン65mgを得た。¹H-NMR(CDCl₃)δ値：1.70-1.80(4H,m),1.87-1.96(4H,m),2.48-2.56(2H,m),3.92-4.00(4H,m),3.98(3H,s),4.38-4.45(2H,m),6.76(1H,d,J=9.8Hz),7.24-7.32(1H,m),7.87(1H,d,J=9.8Hz),8.30(1H,d,J=2.4Hz) Reference Example 141

Butyl = (2E) -3- (5-fluoro-3-((2- (8-hydroxy-1,4-dioxaspiro (4.5) dec-8-yl) ethyl) amino) pyridin-2-yl) To a mixed solution of 80 mg of acrylate in 4 mL of methanol and tetrahydrofuran (1: 1), 55 mg of 28% sodium methoxide / methanol solution was added at room temperature, and the mixture was stirred for 1 hour while heating under reflux. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the organic layer was separated. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 1- (2- (8-hydroxy-1,4-dioxaspiro (4.5) dec-8 as a yellow oil. -Yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one 65 mg was obtained. ¹ H-NMR (CDCl ₃ ) δ value: 1.70-1.80 (4H, m), 1.87-1.96 (4H, m), 2.48-2.56 (2H, m), 3.92-4.00 (4H, m), 3.98 (3H , s), 4.38-4.45 (2H, m), 6.76 (1H, d, J = 9.8Hz), 7.24-7.32 (1H, m), 7.87 (1H, d, J = 9.8Hz), 8.30 (1H, d, J = 2.4Hz)

１−（２−（８−ヒドロキシ−１，４−ジオキサスピロ（４．５）デカ−８−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン60mgに室温で80％トリフルオロ酢酸水溶液3mLを加え、8時間30分間攪拌した。減圧下で溶媒を留去し得られた残留物に、飽和炭酸水素ナトリウム水溶液およびおよび酢酸エチルを加え、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させた。減圧下で溶媒を留去し、得られた残留物をフラッシュ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＝１００：０−９９：１］で精製し、黄色固体の１−（２−（１−ヒドロキシ−４−オキソシクロヘキシル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン41mgを得た。
¹H-NMR(CDCl₃)δ値：1.60-2.12(6H,m),2.22-2.30(2H,m),2.73-2.83(2H,m),3.67-3.76(1H,broad),4.00(3H,s),4.47(2H,t,J=6.7Hz),6.80(1H,d,J=9.6Hz),7.16(1H,d,J=2.3Hz),7.93(1H,d,J=9.6Hz),8.35(1H,d,J=2.3Hz) Reference Example 142

1- (2- (8-Hydroxy-1,4-dioxaspiro (4.5) dec-8-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one at 80 mg at room temperature A 3% aqueous solution of trifluoroacetic acid was added, and the mixture was stirred for 8 hours and 30 minutes. To the residue obtained by evaporating the solvent under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by flash silica gel column chromatography [gradient elution of chloroform: methanol = 100: 0-99: 1] to give 1- (2- (1 41 mg of -hydroxy-4-oxocyclohexyl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.60-2.12 (6H, m), 2.22-2.30 (2H, m), 2.73-2.83 (2H, m), 3.67-3.76 (1H, broad), 4.00 (3H , s), 4.47 (2H, t, J = 6.7Hz), 6.80 (1H, d, J = 9.6Hz), 7.16 (1H, d, J = 2.3Hz), 7.93 (1H, d, J = 9.6Hz) ), 8.35 (1H, d, J = 2.3Hz)

１−（トリフルオロアセチル）ピペリジン−４−アミン0.50gのＮ，Ｎ−ジメチルホルムアミド−テトラヒドロフラン（１：１）の混合溶媒10mL溶液に炭酸カリウム0.41gおよびプロパルギルブロミド0.42mLを加え、加熱還流下2時間攪拌した。水および酢酸エチルを加え、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、Ｎ−（２−プロピン−１−イル）−１−（トリフルオロアセチル）ピペリジン−４−アミンの粗生成物0.60gを得た（粗生成物A）。一方、１−（トリフルオロアセチル）ピペリジン−４−アミン0.70gのＮ，Ｎ−ジメチルホルムアミド−テトラヒドロフラン（１：１）の混合溶媒7.2mL溶液に炭酸カリウム0.59gおよびプロパルギルブロミド0.30mLを加え、加熱還流下1時間50分間攪拌した。水および酢酸エチルを加え、先に得られた粗生成物A0.60gと混合し、6mol/L塩酸でpH1に調整した。水層を分取し、酢酸エチルで洗浄し、酢酸エチルを加え、炭酸カリウムで飽和した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、褐色油状物のＮ−（２−プロピン−１−イル）−１−（トリフルオロアセチル）ピペリジン−４−アミン1.0gを得た。
¹H-NMR(CDCl₃)δ値：1.36-1.48(2H,m),1.90-1.98(2H,m),2.23(1H,t,J=2.3Hz),3.03-3.34(3H,m),3.48(2H,d,J=2.3Hz),3.90-3.98(1H,m),4.22-4.31(1H,m) Reference Example 143

0.41 g of potassium carbonate and 0.42 mL of propargyl bromide are added to 10 mL of a mixed solvent of 0.50 g of 1- (trifluoroacetyl) piperidin-4-amine in N, N-dimethylformamide-tetrahydrofuran (1: 1), and the mixture is heated under reflux. Stir for hours. Water and ethyl acetate were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and N- (2-propyn-1-yl) -1- (tri 0.60 g of a crude product of (fluoroacetyl) piperidin-4-amine was obtained (crude product A). Meanwhile, 0.59 g of potassium carbonate and 0.30 mL of propargyl bromide were added to a 7.2 mL mixed solvent solution of 0.70 g of 1- (trifluoroacetyl) piperidin-4-amine in N, N-dimethylformamide-tetrahydrofuran (1: 1) and heated. The mixture was stirred for 1 hour and 50 minutes under reflux. Water and ethyl acetate were added, mixed with 0.60 g of the previously obtained crude product A, and adjusted to pH 1 with 6 mol / L hydrochloric acid. The aqueous layer was separated, washed with ethyl acetate, ethyl acetate was added, and the mixture was saturated with potassium carbonate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and N- (2-propyn-1-yl) -1- ( 1.0 g of (trifluoroacetyl) piperidin-4-amine was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.36-1.48 (2H, m), 1.90-1.98 (2H, m), 2.23 (1H, t, J = 2.3 Hz), 3.03-3.34 (3H, m), 3.48 (2H, d, J = 2.3Hz), 3.90-3.98 (1H, m), 4.22-4.31 (1H, m)

（１）Ｎ−（２−プロピン−１−イル）−１−（トリフルオロアセチル）ピペリジン−４−アミン0.60gのジオキサン5.2mL溶液にジ−ｔｅｒｔ−ブチル＝ジカルボナート0.56gを加え、室温で1時間45分間攪拌した。減圧下で溶媒を留去し、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［溶離液；ヘキサン：酢酸エチル＝３：１］で精製し、無色油状物のｔｅｒｔ−ブチル＝（２−プロピン−１−イル）（１−（トリフルオロアセチル）ピペリジン−４−イル）カルバマート0.70gを得た。
（２）ｔｅｒｔ−ブチル＝（２−プロピン−１−イル）（１−（トリフルオロアセチル）ピペリジン−４−イル）カルバマート0.20gのトリエチルアミン6.0mL溶液に窒素雰囲気下ヨードピラジン59μL、よう化銅（I）0.57mgおよびジクロロビス（トリフェニルホスフィン）パラジウム（II）4.2mgを加え、60〜70℃で4時間30分間攪拌した。不溶物を濾去し、減圧下で溶媒を留去した。得られた残留物をフラッシュ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＝６０：４０−５０：５０］で精製し、無色油状物のｔｅｒｔ−ブチル＝（３−（ピラジン−２−イル）−２−プロピン−１−イル）（１−（トリフルオロアセチル）ピペリジン−４−イル）カルバマート0.17gを得た。
¹H-NMR(CDCl₃)δ値：1.51(9H,s),1.76-2.02(4H,m),2.72-2.84(1H,m),3.12-3.22(1H,m),4.08-4.26(4H,m),4.64-4.72(1H,m),8.49(1H,d,J=2.7Hz),8.53-8.56(1H,m),8.60(1H,d,J=1.2Hz) Reference Example 144

(1) N- (2-propyn-1-yl) -1- (trifluoroacetyl) piperidin-4-amine (0.60 g) in dioxane (5.2 mL) was added with di-tert-butyl dicarbonate (0.56 g) at room temperature. Stir for 45 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 3: 1] to give tert-butyl = (2-propyne-1) as a colorless oil. 0.70 g of -yl) (1- (trifluoroacetyl) piperidin-4-yl) carbamate was obtained.
(2) tert-butyl = (2-propyn-1-yl) (1- (trifluoroacetyl) piperidin-4-yl) carbamate 0.20 g of triethylamine 6.0 mL in a nitrogen atmosphere 59 μL of iodopyrazine, copper iodide ( I) 0.57 mg and dichlorobis (triphenylphosphine) palladium (II) 4.2 mg were added, and it stirred at 60-70 degreeC for 4 hours and 30 minutes. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash silica gel column chromatography [gradient elution of hexane: ethyl acetate = 60: 40-50: 50], and tert-butyl = (3- (pyrazin-2-yl) was obtained as a colorless oil. There was obtained 0.17 g of 2-propyn-1-yl) (1- (trifluoroacetyl) piperidin-4-yl) carbamate.
¹ H-NMR (CDCl ₃ ) δ value: 1.51 (9H, s), 1.76-2.02 (4H, m), 2.72-2.84 (1H, m), 3.12-3.22 (1H, m), 4.08-4.26 (4H , m), 4.64-4.72 (1H, m), 8.49 (1H, d, J = 2.7Hz), 8.53-8.56 (1H, m), 8.60 (1H, d, J = 1.2Hz)

参考例６２と同様の手法により、ｔｅｒｔ−ブチル＝（３−（ピラジン−２−イル）−２−プロピン−１−イル）（１−（トリフルオロアセチル）ピペリジン−４−イル）カルバマートからｔｅｒｔ−ブチル＝（ピペリジン−４−イル）（３−ピラジン−２−イル）−２−プロピン−１−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.51(9H,s),1.72-1.92(4H,m),2.66-2.76(2H,m),3.17-3.24(2H,m),3.96-4.30(3H,m),8.47(1H,d,J=2.4Hz),8.51-8.54(1H,m),8.62(1H,d,J=1.2Hz) Reference Example 145

In the same manner as in Reference Example 62, tert-butyl = (3- (pyrazin-2-yl) -2-propin-1-yl) (1- (trifluoroacetyl) piperidin-4-yl) carbamate was converted to tert- Butyl = (piperidin-4-yl) (3-pyrazin-2-yl) -2-propin-1-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.51 (9H, s), 1.72-1.92 (4H, m), 2.66-2.76 (2H, m), 3.17-3.24 (2H, m), 3.96-4.30 (3H , m), 8.47 (1H, d, J = 2.4Hz), 8.51-8.54 (1H, m), 8.62 (1H, d, J = 1.2Hz)

参考例１４０と同様の手法により、８−ヒドロキシ−１，４−ジオキサスピロ（４．５）デカ−８−イル）アセトアルデヒドおよびエチル＝（２Ｅ）−３−（３−アミノ−５−メトキシピラジン−２−イル）アクリラートからエチル＝（２Ｅ）−３−（３−（（２−（８−ヒドロキシ−１，４−ジオキサスピロ（４．５）デカ−８−イル）エチル）アミノ）−５−メトキシピラジン−２−イル）アクリラートを得た。
¹H-NMR(CDCl₃)δ値：1.31(3H,t,J=7.2Hz),1.71-1.90(8H,m),3.60-3.65(2H,m),3.90-4.00(6H,m),3.94(3H,s),4.24(2H,q,J=7.2Hz),5.80-5.94(1H,m),6.68(1H,d,J=15.1Hz),7.51(1H,s),7.63(1H,d,J=15.1Hz) Reference Example 146

In the same manner as in Reference Example 140, 8-hydroxy-1,4-dioxaspiro (4.5) dec-8-yl) acetaldehyde and ethyl = (2E) -3- (3-amino-5-methoxypyrazine-2 -Yl) acrylate to ethyl = (2E) -3- (3-((2- (8-hydroxy-1,4-dioxaspiro (4.5) dec-8-yl) ethyl) amino) -5-methoxypyrazine -2-yl) acrylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.31 (3H, t, J = 7.2 Hz), 1.71-1.90 (8H, m), 3.60-3.65 (2H, m), 3.90-4.00 (6H, m), 3.94 (3H, s), 4.24 (2H, q, J = 7.2Hz), 5.80-5.94 (1H, m), 6.68 (1H, d, J = 15.1Hz), 7.51 (1H, s), 7.63 (1H , d, J = 15.1Hz)

参考例２と同様の手法により、エチル＝（２Ｅ）−３−（３−（（２−（８−ヒドロキシ−１，４−ジオキサスピロ（４．５）デカ−８−イル）エチル）アミノ）−５−メトキシピラジン−２−イル）アクリラートから５−（２−（８−ヒドロキシ−１，４−ジオキサスピロ（４．５）デカ−８−イル）エチル）−３−メトキシピリド（２，３−ｂ）ピラジン−６（５Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.50-1.80(6H,m),1.90-2.00(4H,m),2.40-2.44(1H,broad),3.89-3.99(4H,m),4.08(3H,s),4.58-4.62(2H,m),6.78(1H,d,J=9.6Hz),7.87(1H,d,J=9.6Hz),8.14(1H,s) Reference Example 147

In the same manner as in Reference Example 2, ethyl = (2E) -3- (3-((2- (8-hydroxy-1,4-dioxaspiro (4.5) dec-8-yl) ethyl) amino)- 5-methoxypyrazin-2-yl) acrylate to 5- (2- (8-hydroxy-1,4-dioxaspiro (4.5) dec-8-yl) ethyl) -3-methoxypyrido (2,3-b) Pyrazin-6 (5H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.50-1.80 (6H, m), 1.90-2.00 (4H, m), 2.40-2.44 (1H, broad), 3.89-3.99 (4H, m), 4.08 (3H , s), 4.58-4.62 (2H, m), 6.78 (1H, d, J = 9.6Hz), 7.87 (1H, d, J = 9.6Hz), 8.14 (1H, s)

参考例１４２と同様の手法により、５−（２−（８−ヒドロキシ−１，４−ジオキサスピロ（４．５）デカ−８−イル）エチル）−３−メトキシピリド（２，３−ｂ）ピラジン−６（５Ｈ）−オンから５−（２−（１−ヒドロキシ−４−オキソシクロヘキシル）エチル）−３−メトキシピリド（２，３−ｂ）ピラジン−６（５Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.79(2H,td,J=13.8,4.9Hz),2.04(2H,t,J=6.8Hz),2.03-2.12(2H,m),2.20-2.29(2H,m),2.80(2H,td,J=13.8,6.2Hz),3.30-3.45(1H,broad),4.09(3H,s),4.65(2H,t,J=6.8Hz),6.81(1H,d,J=9.6Hz),7.92(1H,d,J=9.6Hz),8.18(1H,s) Reference Example 148

In the same manner as in Reference Example 142, 5- (2- (8-hydroxy-1,4-dioxaspiro (4.5) dec-8-yl) ethyl) -3-methoxypyrido (2,3-b) pyrazine- 6 (5H) -one gave 5- (2- (1-hydroxy-4-oxocyclohexyl) ethyl) -3-methoxypyrido (2,3-b) pyrazin-6 (5H) -one.
¹ H-NMR (CDCl ₃ ) δ value: 1.79 (2H, td, J = 13.8, 4.9 Hz), 2.04 (2H, t, J = 6.8 Hz), 2.03-2.12 (2H, m), 2.20-2.29 ( 2H, m), 2.80 (2H, td, J = 13.8,6.2Hz), 3.30-3.45 (1H, broad), 4.09 (3H, s), 4.65 (2H, t, J = 6.8Hz), 6.81 (1H , d, J = 9.6Hz), 7.92 (1H, d, J = 9.6Hz), 8.18 (1H, s)

ｔｅｒｔ−ブチル＝３−（アミノメチル）ピロリジン−１−カルボキシラート0.28gのメタノール7mL-ジクロロメタン20mL混合溶液に２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−カルバルデヒド0.23gおよびモレキュラーシーブス３Ａ0.50gを加え、室温で3時間攪拌した後、反応混合物に水素化ホウ素ナトリウム79mgを加え、室温で5時間30分間攪拌した。氷冷下、水を加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、無色油状物のｔｅｒｔ−ブチル＝３−（（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）メチル）ピロリジン−１−カルボキシラート0.48gを得た。
¹H-NMR(CDCl₃)δ値：1.45(9H,s),1.50-3.60(9H,m),3.77(2H,s),4.26-4.36(4H,m),6.81(1H,s),8.11(1H,s) Reference Example 149

tert-Butyl = 3- (aminomethyl) pyrrolidine-1-carboxylate 0.28 g in a mixed solution of methanol 7 mL-dichloromethane 20 mL was mixed with 2,3-dihydro (1,4) dioxyno (2,3-c) pyridine-7-carbamate. After adding 0.23 g of aldehyde and 0.50 g of molecular sieves 3A and stirring at room temperature for 3 hours, 79 mg of sodium borohydride was added to the reaction mixture and stirred at room temperature for 5 hours and 30 minutes. Water was added under ice cooling, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give tert-butyl = (((2,3-dihydro 0.48 g of (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) methyl) pyrrolidine-1-carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.45 (9H, s), 1.50-3.60 (9H, m), 3.77 (2H, s), 4.26-4.36 (4H, m), 6.81 (1H, s), 8.11 (1H, s)

参考例１３と同様の手法により、ｔｅｒｔ−ブチル＝３−（（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）メチル）ピロリジン−１−カルボキシラートから１−（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イル）−Ｎ−（ピロリジン−３−イルメチル）メタンアミン塩酸塩を得た。
¹H-NMR(D₂O)δ値：1.76-1.89(1H,m),2.31-2.41(1H,m),2.73-2.87(1H,m),3.02-3.11(1H,m),3.28-3.40(3H,m),3.45-3.54(1H,m),3.64(1H,dd,J=11.8,8.2Hz),4.41-4.49(4H,m),4.54-4.60(2H,m),7.35-7.46(1H,m),8.30-8.36(1H,m)
参考例１５１

７−メチル−１，８−ナフチリジン−２（１Ｈ）−オン2.0gのエタノール150mL溶液に5％パラジウム−炭素1.0gを加え、水素雰囲気下、40〜50℃で17時間攪拌した。反応混合物を室温まで冷却し、不溶物を濾去し、濾滓をメタノールで洗浄した。減圧下で溶媒を留去し、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［溶離液；ヘキサン：酢酸エチル＝１：１］で精製し、白色固体の７−メチル−３，４−ジヒドロ−１，８−ナフチリジン−２（１Ｈ）−オン0.92gを得た。
¹H-NMR(CDCl₃)δ値：2.52(3H,s),2.61-2.68(2H,m),2.86-2.94(2H,m),6.78(1H,d,J=7.6Hz),7.36(1H,d,J=7.6Hz),9.86(1H,s) Reference Example 150

In the same manner as in Reference Example 13, tert-butyl = 3-(((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) methyl) pyrrolidine-1- 1- (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-yl) -N- (pyrrolidin-3-ylmethyl) methanamine hydrochloride was obtained from the carboxylate.
¹ H-NMR (D ₂ O) δ value: 1.76-1.89 (1H, m), 2.31-2.41 (1H, m), 2.73-2.87 (1H, m), 3.02-3.11 (1H, m), 3.28- 3.40 (3H, m), 3.45-3.54 (1H, m), 3.64 (1H, dd, J = 11.8,8.2Hz), 4.41-4.49 (4H, m), 4.54-4.60 (2H, m), 7.35- 7.46 (1H, m), 8.30-8.36 (1H, m)
Reference Example 151

To a 150 mL ethanol solution of 7-methyl-1,8-naphthyridin-2 (1H) -one 2.0 g was added 1.0 g of 5% palladium-carbon, and the mixture was stirred at 40 to 50 ° C. for 17 hours in a hydrogen atmosphere. The reaction mixture was cooled to room temperature, insolubles were filtered off, and the filter cake was washed with methanol. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 1: 1] to give 7-methyl-3,4-dihydro-1 as a white solid. , 8-naphthyridin-2 (1H) -one 0.92 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.52 (3H, s), 2.61-2.68 (2H, m), 2.86-2.94 (2H, m), 6.78 (1H, d, J = 7.6 Hz), 7.36 ( 1H, d, J = 7.6Hz), 9.86 (1H, s)

７−メチル−３，４−ジヒドロ−１，８−ナフチリジン−２（１Ｈ）−オン0.90ｇのジオキサン150mL溶液に加熱還流下、二酸化セレン25.7ｇを分割して加えながら10日間攪拌した。不溶物をセライト濾去し、減圧下で溶媒を留去した。得られた残留物に２−プロパノールを加え、固形物を濾取した。得られた固形物をシリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝２０：１］で精製し、酢酸エチルを加え、固形物を濾取し、淡橙色固体の７−オキソ−７，８−ジヒドロ−１，８−ナフチリジン−２−カルバルデヒド0.48ｇを得た
¹H-NMR(CDCl₃)δ値：6.87(1H,d,J=9.6Hz),7.80(1H,d,J=9.6Hz),7.85(1H,dd,J=7.8,1.0Hz),8.07(1H,d,J=7.8Hz),10.11(1H,s) Reference Example 152

7-Methyl-3,4-dihydro-1,8-naphthyridin-2 (1H) -one A solution of 0.90 g of dioxane in 150 mL was heated to reflux and stirred for 10 days while adding 25.7 g of selenium dioxide in portions. The insoluble material was filtered off through celite, and the solvent was distilled off under reduced pressure. 2-Propanol was added to the obtained residue, and the solid was collected by filtration. The obtained solid was purified by silica gel column chromatography [eluent: chloroform: methanol = 20: 1], ethyl acetate was added, the solid was collected by filtration, and a light orange solid 7-oxo-7,8- 0.48 g of dihydro-1,8-naphthyridine-2-carbaldehyde was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 6.87 (1H, d, J = 9.6 Hz), 7.80 (1H, d, J = 9.6 Hz), 7.85 (1H, dd, J = 7.8,1.0 Hz), 8.07 (1H, d, J = 7.8Hz), 10.11 (1H, s)

１−（トリフルオロアセチル）ピペリジン−４−アミン0.53gのジクロロメタン100mL溶液に７−オキソ−７，８−ジヒドロ−１，８−ナフチリジン−２−カルバルデヒド0.47gおよび酢酸0.16mLを加え、室温で45分間攪拌した。反応混合物に水素化トリアセトキシホウ素ナトリウム0.86gを加え、同温度で5時間攪拌した。水、飽和炭酸水素ナトリウム水溶液およびクロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。さらに、水層に塩化ナトリウムを加えてクロロホルムで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［溶離液；クロロホルム：メタノール＝２０：１］で精製し、淡橙色泡状物の７−（（（１−（トリフルオロアセチル）ピペリジン−４−イル）アミノ）メチル）−１，８−ナフチリジン−２（１Ｈ）−オン0.59gを得た。
¹H-NMR(CDCl₃)δ値：1.42-1.56(2H,m),1.98-2.08(2H,m),2.85-2.94(1H,m),3.01-3.11(1H,m),3.19-3.29(1H,m),3.93-4.02(1H,m),4.06(2H,s),4.29-4.38(1H,m),6.70(1H,d,J=9.4Hz),7.24(1H,d,J=7.8Hz),7.72(1H,d,J=9.4Hz),7.86(1H,d,J=7.8Hz) Reference Example 153

To a solution of 0.53 g of 1- (trifluoroacetyl) piperidin-4-amine in 100 mL of dichloromethane was added 0.47 g of 7-oxo-7,8-dihydro-1,8-naphthyridine-2-carbaldehyde and 0.16 mL of acetic acid at room temperature. Stir for 45 minutes. To the reaction mixture, 0.86 g of sodium triacetoxyborohydride was added and stirred at the same temperature for 5 hours. Water, saturated aqueous sodium hydrogen carbonate solution and chloroform were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. Further, sodium chloride was added to the aqueous layer and extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 20: 1] to give 7-(((1- (trifluoroacetyl) piperidin-4-yl) as a pale orange foam. 0.59 g of amino) methyl) -1,8-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.42-1.56 (2H, m), 1.98-2.08 (2H, m), 2.85-2.94 (1H, m), 3.01-3.11 (1H, m), 3.19-3.29 (1H, m), 3.93-4.02 (1H, m), 4.06 (2H, s), 4.29-4.38 (1H, m), 6.70 (1H, d, J = 9.4Hz), 7.24 (1H, d, J = 7.8Hz), 7.72 (1H, d, J = 9.4Hz), 7.86 (1H, d, J = 7.8Hz)

７−（（（１−（トリフルオロアセチル）ピペリジン−４−イル）アミノ）メチル）−１，８−ナフチリジン−２（１Ｈ）−オン0.58gのクロロホルム25mL溶液にジ−ｔｅｒｔ−ブチル＝ジカルボナート0.43gを加え、室温で3日間攪拌した。反応混合物に水を加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、ヘキサン：酢酸エチル（１：１）の混合溶媒を加え、固形物を濾取し、淡桃白色固体のｔｅｒｔ−ブチル＝（（７−オキソ−７，８−ジヒドロ−１，８−ナフチリジン−２−イル）メチル）（１−（トリフルオロアセチル）ピペリジン−４−イル）カルバマート0.56gを得た。
¹H-NMR(CDCl₃)δ値：1.29-2.00(13H,m),2.67-2.84(1H,m),3.06-3.24(1H,m),4.06-4.20(2H,m),4.35-4.67(3H,m),6.69(1H,d,J=9.5Hz),7.04-7.19(1H,m),7.70(1H,d,J=9.5Hz),7.85(1H,d,J=8.0Hz),9.69(1H,s) Reference Example 154

7-(((1- (trifluoroacetyl) piperidin-4-yl) amino) methyl) -1,8-naphthyridin-2 (1H) -one in 0.58 g of chloroform in 25 mL of chloroform di-tert-butyl dicarbonate 0.43 g was added and stirred at room temperature for 3 days. Water was added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, a mixed solvent of hexane: ethyl acetate (1: 1) was added, and the solid was The solution was collected by filtration, and was obtained as a peach-white solid tert-butyl = ((7-oxo-7,8-dihydro-1,8-naphthyridin-2-yl) methyl) (1- (trifluoroacetyl) piperidin-4-yl ) 0.56 g of carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.29-2.00 (13H, m), 2.67-2.84 (1H, m), 3.06-3.24 (1H, m), 4.06-4.20 (2H, m), 4.35-4.67 (3H, m), 6.69 (1H, d, J = 9.5Hz), 7.04-7.19 (1H, m), 7.70 (1H, d, J = 9.5Hz), 7.85 (1H, d, J = 8.0Hz) , 9.69 (1H, s)

ｔｅｒｔ−ブチル＝（（７−オキソ−７，８−ジヒドロ−１，８−ナフチリジン−２−イル）メチル）（１−（トリフルオロアセチル）ピペリジン−４−イル）カルバマート0.30gのメタノール40mL溶液に10％パラジウム−炭素0.10gを加え、水素雰囲気下、45〜50℃で9時間30分間攪拌した。反応混合物を室温まで冷却し、不溶物を濾去し、濾滓をメタノールで洗浄した。減圧下で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［溶離液；クロロホルム：メタノール＝１００：３］で精製し、無色泡状物のｔｅｒｔ−ブチル＝（（７−オキソ−５，６，７，８−テトラヒドロ−１，８−ナフチリジン−２−イル）メチル）（１−（トリフルオロアセチル）ピペリジン−４−イル）カルバマート0.18gを得た。
¹H-NMR(CDCl₃)δ値：1.24-1.88(13H,m),2.59-2.81(3H,m),2.87-2.98(2H,m),3.04-3.20(1H,m),3.98-4.08(1H,m),4.26-4.48(3H,m),4.54-4.63(1H,m),6.76-6.92(1H,m),7.43(1H,d,J=7.6Hz),8.20-8.60(1H,broad) Reference Example 155

tert-Butyl = ((7-oxo-7,8-dihydro-1,8-naphthyridin-2-yl) methyl) (1- (trifluoroacetyl) piperidin-4-yl) carbamate 0.30 g in a 40 mL methanol solution 10% palladium-carbon (0.10 g) was added, and the mixture was stirred at 45 to 50 ° C. for 9 hours and 30 minutes in a hydrogen atmosphere. The reaction mixture was cooled to room temperature, insolubles were filtered off, and the filter cake was washed with methanol. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography [eluent: chloroform: methanol = 100: 3], and tert-butyl = ((7-oxo-5 , 6,7,8-tetrahydro-1,8-naphthyridin-2-yl) methyl) (1- (trifluoroacetyl) piperidin-4-yl) carbamate 0.18 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.24-1.88 (13H, m), 2.59-2.81 (3H, m), 2.87-2.98 (2H, m), 3.04-3.20 (1H, m), 3.98-4.08 (1H, m), 4.26-4.48 (3H, m), 4.54-4.63 (1H, m), 6.76-6.92 (1H, m), 7.43 (1H, d, J = 7.6Hz), 8.20-8.60 (1H , broad)

ｔｅｒｔ−ブチル＝（（７−オキソ−５，６，７，８−テトラヒドロ−１，８−ナフチリジン−２−イル）メチル）（１−（トリフルオロアセチル）ピペリジン−４−イル）カルバマート0.30ｇのメタノール12mL溶液に炭酸カリウム0.10gおよび水3mLを加え、室温で7時間30間攪拌した。反応混合物に水、飽和炭酸水素ナトリウム水溶液およびクロロホルムを加え、有機層を分取し、水層に塩化ナトリウムを加え、クロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、無色泡状物のｔｅｒｔ−ブチル＝（（７−オキソ−５，６，７，８−テトラヒドロ−１，８−ナフチリジン−２−イル）メチル）（ピペリジン−４−イル）カルバマート0.24ｇを得た。
¹H-NMR(CDCl₃)δ値：1.28-1.78(13H,m),2.55-2.72(4H,m),2.87-2.97(2H,m),3.02-3.12(2H,m),4.15-4.50(3H,m),6.80-6.91(1H,m),7.41(1H,d,J=7.6Hz),8.00-8.30(1H,broad) Reference Example 156

tert-butyl = ((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) methyl) (1- (trifluoroacetyl) piperidin-4-yl) carbamate 0.30 g To a 12 mL methanol solution were added potassium carbonate (0.10 g) and water (3 mL), and the mixture was stirred at room temperature for 7 hours and 30 hours. Water, saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction mixture, the organic layer was separated, sodium chloride was added to the aqueous layer, and the mixture was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and tert-butyl = ((7-oxo-5,6 , 7,8-tetrahydro-1,8-naphthyridin-2-yl) methyl) (piperidin-4-yl) carbamate 0.24 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.28-1.78 (13H, m), 2.55-2.72 (4H, m), 2.87-2.97 (2H, m), 3.02-3.12 (2H, m), 4.15-4.50 (3H, m), 6.80-6.91 (1H, m), 7.41 (1H, d, J = 7.6Hz), 8.00-8.30 (1H, broad)

（４−メトキシ−５−メチルピリジン−２−イル）メタノール0.13gのジクロロメタン2mL溶液に二酸化マンガン0.14gを加えた。さらに室温で二酸化マンガン0.36gを分割して加えながら6時間攪拌した。不溶物を濾去し、減圧下で溶媒を留去し、得られた残留物をフラッシュ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解離＝９：１−４：１］で精製し、白色固体の４−メトキシ−５−メチルピリジン−２−カルバルデヒド77mgを得た。
¹H-NMR(CDCl₃)δ値：2.26(3H,s),3.95(3H,s),7.43(1H,s),8.42(1H,s),10.00(1H,s) Reference Example 157

Manganese dioxide (0.14 g) was added to a dichloromethane (2 mL) solution of (4-methoxy-5-methylpyridin-2-yl) methanol (0.13 g). The mixture was further stirred at room temperature for 6 hours while adding 0.36 g of manganese dioxide in portions. The insoluble material was removed by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by flash column chromatography [gradient dissolution of hexane: ethyl acetate = 9: 1-4: 1] to give a white solid. Of 77 mg of 4-methoxy-5-methylpyridine-2-carbaldehyde was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.26 (3H, s), 3.95 (3H, s), 7.43 (1H, s), 8.42 (1H, s), 10.00 (1H, s)

（５−エチル−４−メトキシピリジン−２−イル）メタノール49mgのジクロロメタン1mL溶液に二酸化マンガン0.13gを加えた。室温で1時間30分間攪拌後、二酸化マンガン0.13gを加え、1時間30分間攪拌した。反応混合物にクロロホルムを加え、不溶物を濾去し、減圧下で溶媒を留去し、褐色油状物の５−エチル−４−メトキシピリジン−２−カルバルデヒド54mgを得た。
¹H-NMR(CDCl₃)δ値：1.24(3H,t,J=7.5Hz),2.70(2H,q,J=7.5Hz),3.95(3H,s),7.45(1H,s),8.43(1H,s),10.00(1H,s) Reference Example 158

0.13 g of manganese dioxide was added to a solution of 49 mg of (5-ethyl-4-methoxypyridin-2-yl) methanol in 1 mL of dichloromethane. After stirring for 1 hour and 30 minutes at room temperature, 0.13 g of manganese dioxide was added and stirred for 1 hour and 30 minutes. Chloroform was added to the reaction mixture, the insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 54 mg of brown oily 5-ethyl-4-methoxypyridine-2-carbaldehyde.
¹ H-NMR (CDCl ₃ ) δ value: 1.24 (3H, t, J = 7.5 Hz), 2.70 (2H, q, J = 7.5 Hz), 3.95 (3H, s), 7.45 (1H, s), 8.43 (1H, s), 10.00 (1H, s)

２−（ヒドロキシメチル）−５−メトキシピリジン−４（１Ｈ）−オン8.3gのピリジン30mL懸濁液に氷冷下アセチルクロリド5.7mLを滴下した。室温まで昇温後、55〜60℃で2時間30分間攪拌した。室温まで冷却後、減圧下で溶媒留去し、得られた残留物をフラッシュ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＝９５：１−８０：２０］で精製し、褐色泡状物の（５−メトキシ−４−オキソ−１，４−ジヒドロピリジン−２−イル）メチル アセタート6.7gを得た。
¹H-NMR(CDCl₃)δ値：2.15(3H,s),3.86(3H,s),5.15(2H,s),6.83(1H,s),7.68(1H,s) Reference Example 159

To a suspension of 2- (hydroxymethyl) -5-methoxypyridin-4 (1H) -one in 8.3 g of pyridine in 30 mL of pyridine was added dropwise 5.7 mL of acetyl chloride under ice cooling. After raising the temperature to room temperature, the mixture was stirred at 55 to 60 ° C. for 2 hours and 30 minutes. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the obtained residue was purified by flash silica gel column chromatography [gradient elution of chloroform: methanol = 95: 1-80: 20] to give a brown foam ( 6.7 g of 5-methoxy-4-oxo-1,4-dihydropyridin-2-yl) methyl acetate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.15 (3H, s), 3.86 (3H, s), 5.15 (2H, s), 6.83 (1H, s), 7.68 (1H, s)

（５−メトキシ−４−オキソ−１，４−ジヒドロピリジン−２−イル）メチル＝アセタート4.6gのジクロロメタン120mL溶液にトリエチルアミン6.5mLを加え、氷冷下でトリフルオロメタンスルホン酸無水物5.9mLを滴下し、同温度で3時間攪拌した。反応混合物に水およびクロロホルムを加えて、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をフラッシュ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＝４：１−４：６］で精製し、黄色固体の（５−メトキシ−４−（（（トリフルオロメチル）スルホニル）オキシ）ピリジン−２−イル）メチル＝アセタート5.2gを得た。
¹H-NMR(CDCl₃)δ値：2.16(3H,S),4.03(3H,s),5.18(2H,s),7.26(1H,s),8.43(1H,s) Reference Example 160

To a solution of 4.6 g of (5-methoxy-4-oxo-1,4-dihydropyridin-2-yl) methyl acetate in 120 mL of dichloromethane was added 6.5 mL of triethylamine, and 5.9 mL of trifluoromethanesulfonic anhydride was added dropwise under ice cooling. The mixture was stirred at the same temperature for 3 hours. Water and chloroform were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash silica gel column chromatography [gradient elution of hexane: ethyl acetate = 4: 1-4: 6] to give (5-methoxy-4-(((trifluoromethyl) sulfonyl) as a yellow solid. ) Oxy) pyridin-2-yl) methyl acetate 5.2 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.16 (3H, S), 4.03 (3H, s), 5.18 (2H, s), 7.26 (1H, s), 8.43 (1H, s)

（５−メトキシ−４−（（（トリフルオロメチル）スルホニル）オキシ）ピリジン−２−イル）メチル＝アセタート0.50gのジオキサン5mL溶液に炭酸カリウム0.63g、トリメチルボロキシン0.21mLおよびテトラキス（トリフェニルホスフィン）パラジウム（０）0.18gを加え、窒素雰囲気下、70〜90℃で3間攪拌した。さらに、加熱還流下、3時間攪拌し、室温まで冷却後、反応混合物に水および酢酸エチルを加え、有機層を分取した。水層を酢酸エチルで抽出し、有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去た。得られた残留物をフラッシュ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＝８０：２０−５０：５０］で精製し、黄色油状物の（５−メトキシ−４−メチルピリジン−２−イル）メチル＝アセタート0.22gを得た。
¹H-NMR(CDCl₃)δ値：2.13(3H,s),2.23(3H,s),3.92(3H,s),5.12(2H,s),7.15(1H,s),8.14(1H,s) Reference Example 161

(5-methoxy-4-(((trifluoromethyl) sulfonyl) oxy) pyridin-2-yl) methyl acetate 0.50 g in dioxane 5 mL solution, potassium carbonate 0.63 g, trimethylboroxine 0.21 mL and tetrakis (triphenylphosphine ) 0.18 g of palladium (0) was added, and the mixture was stirred at 70 to 90 ° C. for 3 hours under a nitrogen atmosphere. Further, the mixture was stirred for 3 hours under reflux with heating, and after cooling to room temperature, water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, the organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash silica gel column chromatography [gradient elution of hexane: ethyl acetate = 80: 20-50: 50] to give (5-methoxy-4-methylpyridin-2-yl) as a yellow oil 0.22 g of methyl acetate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.13 (3H, s), 2.23 (3H, s), 3.92 (3H, s), 5.12 (2H, s), 7.15 (1H, s), 8.14 (1H, s)

（５−メトキシ−４−メチルピリジン−２−イル）メチル＝アセタート0.21gのメタノール2mL溶液に20％水酸化ナトリウム水溶液0.64mLを加え、室温で1時間攪拌した。減圧下で溶媒を留去し、得られた残留物に水および酢酸エチルを加え、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、白色固体の（５−メトキシ−４−メチルピリジン−２−イル）メタノール0.16gを得た。
¹H-NMR(CDCl₃)δ値：2.24(3H,s),3.92(3H,s),4.66(2H,s),7.02(1H,s),8.09(1H,s) Reference Example 162

To a solution of (5-methoxy-4-methylpyridin-2-yl) methyl acetate 0.21 g in 2 mL of methanol was added 0.64 mL of 20% aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, water and ethyl acetate were added to the obtained residue, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.16 g of (5-methoxy-4-methylpyridin-2-yl) methanol as a white solid.
¹ H-NMR (CDCl ₃ ) δ value: 2.24 (3H, s), 3.92 (3H, s), 4.66 (2H, s), 7.02 (1H, s), 8.09 (1H, s)

参考例６７と同様な手法により、（５−メトキシ−４−メチルピリジン−２−イル）メタノールから５−メトキシ−４−メチルピリジン−２−カルバルデヒドを得た。
¹H-NMR(CDCl₃)δ値：2.29(3H,s),4.03(3H,s),7.80(1H,s),8.31(1H,s),9.96(1H,s) Reference Example 163

In the same manner as in Reference Example 67, 5-methoxy-4-methylpyridine-2-carbaldehyde was obtained from (5-methoxy-4-methylpyridin-2-yl) methanol.
¹ H-NMR (CDCl ₃ ) δ value: 2.29 (3H, s), 4.03 (3H, s), 7.80 (1H, s), 8.31 (1H, s), 9.96 (1H, s)

（５−（３−チエニル）イソオキサゾール−３−イル）メタノール30mgのジクロロメタン5mL溶液に氷冷下デス−マーチン＝ペルヨージナン84mgを加え、室温で1時間30分間攪拌した。さらにデス−マーチン＝ペルヨージナン40mgを加え、室温で1時間30分間攪拌した。反応混合物にジエチルエーテルを加え、不溶物を濾去し、減圧下で溶媒を留去し、黄色固体の５−（３−チエニル）イソオキサゾール−３−カルバルデヒド30mgを得た。
¹H-NMR(CDCl₃)δ値：6.75(1H,s),7.42-7.49(2H,m),7.88(1H,dd,J=2.8,1.3Hz),10.18(1H,s) Reference Example 164

To a solution of 30 mg of (5- (3-thienyl) isoxazol-3-yl) methanol in 5 mL of dichloromethane was added 84 mg of Dess-Martin periodinane under ice cooling, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Further, Dess-Martin = Periodinane (40 mg) was added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Diethyl ether was added to the reaction mixture, insolubles were removed by filtration, and the solvent was distilled off under reduced pressure to obtain 30 mg of yellow solid 5- (3-thienyl) isoxazole-3-carbaldehyde.
¹ H-NMR (CDCl ₃ ) δ value: 6.75 (1H, s), 7.42-7.49 (2H, m), 7.88 (1H, dd, J = 2.8, 1.3 Hz), 10.18 (1H, s)

２，６−ジクロロ−３−フルオロ−５−（（メトキシメトキシ）メチル）ピリジン0.85gのＮ，Ｎ−ジメチルホルムアミド8mL溶液に室温で塩化リチウム0.45g、２，６−ジ−ｔｅｒｔ−ブチル−４−メチルフェノール1欠片、トリブチル（ビニル）スズ1.04mLおよびビス（トリフェニルホスフィン）パラジウム（II）ジクロリド50mgを加えた。窒素雰囲気下、40〜50℃で1時間攪拌し、50〜60℃で1時間30分間攪拌後、70〜80℃で1時間攪拌した。室温まで冷却後、減圧下で溶媒を留居し、得られた残留物をフラッシュシリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝９：１］で精製し、微黄色油状物の２−クロロ−５−フルオロ−３−（（メトキシメトキシ）メチル）−６−ビニルピリジンの粗生成物0.51gを得た。 Reference Example 165

To a solution of 0.85 g of 2,6-dichloro-3-fluoro-5-((methoxymethoxy) methyl) pyridine in 8 mL of N, N-dimethylformamide at room temperature, 0.45 g of lithium chloride, 2,6-di-tert-butyl-4 -Methylphenol 1 fragment, 1.04 mL of tributyl (vinyl) tin and 50 mg of bis (triphenylphosphine) palladium (II) dichloride were added. The mixture was stirred at 40-50 ° C for 1 hour under a nitrogen atmosphere, stirred at 50-60 ° C for 1 hour 30 minutes, and then stirred at 70-80 ° C for 1 hour. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography [eluent: chloroform: methanol = 9: 1] to give 2-chloro- 0.51 g of a crude product of 5-fluoro-3-((methoxymethoxy) methyl) -6-vinylpyridine was obtained.

参考例１６５で得た２−クロロ−５−フルオロ−３−（（メトキシメトキシ）メチル）−６−ビニルピリジンの粗生成物0.47gのメタノール5mL溶液に10％パラジウム−炭素0.24gを加え、水素雰囲気下、40℃で1時間攪拌した。不溶物を濾去し、減圧下で溶媒を留去し、得られた残留物をフラッシュシリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝１９：１］で精製し、無色油状物の２−クロロ−６−エチル−５−フルオロ−３−（（メトキシメトキシ）メチル）ピリジンの粗生成物0.36gを得た。 Reference Example 166

To a solution of 0.47 g of the crude product of 2-chloro-5-fluoro-3-((methoxymethoxy) methyl) -6-vinylpyridine obtained in Reference Example 165, 0.24 g of 10% palladium-carbon was added, and hydrogen was added. The mixture was stirred at 40 ° C. for 1 hour under an atmosphere. The insoluble material was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by flash silica gel column chromatography [eluent: chloroform: methanol = 19: 1] to give 2-chloro as a colorless oil. 0.36 g of a crude product of -6-ethyl-5-fluoro-3-((methoxymethoxy) methyl) pyridine was obtained.

参考例１６６で得た２−クロロ−６−エチル−５−フルオロ−３−（（メトキシメトキシ）メチル）ピリジンの粗生成物0.33gのＮ，Ｎ−ジメチルホルムアミド3mL溶液に室温でテトラキス（トリフェニルホスフィン）パラジウム（０）0.16gおよびトリエチルアミン0.98mLを加え、ギ酸0.27mLを滴下した。窒素雰囲気下、70〜80℃で45分間攪拌した。室温まで冷却後、反応混合物に水および酢酸エチルを加え、不溶物を濾去し、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をフラッシュシリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝９：１］で精製し、無色油状物の２−エチル−３−フルオロ−５−（（メトキシメトキシ）メチル）ピリジン0.11gを得た。
¹H-NMR(CDCl₃)δ値：1.29(3H,t,J=7.6Hz),2.87(2H,qd,J=7.6,2.3Hz),3.41(3H,s),4.59(2H,s),4.71(2H,s),7.35(1H,dd,J=10.0,1.7Hz),8.31(1H,s) Reference Example 167

To a solution of 0.33 g of the crude product of 2-chloro-6-ethyl-5-fluoro-3-((methoxymethoxy) methyl) pyridine obtained in Reference Example 166 in 3 mL of N, N-dimethylformamide was added tetrakis (triphenyl) at room temperature. Phosphine) palladium (0) 0.16 g and triethylamine 0.98 mL were added, and 0.27 mL formic acid was added dropwise. The mixture was stirred at 70-80 ° C for 45 minutes in a nitrogen atmosphere. After cooling to room temperature, water and ethyl acetate were added to the reaction mixture, the insoluble material was filtered off, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash silica gel column chromatography [eluent: chloroform: methanol = 9: 1] to give colorless oily 2-ethyl-3-fluoro-5-((methoxymethoxy) methyl) pyridine 0.11. g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.29 (3H, t, J = 7.6 Hz), 2.87 (2H, qd, J = 7.6, 2.3 Hz), 3.41 (3H, s), 4.59 (2H, s) , 4.71 (2H, s), 7.35 (1H, dd, J = 10.0,1.7Hz), 8.31 (1H, s)

２−エチル−３−フルオロ−５−（（メトキシメトキシ）メチル）ピリジン0.11gの１，４−ジオキサン2mL溶液に６mol/L塩酸1mLを加え、30〜40℃で1時間攪拌した。室温まで冷却後、反応混合物に水および酢酸エチルを加え、20％水酸化ナトリウム水溶液および飽和炭酸水素ナトリウム水溶液でpH7.9に調整した。有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、淡黄色油状物の（６−エチル−５−フルオロピリジン−３−イル）メタノール87mgを得た。
¹H-NMR(CDCl₃)δ値：1.29(3H,t,J=7.6Hz),1.93-2.05(1H,broad),2.87(1H,qd,J=7.6,2.3Hz),4.72(2H,d,J=3.4Hz),7.39(1H,dd,J=10.1,1.6Hz),8.30(1H,s) Reference Example 168

1 mL of 6 mol / L hydrochloric acid was added to 2 mL of 1,4-dioxane in 0.11 g of 2-ethyl-3-fluoro-5-((methoxymethoxy) methyl) pyridine, and the mixture was stirred at 30 to 40 ° C. for 1 hour. After cooling to room temperature, water and ethyl acetate were added to the reaction mixture, and the pH was adjusted to 7.9 with 20% aqueous sodium hydroxide solution and saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined and washed with water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 87 mg of (6-ethyl-5-fluoropyridin-3-yl) methanol as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ value: 1.29 (3H, t, J = 7.6 Hz), 1.93-2.05 (1H, broad), 2.87 (1H, qd, J = 7.6, 2.3 Hz), 4.72 (2H, d, J = 3.4Hz), 7.39 (1H, dd, J = 10.1,1.6Hz), 8.30 (1H, s)

参考例６７と同様の手法により（６−エチル−５−フルオロピリジン−３−イル）メタノールから６−エチル−５−フルオロニコチンアルデヒドを得た。
¹H-NMR(CDCl₃)δ値：1.34(3H,t,J=7.6Hz),2.97(2H,t,J=7.6,2.4Hz),7.77(1H,dd,J=9.0,1.7Hz),8.80(1H,s),10.09(1H,d,J=2.2Hz) Reference Example 169

In the same manner as in Reference Example 67, 6-ethyl-5-fluoronicotinaldehyde was obtained from (6-ethyl-5-fluoropyridin-3-yl) methanol.
¹ H-NMR (CDCl ₃ ) δ value: 1.34 (3H, t, J = 7.6 Hz), 2.97 (2H, t, J = 7.6, 2.4 Hz), 7.77 (1H, dd, J = 9.0, 1.7 Hz) , 8.80 (1H, s), 10.09 (1H, d, J = 2.2Hz)

５−ヒドロキシ−２−（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）メチル）−４H−ピラン−４−オン2.0gのジクロロメタン20mL溶液にトリエチルアミン2.1mLを加え、氷冷下でトリフルオロメタンスルホン酸無水物1.9mLを滴下し、40分間攪拌した。反応混合物に水およびクロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、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［溶離液；ヘキサン：酢酸エチル＝２：１］で精製し、淡褐色固体の４−オキソ−６−（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）メチル）−４Ｈ−ピラン−３−イル＝トリフルオロメタンスルホナート2.9gを得た。
¹H-NMR(CDCl₃)δ値：1.53-1.90(6H,m),3.55-3.62(1H,m),3.77-3.85(1H,m),4.38(1H,dd,J=14.9,0.7Hz),4.57(1H,dd,14.9,0.7Hz),4.74(1H,t,J=3.2Hz),6.66(1H,s),8.05(1H,s) Reference Example 170

To a solution of 5-hydroxy-2-((tetrahydro-2H-pyran-2-yloxy) methyl) -4H-pyran-4-one 2.0 g in 20 mL dichloromethane was added 2.1 mL triethylamine, and trifluoromethanesulfonic anhydride was added under ice cooling. 1.9 mL of the product was added dropwise and stirred for 40 minutes. Water and chloroform were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 2: 1] to give 4-oxo as a light brown solid. 2.9 g of -6-((tetrahydro-2H-pyran-2-yloxy) methyl) -4H-pyran-3-yl trifluoromethanesulfonate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.53-1.90 (6H, m), 3.55-3.62 (1H, m), 3.77-3.85 (1H, m), 4.38 (1H, dd, J = 14.9,0.7Hz ), 4.57 (1H, dd, 14.9, 0.7Hz), 4.74 (1H, t, J = 3.2Hz), 6.66 (1H, s), 8.05 (1H, s)

４−オキソ−６−（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）メチル）−４Ｈ−ピラン−３−イル＝トリフルオロメタンスルホナート1.0gのジオキサン10mL溶液に炭酸カリウム1.2g、トリメチルボロキシン0.4mLおよびテトラキス（トリフェニルホスフィン）パラジウム（０）0.33gを加え、アルゴン雰囲気下、70〜80℃で2時間攪拌した。室温まで冷却後、反応混合物に水および酢酸エチルを加え、有機層を分取した。水層を酢酸エチルで抽出し、有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［溶離液；ヘキサン：酢酸エチル＝１：１］で精製し、褐色油状物の５−メチル−２−（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）メチル）−４Ｈ−ピラン−４−オン0.62gを得た。
¹H-NMR(CDCl₃)δ値：1.20-1.66(6H,m),1.66(3H,s),3.25-3.35(1H,m),3.53-3.63(1H,m),4.06(1H,d,J=14.4Hz),4.25(1H,d,J=14.4Hz),4.47(1H,t,J=3.3Hz),6.16(1H,s),7.43(1H,s) Reference Example 171

4-Oxo-6-((tetrahydro-2H-pyran-2-yloxy) methyl) -4H-pyran-3-yl = trifluoromethanesulfonate 1.0 g in 10 mL dioxane solution 1.2 g potassium carbonate, 0.4 mL trimethylboroxine Then, 0.33 g of tetrakis (triphenylphosphine) palladium (0) was added, and the mixture was stirred at 70 to 80 ° C. for 2 hours under an argon atmosphere. After cooling to room temperature, water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, the organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 1: 1] to give 5-methyl-2-((tetrahydro-2H-pyran-2-yloxy) methyl as a brown oily substance. ) 0.62 g of -4H-pyran-4-one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.20-1.66 (6H, m), 1.66 (3H, s), 3.25-3.35 (1H, m), 3.53-3.63 (1H, m), 4.06 (1H, d , J = 14.4Hz), 4.25 (1H, d, J = 14.4Hz), 4.47 (1H, t, J = 3.3Hz), 6.16 (1H, s), 7.43 (1H, s)

５−メチル−２−（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）メチル）−４Ｈ−ピラン−４−オン0.61gのメタノール3mL溶液に濃塩酸0.03mLを加え、室温で1時間攪拌した。反応混合物に炭酸カリウム0.5gおよびクロロホルムを加え、30分間を攪拌した。不溶物を濾去し、減圧下で溶媒を留去し、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［溶離液；クロロホルム：メタノール＝９：１］で精製し、白色固体の２−ヒドロキシメチル−５−メチル−４Ｈ−ピラン−４−オン0.26gを得た。
¹H-NMR(CDCl₃)δ値：1.92(3H,d,J=1.1Hz),3.03(1H,t,J=6.7Hz),4.47(2H,d,J=6.7Hz),6.43(1H,s),7.66(1H,d,J=1.1Hz) Reference Example 172

To a solution of 0.61 g of 5-methyl-2-((tetrahydro-2H-pyran-2-yloxy) methyl) -4H-pyran-4-one in 3 mL of methanol was added concentrated hydrochloric acid 0.03 mL, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, 0.5 g of potassium carbonate and chloroform were added and stirred for 30 minutes. Insoluble matter was removed by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 9: 1] to give 2-hydroxymethyl- 0.26 g of 5-methyl-4H-pyran-4-one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.92 (3H, d, J = 1.1 Hz), 3.03 (1H, t, J = 6.7 Hz), 4.47 (2H, d, J = 6.7 Hz), 6.43 (1H , s), 7.66 (1H, d, J = 1.1Hz)

参考例６７と同様の手法により２−ヒドロキシメチル−５−メチル−４Ｈ−ピラン−４−オンから５−メチル−４−オキソ−４Ｈ−ピラン−２−カルバルデヒドを得た。
¹H-NMR(CDCl₃)δ値：1.99(3H,d,J=1.2Hz),6.89(1H,s),7.80(1H,s),9.67(1H,s) Reference Example 173

5-Methyl-4-oxo-4H-pyran-2-carbaldehyde was obtained from 2-hydroxymethyl-5-methyl-4H-pyran-4-one by the same method as in Reference Example 67.
¹ H-NMR (CDCl ₃ ) δ value: 1.99 (3H, d, J = 1.2 Hz), 6.89 (1H, s), 7.80 (1H, s), 9.67 (1H, s)

メチル＝２，６−ジクロロ−５−フルオロニコチナート1.5gのＮ，Ｎ−ジメチルホルムアミド15mL溶液に室温でトリエチルアミン0.93mLを加え、ピロリジン0.56mLを滴下した。同温度で1時間攪拌し、ピロリジン56μLを追加し、50分間攪拌した。一晩放置後、反応混合物に酢酸エチルおよび水を加えた。有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、白色固体のメチル＝２−クロロ−５−フルオロ−６−（ピロリジン−１−イル）ニコチナート1.7gを得た。
¹H-NMR(CDCl₃)δ値：1.90-1.99(4H,m),3.66-3.74(4H,m),3.86(3H,s),7.73(1H,dd,J=13.0,0.6Hz) Reference Example 174

To a 15 mL N, N-dimethylformamide solution of 1.5 g of methyl = 2,6-dichloro-5-fluoronicotinate, 0.93 mL of triethylamine was added at room temperature, and 0.56 mL of pyrrolidine was added dropwise. The mixture was stirred at the same temperature for 1 hour, 56 μL of pyrrolidine was added, and the mixture was stirred for 50 minutes. After standing overnight, ethyl acetate and water were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined and washed with water and saturated aqueous sodium chloride solution. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain 1.7 g of white solid methyl = 2-chloro-5-fluoro-6- (pyrrolidin-1-yl) nicotinate.
¹ H-NMR (CDCl ₃ ) δ value: 1.90-1.99 (4H, m), 3.66-3.74 (4H, m), 3.86 (3H, s), 7.73 (1H, dd, J = 13.0,0.6Hz)

メチル＝２−クロロ−５−フルオロ−６−（ピロリジン−１−イル）ニコチナート1.7gのＮ，Ｎ−ジメチルホルムアミド15mL溶液に室温でテトラキス（トリフェニルホスフィン）パラジウム（０）0.38gおよびトリエチルアミン1.4mLを加え、ギ酸0.37mLを滴下した。窒素雰囲気下、80〜90℃で2時間30分間攪拌し、室温まで冷却後、反応混合物に水および酢酸エチルを加え、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄した。有機層にクロロホルム：メタノール混合溶媒を加え、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジエテルエーテル：酢酸エチル（１：２）の混合溶媒を加え、不溶物を濾去し、減圧下で溶媒を留去した。得られた残留物をフラッシュシリカゲルカラムクロマトグラフィー［溶離液；クロロホルム］で精製し、淡黄色固体のメチル＝５−フルオロ−６−（ピロリジン−１−イル）ニコチナート1.3gを得た。
¹H-NMR(CDCl₃)δ値：1.95-1.99(4H,m),3.69-3.75(4H,m),3.86(3H,s),7.65(1H,d,J=14.0,1.8Hz),8.56(1H,t,1.8Hz) Reference Example 175

Methyl 2-chloro-5-fluoro-6- (pyrrolidin-1-yl) nicotinate 1.7 g in a solution of N, N-dimethylformamide 15 mL at room temperature with tetrakis (triphenylphosphine) palladium (0) 0.38 g and triethylamine 1.4 mL And 0.37 mL of formic acid was added dropwise. The mixture was stirred at 80 to 90 ° C. for 2 hours and 30 minutes under a nitrogen atmosphere, cooled to room temperature, water and ethyl acetate were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined and washed with a saturated aqueous sodium chloride solution. A chloroform: methanol mixed solvent was added to the organic layer, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. A mixed solvent of diethyl ether: ethyl acetate (1: 2) was added to the obtained residue, insoluble matters were filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash silica gel column chromatography [eluent: chloroform] to obtain 1.3 g of methyl = 5-fluoro-6- (pyrrolidin-1-yl) nicotinate as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ value: 1.95-1.99 (4H, m), 3.69-3.75 (4H, m), 3.86 (3H, s), 7.65 (1H, d, J = 14.0,1.8 Hz), 8.56 (1H, t, 1.8Hz)

水素化アルミニウムリチウム0.24gのＴＨＦ5mL溶液に氷冷下でメチル＝５−フルオロ−６−（ピロリジン−１−イル）ニコチナート0.70gのテトラヒドロフラン5mL溶液を滴下した。室温まで昇温後、45分間攪拌し、氷冷下で飽和炭酸水素ナトリウム水溶液を滴下し10分間攪拌した。反応混合物を濾過し、濾滓を酢酸エチルおよび水で洗浄した。濾液の有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、褐色油状物の（５−フルオロ−６−（ピロリジン−１−イル）ピリジン−３−イル）メタノール0.68gを得た。
¹H-NMR(CDCl₃)δ値：1.52-1.57(1H,m),1.92-1.98(4H,m),3.61-3.66(4H,m),4.52-4.56(2H,m),7.21(1H,dd,J=13.9,1.8Hz),7.87(1H,t,J=1.8Hz) Reference Example 176

To a solution of 0.24 g of lithium aluminum hydride in 5 mL of THF was added dropwise a solution of 0.70 g of methyl = 5-fluoro-6- (pyrrolidin-1-yl) nicotinate in 5 mL of tetrahydrofuran under ice cooling. After warming to room temperature, the mixture was stirred for 45 minutes, saturated aqueous sodium hydrogen carbonate solution was added dropwise under ice cooling, and the mixture was stirred for 10 minutes. The reaction mixture was filtered and the filter cake was washed with ethyl acetate and water. The organic layer of the filtrate was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give (5-fluoro-6- (pyrrolidine-1- Yl) pyridin-3-yl) methanol 0.68 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.52-1.57 (1H, m), 1.92-1.98 (4H, m), 3.61-3.66 (4H, m), 4.52-4.56 (2H, m), 7.21 (1H , dd, J = 13.9,1.8Hz), 7.87 (1H, t, J = 1.8Hz)

参考例６７と同様の手法により、（５−フルオロ−６−（ピロリジン−１−イル）ピリジン−３−イル）メタノールから５−フルオロ−６−（ピロリジン−１−イル）ニコチンアルデヒドを得た。
¹H-NMR(CDCl₃)δ値：1.97-2.03(4H,m),3.74-3.80(4H,m),7.56(1H,dd,J=13.5,1.8Hz),8.32(1H,t,J=1.8Hz),9.76(1H,d,J=3.2Hz) Reference Example 177

In the same manner as in Reference Example 67, 5-fluoro-6- (pyrrolidin-1-yl) nicotinaldehyde was obtained from (5-fluoro-6- (pyrrolidin-1-yl) pyridin-3-yl) methanol.
¹ H-NMR (CDCl ₃ ) δ value: 1.97-2.03 (4H, m), 3.74-3.80 (4H, m), 7.56 (1H, dd, J = 13.5,1.8Hz), 8.32 (1H, t, J = 1.8Hz), 9.76 (1H, d, J = 3.2Hz)

参考例５８と同様の手法により、メチル＝５−（２−フリル）イソオキサゾール−３−カルボキシラートから（５−（２−フリル）イソオキサゾール−３−イル）メタノールを得た。
¹H-NMR(CDCl₃)δ値：1.94-1.99(1H,m),4.81(2H,d,J=6.4Hz),6.50(1H,s),6.54(1H,dd,J=3.6,1.6Hz),6.91(1H,d,J=3.6Hz),7.53-7.56(1H,m) Reference Example 178

In the same manner as in Reference Example 58, (5- (2-furyl) isoxazol-3-yl) methanol was obtained from methyl = 5- (2-furyl) isoxazole-3-carboxylate.
¹ H-NMR (CDCl ₃ ) δ value: 1.94-1.99 (1H, m), 4.81 (2H, d, J = 6.4 Hz), 6.50 (1H, s), 6.54 (1H, dd, J = 3.6, 1.6) Hz), 6.91 (1H, d, J = 3.6Hz), 7.53-7.56 (1H, m)

参考例１６４と同様の手法により、（５−（２−フリル）イソオキサゾール−３−イル）メタノールから５−（２−フリル）イソオキサゾール−３−カルバルデヒドを得た。
¹H-NMR(CDCl₃)δ値：6.58(1H,dd,J=3.6,1.7Hz),6.80(1H,s),7.01(1H,d,J=3.6Hz),7.60(1H,d,J=1.7Hz),10.18(1H,s) Reference Example 179

By the same method as in Reference Example 164, 5- (2-furyl) isoxazole-3-carbaldehyde was obtained from (5- (2-furyl) isoxazol-3-yl) methanol.
¹ H-NMR (CDCl ₃ ) δ value: 6.58 (1H, dd, J = 3.6, 1.7 Hz), 6.80 (1H, s), 7.01 (1H, d, J = 3.6 Hz), 7.60 (1H, d, J = 1.7Hz), 10.18 (1H, s)

水酸化ナトリウム0.11kgの水1000mL溶液に12％次亜塩素酸ナトリウム水溶液1.4kgおよび２‐クロロ−５−フルオロニコチンアミド0.40kgを加え、室温で2時間30分間攪拌した。反応混合物を45℃まで加熱し、4時間攪拌した。反応混合物を室温まで冷却し、酢酸エチルおよび６mol/L塩酸水溶液を加えた。有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムおよび活性炭素を加え、室温で30分間攪拌した。不溶物を濾去し、減圧下で溶媒を留去し、褐色固体の２−クロロ−５−フルオロピリジン−３−アミン0.29kgを得た。
¹H-NMR(CDCl₃)δ値：4.22(2H,s),6.79(1H,dd,J=9.3,2.7Hz),7.67(1H,d,J=2.7Hz) Reference Example 180

To a 1000 mL solution of 0.11 kg of sodium hydroxide was added 1.4 kg of 12% aqueous sodium hypochlorite solution and 0.40 kg of 2-chloro-5-fluoronicotinamide, and the mixture was stirred at room temperature for 2 hours and 30 minutes. The reaction mixture was heated to 45 ° C. and stirred for 4 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and a 6 mol / L aqueous hydrochloric acid solution were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, anhydrous magnesium sulfate and activated carbon were added, and the mixture was stirred at room temperature for 30 minutes. Insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 0.29 kg of 2-chloro-5-fluoropyridin-3-amine as a brown solid.
¹ H-NMR (CDCl ₃ ) δ value: 4.22 (2H, s), 6.79 (1H, dd, J = 9.3, 2.7 Hz), 7.67 (1H, d, J = 2.7 Hz)

２−クロロ−５−フルオロピリジン−３−アミン1.2gのピリジン溶液5mLに氷冷下２−メチルアクリロイルクロリド0.86mLを加え、室温で30分間攪拌した。反応混合物に水および酢酸エチルを加え、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をフラッシュ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＝１００：０−５０：５０］で精製し、無色油状物のＮ−（２−クロロ−５−フルオロピリジン−３−イル）−２−メチルアクリルアミド1.1gを得た。
¹H-NMR(CDCl₃)δ値：2.11(3H,dd,J=1.5,1.0Hz),5.60-5.63(1H,m),5.93-5.96(1H,m),7.99-8.02(1H,m),8.15(1H,s),8.72(1H,dd,J=9.9,2.8Hz) Reference Example 181

To 6 mL of a pyridine solution of 1.2 g of 2-chloro-5-fluoropyridin-3-amine, 0.86 mL of 2-methylacryloyl chloride was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash silica gel column chromatography [hexane: ethyl acetate gradient elution = 100: 0-50: 50], and colorless oily N- (2-chloro-5-fluoropyridine-3- Yl) -2-methylacrylamide 1.1g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.11 (3H, dd, J = 1.5,1.0 Hz), 5.60-5.63 (1H, m), 5.93-5.96 (1H, m), 7.99-8.02 (1H, m ), 8.15 (1H, s), 8.72 (1H, dd, J = 9.9,2.8Hz)

Ｎ−（２−クロロ−５−フルオロピリジン−３−イル）−２−メチルアクリルアミド1.1gのＮ，Ｎ−ジメチルホルムアミド10mL溶液にトリエチルアミン1.5mLおよびビス（トリ−ｔｅｒｔ−ブチルホスフィン）パラジウム（０）0.13gを加え、窒素気流下、110℃で3時間40分間攪拌した。さらに、ビス（トリ−ｔｅｒｔ−ブチルホスフィン）パラジウム（０）0.13gを加え、2時間攪拌した。さらに、ビス（トリ−ｔｅｒｔ−ブチルホスフィン）パラジウム（０）0.13gを加え、2時間攪拌した。反応混合物を室温まで冷却後、減圧下で溶媒を留去し、得られた残留物にジイソプロピルエーテルおよび酢酸エチルを加え、固形物を濾取し、酢酸エチルで洗浄した。得られた固体に水、クロロホルムおよびメタノールを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルを加え、固形物を濾取し、淡褐色固体の７−フルオロ−４−メチル−１，５−ナフチリジン−２（１Ｈ）−オン0.25gを得た。
¹H-NMR(DMSO-d₆)δ値：2.45(3H,d,J=1.0Hz),6.61-6.64(1H,m),7.45(1H,dd,J=9.6,2.6Hz),8.51(1H,d,J=2.6Hz),11.78-11.83(1H,broad) Reference Example 182

To a solution of 1.1 g of N- (2-chloro-5-fluoropyridin-3-yl) -2-methylacrylamide in 10 mL of N, N-dimethylformamide was added 1.5 mL of triethylamine and bis (tri-tert-butylphosphine) palladium (0). 0.13 g was added, and the mixture was stirred at 110 ° C. for 3 hours and 40 minutes under a nitrogen stream. Further, 0.13 g of bis (tri-tert-butylphosphine) palladium (0) was added and stirred for 2 hours. Further, 0.13 g of bis (tri-tert-butylphosphine) palladium (0) was added and stirred for 2 hours. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, diisopropyl ether and ethyl acetate were added to the obtained residue, and the solid was collected by filtration and washed with ethyl acetate. Water, chloroform and methanol were added to the obtained solid, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to obtain 0.25 g of a light brown solid 7-fluoro-4-methyl-1,5-naphthyridin-2 (1H) -one.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.45 (3H, d, J = 1.0 Hz), 6.61-6.64 (1 H, m), 7.45 (1 H, dd, J = 9.6, 2.6 Hz), 8.51 ( 1H, d, J = 2.6Hz), 11.78-11.83 (1H, broad)

参考例３と同様の手法により、７−フルオロ−４−メチル−１，５−ナフチリジン−２（１Ｈ）−オンおよび２−ブロモメチル−１，３−ジオキソランから１−（１，３−ジオキソラン−２−イルメチル）−７−フルオロ−４−メチル−１，５−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：2.54(3H,d,J=1.2Hz),3.82-4.06(4H,m),4.43(2H,d,J=4.1Hz),5.18(1H,t,J=4.1Hz),6.75-6.78(1H,m),7.67(1H,dd,J=10.6,2.4Hz),8.41(1H,d,J=2.4Hz) Reference Example 183

In the same manner as in Reference Example 3, from 7-fluoro-4-methyl-1,5-naphthyridin-2 (1H) -one and 2-bromomethyl-1,3-dioxolane to 1- (1,3-dioxolane-2 -Ilmethyl) -7-fluoro-4-methyl-1,5-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.54 (3H, d, J = 1.2 Hz), 3.82-4.06 (4H, m), 4.43 (2H, d, J = 4.1 Hz), 5.18 (1H, t, J = 4.1Hz), 6.75-6.78 (1H, m), 7.67 (1H, dd, J = 10.6,2.4Hz), 8.41 (1H, d, J = 2.4Hz)

参考例４と同様の手法により、１−（１，３−ジオキソラン−２−イルメチル）−７−フルオロ−４−メチル−１，５−ナフチリジン−２（１Ｈ）−オンから（７−フルオロ−４−メチル−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒドを得た。
¹H-NMR(CDCl₃)δ値：2.58(3H,s),5.11(2H,s),6.80(1H,s),7.02(1H,dd,J=9.6,2.3Hz),8.45(1H,d,J=2.3Hz),9.75(1H,s) Reference Example 184

In the same manner as in Reference Example 4, from 1- (1,3-dioxolan-2-ylmethyl) -7-fluoro-4-methyl-1,5-naphthyridin-2 (1H) -one to (7-fluoro-4 -Methyl-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.58 (3H, s), 5.11 (2H, s), 6.80 (1H, s), 7.02 (1H, dd, J = 9.6, 2.3 Hz), 8.45 (1H, d, J = 2.3Hz), 9.75 (1H, s)

（５−ブロモピリジン−３−イル）メタノール0.10gのジオキサン5mL溶液に室温で２−フランボロン酸72mg、塩化リチウム67mg、炭酸セシウム0.51g、酢酸パラジウム5.4mgおよび２−ジシクロヘキシルホスフィノ−２’，６’−ジメトキシビフェニル20mgを加え、窒素雰囲気下、1時間30分間加熱還流した。反応混合物を室温まで冷却した後、減圧下で溶媒を留去した。得られた残留物をフラッシュ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＝９５：５−９０：１０］で精製し、黄色油状物の（５−（２−フリル）ピリジン−３−イル）メタノール39mgを得た。
¹H-NMR(CDCl₃)δ値：1.50-1.80(1H,broad),4.78(2H,s),6.52(1H,dd,J=3.4,1.7Hz),6.77(1H,d,J=3.4Hz),7.53(1H,d,J=1.7Hz),7.98(1H,s),8.47(1H,d,J=1.8Hz),8.85(1H,d,J=1.8Hz) Reference Example 185

(5-bromopyridin-3-yl) methanol in 0.10 g of dioxane in 5 mL at room temperature 72 mg 2-furanboronic acid, 67 mg lithium chloride, 0.51 g cesium carbonate, 5.4 mg palladium acetate and 2-dicyclohexylphosphino-2 ′, 6 20 mg of '-dimethoxybiphenyl was added, and the mixture was heated to reflux for 1 hour and 30 minutes under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was purified by flash silica gel column chromatography [gradient elution of chloroform: methanol = 95: 5-90: 10] to give (5- (2-furyl) pyridin-3-yl) methanol as a yellow oil. 39 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.50-1.80 (1H, broad), 4.78 (2H, s), 6.52 (1H, dd, J = 3.4, 1.7 Hz), 6.77 (1H, d, J = 3.4 Hz), 7.53 (1H, d, J = 1.7Hz), 7.98 (1H, s), 8.47 (1H, d, J = 1.8Hz), 8.85 (1H, d, J = 1.8Hz)

参考例１６４と同様の手法により、（５−（２−フリル）ピリジン−３−イル）メタノールから５−（２−フリル）ニコチンアルデヒドを得た。
¹H-NMR(CDCl₃)δ値：6.56(1H,dd,J=3.3,1.7Hz),6.88(1H,d,J=3.3Hz),7.58(1H,d,J=1.7Hz),8.39(1H,t,J=1.9Hz),8.95(1H,d,J=1.9Hz),9.15(1H,d,J=1.9Hz),10.16(1H,s) Reference Example 186

In the same manner as in Reference Example 164, 5- (2-furyl) nicotinaldehyde was obtained from (5- (2-furyl) pyridin-3-yl) methanol.
¹ H-NMR (CDCl ₃ ) δ value: 6.56 (1H, dd, J = 3.3,1.7 Hz), 6.88 (1H, d, J = 3.3 Hz), 7.58 (1H, d, J = 1.7 Hz), 8.39 (1H, t, J = 1.9Hz), 8.95 (1H, d, J = 1.9Hz), 9.15 (1H, d, J = 1.9Hz), 10.16 (1H, s)

１−（１，３−ジオキソラン−２−イルメチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン0.50gのテトラヒドロフラン3mL懸濁液に20％水酸化ナトリウム水溶液3mLを加え、加熱還流下、1時間攪拌した。水3mLを加え、加熱還流下、3時間30分間攪拌した。20％水酸化ナトリウム水溶液3mLを加え、加熱還流下、4時間攪拌した。減圧下でテトラヒドロフランを留去した後、加熱還流下、1時間30分間攪拌した。室温まで冷却した後、反応混合物に2mol/L塩酸を加え、pH5に調整した。酢酸エチルを加え、有機層を分取し、水層を酢酸エチルで2回抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジエチルエーテルを加え、固形物を濾取し、黄色固体の１−（１，３−ジオキソラン−２−イルメチル）−７−ヒドロキシ−１，５−ナフチリジン−２（１Ｈ）−オン0.32gを得た。
¹H-NMR(DMSO-d₆)δ値：3.76-3.86(2H,m),3.92-4.06(2H,m),4.32(2H,d,J=4.6Hz),5.08(1H,t,J=4.6Hz),6.61(1H,d,J=9.6Hz),7.37(1H,d,J=2.2Hz),7.84(1H,d,J=9.6Hz),8.14(1H,d,J=2.2Hz),10.6-11.0(1H,broad) Reference Example 187

To a suspension of 0.50 g of 1- (1,3-dioxolan-2-ylmethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one in 3 mL of tetrahydrofuran was added 3 mL of 20% aqueous sodium hydroxide and heated. The mixture was stirred for 1 hour under reflux. 3 mL of water was added, and the mixture was stirred for 3 hours and 30 minutes under reflux. 3 mL of a 20% aqueous sodium hydroxide solution was added, and the mixture was stirred for 4 hours with heating under reflux. Tetrahydrofuran was distilled off under reduced pressure, and the mixture was stirred for 1 hour and 30 minutes under reflux. After cooling to room temperature, 2 mol / L hydrochloric acid was added to the reaction mixture to adjust to pH5. Ethyl acetate was added, the organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the obtained residue, the solid was collected by filtration, and 1- (1,3-dioxolan-2-ylmethyl) -7-hydroxy-1,5-naphthyridine-2 (1H)-of a yellow solid was collected. 0.32g on was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.76 to 3.86 (2H, m), 3.92 to 4.06 (2H, m), 4.32 (2H, d, J = 4.6Hz), 5.08 (1H, t, J = 4.6Hz), 6.61 (1H, d, J = 9.6Hz), 7.37 (1H, d, J = 2.2Hz), 7.84 (1H, d, J = 9.6Hz), 8.14 (1H, d, J = 2.2 Hz), 10.6-11.0 (1H, broad)

１−（１，３−ジオキソラン−２−イルメチル）−７−ヒドロキシ−１，５−ナフチリジン−２（１Ｈ）−オン0.15gのトルエン1.5mL懸濁液に40％水酸化ナトリウム水溶液1mL、テトラブチルアンモニウムブロマイド97mgおよび10mol/Lクロロ（ジフルオロ）メタンのＮ，Ｎ−ジメチルホルムアミド溶液0.25mLを加え、50分間攪拌した後、10mol/Lクロロ（ジフルオロ）メタンのＮ，Ｎ−ジメチルホルムアミド溶液1mLを加え、3時間40分間攪拌した。反応混合物に水およびトルエンを加え、有機層を分取し、水層をトルエンで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、淡褐色固体の７−（ジフルオロメトキシ）−１−（１，３−ジオキソラン−２−イルメチル）−１，５−ナフチリジン−２（１Ｈ）−オン95mgを得た。
¹H-NMR(CDCl₃)δ値：3.83-4.04(4H,m),4.47(2H,d,J=4.2Hz),5.20(1H,t,J=4.2Hz),6.65(1H,t,J=72.2Hz),6.90(1H,d,J=9.9Hz),7.77(1H,d,J=2.2Hz),7.90(1H,dd,J=9.9,0.7Hz),8.40(1H,d,J=2.2Hz) Reference Example 188

1- (1,3-Dioxolan-2-ylmethyl) -7-hydroxy-1,5-naphthyridin-2 (1H) -one 0.15 g of toluene in 1.5 mL suspension of 40% aqueous sodium hydroxide solution in 1 mL, tetrabutyl Add 97 mg of ammonium bromide and 0.25 mL of 10 mol / L chloro (difluoro) methane in N, N-dimethylformamide and stir for 50 minutes, then add 1 mL of 10 mol / L chloro (difluoro) methane in N, N-dimethylformamide. And stirred for 3 hours and 40 minutes. Water and toluene were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with toluene. The organic layer and the extract were combined, washed sequentially with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give a pale brown solid 7- (difluoromethoxy) -1- (1 , 3-Dioxolan-2-ylmethyl) -1,5-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.83 to 4.04 (4H, m), 4.47 (2H, d, J = 4.2 Hz), 5.20 (1H, t, J = 4.2 Hz), 6.65 (1H, t, J = 72.2Hz), 6.90 (1H, d, J = 9.9Hz), 7.77 (1H, d, J = 2.2Hz), 7.90 (1H, dd, J = 9.9,0.7Hz), 8.40 (1H, d, (J = 2.2Hz)

参考例４と同様の手法により、７−（ジフルオロメトキシ）−１−（１，３−ジオキソラン−２−イルメチル）−１，５−ナフチリジン−２（１Ｈ）−オンから（７−（ジフルオロメトキシ）−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒドを得た。
¹H-NMR(CDCl₃)δ値：5.13(2H,s),6.63(1H,t,J=71.9Hz),6.94(1H,d,J=9.8Hz),7.09(1H,d,J=2.2Hz),7.95-8.00(1H,m),8.45(1H,d,J=2.2Hz),9.77(1H,s) Reference Example 189

In the same manner as in Reference Example 4, from 7- (difluoromethoxy) -1- (1,3-dioxolan-2-ylmethyl) -1,5-naphthyridin-2 (1H) -one to (7- (difluoromethoxy) 2-Oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 5.13 (2H, s), 6.63 (1H, t, J = 71.9 Hz), 6.94 (1H, d, J = 9.8 Hz), 7.09 (1H, d, J = 2.2Hz), 7.95-8.00 (1H, m), 8.45 (1H, d, J = 2.2Hz), 9.77 (1H, s)

３−メチル−１，５−ナフチリジン0.26gのベンゼン4mL溶液にＮ−ブロモスクシンイミド0.35g、アゾビスイソブチロニトリル29mgを加え、加熱還流下2時間15分間攪拌した。さらにＮ−ブロモスクシンイミド0.13gを追加し、加熱還流下30分間攪拌した。室温まで冷却後、反応混合物に氷冷下でヘキサメチレンテトラミン0.50gの水1.5mL溶液を滴下し、酢酸1.5mLを加え、加熱還流下、1時間20分間攪拌した。室温まで冷却後、反応混合物にクロロホルムおよび20％水酸化ナトリウム水溶液を加えてpH8.5に調整した。有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、得られた残留物をフラッシュシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝１：１］で精製し、微黄色固体の１，５−ナフチリジン−３−カルバルデヒド25mgを得た。
¹H-NMR(CDCl₃)δ値：7.80(1H,dd,8.5,4.2Hz),8.49-8.52(1H,m),8.82-8.85(1H,m),9.12(1H,dd,J=4.2,1.5Hz),9.46(1H,d,J=2.2Hz),10.35(1H,s) Reference Example 190

0.35 g of N-bromosuccinimide and 29 mg of azobisisobutyronitrile were added to a solution of 0.26 g of 3-methyl-1,5-naphthyridine in 4 mL of benzene, and the mixture was stirred for 2 hours and 15 minutes with heating under reflux. Further, 0.13 g of N-bromosuccinimide was added, and the mixture was stirred for 30 minutes with heating under reflux. After cooling to room temperature, a 1.5 mL aqueous solution of 0.50 g of hexamethylenetetramine was added dropwise to the reaction mixture under ice-cooling, 1.5 mL of acetic acid was added, and the mixture was stirred for 1 hour and 20 minutes with heating under reflux. After cooling to room temperature, the reaction mixture was adjusted to pH 8.5 by adding chloroform and 20% aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by flash silica gel column chromatography [eluent: hexane: ethyl acetate = 1: 1]. 25 mg of 5-naphthyridine-3-carbaldehyde was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 7.80 (1H, dd, 8.5,4.2 Hz), 8.49-8.52 (1H, m), 8.82-8.85 (1H, m), 9.12 (1H, dd, J = 4.2 , 1.5Hz), 9.46 (1H, d, J = 2.2Hz), 10.35 (1H, s)

メチル＝６−クロロピラジン−２−カルボキシラート0.10gのジオキサン2.9mL溶液に２−フランボロン酸65mg、塩化リチウム74mg、炭酸セシウム0.57g、２−ジシクロヘキシルホスフィノ−２’，６’−ジメトキシビフェニル21mgおよびトリス（ジベンジリデンアセトン）ジパラジウム（０）24mgを加え、2時間加熱還流した。反応混合物に水および酢酸エチルを加え、有機層を分取し、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をフラッシュ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＝８７：１３−８３：１７］で精製し、白色固体のメチル＝６−（２−フリル）ピラジン−２−カルボキシラート74mgを得た。
¹H-NMR(CDCl₃)δ値：4.05(3H,s),6.60(1H,dd,J=3.5,1.8Hz),7.30-7.32(1H,m),7.62-7.65(1H,m),9.12(1H,s),9.12(1H,s) Reference Example 191

Methyl 6-chloropyrazine-2-carboxylate (0.10 g) in dioxane (2.9 mL) was added 2-furanboronic acid (65 mg), lithium chloride (74 mg), cesium carbonate (0.57 g), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (21 mg) and 24 mg of tris (dibenzylideneacetone) dipalladium (0) was added, and the mixture was heated to reflux for 2 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash silica gel column chromatography [gradient elution of hexane: ethyl acetate = 87: 13-83: 17], and methyl = 6- (2-furyl) pyrazine-2-carboxylate as a white solid 74 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 4.05 (3H, s), 6.60 (1H, dd, J = 3.5, 1.8 Hz), 7.30-7.32 (1H, m), 7.62-7.65 (1H, m), 9.12 (1H, s), 9.12 (1H, s)

参考例５８と同様の手法により、メチル＝６−（２−フリル）ピラジン−２−カルボキシラートから（６−（２−フリル）ピラジン−２−イル）メタノールを得た。
¹H-NMR(CDCl₃)δ値：3.08-3.24(1H,m),4.86(2H,s),6.59(1H,dd,J=3.4,1.7Hz),7.18(1H,d,J=3.4Hz),7.58-7.62(1H,m),8.46(1H,s),8.89(1H,s) Reference Example 192

In the same manner as in Reference Example 58, (6- (2-furyl) pyrazin-2-yl) methanol was obtained from methyl = 6- (2-furyl) pyrazin-2-carboxylate.
¹ H-NMR (CDCl ₃ ) δ value: 3.08-3.24 (1H, m), 4.86 (2H, s), 6.59 (1H, dd, J = 3.4, 1.7 Hz), 7.18 (1H, d, J = 3.4 Hz), 7.58-7.62 (1H, m), 8.46 (1H, s), 8.89 (1H, s)

参考例６７と同様の手法により、（６−（２−フリル）ピラジン−２−イル）メタノールから６−（２−フリル）ピラジン−２−カルバルデヒドを得た。
¹H-NMR(CDCl₃)δ値：6.63(1H,dd,J=3.4,1.7Hz),7.30(1H,dd,J=3.4,0.7Hz),7.66(1H,dd,J=1.7,0.7Hz),8.99(1H,s),9.16(1H,s),10.18(1H,s) Reference Example 193

In the same manner as in Reference Example 67, 6- (2-furyl) pyrazine-2-carbaldehyde was obtained from (6- (2-furyl) pyrazin-2-yl) methanol.
¹ H-NMR (CDCl ₃ ) δ value: 6.63 (1H, dd, J = 3.4,1.7 Hz), 7.30 (1H, dd, J = 3.4,0.7 Hz), 7.66 (1H, dd, J = 1.7,0.7 Hz), 8.99 (1H, s), 9.16 (1H, s), 10.18 (1H, s)

参考例５８と同様の手法により、エチル＝５−（２−フリル）−１，３−オキサゾール−２−カルボキシラートから（５−（２−フリル）−１，３−オキサゾール−２−イル）メタノールを得た。
¹H-NMR(CDCl₃)δ値：4.78(2H,s),6.50(1H,dd,J=3.4,2.0Hz),6.64(1H,d,J=3.4Hz),7.21(1H,s),7.46-7.48(1H,m) Reference Example 194

In the same manner as in Reference Example 58, ethyl = 5- (2-furyl) -1,3-oxazol-2-carboxylate to (5- (2-furyl) -1,3-oxazol-2-yl) methanol Got.
¹ H-NMR (CDCl ₃ ) δ value: 4.78 (2H, s), 6.50 (1H, dd, J = 3.4, 2.0 Hz), 6.64 (1H, d, J = 3.4 Hz), 7.21 (1H, s) , 7.46-7.48 (1H, m)

参考例１６４と同様の手法により、（５−（２−フリル）−１，３−オキサゾール−２−イル）メタノールから５−（２−フリル）−１，３−オキサゾール−２−カルバルデヒドを得た。
¹H-NMR(CDCl₃)δ値：6.57(1H,dd,J=3.5,1.8Hz),6.94(1H,d,J=3.5Hz),7.53(1H,s),7.56-7.58(1H,m),9.75(1H,s) Reference Example 195

In the same manner as in Reference Example 164, 5- (2-furyl) -1,3-oxazole-2-carbaldehyde is obtained from (5- (2-furyl) -1,3-oxazol-2-yl) methanol. It was.
¹ H-NMR (CDCl ₃ ) δ value: 6.57 (1H, dd, J = 3.5, 1.8 Hz), 6.94 (1H, d, J = 3.5 Hz), 7.53 (1H, s), 7.56-7.58 (1H, m), 9.75 (1H, s)

４−オキソ−６−（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）メチル）−４Ｈ−ピラン−３−イル＝トリフルオロメタンスルホナート16gのアセトニトリル100mL溶液に窒素雰囲気下、プロパギルアルコール5.1mL、トリエチルアミン18mL、ジクロロビス（トリフェニルホスフィン）パラジウム（II）0.62gおよびよう化銅（I）0.42gを加え、室温で2時間攪拌した。不溶物を濾去し、減圧下で溶媒を留去した。得られた残留物をフラッシュ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＝１００：０−９７：３］で精製し、褐色油状物の５−（３−ヒドロキシ−１−プロピン−１−イル）−２−（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）メチル）−４Ｈ−ピラン−４−オン6.2gを得た。
¹H-NMR(CDCl₃)δ値：1.51-1.90(6H,m),2.27-2.40(1H,broad),3.52-3.60(1H,m),3.78-3.86(1H,m),4.34(1H,d,J=14.9Hz),4.50(2H,s),4.54(1H,d,J=14.9Hz),4.73(1H,t,J=3.3Hz),6.51(1H,s),8.00(1H,s) Reference Example 196

4-oxo-6-((tetrahydro-2H-pyran-2-yloxy) methyl) -4H-pyran-3-yl = trifluoromethanesulfonate in 100 mL of acetonitrile in a nitrogen atmosphere, propargyl alcohol 5.1 mL, triethylamine 18 mL, dichlorobis (triphenylphosphine) palladium (II) 0.62 g and copper iodide (I) 0.42 g were added, and the mixture was stirred at room temperature for 2 hours. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue was purified by flash silica gel column chromatography [gradient elution of chloroform: methanol = 100: 0-97: 3] to give 5- (3-hydroxy-1-propyn-1-yl) as a brown oil. There was obtained 6.2 g of 2-((tetrahydro-2H-pyran-2-yloxy) methyl) -4H-pyran-4-one.
¹ H-NMR (CDCl ₃ ) δ value: 1.51-1.90 (6H, m), 2.27-2.40 (1H, broad), 3.52-3.60 (1H, m), 3.78-3.86 (1H, m), 4.34 (1H , d, J = 14.9Hz), 4.50 (2H, s), 4.54 (1H, d, J = 14.9Hz), 4.73 (1H, t, J = 3.3Hz), 6.51 (1H, s), 8.00 (1H , s)

参考例１５１と同様の手法により５−（３−ヒドロキシ−１−プロピン−１−イル）−２−（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）メチル）−４Ｈ−ピラン−４−オンから５−（３−ヒドロキシプロピル）−２−（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）メチル）−４Ｈ−ピラン−４−オンを得た。
¹H-NMR(CDCl₃)δ値：1.52-1.92(8H,m),2.51(2H,t,J=7.0Hz),2.85-3.17(1H,broad),3.52-3.60(1H,m),3.57(2H,t,J=5.9Hz),3.80-3.88(1H,m),4.33(1H,d,J=14.4Hz),4.53(1H,d,J=14.4Hz),4.73(1H,t,J=3.2Hz),6.46(1H,s),7.70(1H,s) Reference Example 197

In the same manner as in Reference Example 151, 5- (3-hydroxy-1-propyn-1-yl) -2-((tetrahydro-2H-pyran-2-yloxy) methyl) -4H-pyran-4-one -(3-Hydroxypropyl) -2-((tetrahydro-2H-pyran-2-yloxy) methyl) -4H-pyran-4-one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.52-1.92 (8H, m), 2.51 (2H, t, J = 7.0 Hz), 2.85-3.17 (1H, broad), 3.52-3.60 (1H, m), 3.57 (2H, t, J = 5.9Hz), 3.80-3.88 (1H, m), 4.33 (1H, d, J = 14.4Hz), 4.53 (1H, d, J = 14.4Hz), 4.73 (1H, t , J = 3.2Hz), 6.46 (1H, s), 7.70 (1H, s)

（５−（３−ヒドロキシプロピル）−２−（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）メチル）−４Ｈ−ピラン−４−オン1.2gのエタノール5mL溶液に25％アンモニア水16mLを加え、加熱還流下9時間30分間攪拌した。減圧下で溶媒を留去し、得られた残留物をフラッシュ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＝９５：５−９０：１０］で精製し、褐色油状物の５−（３−ヒドロキシプロピル）−２−（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）メチル）ピリジン−４（１Ｈ）−オン0.42gを得た。
¹H-NMR(CDCl₃)δ値：1.52-1.92(8H,m),2.64(2H,t,J=6.5Hz),3.51(2H,t,J=5.6Hz),3.55-3.62(1H,m),3.93-4.02(1H,m),4.55-4.68(3H,m),6.31(1H,s),7.47(1H,s) Reference Example 198

(5- (3-hydroxypropyl) -2-((tetrahydro-2H-pyran-2-yloxy) methyl) -4H-pyran-4-one 1.2 g of ethanol in 5 mL solution was added with 25% aqueous ammonia 16 mL and heated. The mixture was stirred for 9 hours and 30 minutes under reflux, the solvent was distilled off under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography [gradient elution of chloroform: methanol = 95: 5-90: 10], brown 0.42 g of oily 5- (3-hydroxypropyl) -2-((tetrahydro-2H-pyran-2-yloxy) methyl) pyridin-4 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.52-1.92 (8H, m), 2.64 (2H, t, J = 6.5 Hz), 3.51 (2H, t, J = 5.6 Hz), 3.55-3.62 (1H, m), 3.93-4.02 (1H, m), 4.55-4.68 (3H, m), 6.31 (1H, s), 7.47 (1H, s)

（１）５−（３−ヒドロキシプロピル）−２−（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）メチル）ピリジン−４（１Ｈ）−オン0.42gのテトラヒドロフラン8mL溶液に、トリフェニルホスフィン0.54gおよび40％ジエチル＝アゾジカルボキシラート/トルエン溶液0.89gを加え10分間攪拌した。減圧下で溶媒を留去し、褐色油状物の７−（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）メチル）−３，４−ジヒドロ−２Ｈ−ピラノ（３，２−ｃ）ピリジンを得た。
（２）参考例１７２と同様の手法により７−（（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）メチル）−３，４−ジヒドロ−２Ｈ−ピラノ（３，２−ｃ）ピリジンから（３，４−ジヒドロ−２Ｈ−ピラノ（３，２−ｃ）ピリジン−７−イル）メタノール塩酸塩を得た。
¹H-NMR(DMSO-d₆)δ値：1.99(2H,quint,J=5.8Hz),2.84(2H,t,J=6.2Hz),4.46(2H,t,J=5.2Hz),4.70(2H,s),6.06-6.36(1H,broad),7.22(1H,s),8.48(1H,s) Reference Example 199

(1) 5- (3-hydroxypropyl) -2-((tetrahydro-2H-pyran-2-yloxy) methyl) pyridin-4 (1H) -one in 0.42 g of tetrahydrofuran in 8 mL of tetrahydrofuran, 0.54 g of triphenylphosphine and 0.89 g of 40% diethyl azodicarboxylate / toluene solution was added and stirred for 10 minutes. The solvent was distilled off under reduced pressure to obtain 7-((tetrahydro-2H-pyran-2-yloxy) methyl) -3,4-dihydro-2H-pyrano (3,2-c) pyridine as a brown oil. .
(2) From 7-((tetrahydro-2H-pyran-2-yloxy) methyl) -3,4-dihydro-2H-pyrano (3,2-c) pyridine in the same manner as in Reference Example 172 (3,4) -Dihydro-2H-pyrano (3,2-c) pyridin-7-yl) methanol hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.99 (2H, quint, J = 5.8Hz), 2.84 (2H, t, J = 6.2Hz), 4.46 (2H, t, J = 5.2Hz), 4.70 (2H, s), 6.06-6.36 (1H, broad), 7.22 (1H, s), 8.48 (1H, s)

参考例１２３と同様の手法により（３，４−ジヒドロ−２Ｈ−ピラノ（３，２−ｃ）ピリジン−７−イル）メタノール塩酸塩から３，４−ジヒドロ−２Ｈ−ピラノ（３，２−ｃ）ピリジン−７−カルバルデヒドを得た。
¹H-NMR(CDCl₃)δ値：2.08(2H,quint,J=5.8Hz),2.85(2H,t,J=6.4Hz),4.30(2H,t,J=5.1Hz),7.36(1H,s),8.38(1H,s),9.97(1H,s) Reference Example 200

In the same manner as in Reference Example 123, (3,4-dihydro-2H-pyrano (3,2-c) pyridin-7-yl) methanol hydrochloride to 3,4-dihydro-2H-pyrano (3,2-c ) Pyridine-7-carbaldehyde was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.08 (2H, quint, J = 5.8Hz), 2.85 (2H, t, J = 6.4Hz), 4.30 (2H, t, J = 5.1Hz), 7.36 (1H , s), 8.38 (1H, s), 9.97 (1H, s)

２−クロロ−３−ニトロ−５−（トリフルオロメチル）ピリジン1.8gのテトラヒドロフラン8mL溶液に氷冷下トリエチル＝１，１，２−エタントリカルボキシラート2.0mLおよび60％水素化ナトリウム0.63gを加え、室温で2時間攪拌した。水および酢酸エチルを加え、有機層を分取し、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、褐色油状物のトリエチル＝１−（３−ニトロ−５−（トリフルオロメチル）ピリジン−２−イル）エタン−１，１，２−トリカルボキシラート3.5gを得た。
¹H-NMR(CDCl₃)δ値：1.20-1.28(9H,m),3.57(2H,s),4.10(2H,q,J=7.2Hz),4.25(4H,q,J=7.2Hz),8.64-8.67(1H,m),8.96-8.99(1H,m) Reference Example 201

To a solution of 1.8 g of 2-chloro-3-nitro-5- (trifluoromethyl) pyridine in 8 mL of tetrahydrofuran was added 2.0 mL of triethyl = 1,1,2-ethanetricarboxylate and 0.63 g of 60% sodium hydride under ice cooling. And stirred at room temperature for 2 hours. Water and ethyl acetate were added, the organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and a brown oily triethyl = 1- (3-nitro 3.5 g of -5- (trifluoromethyl) pyridin-2-yl) ethane-1,1,2-tricarboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.20-1.28 (9H, m), 3.57 (2H, s), 4.10 (2H, q, J = 7.2Hz), 4.25 (4H, q, J = 7.2Hz) , 8.64-8.67 (1H, m), 8.96-8.99 (1H, m)

（１）トリエチル＝１−（３−ニトロ−５−（トリフルオロメチル）ピリジン−２−イル）エタン−１，１，２−トリカルボキシラート3.5gのエタノール35mLおよび水8.8mLの混合溶液に塩化アンモニウム0.27gおよび鉄粉1.6gを加え、加熱還流下2時間20分間攪拌した。室温まで冷却後不溶物を濾去し、酢酸エチルおよび水で洗浄した。食塩を加え、有機層を分取し、水層を酢酸エチルで抽出した。有機層と抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、褐色油状物の残留物を得た。
（２）（１）で得られた残留物のジオキサン8mL溶液に塩酸8.0mLを加え、加熱還流下1時間30分間攪拌した。減圧下で溶媒を留去し、エタノールおよびジエチルエーテルを加え析出物を濾取し、淡褐色固体の７−（トリフルオロメチル）−３，４−ジヒドロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.44gを得た。
¹H-NMR(DMSO-d₆)δ値：2.65(2H,t,J=7.7Hz),3.13(2H,t,J=7.7Hz),7.46(1H,d,J=1.3Hz),8.46(1H,d,J=1.3Hz),10.43(1H,s) Reference Example 202

(1) Triethyl = 1- (3-nitro-5- (trifluoromethyl) pyridin-2-yl) ethane-1,1,2-tricarboxylate 3.5 g of ethanol in a mixed solution of 35 mL of ethanol and 8.8 mL of water 0.27 g of ammonium and 1.6 g of iron powder were added, and the mixture was stirred for 2 hours and 20 minutes with heating under reflux. After cooling to room temperature, the insoluble material was filtered off and washed with ethyl acetate and water. Sodium chloride was added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a brown oily residue.
(2) 8.0 mL of hydrochloric acid was added to a dioxane 8 mL solution of the residue obtained in (1), and the mixture was stirred for 1 hour and 30 minutes with heating under reflux. The solvent was distilled off under reduced pressure, ethanol and diethyl ether were added, and the precipitate was collected by filtration. 0.44 g of on-hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.65 (2H, t, J = 7.7Hz), 3.13 (2H, t, J = 7.7Hz), 7.46 (1H, d, J = 1.3Hz), 8.46 (1H, d, J = 1.3Hz), 10.43 (1H, s)

参考例３と同様の手法により、７−（トリフルオロメチル）−３，４−ジヒドロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩および２−ブロモ−１，１−ジメトキシエタンから１−（２，２−ジメトキシエチル）−７−（トリフルオロメチル）−３，４−ジヒドロ−１，５−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：2.82(2H,t,J=7.5Hz),3.22(2H,t,J=7.5Hz),3.43-3.46(6H,m),3.99(2H,d,J=5.1Hz),4.61(1H,t,J=5.1Hz),7.89-7.92(1H,m),8.45-8.48(1H,m) Reference Example 203

In the same manner as in Reference Example 3, 1-from 7- (trifluoromethyl) -3,4-dihydro-1,5-naphthyridin-2 (1H) -one hydrochloride and 2-bromo-1,1-dimethoxyethane -(2,2-Dimethoxyethyl) -7- (trifluoromethyl) -3,4-dihydro-1,5-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.82 (2H, t, J = 7.5 Hz), 3.22 (2H, t, J = 7.5 Hz), 3.43-3.46 (6H, m), 3.99 (2H, d, J = 5.1Hz), 4.61 (1H, t, J = 5.1Hz), 7.89-7.92 (1H, m), 8.45-8.48 (1H, m)

１−（２，２−ジメトキシエチル）−７−（トリフルオロメチル）−３，４−ジヒドロ−１，５−ナフチリジン−２（１Ｈ）−オン0.11gのジオキサン2mL溶液に２，３−ジクロロ−５，６−ジシアノ−ｐ−ベンゾキノン0.16gを加え、加熱還流下3時間攪拌した。水および酢酸エチルを加え、2.0mol/L水酸化ナトリウム水溶液でpH12に調整し、有機層を分取した。水酸化ナトリウム水溶液および飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、褐色固体の１−（２，２−ジメトキシエチル）−７−（トリフルオロメチル）−１，５−ナフチリジン−２（１Ｈ）−オン90mgを得た
¹H-NMR(CDCl₃)δ値：3.44(6H,s),4.38(2H,d,J=5.1Hz),4.63(1H,t,J=5.1Hz),7.03(1H,d,J=9.8Hz),7.98(1H,d,J=9.8Hz),8.24(1H,s),8.75(1H,d.J=1.0Hz) Reference Example 204

1- (2,2-dimethoxyethyl) -7- (trifluoromethyl) -3,4-dihydro-1,5-naphthyridin-2 (1H) -one in a solution of 0.11 g of dioxane in 2 mL of 2,3-dichloro- 5,6-Dicyano-p-benzoquinone (0.16 g) was added, and the mixture was stirred for 3 hours with heating under reflux. Water and ethyl acetate were added, the pH was adjusted to 12 with a 2.0 mol / L aqueous sodium hydroxide solution, and the organic layer was separated. Wash with aqueous sodium hydroxide and saturated aqueous sodium chloride, dry over anhydrous magnesium sulfate, and evaporate the solvent under reduced pressure to give 1- (2,2-dimethoxyethyl) -7- (trifluoromethyl) as a brown solid 90 mg of -1,5-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.44 (6H, s), 4.38 (2H, d, J = 5.1 Hz), 4.63 (1H, t, J = 5.1 Hz), 7.03 (1H, d, J = 9.8Hz), 7.98 (1H, d, J = 9.8Hz), 8.24 (1H, s), 8.75 (1H, dJ = 1.0Hz)

１−（２，２−ジメトキシエチル）−７−（トリフルオロメチル）−１，５−ナフチリジン−２（１Ｈ）−オン90mgのメチルエチルケトン0.72mL溶液に濃塩酸38μLを加え、加熱還流下、1時間30分間攪拌した。反応混合物を室温まで冷却し、クロロホルムおよび飽和炭酸水素ナトリウム水溶液を加え、有機層を分取し、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、褐色油状物の（２−オキソ−７−（トリフルオロメチル）−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド67mgを得た。
¹H-NMR(CDCl₃)δ値：5.21(2H,s),7.09(1H,d,J=9.8Hz),7.49(1H,s),8.04(1H,d,J=9.8Hz),8.79-8.82(1H,m),9.82(1H,s) Reference Example 205

To a solution of 90 mg of 1- (2,2-dimethoxyethyl) -7- (trifluoromethyl) -1,5-naphthyridin-2 (1H) -one in 0.72 mL of methyl ethyl ketone was added 38 μL of concentrated hydrochloric acid, and the mixture was heated under reflux for 1 hour. Stir for 30 minutes. The reaction mixture was cooled to room temperature, chloroform and saturated aqueous sodium hydrogen carbonate solution were added, the organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, brown An oily product of (2-oxo-7- (trifluoromethyl) -1,5-naphthyridin-1 (2H) -yl) acetaldehyde (67 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 5.21 (2H, s), 7.09 (1H, d, J = 9.8Hz), 7.49 (1H, s), 8.04 (1H, d, J = 9.8Hz), 8.79 -8.82 (1H, m), 9.82 (1H, s)

２，６−ジクロロ−５−フルオロニコチン酸10gのトルエン30mL懸濁液に塩化チオニル8.5gおよびＮ，Ｎ−ジメチルホルムアミド0.10mLを加え、72℃で1時間30分間攪拌した。反応混合物を室温まで冷却し、減圧下で溶媒を留去した。得られた残留物を25％アンモニア水30mLに−20℃で滴下した。5℃まで昇温し、30分間攪拌した。固形物を濾取し、白色固体の２，６−ジクロロ−５−フルオロニコチナミド9.9gを得た。
¹H-NMR(DMSO-d₆)δ値：7.94(1H,s),8.11(1H,s),8.23(1H,d,J=7.8Hz) Reference Example 206

To a suspension of 10 g of 2,6-dichloro-5-fluoronicotinic acid in 30 mL of toluene were added 8.5 g of thionyl chloride and 0.10 mL of N, N-dimethylformamide, and the mixture was stirred at 72 ° C. for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The obtained residue was added dropwise to 30 mL of 25% aqueous ammonia at −20 ° C. The temperature was raised to 5 ° C. and stirred for 30 minutes. The solid was collected by filtration to obtain 9.9 g of 2,6-dichloro-5-fluoronicotinamide as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.94 (1H, s), 8.11 (1H, s), 8.23 (1H, d, J = 7.8 Hz)

参考例１０１と同様の手法により、２，６−ジクロロ−５−フルオロニコチナミドから２−クロロ−５−フルオロ−６−メチルニコチナミドを得た。
¹H-NMR(CDCl₃)δ値：2.56(3H,d,J=2.9Hz),5.91(1H,s),6.85(1H,s),8.00(1H,d,J=8.5Hz) Reference Example 207

In the same manner as in Reference Example 101, 2-chloro-5-fluoro-6-methylnicotinamide was obtained from 2,6-dichloro-5-fluoronicotinamide.
¹ H-NMR (CDCl ₃ ) δ value: 2.56 (3H, d, J = 2.9 Hz), 5.91 (1H, s), 6.85 (1H, s), 8.00 (1H, d, J = 8.5 Hz)

参考例１８０と同様の手法により、２−クロロ−５−フルオロ−６−メチルニコチナミドから２−クロロ−５−フルオロ−６−メチルピリジン−３−アミンを得た。
¹H-NMR(CDCl₃)δ値：2.37(3H,d,J=2.7Hz),4.04(2H,s),6.78(1H,d,J=9.5Hz) Reference Example 208

In the same manner as in Reference Example 180, 2-chloro-5-fluoro-6-methylpyridin-3-amine was obtained from 2-chloro-5-fluoro-6-methylnicotinamide.
¹ H-NMR (CDCl ₃ ) δ value: 2.37 (3H, d, J = 2.7 Hz), 4.04 (2H, s), 6.78 (1H, d, J = 9.5 Hz)

参考例１と同様の手法により、２−クロロ−５−フルオロ−６−メチルピリジン−３−アミンおよびブチル＝アクリラートからブチル＝（２Ｅ）−３−（３−アミノ−５−フルオロ−６−メチルピリジン−２−イル）アクリラートを得た。
¹H-NMR(CDCl₃)δ値：0.95(3H,t,J=7.3Hz),1.40-1.48(2H,m),1.68(2H,quint,J=6.8Hz),2.40(3H,d,J=2.7Hz),3.93(2H,s),4.21(2H,t,J=6.8Hz),6.67(1H,d,J=10.2Hz),6.87(1H,d,J=15.2Hz),7.71(1H,d,J=15.2Hz) Reference Example 209

In the same manner as in Reference Example 1, 2-chloro-5-fluoro-6-methylpyridin-3-amine and butyl acrylate to butyl = (2E) -3- (3-amino-5-fluoro-6-methyl) Pyridin-2-yl) acrylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 0.95 (3H, t, J = 7.3 Hz), 1.40-1.48 (2H, m), 1.68 (2H, quint, J = 6.8 Hz), 2.40 (3H, d, J = 2.7Hz), 3.93 (2H, s), 4.21 (2H, t, J = 6.8Hz), 6.67 (1H, d, J = 10.2Hz), 6.87 (1H, d, J = 15.2Hz), 7.71 (1H, d, J = 15.2Hz)

参考例２と同様の手法により、ブチル＝（２Ｅ）−３−（３−アミノ−５−フルオロ−６−メチルピリジン−２−イル）アクリラートから７−フルオロ−６−メチル−１、５−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(DMSO-d₆)δ値：2.49(3H,d,J=2.9Hz),6.68(1H,d,J=9.8Hz),7.41(1H,J=10.2Hz),7.89(1H,d,J=9.8Hz),11.9(1H,s) Reference Example 210

In the same manner as in Reference Example 2, butyl = (2E) -3- (3-amino-5-fluoro-6-methylpyridin-2-yl) acrylate was converted to 7-fluoro-6-methyl-1,5-naphthyridine. -2 (1H) -one was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.49 (3H, d, J = 2.9 Hz), 6.68 (1H, d, J = 9.8 Hz), 7.41 (1H, J = 10.2 Hz), 7.89 (1H , d, J = 9.8Hz), 11.9 (1H, s)

７−フルオロ−６−メチル−１，５−ナフチリジン−２（１Ｈ）−オン0.74gのＮ，Ｎ−ジメチルホルムアミド5mL溶液に炭酸セシウム2.0gおよび２−ブロモ−１，１−ジメトキシエタン0.84gを加え、90〜100℃まで昇温し、2時間30分間攪拌した。反応混合物を室温まで冷却し、酢酸エチルを加え、不溶物を濾去し、減圧下で溶媒を留去した。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［溶離液；クロロホルム：メタノール＝１００：１］で精製し、淡黄色固体の１−（２，２−ジメトキシエチル）−７−フルオロ−６−メチル−１，５−ナフチルジン−２（１Ｈ）−オン0.69gを得た。
¹H-NMR(CDCl₃)δ値：2.58(3H,d,J=2.7Hz),3.43(6H,s),4.28(2H,d,J=5.2Hz),4.64(1H,t,J=5.2Hz),6.83(1H,d,J=9.8Hz),7.64(1H,d,J=11.2Hz),7.86(1H,d,J=9.8Hz) Reference Example 211

7-Fluoro-6-methyl-1,5-naphthyridin-2 (1H) -one In a solution of 0.74 g of N, N-dimethylformamide in 5 mL was added cesium carbonate 2.0 g and 2-bromo-1,1-dimethoxyethane 0.84 g. In addition, the temperature was raised to 90-100 ° C. and stirred for 2 hours 30 minutes. The reaction mixture was cooled to room temperature, ethyl acetate was added, insolubles were filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 100: 1] to give 1- (2,2-dimethoxyethyl) -7-fluoro-6-methyl-1 as a pale yellow solid. , 5-naphthylzin-2 (1H) -one 0.69 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.58 (3H, d, J = 2.7 Hz), 3.43 (6H, s), 4.28 (2H, d, J = 5.2 Hz), 4.64 (1H, t, J = 5.2Hz), 6.83 (1H, d, J = 9.8Hz), 7.64 (1H, d, J = 11.2Hz), 7.86 (1H, d, J = 9.8Hz)

１−（２，２−ジメトキシエチル）−７−フルオロ−６−メチル−１，５−ナフチルジン−２（１Ｈ）−オン0.69gのメチルエチルケトン6mL溶液に濃塩酸0.35mLを加え、74℃まで昇温し、2時間50分間攪拌した。反応混合物を室温まで冷却し、減圧下で溶媒を留去した。得られた残留物に酢酸エチルおよび飽和炭酸水素ナトリウム水溶液を加え、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、無水硫酸ナトリウムで乾燥させ、淡黄色固体の（７−フルオロ−６−メチル−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド0.52gを得た。
¹H-NMR(CDCl₃)δ値：2.59(3H,d,J=2.7Hz),5.10(2H,s),6.89(1H,d,J=10.0Hz),7.00(1H,d,J=10.0Hz),7.92(1H,d,J=9.8Hz),9.75(1H,s) Reference Example 212

1- (2,2-Dimethoxyethyl) -7-fluoro-6-methyl-1,5-naphthylzin-2 (1H) -one 0.69 g of methyl ethyl ketone in 6 mL solution was added concentrated hydrochloric acid 0.35 mL, and the temperature was raised to 74 ° C. And stirred for 2 hours and 50 minutes. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the obtained residue, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined and dried over anhydrous sodium sulfate to obtain 0.52 g of (7-fluoro-6-methyl-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde as a pale yellow solid. It was.
¹ H-NMR (CDCl ₃ ) δ value: 2.59 (3H, d, J = 2.7 Hz), 5.10 (2H, s), 6.89 (1H, d, J = 10.0 Hz), 7.00 (1H, d, J = 10.0Hz), 7.92 (1H, d, J = 9.8Hz), 9.75 (1H, s)

ｔｅｒｔ−ブチル＝（５−（ブロモメチル）ピラジン−２−イル）カルバマート0.17gのジメチルスルホキシド4mLおよびジクロロメタン2mLの混合溶液に氷冷下トリメチルアミン＝Ｎ−オキシド２水和物0.26gを加え、2時間攪拌した。水およびクロロホルムを加え、有機層を分取し、飽和炭酸水素ナトリウム水溶液、水および飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、ヘキサンを加え、固形物を濾取し、白色固体のｔｅｒｔ−ブチル＝（５−ホルミルピラジン−２−イル）カルバマート0.10gを得た。
¹H-NMR(CDCl₃)δ値：1.55-1.59(9H,m),7.63-7.70(1H,broad),8.82(1H,d,J=1.2Hz),9.44(1H,d,J=1.2Hz),10.07(1H,s) Reference Example 213

To a mixed solution of tert-butyl = (5- (bromomethyl) pyrazin-2-yl) carbamate 0.17 g of dimethyl sulfoxide 4 mL and dichloromethane 2 mL was added 0.26 g of trimethylamine = N-oxide dihydrate under ice cooling, and the mixture was stirred for 2 hours. did. Water and chloroform were added, and the organic layer was separated and washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, hexane was added, and the solid was collected by filtration to obtain 0.10 g of tert-butyl = (5-formylpyrazin-2-yl) carbamate as a white solid. .
¹ H-NMR (CDCl ₃ ) δ value: 1.55-1.59 (9H, m), 7.63-7.70 (1H, broad), 8.82 (1H, d, J = 1.2 Hz), 9.44 (1H, d, J = 1.2 Hz), 10.07 (1H, s)

（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド1.66gのクロロホルム42mL溶液にｔｅｒｔ−ブチル＝（ピペリジン−４−イル）カルバマート1.61gおよび酢酸0.48gを加え、室温で7.5時間攪拌した。反応混合物に水素化トリアセトキシホウ素ナトリウム2.56gを加え、10時間攪拌した。飽和炭酸水素ナトリウム水溶液を加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にエタノールを加え、固形物を濾取し、白色固体のｔｅｒｔ−ブチル＝（１−（２−（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.59gを得た。
¹H-NMR(CDCl₃)δ値：1.31-1.49(11H,m),1.84-2.04(2H,m),2.14-2.37(2H,m),2.56-2.71(2H,m),2.82-3.05(2H,m),3.35-3.60(1H,m),4.20-4.52(3H,m),6.79-6.93(1H,m),7.44-7.58(1H,m),7.79-7.96(1H,m),8.37-8.48(1H,m) Reference Example 214

To a solution of (7-fluoro-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde (1.66 g) in chloroform (42 mL) was added tert-butyl = (piperidin-4-yl) carbamate (1.61 g) and acetic acid (0.48 g). And stirred at room temperature for 7.5 hours. To the reaction mixture, 2.56 g of sodium triacetoxyborohydride was added and stirred for 10 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethanol was added to the obtained residue, and the solid substance was collected by filtration, and the white solid tert-butyl = (1- (2- (7-fluoro-2-oxo-1,5-naphthyridine-1 (2H)- 0.59 g of yl) ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.31-1.49 (11H, m), 1.84-2.04 (2H, m), 2.14-2.37 (2H, m), 2.56-2.71 (2H, m), 2.82-3.05 (2H, m), 3.35-3.60 (1H, m), 4.20-4.52 (3H, m), 6.79-6.93 (1H, m), 7.44-7.58 (1H, m), 7.79-7.96 (1H, m) , 8.37-8.48 (1H, m)

ｔｅｒｔ−ブチル＝（１−（２−（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.59gの2mol/L塩化水素／エタノール30mL溶液を室温で18時間攪拌した。反応混合物にクロロホルム2mLを加え、40℃で4時間攪拌し、室温で18時間攪拌した。反応混合物を減圧下で溶媒留去し、飽和炭酸水素ナトリウム水溶液で中和した後、減圧下で溶媒を留去した。得られた残留物をエタノールで洗浄し、母液を減圧下で溶媒留去し、シリカゲルカラムクロマトグラフィー［シリカゲル；富士シリシア化学株式会社、Chromatorex-NH、溶離液；クロロホルム：メタノール＝１０：１］で精製し、淡黄色固体の１−（２−（４−アミノピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン421mgを得た。
¹H-NMR(CDCl₃)δ値：1.30-1.45(2H,m),1.54(2H,s),1.75-1.87(2H,m),2.11-2.24(2H,m),2.60-2.76(3H,m),2.86-2.99(2H,m),4.25-4.39(2H,m),6.86(1H,d,J=9.6Hz),7.48-7.60(1H,m),7.89(1H,d,J=9.6Hz),8.36-8.49(1H,m) Reference Example 215

tert-butyl = (1- (2- (7-fluoro-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate 0.59 g of 2 mol / L hydrogen chloride / A 30 mL solution of ethanol was stirred at room temperature for 18 hours. Chloroform 2mL was added to the reaction mixture, and it stirred at 40 degreeC for 4 hours, and stirred at room temperature for 18 hours. The reaction mixture was evaporated under reduced pressure, neutralized with saturated aqueous sodium hydrogen carbonate solution, and the solvent was evaporated under reduced pressure. The obtained residue was washed with ethanol, the mother liquor was evaporated under reduced pressure, and silica gel column chromatography [silica gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent: chloroform: methanol = 10: 1]. Purification gave 421 mg of 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ value: 1.30-1.45 (2H, m), 1.54 (2H, s), 1.75-1.87 (2H, m), 2.11-2.24 (2H, m), 2.60-2.76 (3H , m), 2.86-2.99 (2H, m), 4.25-4.39 (2H, m), 6.86 (1H, d, J = 9.6Hz), 7.48-7.60 (1H, m), 7.89 (1H, d, J = 9.6Hz), 8.36-8.49 (1H, m)

３−ブロモ−１，５−ナフチリジン1.00gの１，４−ジオキサン5mL溶液にｔｅｒｔ−ブチルカルバマート0.67g、炭酸セシウム2.18g、トリス（ベンジリデンアセトン）ジパラジウム44mgおよび４，５−ビス（ジフェニルホスフィノ）−９，９−ジメチルキサンテン83mgを加え、アルゴン雰囲気下、80℃で12.5時間攪拌した。反応混合物に水およびクロロホルムを加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［シリカゲル；関東化学株式会社、シリカゲル６０Ｎ、溶離液；クロロホルム：メタノール＝１０：１］で精製し、黄色油状物のｔｅｒｔ−ブチル＝１，５−ナフチリジン−３−イルカルバマート1.03gを得た。
¹H-NMR(DMSO-d₆)δ値：1.53(9H,s),7.60-7.65(1H,m),8.32(1H,d,J=4.1Hz),8.52(1H,s),8.90-8.93(1H,m),8.97-9.00(1H,m),10.08(1H,s) Reference Example 216

To a solution of 1.00 g of 3-bromo-1,5-naphthyridine in 5 mL of 1,4-dioxane, 0.67 g of tert-butyl carbamate, 2.18 g of cesium carbonate, 44 mg of tris (benzylideneacetone) dipalladium and 4,5-bis (diphenylphosphine) Fino) -9,9-dimethylxanthene (83 mg) was added, and the mixture was stirred at 80 ° C. for 12.5 hours under an argon atmosphere. Water and chloroform were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60N, eluent: chloroform: methanol = 10: 1], and tert-butyl = 1,5-naphthyridine as a yellow oily substance. 1.03 g of 3-ylcarbamate was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.53 (9H, s), 7.60-7.65 (1H, m), 8.32 (1H, d, J = 4.1 Hz), 8.52 (1H, s), 8.90- 8.93 (1H, m), 8.97-9.00 (1H, m), 10.08 (1H, s)

ｔｅｒｔ−ブチル＝１，５−ナフチリジン−３−イルカルバマート1.00gのメタノール6mL溶液に12mol/L塩化水素水溶液1mLを加え、30分間攪拌した。反応混合物にメタノール5mLおよび12mol/L塩化水素水溶液1mLを加え、40℃で40分間、80℃で40分間攪拌した。反応混合物を減圧下で溶媒留去し、飽和炭酸水素ナトリウム水溶液で中和した後、減圧下で溶媒を留去した。得られた残留物をエタノールで洗浄し、母液を減圧下で溶媒留去した後、シリカゲルカラムクロマトグラフィー［シリカゲル；富士シリシア化学株式会社、Chromatorex-NH、溶離液；クロロホルム：メタノール＝１０：１］で精製し、黄色固体の１，５−ナフチリジン−３−アミン0.50gを得た。
¹H-NMR(CDCl₃)δ値：4.18(2H,s),7.31-7.42(1H,m),7.43-7.50(1H,m),8.21-8.30(1H,m),8.51-8.62(1H,m),8.77-8.88(1H,m) Reference Example 217

To a solution of tert-butyl = 1,5-naphthyridin-3-ylcarbamate 1.00 g in 6 mL of methanol was added 1 mL of a 12 mol / L aqueous solution of hydrogen chloride, and the mixture was stirred for 30 minutes. To the reaction mixture, 5 mL of methanol and 1 mL of 12 mol / L aqueous hydrogen chloride were added, and the mixture was stirred at 40 ° C. for 40 minutes and at 80 ° C. for 40 minutes. The reaction mixture was evaporated under reduced pressure, neutralized with saturated aqueous sodium hydrogen carbonate solution, and the solvent was evaporated under reduced pressure. The obtained residue was washed with ethanol, and the mother liquor was evaporated under reduced pressure, followed by silica gel column chromatography [silica gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent: chloroform: methanol = 10: 1] To obtain 0.50 g of 1,5-naphthyridin-3-amine as a yellow solid.
¹ H-NMR (CDCl ₃ ) δ value: 4.18 (2H, s), 7.31-7.42 (1H, m), 7.43-7.50 (1H, m), 8.21-8.30 (1H, m), 8.51-8.62 (1H , m), 8.77-8.88 (1H, m)

１，５−ナフチリジン−３−アミン145mgを0℃でフッ化水素／ピリジン2mLに加え、反応混合物に亜硝酸ナトリウム76mgを加え0℃で1時間攪拌した。反応混合物を60℃で1時間攪拌し、0℃で飽和炭酸水素ナトリウム水溶液で中和した後、クロロホルムを加えて有機層を分取した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、シリカゲルカラムクロマトグラフィー［シリカゲル；関東化学株式会社、シリカゲル６０Ｎ、溶離液；クロロホルム：メタノール＝２０：１］で精製し、淡黄色固体の３−フルオロ−１，５−ナフチリジン77mgを得た。
¹H-NMR(CDCl₃)δ値：7.62-7.67(1H,m),8.03-8.08(1H,m),8.42-8.47(1H,m),8.90-8.94(1H,m),8.98-9.03(1H,m) Reference Example 218

145 mg of 1,5-naphthyridin-3-amine was added to 2 mL of hydrogen fluoride / pyridine at 0 ° C., 76 mg of sodium nitrite was added to the reaction mixture, and the mixture was stirred at 0 ° C. for 1 hour. The reaction mixture was stirred at 60 ° C. for 1 hour, neutralized with saturated aqueous sodium hydrogen carbonate solution at 0 ° C., chloroform was added, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60N, eluent; chloroform: methanol = 20 1] to obtain 77 mg of 3-fluoro-1,5-naphthyridine as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ value: 7.62-7.67 (1H, m), 8.03-8.08 (1H, m), 8.42-8.47 (1H, m), 8.90-8.94 (1H, m), 8.98-9.03 (1H, m)

３−フルオロ−１，５−ナフチリジン76mgのクロロホルム3mL溶液にｍ−クロロ過安息香酸136mgを加え、室温で2.5時間攪拌した。ｍ−クロロ過安息香酸27mgを加え、室温で1時間攪拌した。反応混合物に5％チオ硫酸ナトリウム水溶液、クロロホルムを加え、有機層を分取し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［シリカゲル；関東化学株式会社、シリカゲル６０Ｎ、溶離液；クロロホルム：メタノール＝５０：１］で精製し、淡黄色固体の７−フルオロ−１，５−ナフチリジン＝１−オキシド60mgを得た。
¹H-NMR(CDCl₃)δ値：7.53(1H,dd,J=8.7,6.0Hz),8.04(1H,d,J=8.7Hz),8.59(1H,d,J=6.0Hz),8.66-8.77(1H,m),8.91-9.02(1H,m) Reference Example 219

To a solution of 3-fluoro-1,5-naphthyridine (76 mg) in chloroform (3 mL) was added m-chloroperbenzoic acid (136 mg), and the mixture was stirred at room temperature for 2.5 hours. 27 mg of m-chloroperbenzoic acid was added and stirred at room temperature for 1 hour. A 5% aqueous sodium thiosulfate solution and chloroform were added to the reaction mixture, the organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60N, eluent: chloroform: methanol = 50: 1], and 7-fluoro-1,5-naphthyridine = pale yellow solid = 60 mg of 1-oxide was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 7.53 (1H, dd, J = 8.7,6.0 Hz), 8.04 (1H, d, J = 8.7 Hz), 8.59 (1H, d, J = 6.0 Hz), 8.66 -8.77 (1H, m), 8.91-9.02 (1H, m)

７−フルオロ−１，５−ナフチリジン＝１−オキシド60mgのクロロホルム1.6mL溶液に、ｐ−トルエンスルホニルクロリド84mg、炭酸カリウム171mgおよび水0.5mLを加え、室温で一晩攪拌した。固形物を濾取し、シリカゲルカラムクロマトグラフィー［シリカゲル；富士シリシア化学株式会社、Chromatorex-NH、溶離液；クロロホルム：メタノール＝１０：１］で精製し、白色固体の７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン14mgを得た。
¹H-NMR(CDCl₃)δ値：6.71(1H,d,J=10.1Hz),7.29-7.57(1H,m),7.94(1H,d,J=10.1Hz),8.50(1H,d,J=2.3Hz),12.00(1H,s) Reference Example 220

To a 1.6 mL chloroform solution of 7-fluoro-1,5-naphthyridine = 1-oxide 60 mg, 84 mg p-toluenesulfonyl chloride, 171 mg potassium carbonate and 0.5 mL water were added and stirred overnight at room temperature. The solid was collected by filtration and purified by silica gel column chromatography [silica gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent: chloroform: methanol = 10: 1], and white solid 7-fluoro-1,5- 14 mg of naphthyridine-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 6.71 (1H, d, J = 10.1 Hz), 7.29-7.57 (1H, m), 7.94 (1H, d, J = 10.1 Hz), 8.50 (1H, d, J = 2.3Hz), 12.00 (1H, s)

７−ブロモ−１−（１，３−ジオキソラン−２−イルメチル）−１，５−ナフチリジン−２（１Ｈ）−オン20.02gに80％トリフルオロ酢酸水溶液400mLを加え、90℃で3.5時間攪拌した。反応混合物を室温まで冷却した後、減圧下で溶媒を留去した。得られた残留物に2mol/L水酸化ナトリウム水溶液でpH7.7に調整した。次いで析出物を濾取し、褐色固体の（７−ブロモ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド13.43gを得た。
¹H-NMR(CDCl₃)δ値：5.13(2H,s),6.98(1H,d,J=9.6Hz),7.49(1H,d,J=1.4Hz),7.95(1H,d,J=9.6Hz),8.60(1H,d,J=1.4Hz),9.78(1H,s) Reference Example 221

To 20.02 g of 7-bromo-1- (1,3-dioxolan-2-ylmethyl) -1,5-naphthyridin-2 (1H) -one was added 400 mL of an 80% aqueous trifluoroacetic acid solution, and the mixture was stirred at 90 ° C. for 3.5 hours. . After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was adjusted to pH 7.7 with 2 mol / L sodium hydroxide aqueous solution. Next, the precipitate was collected by filtration to obtain 13.43 g of (7-bromo-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde as a brown solid.
¹ H-NMR (CDCl ₃ ) δ value: 5.13 (2H, s), 6.98 (1H, d, J = 9.6 Hz), 7.49 (1H, d, J = 1.4 Hz), 7.95 (1H, d, J = 9.6Hz), 8.60 (1H, d, J = 1.4Hz), 9.78 (1H, s)

（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド0.11gにｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（ピペリジン−４−イル）カルバマート0.15gのジクロロメタン4mL溶液、酢酸24μLおよび水素化トリアセトキシホウ素ナトリウム0.13gを加え、室温で1時間攪拌した。反応混合物にクロロホルムおよび飽和炭酸水素ナトリウム水溶液を加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をフラッシュ塩基性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＝１００：０−２０：８０、次いでクロロホルム：メタノールの勾配溶離＝１００：０−９０：１０］で精製し、淡黄色泡状物のｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.18gを得た。
¹H-NMR(CDCl₃)δ値：1.39(9H,s),1.40-1.72(4H,m),2.06-2.25(2H,m),2.57-2.64(2H,m),2.96-3.05(2H,m),3.96(3H,s),4.05-4.18(1H,m),4.23-4.50(8H,m),6.73(1H,d,J=9.8Hz),6.73(1H,s),7.17(1H,d,J=2.3Hz),7.83(1H,d,J=9.8Hz),8.05(1H,s),8.27(1H,d,J=2.3Hz) Example 1

(7-Methoxy-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde (0.11 g) and tert-butyl = (2,3-dihydro (1,4) dioxino (2,3-c) pyridine A solution of 0.15 g of -7-ylmethyl) (piperidin-4-yl) carbamate in 4 mL of dichloromethane, 24 μL of acetic acid and 0.13 g of sodium triacetoxyborohydride were added and stirred at room temperature for 1 hour. Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by flash basic silica gel column chromatography [hexane: ethyl acetate gradient elution = 100: 0-20: 80, then chloroform: methanol gradient elution = 100: 0-90: 10] Pale yellow foam tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (1- (2- (7-methoxy-2-oxo- 0.18 g of 1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.39 (9H, s), 1.40-1.72 (4H, m), 2.06-2.25 (2H, m), 2.57-2.64 (2H, m), 2.96-3.05 (2H , m), 3.96 (3H, s), 4.05-4.18 (1H, m), 4.23-4.50 (8H, m), 6.73 (1H, d, J = 9.8Hz), 6.73 (1H, s), 7.17 ( 1H, d, J = 2.3Hz), 7.83 (1H, d, J = 9.8Hz), 8.05 (1H, s), 8.27 (1H, d, J = 2.3Hz)

ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.17gの酢酸エチル3mL溶液に室温で4.0mol/L塩化水素／酢酸エチル溶液6.0mLを加えた。同温度で1時間攪拌し、減圧下で溶媒を留去した。得られた残留物にジエチルエーテルを加え、固形物を濾取し、淡黄色固体の１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.16gを得た。
¹H-NMR(D₂O)δ値：1.98-2.13(2H,m),2.50-2.60(2H,m),3.21-3.34(2H,m),3.60-3.77(3H,m),3.95-4.08(2H,m),4.05(3H,s),4.42-4.49(4H,m),4.53-4.59(2H,m),4.72-4.87(2H,m),6.89(1H,d,J=9.6Hz),7.37(1H,s),7.48-7.53(1H,m),8.06(1H,d,J=9.6Hz),8.31(1H,s),8.40-8.44(1H,m) Example 2

tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (1- (2- (7-methoxy-2-oxo-1,5-naphthyridine- 1 (2H) -yl) ethyl) piperidin-4-yl) carbamate (0.17 g) in ethyl acetate (3 mL) was added at room temperature with 4.0 mol / L hydrogen chloride / ethyl acetate solution (6.0 mL). The mixture was stirred at the same temperature for 1 hour, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the obtained residue, and the solid was collected by filtration to give 1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-c)) as a pale yellow solid. 0.16 g of pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.98-2.13 (2H, m), 2.50-2.60 (2H, m), 3.21-3.34 (2H, m), 3.60-3.77 (3H, m), 3.95 4.08 (2H, m), 4.05 (3H, s), 4.42-4.49 (4H, m), 4.53-4.59 (2H, m), 4.72-4.87 (2H, m), 6.89 (1H, d, J = 9.6 Hz), 7.37 (1H, s), 7.48-7.53 (1H, m), 8.06 (1H, d, J = 9.6Hz), 8.31 (1H, s), 8.40-8.44 (1H, m)

（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド0.11gに、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（ピペリジン−４−イル）カルバマート0.19gのジクロロメタン3mL溶液に酢酸31μLおよび水素化トリアセトキシホウ素ナトリウム0.17gを加え、室温で1時間攪拌した後、一晩放置した。クロロホルムおよび飽和炭酸水素ナトリウム水溶液を加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝１９：１］で精製し、白色泡状物のｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.21gを得た。
¹H-NMR(CDCl₃)δ値：1.39(9H,s),1.33-1.71(4H,m),2.08-2.24(2H,m),2.57-2.63(2H,m),2.94-3.01(2H,m),4.02-4.18(1H,m),4.23-4.46(8H,m),6.73(1H,s),6.84(1H,d,J=9.8Hz),7.47(1H,dd,J=10.1,2.4Hz),7.87(1H,d,J=9.8Hz),8.05(1H,s),8.41(1H,d,J=2.4Hz) Example 3

To 0.11 g of (7-fluoro-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde, tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) To a solution of 0.19 g of pyridin-7-ylmethyl) (piperidin-4-yl) carbamate in 3 mL of dichloromethane were added 31 μL of acetic acid and 0.17 g of sodium triacetoxyborohydride, and the mixture was stirred at room temperature for 1 hour and allowed to stand overnight. Chloroform and saturated aqueous sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography [eluent: chloroform: methanol = 19: 1], and white foam tert-butyl = (2,3-dihydro (1,4) dioxino ( 2,3-c) pyridin-7-ylmethyl) (1- (2- (7-fluoro-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate 0.21 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.39 (9H, s), 1.33-1.71 (4H, m), 2.08-2.24 (2H, m), 2.57-2.63 (2H, m), 2.94-3.01 (2H , m), 4.02-4.18 (1H, m), 4.23-4.46 (8H, m), 6.73 (1H, s), 6.84 (1H, d, J = 9.8Hz), 7.47 (1H, dd, J = 10.1 , 2.4Hz), 7.87 (1H, d, J = 9.8Hz), 8.05 (1H, s), 8.41 (1H, d, J = 2.4Hz)

ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.21gのエタノール4mL溶液に室温で6.0mol/L塩化水素／エタノール溶液4mLを加え、1時間30分間攪拌した。減圧下で溶媒を留去し、得られた残留物にジエチルエーテルを加え、固形物を濾取し、微黄色固体の１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.21gを得た。
¹H-NMR(D₂O)δ値：2.00-2.16(2H,m),2.52-2.61(2H,m),3.23-3.35(2H,m),3.61-3.67(2H,m),3.69-3.80(1H,m),3.98-4.07(2H,m),4.46-4.51(2H,m),4.53(2H,s),4.58-4.63(2H,m),4.71-4.96(2H,m),7.00(1H,d,J=9.8Hz),7.47(1H,s),7.93-7.99(1H,m),8.10(1H,d,J=9.8Hz),8.37(1H,s),8.56-8.58(1H,m) Example 4

tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (1- (2- (7-fluoro-2-oxo-1,5-naphthyridine- To a solution of 1 (2H) -yl) ethyl) piperidin-4-yl) carbamate 0.21 g in ethanol 4 mL was added 6.0 mL / L hydrogen chloride / ethanol solution 4 mL at room temperature, and the mixture was stirred for 1 hour 30 minutes. The solvent was distilled off under reduced pressure, diethyl ether was added to the obtained residue, the solid was collected by filtration, and 1- (2- (4-((2,3-dihydro (1,4 0.21 g of dioxino (2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 2.00-2.16 (2H, m), 2.52-2.61 (2H, m), 3.23-3.35 (2H, m), 3.61-3.67 (2H, m), 3.69- 3.80 (1H, m), 3.98-4.07 (2H, m), 4.46-4.51 (2H, m), 4.53 (2H, s), 4.58-4.63 (2H, m), 4.71-4.96 (2H, m), 7.00 (1H, d, J = 9.8Hz), 7.47 (1H, s), 7.93-7.99 (1H, m), 8.10 (1H, d, J = 9.8Hz), 8.37 (1H, s), 8.56-8.58 (1H, m)

ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.30gのイソプロピルアルコール1.8mL懸濁液に濃塩酸0.23mLを加え、加熱還流下、１時間50分間攪拌した。反応混合物を5℃まで冷却し、固形物を濾取し、微黄色固体の１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン三塩酸塩0.28gを得た。
¹H-NMR(D₂O)δ値：2.00-2.16(2H,m),2.52-2.61(2H,m),3.23-3.35(2H,m),3.61-3.67(2H,m),3.69-3.80(1H,m),3.98-4.07(2H,m),4.46-4.51(2H,m),4.52(2H,s),4.55-4.63(2H,m),4.71-4.96(2H,m),6.99(1H,d,J=9.8Hz),7.44(1H,s),7.93-7.99(1H,m),8.10(1H,d,J=9.8Hz),8.36(1H,s),8.57(1H,d,J=2.2Hz) Example 4 (2)

tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (1- (2- (7-fluoro-2-oxo-1,5-naphthyridine- Concentrated hydrochloric acid (0.23 mL) was added to a suspension of 1 (2H) -yl) ethyl) piperidin-4-yl) carbamate (0.30 g) in isopropyl alcohol (1.8 mL), and the mixture was stirred with heating under reflux for 1 hour and 50 minutes. The reaction mixture was cooled to 5 ° C., and the solid was collected by filtration to give 1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-c) pyridine- 0.28 g of 7-ylmethyl) amino) piperidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one trihydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 2.00-2.16 (2H, m), 2.52-2.61 (2H, m), 3.23-3.35 (2H, m), 3.61-3.67 (2H, m), 3.69- 3.80 (1H, m), 3.98-4.07 (2H, m), 4.46-4.51 (2H, m), 4.52 (2H, s), 4.55-4.63 (2H, m), 4.71-4.96 (2H, m), 6.99 (1H, d, J = 9.8Hz), 7.44 (1H, s), 7.93-7.99 (1H, m), 8.10 (1H, d, J = 9.8Hz), 8.36 (1H, s), 8.57 (1H , d, J = 2.2Hz)

実施例１と同様の手法により、（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒドおよびｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（２−メチルピペリジン−４−イル）カルバマート酢酸塩からｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）−２−メチルピペリジン−４−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：0.99-1.10(3H,m),1.33-1.83(13H,m),2.57-2.78(4H,m),3.14-3.23(1H,m),3.96(3H,s),4.13-4.53(9H,m),6.73(1H,s),6.73(1H,d,J=9.6Hz),7.19(1H,d,J=2.2Hz),7.83(1H,d,J=9.6Hz),8.05(1H,s),8.27(1H,d,J=2.2Hz) Example 5

In the same manner as in Example 1, (7-methoxy-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde and tert-butyl = (2,3-dihydro (1,4) dioxino ( 2,3-c) pyridin-7-ylmethyl) (2-methylpiperidin-4-yl) carbamate acetate to tert-butyl = (2,3-dihydro (1,4) dioxino (2,3-c) pyridine -7-ylmethyl) (1- (2- (7-methoxy-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) -2-methylpiperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 0.99-1.10 (3H, m), 1.33-1.83 (13H, m), 2.57-2.78 (4H, m), 3.14-3.23 (1H, m), 3.96 (3H , s), 4.13-4.53 (9H, m), 6.73 (1H, s), 6.73 (1H, d, J = 9.6Hz), 7.19 (1H, d, J = 2.2Hz), 7.83 (1H, d, J = 9.6Hz), 8.05 (1H, s), 8.27 (1H, d, J = 2.2Hz)

実施例２と同様の手法により、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）−２−メチルピペリジン−４−イル）カルバマートから１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）−２−メチルピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.03(3H,d,J=6.6Hz),1.20-1.90(4H,m),2.66-2.88(5H,m),2.95-3.05(1H,m),3.77(2H,d,J=2.7Hz),3.97(3H,s),4.25-4.43(6H,m),6.74(1H,d,J=9.6Hz),6.82(1H,s),7.20-7.25(1H,m),7.84(1H,d,J=9.6Hz),8.10(1H,s),8.27(1H,d,J=2.4Hz)
１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）−２−メチルピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン53mgの酢酸エチル1mL溶液に室温で4mol/L塩化水素／酢酸エチル溶液0.23mLを加え、攪拌後、固形物を濾取し、淡黄色固体の１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）−２−メチルピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩40mgを得た。
¹H-NMR(DMSO-d₆-D₂O)δ値：1.03(3H,d,J=6.6Hz),2.00-2.35(4H,m),3.12-3.60(5H,m),3.90-4.30(3H,m),4.07(3H,s),4.33-4.45(4H,m),4.58-4.86(2H,m),6.72(1H,d,J=9.5Hz),7.22(1H,s),7.66-7.75(1H,m),7.96(1H,d,J=9.5Hz),8.26(1H,s),8.34(1H,d,J=1.9Hz) Example 6

In the same manner as in Example 2, tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (1- (2- (7-methoxy-2 1- (2- (4-((2,3-dihydro (1,4)) from -oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) -2-methylpiperidin-4-yl) carbamate Dioxino (2,3-c) pyridin-7-ylmethyl) amino) -2-methylpiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.03 (3H, d, J = 6.6 Hz), 1.20-1.90 (4H, m), 2.66-2.88 (5H, m), 2.95-3.05 (1H, m), 3.77 (2H, d, J = 2.7Hz), 3.97 (3H, s), 4.25-4.43 (6H, m), 6.74 (1H, d, J = 9.6Hz), 6.82 (1H, s), 7.20-7.25 (1H, m), 7.84 (1H, d, J = 9.6Hz), 8.10 (1H, s), 8.27 (1H, d, J = 2.4Hz)
1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) -2-methylpiperidin-1-yl) ethyl) -7 To a solution of 53 mg of -methoxy-1,5-naphthyridin-2 (1H) -one in 1 mL of ethyl acetate was added 0.23 mL of a 4 mol / L hydrogen chloride / ethyl acetate solution at room temperature. After stirring, the solid was collected by filtration to give a pale yellow Solid 1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) -2-methylpiperidin-1-yl) ethyl) 40 mg of -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ -D ₂ O) δ value: 1.03 (3H, d, J = 6.6 Hz), 2.00-2.35 (4H, m), 3.12-3.60 (5H, m), 3.90-4.30 (3H, m), 4.07 (3H, s), 4.33-4.45 (4H, m), 4.58-4.86 (2H, m), 6.72 (1H, d, J = 9.5Hz), 7.22 (1H, s), 7.66-7.75 (1H, m), 7.96 (1H, d, J = 9.5Hz), 8.26 (1H, s), 8.34 (1H, d, J = 1.9Hz)

１−（２−（４−アミノピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オン塩酸塩0.20gのメタノール3mL懸濁液に室温で水素化シアノホウ素ナトリウム66mg、３−フルオロ−４−メチルベンズアルデヒド64μLおよび酢酸0.12mLを加え、同温度で1時間30分間攪拌した。３−フルオロ−４−メチルベンズアルデヒド64μLを加え、同温度で1時間30分間攪拌した。さらに水素化シアノホウ素ナトリウム33mg、３−フルオロ−４−メチルベンズアルデヒド64μLを加え、同温度で3時間攪拌した後、一晩放置した。クロロホルムを加え、飽和炭酸水素ナトリウム水溶液および1mol/L水酸化ナトリウム水溶液でpH9.9に調整した。有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝１０：１］で精製し、微黄色油状物の１−（２−（４−（（３−フルオロ−４−メチルベンジル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オン0.16gを得た。
¹H-NMR(CDCl₃)δ値：1.37-1.49(2H,m),1.87-1.95(2H,m),2.17-2.25(2H,m),2.26(3H,d,J=1.7Hz),2.48-2.57(1H,m),2.68-2.74(2H,m),2.97-3.04(2H,m),3.78(2H,s),4.45-4.51(2H,m),6.90(1H,d,J=9.5Hz),6.97-7.02(2H,m),7.10-7.15(1H,m),7.43(1H,d,J=5.1Hz),7.66(1H,d,J=9.5Hz),8.46(1H,d,J=5.1Hz),8.92(1H,s) Example 7

1- (2- (4-aminopiperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one hydrochloride 0.20 g in methanol 3 mL suspension at room temperature 66 mg sodium cyanoborohydride, 3-Fluoro-4-methylbenzaldehyde (64 μL) and acetic acid (0.12 mL) were added, and the mixture was stirred at the same temperature for 1 hour and 30 minutes. 3-Fluoro-4-methylbenzaldehyde (64 μL) was added, and the mixture was stirred at the same temperature for 1 hour and 30 minutes. Further, 33 mg of sodium cyanoborohydride and 64 μL of 3-fluoro-4-methylbenzaldehyde were added, and the mixture was stirred at the same temperature for 3 hours and then left overnight. Chloroform was added, and the pH was adjusted to 9.9 with a saturated aqueous sodium hydrogen carbonate solution and a 1 mol / L aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography [eluent: chloroform: methanol = 10: 1] to give 1- (2- (4-((3-fluoro-4-methyl) as a pale yellow oil. 0.16 g of benzyl) amino) piperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.37-1.49 (2H, m), 1.87-1.95 (2H, m), 2.17-2.25 (2H, m), 2.26 (3H, d, J = 1.7Hz), 2.48-2.57 (1H, m), 2.68-2.74 (2H, m), 2.97-3.04 (2H, m), 3.78 (2H, s), 4.45-4.51 (2H, m), 6.90 (1H, d, J = 9.5Hz), 6.97-7.02 (2H, m), 7.10-7.15 (1H, m), 7.43 (1H, d, J = 5.1Hz), 7.66 (1H, d, J = 9.5Hz), 8.46 (1H , d, J = 5.1Hz), 8.92 (1H, s)

１−（２−（４−（（３−フルオロ−４−メチルベンジル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オン0.16gの酢酸エチル3mL溶液に室温で4.0mol/L塩化水素／酢酸エチル溶液5mLを加えた。酢酸エチル2mLを加え、同温度で10分間攪拌し、減圧下で溶媒を留去した。得られた残留物に酢酸エチルを加え、固形物を濾取し、淡黄色固体の１−（２−（４−（（３−フルオロ−４−メチルベンジル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オン塩酸塩0.18gを得た。
¹H-NMR(D₂O)δ値：1.98-2.11(2H,m),2.28(3H,d,J=1.5Hz),2.50-2.58(2H,m),3.22-3.33(2H,m),3.60-3.70(3H,m),3.97-4.05(2H,m),4.30(2H,s),4.81-4.87(2H,m),7.17-7.22(2H,m),7.20(1H,d,J=9.5Hz),7.36(1H,t,J=7.7Hz),8.17(1H,d,J=5.9Hz),8.17(1H,d,J=9.5Hz),8.61(1H,d,J=5.9Hz),9.12(1H,s) Example 8

1- (2- (4-((3-Fluoro-4-methylbenzyl) amino) piperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one in a solution of 0.16 g of ethyl acetate in 3 mL of ethyl acetate At room temperature, 5 mL of 4.0 mol / L hydrogen chloride / ethyl acetate solution was added. 2 mL of ethyl acetate was added, stirred at the same temperature for 10 minutes, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the solid was collected by filtration to give 1- (2- (4-((3-fluoro-4-methylbenzyl) amino) piperidin-1-yl) ethyl as a pale yellow solid. ) -1,7-naphthyridin-2 (1H) -one hydrochloride 0.18 g was obtained.
¹ H-NMR (D ₂ O) δ value: 1.98-2.11 (2H, m), 2.28 (3H, d, J = 1.5Hz), 2.50-2.58 (2H, m), 3.22-3.33 (2H, m) , 3.60-3.70 (3H, m), 3.97-4.05 (2H, m), 4.30 (2H, s), 4.81-4.87 (2H, m), 7.17-7.22 (2H, m), 7.20 (1H, d, J = 9.5Hz), 7.36 (1H, t, J = 7.7Hz), 8.17 (1H, d, J = 5.9Hz), 8.17 (1H, d, J = 9.5Hz), 8.61 (1H, d, J = 5.9Hz), 9.12 (1H, s)

ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（ピペリジン−４−イル）カルバマート0.16gのジクロロメタン3mL溶液に（６−メトキシ−３−オキソピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）アセトアルデヒド0.10g、酢酸26μLおよび水素化トリアセトキシホウ素ナトリウム0.15gを加え、室温で30分間攪拌した。反応混合物にクロロホルムおよび飽和炭酸水素ナトリウム水溶液を加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をフラッシュ塩基性シリカゲルカラムクロマトグラフィー［溶離液；クロロホルム］で精製し、淡褐色油状物のｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（６−メトキシ−３−オキソピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.15gを得た。
¹H-NMR(CDCl₃)δ値：1.38(9H,s),1.40-1.70(4H,m),2.03-2.23(2H,m),2.66-2.73(2H,m),3.02-3.10(2H,m),4.00(3H,s),4.03-4.20(1H,m),4.23-4.46(6H,m),4.48-4.55(2H,m),6.71(1H,s),6.72(1H,d,J=8.5Hz),8.01(1H,d,J=8.5Hz),8.04(1H,s),8.14(1H,s) Example 9

tert-Butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (piperidin-4-yl) carbamate 0.16 g of (6-methoxy-3 -Oxopyrido (2,3-b) pyrazin-4 (3H) -yl) acetaldehyde (0.10 g), acetic acid (26 μL) and sodium triacetoxyborohydride (0.15 g) were added, and the mixture was stirred at room temperature for 30 minutes. Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash basic silica gel column chromatography [eluent: chloroform], and tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c ) Pyridin-7-ylmethyl) (1- (2- (6-methoxy-3-oxopyrido (2,3-b) pyrazin-4 (3H) -yl) ethyl) piperidin-4-yl) carbamate 0.15 g is obtained. It was.
¹ H-NMR (CDCl ₃ ) δ value: 1.38 (9H, s), 1.40-1.70 (4H, m), 2.03-2.23 (2H, m), 2.66-2.73 (2H, m), 3.02-3.10 (2H , m), 4.00 (3H, s), 4.03-4.20 (1H, m), 4.23-4.46 (6H, m), 4.48-4.55 (2H, m), 6.71 (1H, s), 6.72 (1H, d , J = 8.5Hz), 8.01 (1H, d, J = 8.5Hz), 8.04 (1H, s), 8.14 (1H, s)

ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（６−メトキシ−３−オキソピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.14gのエタノール3.0mL溶液に室温で、6.0mol/L塩化水素／エタノール溶液3mLを加えた。同温度で3時間攪拌し、減圧下で溶媒を留去した。得られた残留物にジエチルエーテルを加え、固形物を濾取し、淡褐色固体の４−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−６−メトキシピリド（２，３−ｂ）ピラジン−３（４Ｈ）−オン塩酸塩0.11gを得た。
¹H-NMR(D₂O)δ値：1.97-2.12(2H,m),2.49-2.58(2H,m),3.20-3.34(2H,m),3.66-3.78(3H,m),3.97-4.08(2H,m),4.07(3H,s),4.44-4.49(2H,m),4.49(2H,s),4.55-4.60(2H,m),4.88-4.94(2H,m),6.98(1H,d,J=8.9Hz),7.41(1H,s),8.18(1H,d,J=8.9Hz),8.19(1H,s),8.34(1H,s) Example 10

tert-Butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (1- (2- (6-methoxy-3-oxopyrido (2,3-b) Pyrazin-4 (3H) -yl) ethyl) piperidin-4-yl) carbamate 0.14 g in ethanol 3.0 mL was added at room temperature with 3 mL of 6.0 mol / L hydrogen chloride / ethanol solution. The mixture was stirred at the same temperature for 3 hours, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the obtained residue, and the solid was collected by filtration to give 4- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-c)) as a light brown solid. 0.11 g of pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -6-methoxypyrido (2,3-b) pyrazin-3 (4H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.97-2.12 (2H, m), 2.49-2.58 (2H, m), 3.20-3.34 (2H, m), 3.66-3.78 (3H, m), 3.97- 4.08 (2H, m), 4.07 (3H, s), 4.44-4.49 (2H, m), 4.49 (2H, s), 4.55-4.60 (2H, m), 4.88-4.94 (2H, m), 6.98 ( 1H, d, J = 8.9Hz), 7.41 (1H, s), 8.18 (1H, d, J = 8.9Hz), 8.19 (1H, s), 8.34 (1H, s)

実施例７と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オン塩酸塩および４−エチルベンズアルデヒドから１−（２−（４−（（４−エチルベンジル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.23(3H,t,J=7.6Hz),1.37-1.49(2H,m),1.87-1.95(2H,m),2.16-2.24(2H,m),2.49-2.58(1H,m),2.63(2H,q,J=7.6Hz),2.67-2.73(2H,m),2.96-3.03(2H,m),3.78(2H,s),4.44-4.50(2H,m),6.89(1H,d,J=9.5Hz),7.15(2H,d,J=8.0Hz),7.23(2H,d,J=8.0Hz),7.41(1H,d,J=5.1Hz),7.65(1H,d,J=9.5Hz),8.44(1H,d,J=5.1Hz),8.91(1H,s) Example 11

In the same manner as in Example 7, 1- (2- (4-aminopiperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one hydrochloride and 4-ethylbenzaldehyde gave 1- ( 2- (4-((4-Ethylbenzyl) amino) piperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.23 (3H, t, J = 7.6 Hz), 1.37-1.49 (2H, m), 1.87-1.95 (2H, m), 2.16-2.24 (2H, m), 2.49-2.58 (1H, m), 2.63 (2H, q, J = 7.6Hz), 2.67-2.73 (2H, m), 2.96-3.03 (2H, m), 3.78 (2H, s), 4.44-4.50 ( 2H, m), 6.89 (1H, d, J = 9.5Hz), 7.15 (2H, d, J = 8.0Hz), 7.23 (2H, d, J = 8.0Hz), 7.41 (1H, d, J = 5.1 Hz), 7.65 (1H, d, J = 9.5Hz), 8.44 (1H, d, J = 5.1Hz), 8.91 (1H, s)

実施例８と同様の手法により、１−（２−（４−（（４−エチルベンジル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オンから１−（２−（４−（（４−エチルベンジル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：1.21(3H,t,J=7.7Hz),1.99-2.12(2H,m),2.50-2.59(2H,m),2.68(2H,q,J=7.7Hz),3.22-3.33(2H,m),3.58-3.71(3H,m),3.97-4.06(2H,m),4.30(2H,s),4.81-4.87(2H,m),7.24(1H,d,J=9.8Hz),7.38(2H,d,J=8.2Hz),7.42(2H,d,J=8.2Hz),8.19(1H,d,J=9.8Hz),8.24(1H,d,J=5.9Hz),8.63(1H,d,J=5.9Hz),9.16(1H,s) Example 12

In the same manner as in Example 8, from 1- (2- (4-((4-ethylbenzyl) amino) piperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one to 1- (2- (4-((4-Ethylbenzyl) amino) piperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.21 (3H, t, J = 7.7 Hz), 1.99-2.12 (2H, m), 2.50-2.59 (2H, m), 2.68 (2H, q, J = 7.7Hz), 3.22-3.33 (2H, m), 3.58-3.71 (3H, m), 3.97-4.06 (2H, m), 4.30 (2H, s), 4.81-4.87 (2H, m), 7.24 (1H , d, J = 9.8Hz), 7.38 (2H, d, J = 8.2Hz), 7.42 (2H, d, J = 8.2Hz), 8.19 (1H, d, J = 9.8Hz), 8.24 (1H, d , J = 5.9Hz), 8.63 (1H, d, J = 5.9Hz), 9.16 (1H, s)

（２−オキソ−１，８−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド0.75gのジクロロメタン溶液40mLにｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（ピペリジン−４−イル）カルバマート1.4g、酢酸0.23mLおよび水素化トリアセトキシホウ素ナトリウム1.3gを加え、室温で2時間攪拌した。水、飽和炭酸水素ナトリウム水溶液およびクロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［溶離液；クロロホルム：メタノール＝２００：３］で精製し、白色泡状物のｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（１−（２−（２−オキソ−１，８−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート1.4gを得た。
¹H-NMR(CDCl₃)δ値：1.41(9H,s),1.55-1.70(4H,m),2.05-2.25(2H,m),2.62-2.68(2H,m),3.08-3.14(2H,m),4.00-4.18(1H,m),4.21-4.27(6H,m),4.62-4.67(2H,m),6.64-6.70(1H,m),6.72(1H,d,J=1.7Hz),6.72(1H,d,J=9.5Hz),6.77(1H,d,J=8.3Hz),7.15(1H,dd,J=7.7,4.7Hz),7.61(1H,d,J=9.5Hz),7.84(1H,dd,J=7.7,1.9Hz),8.56(1H,dd,J=4.7,1.9Hz) Example 13

(2-Oxo-1,8-naphthyridin-1 (2H) -yl) acetaldehyde 0.75 g of dichloromethane solution in 40 mL of tert-butyl = (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (piperidine -4-yl) carbamate (1.4 g), acetic acid (0.23 mL) and hydrogenated triacetoxyborohydride (1.3 g) were added, and the mixture was stirred at room temperature for 2 hours. Water, saturated aqueous sodium hydrogen carbonate solution and chloroform were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 200: 3], and white foam tert-butyl = (2,3-dihydro-1,4-benzodioxin-6) 1.4 g of -ylmethyl) (1- (2- (2-oxo-1,8-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.41 (9H, s), 1.55-1.70 (4H, m), 2.05-2.25 (2H, m), 2.62-2.68 (2H, m), 3.08-3.14 (2H , m), 4.00-4.18 (1H, m), 4.21-4.27 (6H, m), 4.62-4.67 (2H, m), 6.64-6.70 (1H, m), 6.72 (1H, d, J = 1.7Hz ), 6.72 (1H, d, J = 9.5Hz), 6.77 (1H, d, J = 8.3Hz), 7.15 (1H, dd, J = 7.7, 4.7Hz), 7.61 (1H, d, J = 9.5Hz) ), 7.84 (1H, dd, J = 7.7,1.9Hz), 8.56 (1H, dd, J = 4.7,1.9Hz)

ｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（１−（２−（２−オキソ−１，８−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート1.4gに4mol/L塩化水素／酢酸エチル溶液50mLを加え、室温で1日間攪拌した。減圧下で溶媒を留去し、エタノールを加え、減圧下で溶媒を留去した。得られた固形物に酢酸エチルを加え、攪拌後、固形物を濾取し、白色固体の１−（２−（４−（（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）エチル）−１，８−ナフチリジン−２（１Ｈ）−オン塩酸塩1.2gを得た。
¹H-NMR(D₂O)δ値：1.93-2.07(2H,m),2.48-2.58(2H,m),3.18-3.29(2H,m),3.57-3.78(3H,m),4.03-4.10(2H,m),4.20-4.27(2H,m),4.30-4.40(4H,m),4.90-4.95(2H,m),6.85(1H,d,J=9.5Hz),6.98-7.06(3H,m),7.47(1H,dd,J=7.7,4.8Hz),8.06(1H,d,J=9.5Hz),8.24(1H,d,J=7.7Hz),8.70(1H,d,J=4.8Hz) Example 14

tert-butyl = (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (1- (2- (2-oxo-1,8-naphthyridin-1 (2H) -yl) ethyl) piperidine- 4-yl) carbamate (1.4 g) was added with 4 mL / L hydrogen chloride / ethyl acetate solution (50 mL) and stirred at room temperature for 1 day. The solvent was distilled off under reduced pressure, ethanol was added, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained solid, and after stirring, the solid was collected by filtration to give 1- (2- (4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl) as a white solid. 1.2 g of amino) piperidin-1-yl) ethyl) -1,8-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.93-2.07 (2H, m), 2.48-2.58 (2H, m), 3.18-3.29 (2H, m), 3.57-3.78 (3H, m), 4.03- 4.10 (2H, m), 4.20-4.27 (2H, m), 4.30-4.40 (4H, m), 4.90-4.95 (2H, m), 6.85 (1H, d, J = 9.5Hz), 6.98-7.06 ( 3H, m), 7.47 (1H, dd, J = 7.7,4.8Hz), 8.06 (1H, d, J = 9.5Hz), 8.24 (1H, d, J = 7.7Hz), 8.70 (1H, d, J = 4.8Hz)

（１）１−（１，３−ジオキソラン−２−イルメチル）−１，６−ナフチリジン−２（１Ｈ）−オン0.60gに90％トリフルオロ酢酸水溶液6mLを加え、室温で12時間攪拌した。水1.0mLを加え、1時間攪拌し、55〜75℃で3時間30分間攪拌した。減圧下で溶媒を留去し、飽和炭酸水素ナトリウム水溶液およびクロロホルムを加え、室温で1時間30分間攪拌後、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、（２−オキソ−１，６−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒドを得た。
（２）（２−オキソ−１，６−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド0.38gのジクロロメタン14mL溶液に、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（ピペリジン−４−イル）カルバマート0.35gおよび酢酸0.12mLを加え、5分間攪拌した後、反応混合物に水素化トリアセトキシホウ素ナトリウム0.32gを加え、4時間20分間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液およびクロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［溶離液；クロロホルム：メタノール＝１００：１］で精製し、無色油状物のｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（１−（２−（２−オキソ−１，６−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.36gを得た。
¹H-NMR(CDCl₃)δ値：1.43(9H,s),1.61-1.70(4H,m),2.09-2.23(2H,m),2.58-2.63(2H,m),2.98-3.04(2H,m),3.95-4.35(9H,m),6.64-6.70(1H,m),6.73(1H,d,J=9.5Hz),6.74(1H,d,J=2.4Hz),6.78(1H,d,J=8.3Hz),7.24(1H,d,J=5.9Hz),7.73(1H,d,J=9.5Hz),8.58(1H,d,J=5.9Hz),8.77(1H,s) Example 15

(1) 6% of 90% aqueous trifluoroacetic acid solution was added to 0.60 g of 1- (1,3-dioxolan-2-ylmethyl) -1,6-naphthyridin-2 (1H) -one, and the mixture was stirred at room temperature for 12 hours. 1.0 mL of water was added, and the mixture was stirred for 1 hour, and stirred at 55 to 75 ° C. for 3 hours and 30 minutes. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution and chloroform were added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain (2-oxo-1,6-naphthyridin-1 (2H) -yl) acetaldehyde.
(2) To a solution of 0.38 g of (2-oxo-1,6-naphthyridin-1 (2H) -yl) acetaldehyde in 14 mL of dichloromethane was added tert-butyl = (2,3-dihydro-1,4-benzodioxin-6 After adding 0.35 g of ylmethyl) (piperidin-4-yl) carbamate and 0.12 mL of acetic acid and stirring for 5 minutes, 0.32 g of sodium triacetoxyborohydride was added to the reaction mixture, and the mixture was stirred for 4 hours and 20 minutes. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 100: 1], and tert-butyl = (2,3-dihydro-1,4-benzodioxin-6) as a colorless oily substance. 0.36 g of ylmethyl) (1- (2- (2-oxo-1,6-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.43 (9H, s), 1.61-1.70 (4H, m), 2.09-2.23 (2H, m), 2.58-2.63 (2H, m), 2.98-3.04 (2H , m), 3.95-4.35 (9H, m), 6.64-6.70 (1H, m), 6.73 (1H, d, J = 9.5Hz), 6.74 (1H, d, J = 2.4Hz), 6.78 (1H, d, J = 8.3Hz), 7.24 (1H, d, J = 5.9Hz), 7.73 (1H, d, J = 9.5Hz), 8.58 (1H, d, J = 5.9Hz), 8.77 (1H, s)

ｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（１−（２−（２−オキソ−１，６−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.15gに4mol/L塩化水素／酢酸エチル溶液10mLを加え、室温で2時間30分間攪拌した。さらに、4mol/L塩化水素／酢酸エチル溶液5mLを加え、室温で20時間反応させ、減圧下で溶媒を留去した。6mol/L塩酸8mLに溶解後、減圧下で溶媒を留去した。得られた残留物にエタノールを加え、減圧下で溶媒を留去した後、得られた残留物に酢酸エチルを加え、固形物を濾取し、淡黄色固体の１−（２−（４−（（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）エチル）−１，６−ナフチリジン−２（１Ｈ）−オン塩酸塩0.13gを得た。
¹H-NMR(D₂O)δ値：2.02-2.14(2H,m),2.52-2.59(2H,m),3.27-3.36(2H,m),3.64-3.70(3H,m),3.99-4.07(2H,m),4.24-4.26(2H,m),4.35(4H,s),4.80-4.90(2H,m),6.98-7.07(3H,m),7.08(1H,d,J=9.8Hz),8.06(1H,d,J=7.3Hz),8.25(1H,d,J=9.8Hz),8.79(1H,d,J=7.1Hz),9.23(1H,s) Example 16

tert-butyl = (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (1- (2- (2-oxo-1,6-naphthyridin-1 (2H) -yl) ethyl) piperidine- 4-Il) carbamate (0.15 g) was added with 10 mL of a 4 mol / L hydrogen chloride / ethyl acetate solution and stirred at room temperature for 2 hours and 30 minutes. Furthermore, 5 mL of a 4 mol / L hydrogen chloride / ethyl acetate solution was added and reacted at room temperature for 20 hours, and the solvent was distilled off under reduced pressure. After dissolving in 8 mL of 6 mol / L hydrochloric acid, the solvent was distilled off under reduced pressure. Ethanol was added to the obtained residue, the solvent was distilled off under reduced pressure, ethyl acetate was added to the obtained residue, and the solid was collected by filtration to give 1- (2- (4- (4- 0.13 g of ((2,3-dihydro-1,4-benzodioxin-6-ylmethyl) amino) piperidin-1-yl) ethyl) -1,6-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 2.02-2.14 (2H, m), 2.52-2.59 (2H, m), 3.27-3.36 (2H, m), 3.64-3.70 (3H, m), 3.99- 4.07 (2H, m), 4.24-4.26 (2H, m), 4.35 (4H, s), 4.80-4.90 (2H, m), 6.98-7.07 (3H, m), 7.08 (1H, d, J = 9.8 Hz), 8.06 (1H, d, J = 7.3Hz), 8.25 (1H, d, J = 9.8Hz), 8.79 (1H, d, J = 7.1Hz), 9.23 (1H, s)

実施例８と同様の手法により、１−（２−（４−（（３−フルオロ−４−メチルベンジル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オンから１−（２−（４−（（３−フルオロ−４−メチルベンジル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：1.96-2.10(2H,m),2.28(3H,s),2.48-2.57(2H,m),3.18-3.31(2H,m),3.59-3.68(3H,m),3.95-4.06(2H,m),4.04(3H,s),4.29(2H,s),4.74-4.83(2H,m),6.87(1H,d,J=9.8Hz),7.17-7.22(2H,m),7.36(1H,t,J=7.8Hz),7.44(1H,d,J=2.2Hz),8.06(1H,d,J=9.8Hz),8.40(1H,d,J=2.2Hz) Example 17

In the same manner as in Example 8, 1- (2- (4-((3-fluoro-4-methylbenzyl) amino) piperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridine-2 (1H) -one to 1- (2- (4-((3-fluoro-4-methylbenzyl) amino) piperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridine-2 (1H) -On hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.96-2.10 (2H, m), 2.28 (3H, s), 2.48-2.57 (2H, m), 3.18-3.31 (2H, m), 3.59-3.68 ( 3H, m), 3.95-4.06 (2H, m), 4.04 (3H, s), 4.29 (2H, s), 4.74-4.83 (2H, m), 6.87 (1H, d, J = 9.8Hz), 7.17 -7.22 (2H, m), 7.36 (1H, t, J = 7.8Hz), 7.44 (1H, d, J = 2.2Hz), 8.06 (1H, d, J = 9.8Hz), 8.40 (1H, d, (J = 2.2Hz)

（２−オキソ−１，７−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド0.32gのジクロロメタン10mL溶液にｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（ピペリジン−４−イル）カルバマート0.59gおよび酢酸97μLを加え、次いで、反応混合物に水素化トリアセトキシホウ素ナトリウム0.54gを加え、室温で2時間30分間攪拌した。水、飽和炭酸水素ナトリウム水溶液およびクロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［溶離液；クロロホルム：メタノール＝１００：１］で精製し、無色油状物のｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（１−（２−（２−オキソ−１，7−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.15gを得た。
¹H-NMR(CDCl₃)δ値：1.42(9H,s),1.62-1.72(4H,m),2.12-2.26(2H,m),2.63-2.69(2H,m),3.00-3.06(2H,m),3.98-4.15(1H,m),4.22-4.33(6H,m),4.41-4.46(2H,m),6.67-6.71(1H,m),6.74(1H,d,J=2.0Hz),6.78(1H,d,J=8.3Hz),6.89(1H,d,J=9.5Hz),7.43(1H,d,J=5.0Hz),7.66(1H,d,J=9.5Hz),8.44(1H,d,J=5.0Hz),8.87(1H,s) Example 18

(2-Oxo-1,7-naphthyridin-1 (2H) -yl) acetaldehyde 0.32 g in dichloromethane 10 mL solution in tert-butyl = (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (piperidine -4-yl) carbamate 0.59 g and acetic acid 97 μL were added, and then 0.54 g of sodium triacetoxyborohydride was added to the reaction mixture and stirred at room temperature for 2 hours 30 minutes. Water, saturated aqueous sodium hydrogen carbonate solution and chloroform were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 100: 1], and tert-butyl = (2,3-dihydro-1,4-benzodioxin-6) as a colorless oily substance. 0.15 g of ylmethyl) (1- (2- (2-oxo-1,7-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.42 (9H, s), 1.62-1.72 (4H, m), 2.12-2.26 (2H, m), 2.63-2.69 (2H, m), 3.00-3.06 (2H , m), 3.98-4.15 (1H, m), 4.22-4.33 (6H, m), 4.41-4.46 (2H, m), 6.67-6.71 (1H, m), 6.74 (1H, d, J = 2.0Hz ), 6.78 (1H, d, J = 8.3Hz), 6.89 (1H, d, J = 9.5Hz), 7.43 (1H, d, J = 5.0Hz), 7.66 (1H, d, J = 9.5Hz), 8.44 (1H, d, J = 5.0Hz), 8.87 (1H, s)

ｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（１−（２−（２−オキソ−１，7−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.15gに4mol/L塩化水素/酢酸エチル溶液8mLを加え、室温で21時間反応させ、減圧下で溶媒を留去した。得られた残留物にエタノールを加え、減圧下で溶媒を留去した後、得られた残留物に酢酸エチルを加え、固形物を濾取し、黄色固体の１−（２−（４−（（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）エチル）−１，7−ナフチリジン−２（１Ｈ）−オン塩酸塩0.15gを得た。
¹H-NMR(D₂O)δ値：2.01-2.13(2H,m),2.52-2.58(2H,m),3.26-3.35(2H,m),3.61-3.72(3H,m),4.00-4.07(2H,m),4.25(2H,s),4.35(4H,s),4.82-4.89(2H,m),6.69-7.07(3H,m),7.27(1H,d,J=9.0Hz),8.22(1H,d,J=9.8Hz),8.28(1H,d,J=5.7Hz),8.65(1H,d,J=5.7Hz),9.19(1H,s) Example 19

tert-butyl = (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (1- (2- (2-oxo-1,7-naphthyridin-1 (2H) -yl) ethyl) piperidine- 4-yl) carbamate (0.15 g) was added with 8 mL of a 4 mol / L hydrogen chloride / ethyl acetate solution, reacted at room temperature for 21 hours, and the solvent was distilled off under reduced pressure. Ethanol was added to the obtained residue, the solvent was distilled off under reduced pressure, ethyl acetate was added to the obtained residue, and the solid was collected by filtration to give a yellow solid 1- (2- (4- ( 0.15 g of (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) amino) piperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 2.01-2.13 (2H, m), 2.52-2.58 (2H, m), 3.26-3.35 (2H, m), 3.61-3.72 (3H, m), 4.00- 4.07 (2H, m), 4.25 (2H, s), 4.35 (4H, s), 4.82-4.89 (2H, m), 6.69-7.07 (3H, m), 7.27 (1H, d, J = 9.0Hz) , 8.22 (1H, d, J = 9.8Hz), 8.28 (1H, d, J = 5.7Hz), 8.65 (1H, d, J = 5.7Hz), 9.19 (1H, s)

１−（２−（４−アミノピペリジン−１−イル）エチル）−１，８−ナフチリジン−２（１Ｈ）−オン0.07gのジクロロメタン3mL溶液に７−クロロ−３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド（３，２−ｂ）（１，４）チアジン−６−カルバルデヒド57mgおよび酢酸14μLを加え、10分間攪拌した後、反応混合物に水素化トリアセトキシホウ素ナトリウム79mgを加え、1日間反応させた。さらに酢酸7μLを加え、35分間攪拌し、酢酸7μLおよび水素化トリアセトキシホウ素ナトリウム26mgを加え、20分間反応させた。反応混合物に、水、飽和炭酸水素ナトリウム水溶液、クロロホルムおよび塩化ナトリウムを加え、有機層を分取し、水層を塩析しながらクロロホルムで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を6mol/L塩酸5mLに溶解後、減圧下で溶媒を留去した。得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；水］で精製し、淡灰色固体の７−クロロ−６−（（（１−（２−（２−オキソ−１，８−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）アミノ）メチル）−２Ｈ−ピリド（３，２−ｂ）（１，４）チアジン−３（４Ｈ）−オン塩酸塩71mgを得た。
¹H-NMR(D₂O)δ値：2.03-2.19(2H,m),2.56-2.66(2H,m),3.22-3.34(2H,m),3.59-3.85(5H,m),4.03-4.15(2H,m),4.56(2H,s),4.70-5.02(2H,m),6.83(1H,d,J=9.4Hz),7.44-7.49(1H,m),7.93(1H,s),8.05(1H,d,J=9.4Hz),8.22(1H,d,J=7.8Hz),8.68-8.73(1H,m) Example 20

1- (2- (4-Aminopiperidin-1-yl) ethyl) -1,8-naphthyridin-2 (1H) -one in a solution of 0.07 g in 3 mL of dichloromethane was added 7-chloro-3-oxo-3,4-dihydro -2H-pyrido (3,2-b) (1,4) thiazine-6-carbaldehyde (57 mg) and acetic acid (14 μL) were added, and after stirring for 10 minutes, 79 mg of sodium triacetoxyborohydride was added to the reaction mixture, Reacted. Further, 7 μL of acetic acid was added and stirred for 35 minutes, and 7 μL of acetic acid and 26 mg of sodium triacetoxyborohydride were added and reacted for 20 minutes. Water, saturated aqueous sodium hydrogen carbonate solution, chloroform and sodium chloride were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform while salting out. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 5 mL of 6 mol / L hydrochloric acid, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by reverse phase silica gel column chromatography [eluent: water], and light gray solid 7-chloro-6-(((1- (2- (2-oxo-1,8-naphthyridine -1 (2H) -yl) ethyl) piperidin-4-yl) amino) methyl) -2H-pyrido (3,2-b) (1,4) thiazin-3 (4H) -one hydrochloride 71 mg was obtained. .
¹ H-NMR (D ₂ O) δ value: 2.03-2.19 (2H, m), 2.56-2.66 (2H, m), 3.22-3.34 (2H, m), 3.59-3.85 (5H, m), 4.03- 4.15 (2H, m), 4.56 (2H, s), 4.70-5.02 (2H, m), 6.83 (1H, d, J = 9.4Hz), 7.44-7.49 (1H, m), 7.93 (1H, s) , 8.05 (1H, d, J = 9.4Hz), 8.22 (1H, d, J = 7.8Hz), 8.68-8.73 (1H, m)

１−（２−（４−アミノピペリジン−１−イル）エチル）−１，８−ナフチリジン−２（１Ｈ）−オン83mgのジクロロメタン15mL溶液に３−オキソ−３，４−ジヒドロ−２Ｈ−１，４−ベンゾオキサジン−６−カルバルデヒド54mg、酢酸86μLおよび水素化トリアセトキシホウ素ナトリウム0.36gを分割添加しながら、室温で1.5日間反応させた。反応溶液に、水、飽和炭酸水素ナトリウム水溶液、クロロホルムおよび塩化ナトリウムを加え、有機層を分取し、水層を塩析しながらクロロホルムで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、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［溶離液；クロロホルム：メタノール＝５：１］で精製し、得られた残留物を6mol/L塩酸5mLに溶解後、減圧下で溶媒を留去した。得られた残留物にジエチルエーテルを加え、固形物を濾取し、淡黄色固体の６−（（（１−（２−（２−オキソ−１，８−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）アミノ）メチル）−２Ｈ−１，４−ベンゾオキサジン−３（４Ｈ）−オン塩酸塩0.12gを得た。
¹H-NMR(D₂O)δ値：1.94-2.09(2H,m),2.50-2.58(2H,m),3.18-3.34(2H,m),3.59-3.70(3H,m),3.98-4.11(2H,m),4.27(2H,s),4.71(2H,s),4.91-4.97(2H,m),6.85(1H,d,J=9.5Hz),7.06-7.11(2H,m),7.15(1H,dd,J=8.4,1.8Hz),7.47(1H,dd,J=7.8,4.8Hz),8.07(1H,d,J=9.5Hz),8.23-8.26(1H,m),8.68-8.72(1H,m) Example 21

1- (2- (4-aminopiperidin-1-yl) ethyl) -1,8-naphthyridin-2 (1H) -one 83 mg of dichloromethane in 15 mL solution of 3-oxo-3,4-dihydro-2H-1, The reaction was carried out at room temperature for 1.5 days while 54 mg of 4-benzoxazine-6-carbaldehyde, 86 μL of acetic acid and 0.36 g of sodium triacetoxyborohydride were added in portions. Water, saturated aqueous sodium hydrogen carbonate solution, chloroform and sodium chloride were added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with chloroform while salting out. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 5: 1] The obtained residue was dissolved in 5 mL of 6 mol / L hydrochloric acid, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the obtained residue, and the solid was collected by filtration to give a pale yellow solid of 6-(((1- (2- (2-oxo-1,8-naphthyridin-1 (2H) -yl) 0.12 g of ethyl) piperidin-4-yl) amino) methyl) -2H-1,4-benzoxazin-3 (4H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.94-2.09 (2H, m), 2.50-2.58 (2H, m), 3.18-3.34 (2H, m), 3.59-3.70 (3H, m), 3.98- 4.11 (2H, m), 4.27 (2H, s), 4.71 (2H, s), 4.91-4.97 (2H, m), 6.85 (1H, d, J = 9.5Hz), 7.06-7.11 (2H, m) 7.15 (1H, dd, J = 8.4,1.8Hz), 7.47 (1H, dd, J = 7.8,4.8Hz), 8.07 (1H, d, J = 9.5Hz), 8.23-8.26 (1H, m), 8.68-8.72 (1H, m)

（２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド0.62gのジクロロメタン20mL溶液にｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（ピペリジン−４−イル）カルバマート1.5gおよび酢酸0.19mLを加え、室温で30分間攪拌後、反応混合物に水素化トリアセトキシホウ素ナトリウム1.0gを加え、室温で4日間攪拌した。水、飽和炭酸水素ナトリウム水溶液およびクロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、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［溶離液；クロロホルム：メタノール＝７５：１］で精製し、淡褐色油状物のｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（１−（２−（２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.70gを得た。
¹H-NMR(CDCl₃)δ値：1.43(9H,s),1.61-1.72(4H,m)2.10-2.21(2H,m),2.61(2H,t,J=7.3Hz),2.97-3.03(2H,m),3.97-4.15(1H,m),4.20-4.38(8H,m),6.65-6.76(2H,m),6.78(1H,d,J=8.3Hz),6.90(1H,d,J=9.8Hz),7.45(1H,dd,J=8.6,4.5Hz),7.75(1H,d,J=8.6Hz),7.90(1H,d,J=9.8Hz),8.53(1H,d,J=4.5Hz) Example 22

(2-Oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde 0.62 g in dichloromethane 20 mL solution tert-butyl = (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (piperidine -4-yl) carbamate (1.5 g) and acetic acid (0.19 mL) were added, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added sodium triacetoxyborohydride (1.0 g), and the mixture was stirred at room temperature for 4 days. Water, saturated aqueous sodium hydrogen carbonate solution and chloroform were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 75: 1] Tert-Butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (1- (2- (2-oxo-1,5-naphthyridin-1 (2H) -yl) 0.70 g)) ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.43 (9H, s), 1.61-1.72 (4H, m) 2.10-2.21 (2H, m), 2.61 (2H, t, J = 7.3Hz), 2.97-3.03 (2H, m), 3.97-4.15 (1H, m), 4.20-4.38 (8H, m), 6.65-6.76 (2H, m), 6.78 (1H, d, J = 8.3Hz), 6.90 (1H, d , J = 9.8Hz), 7.45 (1H, dd, J = 8.6,4.5Hz), 7.75 (1H, d, J = 8.6Hz), 7.90 (1H, d, J = 9.8Hz), 8.53 (1H, d , J = 4.5Hz)

ｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（１−（２−（２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.69gに4mol/L塩化水素／酢酸エチル溶液25mLを加え、室温で42時間攪拌した。減圧下で溶媒を留去し、得られた残留物に酢酸エチルおよびエタノールの混合溶液（５：１）を加え、固形物を濾取し、淡黄色固体の１−（２−（４−（（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.59gを得た。
¹H-NMR(D₂O)δ値：1.98-2.12(2H,m),2.46-2.58(2H,m),3.21-3.36(2H,m),3.56-3.70(3H,m),3.97-4.07(2H,m),4.20-4.25(2H,m),4.33(4H,s),4.80-5.60(2H,m),6.96-7.05(3H,m),7.24(1H,d,J=10.0Hz),8.09(1H,dd,J=8.9,5.2Hz),8.22(1H,d,J=10.0Hz),8.54(1H,d,J=8.9Hz),8.77(1H,d,J=5.2Hz) Example 23

tert-butyl = (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (1- (2- (2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidine- 4-Il) carbamate (0.69 g) was added with 4 mL / L hydrogen chloride / ethyl acetate solution (25 mL) and stirred at room temperature for 42 hours. The solvent was distilled off under reduced pressure, a mixed solution (5: 1) of ethyl acetate and ethanol was added to the obtained residue, the solid was collected by filtration, and 1- (2- (4- ( 0.59 g of (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) amino) piperidin-1-yl) ethyl) -1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.98-2.12 (2H, m), 2.46-2.58 (2H, m), 3.21-3.36 (2H, m), 3.56-3.70 (3H, m), 3.97- 4.07 (2H, m), 4.20-4.25 (2H, m), 4.33 (4H, s), 4.80-5.60 (2H, m), 6.96-7.05 (3H, m), 7.24 (1H, d, J = 10.0 Hz), 8.09 (1H, dd, J = 8.9,5.2Hz), 8.22 (1H, d, J = 10.0Hz), 8.54 (1H, d, J = 8.9Hz), 8.77 (1H, d, J = 5.2 Hz)

実施例７と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オン塩酸塩と２−ナフトアルデヒドから１−（２−（４−（（２−ナフチルメチル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.41-1.51(2H,m),1.91-1.99(2H,m),2.16-2.25(2H,m),2.54-2.62(1H,m),2.68-2.73(2H,m),2.98-3.04(2H,m),3.99(2H,s),4.45-4.50(2H,m),6.89(1H,d,J=9.5Hz),7.42(1H,d,J=5.0Hz),7.43-7.48(3H,m),7.65(1H,d,J=9.5Hz),7.76(1H,s),7.79-7.84(3H,m),8.44(1H,d,J=5.0Hz),8.91(1H,s) Example 24

In the same manner as in Example 7, 1- (2- (4-aminopiperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one hydrochloride and 2-naphthaldehyde were converted to 1- ( 2- (4-((2-naphthylmethyl) amino) piperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.41-1.51 (2H, m), 1.91-1.99 (2H, m), 2.16-2.25 (2H, m), 2.54-2.62 (1H, m), 2.68-2.73 (2H, m), 2.98-3.04 (2H, m), 3.99 (2H, s), 4.45-4.50 (2H, m), 6.89 (1H, d, J = 9.5Hz), 7.42 (1H, d, J = 5.0Hz), 7.43-7.48 (3H, m), 7.65 (1H, d, J = 9.5Hz), 7.76 (1H, s), 7.79-7.84 (3H, m), 8.44 (1H, d, J = 5.0Hz), 8.91 (1H, s)

実施例８と同様の手法により、１−（２−（４−（（２−ナフチルメチル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オンから１−（２−（４−（（２−ナフチルメチル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(DMSO-d₆)δ値：2.08-2.22(2H,m),2.40-2.48(2H,m),3.08-3.20(2H,m),3.28-3.87(5H,m),4.34-4.43(2H,m),4.70-4.79(2H,m),7.01(1H,d,J=9.5Hz),7.56-7.63(2H,m),7.78(1H,d,J=8.3Hz),7.90-8.04(4H,m),8.09(1H,d,J=9.5Hz),8.14(1H,s),8.55(1H,d,J=5.4Hz),9.26(1H,s),9.78-9.97(2H,m),10.82-10.96(1H,m) Example 25

In the same manner as in Example 8, 1- (2- (4-((2-naphthylmethyl) amino) piperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one was converted to 1- (2- (4-((2-naphthylmethyl) amino) piperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.08-2.22 (2H, m), 2.40-2.48 (2H, m), 3.08-3.20 (2H, m), 3.28-3.87 (5H, m), 4.34 -4.43 (2H, m), 4.70-4.79 (2H, m), 7.01 (1H, d, J = 9.5Hz), 7.56-7.63 (2H, m), 7.78 (1H, d, J = 8.3Hz), 7.90-8.04 (4H, m), 8.09 (1H, d, J = 9.5Hz), 8.14 (1H, s), 8.55 (1H, d, J = 5.4Hz), 9.26 (1H, s), 9.78-9.97 (2H, m), 10.82-10.96 (1H, m)

１−（２−（４−アミノピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オン塩酸塩0.20gのメタノール6mL懸濁液に水素化シアノホウ素ナトリウム99mgおよびモレキュラーシーブス（３Ａ）0.40gを加え、室温で15分間攪拌した。フェニルプロパルギルアルデヒド68mgを加え、室温で1時間30分間攪拌した。フェニルプロパルギルアルデヒド68mgを加え、室温で2時間攪拌した。フェニルプロパルギルアルデヒド68mgを加え、室温で1時間30分間攪拌した。飽和炭酸水素ナトリウム水溶液およびクロロホルムを加え、不溶物を濾去した。有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝５０：１］で精製し、淡黄色油状物の１−（２−（４−（ビス（３−フェニル−２−プロピニル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オン0.11gを得た。
¹H-NMR(CDCl₃)δ値：1.59-1.72(2H,m),1.99-2.07(2H,m),2.18-2.26(2H,m),2.66-2.75(3H,m),3.06-3.14(2H,m),3.84(4H,s),4.45-4.52(2H,m),6.89(1H,d,J=9.5Hz),7.27-7.46(11H,m),7.65(1H,d,J=9.8Hz),8.44(1H,d,J=5.1Hz),8.91(1H,s) Example 26

1- (2- (4-Aminopiperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one hydrochloride 0.20 g in methanol 6 mL suspension in methanol cyanoborohydride 99 mg and molecular sieves (3A) 0.40 g was added and stirred at room temperature for 15 minutes. 68 mg of phenylpropargylaldehyde was added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. 68 mg of phenylpropargylaldehyde was added and stirred at room temperature for 2 hours. 68 mg of phenylpropargylaldehyde was added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added, and the insoluble material was removed by filtration. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography [eluent: chloroform: methanol = 50: 1] to give 1- (2- (4- (bis (3-phenyl-2-phenyl)) as a pale yellow oil. 0.11 g of propynyl) amino) piperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.59-1.72 (2H, m), 1.99-2.07 (2H, m), 2.18-2.26 (2H, m), 2.66-2.75 (3H, m), 3.06-3.14 (2H, m), 3.84 (4H, s), 4.45-4.52 (2H, m), 6.89 (1H, d, J = 9.5Hz), 7.27-7.46 (11H, m), 7.65 (1H, d, J = 9.8Hz), 8.44 (1H, d, J = 5.1Hz), 8.91 (1H, s)

実施例８と同様の手法により、１−（２−（４−（ビス（３−フェニル−２−プロピニル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オンから１−（２−（４−（ビス（３−フェニル−２−プロピニル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(DMSO-d₆)δ値：2.10-2.25(2H,m),2.38-2.50(2H,m),3.18-3.30(2H,m),3.38-3.92(5H,m),4.32-4.42(4H,m),4.71-4.79(2H,m),7.04(1H,d,J=9.5Hz),7.34-7.54(10H,m),7.98(1H,d,J=5.4Hz),8.11(1H,d,J=9.5Hz),8.58(1H,d,J=5.4Hz),9.31(1H,s) Example 27

In the same manner as in Example 8, 1- (2- (4- (bis (3-phenyl-2-propynyl) amino) piperidin-1-yl) ethyl) -1,7-naphthyridine-2 (1H)- 1- (2- (4- (bis (3-phenyl-2-propynyl) amino) piperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one hydrochloride was obtained from ON.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.10-2.25 (2H, m), 2.38-2.50 (2H, m), 3.18-3.30 (2H, m), 3.38-3.92 (5H, m), 4.32 -4.42 (4H, m), 4.71-4.79 (2H, m), 7.04 (1H, d, J = 9.5Hz), 7.34-7.54 (10H, m), 7.98 (1H, d, J = 5.4Hz), 8.11 (1H, d, J = 9.5Hz), 8.58 (1H, d, J = 5.4Hz), 9.31 (1H, s)

実施例７と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オン塩酸塩と１−ベンゾチオフェン−２−カルバルデヒドから１−（２−（４−（（１−ベンゾチオフェン−２−イルメチル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.39-1.50(2H,m),1.89-1.97(2H,m),2.15-2.24(2H,m),2.57-2.66(1H,m),2.68-2.73(2H,m),2.97-3.04(2H,m),4.11(2H,d,J=0.8Hz),4.44-4.50(2H,m),6.89(1H,d,J=9.5Hz),7.14(1H,s),7.27-7.34(2H,m),7.42(1H,d,J=5.1Hz),7.65(1H,d,J=9.5Hz),7.67-7.72(1H,m),7.79(1H,d,J=7.6Hz),8.44(1H,d,J=5.1Hz),8.90(1H,s) Example 28

In the same manner as in Example 7, 1- (2- (4-aminopiperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one hydrochloride and 1-benzothiophene-2-carba 1- (2- (4-((1-benzothiophen-2-ylmethyl) amino) piperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one was obtained from aldehyde.
¹ H-NMR (CDCl ₃ ) δ value: 1.39-1.50 (2H, m), 1.89-1.97 (2H, m), 2.15-2.24 (2H, m), 2.57-2.66 (1H, m), 2.68-2.73 (2H, m), 2.97-3.04 (2H, m), 4.11 (2H, d, J = 0.8Hz), 4.44-4.50 (2H, m), 6.89 (1H, d, J = 9.5Hz), 7.14 ( 1H, s), 7.27-7.34 (2H, m), 7.42 (1H, d, J = 5.1Hz), 7.65 (1H, d, J = 9.5Hz), 7.67-7.72 (1H, m), 7.79 (1H , d, J = 7.6Hz), 8.44 (1H, d, J = 5.1Hz), 8.90 (1H, s)

実施例８と同様の手法により、１−（２−（４−（（１−ベンゾチオフェン−２−イルメチル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オンから１−（２−（４−（（１−ベンゾチオフェン−２−イルメチル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(DMSO-d₆)δ値：2.02-2.16(2H,m),2.38-2.46(2H,m),3.11-3.22(2H,m),3.35-3.46(3H,m),3.79-3.88(2H,m),4.58(2H,s),4.69-4.78(2H,m),7.06(1H,d,J=9.6Hz),7.40-7.46(2H,m),7.72(1H,s),7.88-7.94(1H,m),8.00-8.05(2H,m),8.13(1H,d,J=9.6Hz),8.59(1H,d,J=5.4Hz),9.31(1H,s) Example 29

In the same manner as in Example 8, 1- (2- (4-((1-benzothiophen-2-ylmethyl) amino) piperidin-1-yl) ethyl) -1,7-naphthyridine-2 (1H)- 1- (2- (4-((1-benzothiophen-2-ylmethyl) amino) piperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one hydrochloride was obtained from ON.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.02-2.16 (2H, m), 2.38-2.46 (2H, m), 3.11-3.22 (2H, m), 3.35-3.46 (3H, m), 3.79 -3.88 (2H, m), 4.58 (2H, s), 4.69-4.78 (2H, m), 7.06 (1H, d, J = 9.6Hz), 7.40-7.46 (2H, m), 7.72 (1H, s ), 7.88-7.94 (1H, m), 8.00-8.05 (2H, m), 8.13 (1H, d, J = 9.6Hz), 8.59 (1H, d, J = 5.4Hz), 9.31 (1H, s)

１−（２−（４−アミノピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オン塩酸塩0.10gのメタノール3mL懸濁液に28％ナトリウムメトキシド／メタノール溶液0.15mLおよび酢酸15μLを加えた。７−クロロ−３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド（３，２−ｂ）（１，４）チアジン−６−カルバルデヒド51mgおよびモレキュラーシーブス（３Ａ）0.20gを加え、室温で30分間攪拌した。水素化シアノホウ素ナトリウム33mgを加え、室温で1時間30分間攪拌した。７−クロロ−３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド（３，２−ｂ）（１，４）チアジン−６−カルバルデヒド51mgを加え、室温で2時間攪拌した。不溶物を濾去し、クロロホルムおよび飽和炭酸水素ナトリウム水溶液を加えた。有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄した。無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝１０：１］で精製し、白色固体の７−クロロ−６−（（（１−（２−（２−オキソ−１，７−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）アミノ）メチル）−２Ｈ−ピリド（３，２−ｂ）（１，４）チアジン−３（４Ｈ）−オン97mgを得た。
¹H-NMR(CDCl₃)δ値：1.43-1.60(2H,m),1.88-1.96(2H,m),2.18-2.26(2H,m),2.50-2.58(1H,m),2.69-2.76(2H,m),2.97-3.05(2H,m),3.48(2H,s),3.95(2H,s),4.44-4.50(2H,m),6.90(1H,d,J=9.5Hz),7.42(1H,d,J=4.9Hz),7.60(1H,s),7.65(1H,d,J=9.5Hz),8.17(1H,s),8.45(1H,d,J=4.9Hz),8.92(1H,s) Example 30

1- (2- (4-Aminopiperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one hydrochloride 0.10 g in a 3 mL methanol suspension with 28% sodium methoxide / methanol solution 0.15 mL and 15 μL of acetic acid were added. Add 51 mg of 7-chloro-3-oxo-3,4-dihydro-2H-pyrido (3,2-b) (1,4) thiazine-6-carbaldehyde and 0.20 g of molecular sieves (3A) at room temperature. Stir for minutes. 33 mg of sodium cyanoborohydride was added and stirred at room temperature for 1 hour and 30 minutes. 7-Chloro-3-oxo-3,4-dihydro-2H-pyrido (3,2-b) (1,4) thiazine-6-carbaldehyde (51 mg) was added, and the mixture was stirred at room temperature for 2 hours. Insoluble material was removed by filtration, and chloroform and a saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated and washed successively with water and saturated aqueous sodium chloride solution. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography [eluent: chloroform: methanol = 10: 1], and 7-chloro-6-(((1- (2- (2-oxo- 1,7-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) amino) methyl) -2H-pyrido (3,2-b) (1,4) thiazin-3 (4H) -one 97 mg Got.
¹ H-NMR (CDCl ₃ ) δ values: 1.43-1.60 (2H, m), 1.88-1.96 (2H, m), 2.18-2.26 (2H, m), 2.50-2.58 (1H, m), 2.69-2.76 (2H, m), 2.97-3.05 (2H, m), 3.48 (2H, s), 3.95 (2H, s), 4.44-4.50 (2H, m), 6.90 (1H, d, J = 9.5Hz), 7.42 (1H, d, J = 4.9Hz), 7.60 (1H, s), 7.65 (1H, d, J = 9.5Hz), 8.17 (1H, s), 8.45 (1H, d, J = 4.9Hz), 8.92 (1H, s)

実施例３０と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オン塩酸塩および２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−カルバルデヒドから１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.40-1.52(2H,m),1.87-1.95(2H,m),2.16-2.25(2H,m),2.49-2.57(1H,m),2.67-2.74(2H,m),2.97-3.04(2H,m),3.80(2H,s),4.26-4.36(4H,m),4.44-4.51(2H,m),6.83(1H,s),6.89(1H,d,J=9.5Hz),7.42(1H,d,J=5.1Hz),7.65(1H,d,J=9.5Hz),8.11(1H,s),8.45(1H,d,J=5.1Hz),8.91(1H,s) Example 31

In a manner similar to Example 30, 1- (2- (4-aminopiperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one hydrochloride and 2,3-dihydro (1, 4) Dioxino (2,3-c) pyridine-7-carbaldehyde to 1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) Amino) piperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.40-1.52 (2H, m), 1.87-1.95 (2H, m), 2.16-2.25 (2H, m), 2.49-2.57 (1H, m), 2.67-2.74 (2H, m), 2.97-3.04 (2H, m), 3.80 (2H, s), 4.26-4.36 (4H, m), 4.44-4.51 (2H, m), 6.83 (1H, s), 6.89 (1H , d, J = 9.5Hz), 7.42 (1H, d, J = 5.1Hz), 7.65 (1H, d, J = 9.5Hz), 8.11 (1H, s), 8.45 (1H, d, J = 5.1Hz) ), 8.91 (1H, s)

実施例８と同様の手法により、１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オンから１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：1.98-2.11(2H,m),2.49-2.57(2H,m),3.23-3.33(2H,m),3.62-3.72(3H,m),3.96-4.05(2H,m),4.38(2H,s),4.39-4.44(2H,m),4.46-4.51(2H,m),4.80-4.86(2H,m),7.19(1H,d,J=9.5Hz),7.22(1H,s),8.15(1H,d,J=5.7Hz),8.17(1H,d,J=9.5Hz),8.23(1H,s),8.60(1H,d,J=5.7Hz),9.10(1H,s) Example 32

In the same manner as in Example 8, 1- (2- (4-((2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) was synthesized. ) Ethyl) -1,7-naphthyridin-2 (1H) -one to 1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) ) Amino) piperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.98-2.11 (2H, m), 2.49-2.57 (2H, m), 3.23-3.33 (2H, m), 3.62-3.72 (3H, m), 3.96 4.05 (2H, m), 4.38 (2H, s), 4.39-4.44 (2H, m), 4.46-4.51 (2H, m), 4.80-4.86 (2H, m), 7.19 (1H, d, J = 9.5 Hz), 7.22 (1H, s), 8.15 (1H, d, J = 5.7Hz), 8.17 (1H, d, J = 9.5Hz), 8.23 (1H, s), 8.60 (1H, d, J = 5.7) Hz), 9.10 (1H, s)

実施例３０と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オン塩酸塩および３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド（３，２−ｂ）（１，４）チアジン−６−カルバルデヒドから６−（（（１−（２−（２−オキソ−１，７−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）アミノ）メチル）−２Ｈ−ピリド（３，２−ｂ）（１，４）チアジン−３（４Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.39-1.51(2H,m),1.86-1.95(2H,m),2.16-2.25(2H,m),2.47-2.57(1H,m),2.68-2.74(2H,m),2.97-3.04(2H,m),3.48(2H,s),3.83(2H,s),4.44-4.50(2H,m),6.89(1H,d,J=9.4Hz),6.98(1H,d,J=7.8Hz),7.42(1H,d,J=5.1Hz),7.57(1H,d,J=7.8Hz),7.65(1H,d,J=9.4Hz),8.02-8.10(1H,broad),8.45(1H,d,J=5.1Hz),8.91(1H,s) Example 33

In a manner similar to that in Example 30, 1- (2- (4-aminopiperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one hydrochloride and 3-oxo-3,4- Dihydro-2H-pyrido (3,2-b) (1,4) thiazine-6-carbaldehyde to 6-(((1- (2- (2-oxo-1,7-naphthyridine-1 (2H)- Yl) ethyl) piperidin-4-yl) amino) methyl) -2H-pyrido (3,2-b) (1,4) thiazin-3 (4H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.39-1.51 (2H, m), 1.86-1.95 (2H, m), 2.16-2.25 (2H, m), 2.47-2.57 (1H, m), 2.68-2.74 (2H, m), 2.97-3.04 (2H, m), 3.48 (2H, s), 3.83 (2H, s), 4.44-4.50 (2H, m), 6.89 (1H, d, J = 9.4Hz), 6.98 (1H, d, J = 7.8Hz), 7.42 (1H, d, J = 5.1Hz), 7.57 (1H, d, J = 7.8Hz), 7.65 (1H, d, J = 9.4Hz), 8.02- 8.10 (1H, broad), 8.45 (1H, d, J = 5.1Hz), 8.91 (1H, s)

実施例３０と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オン塩酸塩および５−（２−チエニル）イソオキサゾール−３−カルバルデヒドから１−（２−（４−（（（５−（２−チエニル）イソオキサゾール−３−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.38-1.49(2H,m),1.88-1.96(2H,m),2.17-2.26(2H,m),2.52-2.62(1H,m),2.68-2.74(2H,m),2.97-3.04(2H,m),3.91(2H,s),4.44-4.50(2H,m),6.40(1H,s),6.89(1H,d,J=9.5Hz),7.12(1H,dd,J=5.1,3.7Hz),7.40-7.46(2H,m),7.50(1H,dd,J=3.7,1.0Hz),7.65(1H,d,J=9.5Hz),8.44(1H,d,J=5.1Hz),8.90(1H,s) Example 34

In a manner similar to that in Example 30, 1- (2- (4-aminopiperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one hydrochloride and 5- (2-thienyl) iso 1- (2- (4-(((5- (2-thienyl) isoxazol-3-yl) methyl) amino) piperidin-1-yl) ethyl) -1,7-naphthyridine from oxazole-3-carbaldehyde -2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.38-1.49 (2H, m), 1.88-1.96 (2H, m), 2.17-2.26 (2H, m), 2.52-2.62 (1H, m), 2.68-2.74 (2H, m), 2.97-3.04 (2H, m), 3.91 (2H, s), 4.44-4.50 (2H, m), 6.40 (1H, s), 6.89 (1H, d, J = 9.5Hz), 7.12 (1H, dd, J = 5.1,3.7Hz), 7.40-7.46 (2H, m), 7.50 (1H, dd, J = 3.7,1.0Hz), 7.65 (1H, d, J = 9.5Hz), 8.44 (1H, d, J = 5.1Hz), 8.90 (1H, s)

実施例８と同様の手法により、１−（２−（４−（（（５−（２−チエニル）イソオキサゾール−３−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オンから１−（２−（４−（（（５−（２−チエニル）イソオキサゾール−３−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(DMSO-d₆)δ値：2.05-2.18(2H,m),2.36-2.46(2H,m),3.10-3.22(2H,m),3.35-3.40(3H,m),3.60-3.88(2H,m),4.38-4.46(2H,m),4.70-4.79(2H,m),7.02(1H,d,J=9.5Hz),7.15(1H,s),7.28(1H,dd,J=5.1,3.7Hz),7.74(1H,d,J=3.7Hz),7.89(1H,d,J=5.1Hz),7.94(1H,d,J=5.1Hz),8.10(1H,d,J=9.5Hz),8.56(1H,d,J=5.1Hz),9.27(1H,s),10.20-10.40(2H,broad),10.73-10.90(1H,broad) Example 35

In the same manner as in Example 8, 1- (2- (4-(((5- (2-thienyl) isoxazol-3-yl) methyl) amino) piperidin-1-yl) ethyl) -1,7 -Naphthylidin-2 (1H) -one to 1- (2- (4-(((5- (2-thienyl) isoxazol-3-yl) methyl) amino) piperidin-1-yl) ethyl) -1, 7-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.05-2.18 (2H, m), 2.36-2.46 (2H, m), 3.10-3.22 (2H, m), 3.35-3.40 (3H, m), 3.60 -3.88 (2H, m), 4.38-4.46 (2H, m), 4.70-4.79 (2H, m), 7.02 (1H, d, J = 9.5Hz), 7.15 (1H, s), 7.28 (1H, dd , J = 5.1,3.7Hz), 7.74 (1H, d, J = 3.7Hz), 7.89 (1H, d, J = 5.1Hz), 7.94 (1H, d, J = 5.1Hz), 8.10 (1H, d , J = 9.5Hz), 8.56 (1H, d, J = 5.1Hz), 9.27 (1H, s), 10.20-10.40 (2H, broad), 10.73-10.90 (1H, broad)

実施例３０と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オン塩酸塩およびフェニルプロパルギルアルデヒドから１−（２−（４−（（３−フェニル−２−プロピニル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.40-1.52(2H,m),1.88-1.96(2H,m),2.22-2.33(2H,m),2.70-2.85(3H,m),2.99-3.07(2H,m),3.68(2H,s),4.46-4.52(2H,m),6.89(1H,d,J=9.5Hz),7.28-7.32(3H,m),7.38-7.44(3H,m),7.65(1H,d,J=9.5Hz),8.44(1H,d,J=5.1Hz),8.92(1H,s) Example 36

In a manner similar to that in Example 30, 1- (2- (4-aminopiperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one hydrochloride and phenylpropargylaldehyde were converted to 1- (2 -(4-((3-Phenyl-2-propynyl) amino) piperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.40-1.52 (2H, m), 1.88-1.96 (2H, m), 2.22-2.33 (2H, m), 2.70-2.85 (3H, m), 2.99-3.07 (2H, m), 3.68 (2H, s), 4.46-4.52 (2H, m), 6.89 (1H, d, J = 9.5Hz), 7.28-7.32 (3H, m), 7.38-7.44 (3H, m ), 7.65 (1H, d, J = 9.5Hz), 8.44 (1H, d, J = 5.1Hz), 8.92 (1H, s)

実施例８と同様の手法により、１−（２−（４−（（３−フェニル−２−プロピニル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オンから１−（２−（４−（（３−フェニル−２−プロピニル）アミノ）ピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(DMSO-d₆)δ値：2.00-2.13(2H,m),2.32-2.41(2H,m),3.14-3.26(2H,m),3.35-3.75(3H,m),3.80-3.86(2H,m),4.20-4.28(2H,m),4.70-4.78(2H,m),7.01(1H,d,J=9.5Hz),7.42-7.48(3H,m),7.51-7.56(2H,m),7.92(1H,d,J=5.4Hz),8.09(1H,d,J=9.5Hz),8.56(1H,d,J=5.1Hz),9.26(1H,s),9.99-10.08(2H,m),10.70-10.82(1H,m) Example 37

In the same manner as in Example 8, 1- (2- (4-((3-phenyl-2-propynyl) amino) piperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one To 1- (2- (4-((3-phenyl-2-propynyl) amino) piperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one hydrochloride.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.00-2.13 (2H, m), 2.32-2.41 (2H, m), 3.14-3.26 (2H, m), 3.35-3.75 (3H, m), 3.80 -3.86 (2H, m), 4.20-4.28 (2H, m), 4.70-4.78 (2H, m), 7.01 (1H, d, J = 9.5Hz), 7.42-7.48 (3H, m), 7.51-7.56 (2H, m), 7.92 (1H, d, J = 5.4Hz), 8.09 (1H, d, J = 9.5Hz), 8.56 (1H, d, J = 5.1Hz), 9.26 (1H, s), 9.99 -10.08 (2H, m), 10.70-10.82 (1H, m)

実施例３０と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−１，７−ナフチリジン−２（１Ｈ）−オン塩酸塩および３−オキソ−３，４−ジヒドロ−２Ｈ−１，４−ベンゾオキサジン−６−カルバルデヒドから６−（（（１−（２−（２−オキソ−１，７−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）アミノ）メチル）−２Ｈ−１，４−ベンゾオキサジン−３（４Ｈ）−オンを得た。
¹H-NMR(DMSO-d₆)δ値：1.13-1.25(2H,m),1.70-1.79(2H,m),1.97-2.06(2H,m),2.28-2.37(1H,m),2.46-2.57(2H,m),2.84-2.92(2H,m),3.59(2H,s),4.35-4.42(2H,m),4.50(2H,s),6.81-6.90(4H,m),7.67(1H,d,J=5.0Hz),7.94(1H,d,J=9.5Hz),8.40(1H,d,J=5.0Hz),8.92(1H,s),10.61(1H,s) Example 38

In a manner similar to that in Example 30, 1- (2- (4-aminopiperidin-1-yl) ethyl) -1,7-naphthyridin-2 (1H) -one hydrochloride and 3-oxo-3,4- Dihydro-2H-1,4-benzoxazine-6-carbaldehyde to 6-(((1- (2- (2-oxo-1,7-naphthyridin-1 (2H) -yl) ethyl) piperidine-4- Yl) amino) methyl) -2H-1,4-benzoxazin-3 (4H) -one.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.13-1.25 (2H, m), 1.70-1.79 (2H, m), 1.97-2.06 (2H, m), 2.28-2.37 (1H, m), 2.46 -2.57 (2H, m), 2.84-2.92 (2H, m), 3.59 (2H, s), 4.35-4.42 (2H, m), 4.50 (2H, s), 6.81-6.90 (4H, m), 7.67 (1H, d, J = 5.0Hz), 7.94 (1H, d, J = 9.5Hz), 8.40 (1H, d, J = 5.0Hz), 8.92 (1H, s), 10.61 (1H, s)

（１）実施例１と同様の手法により、（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒドおよびｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（２−メチルピペリジン−４−イル）カルバマートからｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）−２−メチルピペリジン−４−イル）カルバマートを得た。
（２）実施例５４と同様の手法により、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）−２−メチルピペリジン−４−イル）カルバマートから１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）−２−メチルピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.11(3H,d,J=6.1Hz),1.22-1.44(2H,m),1.84-1.98(2H,m),2.28-2.44(1H,m),2.56-2.61(2H,m),2.68-2.90(1H,m),2.97-3.07(1H,m),3.08-3.16(1H,m),3.79(2H,s),3.97(3H,s),4.16-4.20(1H,m),4.34-4.38(4H,m),4.55-4.59(1H,m),6.74(1H,d,J=9.6Hz),6.81(1H,s),7.24(1H,d,J=2.3Hz),7.84(1H,d,J=9.6Hz),8.10(1H,s),8.27(1H,d,J=2.3Hz) Example 39

(1) In the same manner as in Example 1, (7-methoxy-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde and tert-butyl = (2,3-dihydro (1,4 ) Dioxino (2,3-c) pyridin-7-ylmethyl) (2-methylpiperidin-4-yl) carbamate to tert-butyl = (2,3-dihydro (1,4) dioxino (2,3-c) Pyridin-7-ylmethyl) (1- (2- (7-methoxy-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) -2-methylpiperidin-4-yl) carbamate was obtained. .
(2) In the same manner as in Example 54, tert-butyl = (2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) (1- (2- (7- Methoxy-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) -2-methylpiperidin-4-yl) carbamate to 1- (2- (4-((2,3-dihydro (1 , 4) Dioxyno (2,3-c) pyridin-7-ylmethyl) amino) -2-methylpiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one It was.
¹ H-NMR (CDCl ₃ ) δ value: 1.11 (3H, d, J = 6.1 Hz), 1.22-1.44 (2H, m), 1.84-1.98 (2H, m), 2.28-2.44 (1H, m), 2.56-2.61 (2H, m), 2.68-2.90 (1H, m), 2.97-3.07 (1H, m), 3.08-3.16 (1H, m), 3.79 (2H, s), 3.97 (3H, s), 4.16-4.20 (1H, m), 4.34-4.38 (4H, m), 4.55-4.59 (1H, m), 6.74 (1H, d, J = 9.6Hz), 6.81 (1H, s), 7.24 (1H, d, J = 2.3Hz), 7.84 (1H, d, J = 9.6Hz), 8.10 (1H, s), 8.27 (1H, d, J = 2.3Hz)

１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.13gのＮ，Ｎ−ジメチルホルムアミド2.6mL溶液に５，６，７，８−テトラヒドロキノキサリン−２−カルバルデヒド75mg、酢酸0.26mL、トリエチルアミン0.21mLおよび水素化トリアセトキシホウ素ナトリウム98mgを加え、室温で9時間40分間攪拌した。水、飽和炭酸水素ナトリウム水溶液および酢酸エチルを加え、20％水酸化ナトリウム水溶液でpH11.5に調整した後、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝１０：１］で精製し、酢酸エチル、4mol/L塩化水素／酢酸エチル溶液を加えた。減圧下で溶媒を留去し、ジエチルエーテルを加え、固形物を濾取し、淡褐色固体の７−メトキシ−１−（２−（４−（（５，６，７，８−テトラヒドロキノキサリン−２−イルメチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩92mgを得た。
¹H-NMR(D₂O)δ値：1.87-1.95(4H,m),2.01-2.14(2H,m),2.51-2.60(2H,m),2.92-3.00(4H,m),3.19-3.34(2H,m),3.59-3.78(3H,m),3.97-4.06(2H,m),4.04(3H,s),4.47(2H,s),4.76-4.79(2H,m),6.88(1H,d,J=9.8Hz),7.47(1H,d,J=2.1Hz),8.06(1H,d,J=9.8Hz),8.39(1H,s),8.41(1H,d,J=2.1Hz) Example 40

In a solution of 0.13 g of 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride in 2.6 mL of N, N-dimethylformamide 5 , 6,7,8-tetrahydroquinoxaline-2-carbaldehyde, 0.26 mL of acetic acid, 0.21 mL of triethylamine and 98 mg of sodium triacetoxyborohydride were added and stirred at room temperature for 9 hours and 40 minutes. Water, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added, and the pH was adjusted to 11.5 with a 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography [eluent: chloroform: methanol = 10: 1], and ethyl acetate and a 4 mol / L hydrogen chloride / ethyl acetate solution were added. The solvent was distilled off under reduced pressure, diethyl ether was added, the solid was collected by filtration, and a light brown solid 7-methoxy-1- (2- (4-((5,6,7,8-tetrahydroquinoxaline- 92 mg of 2-ylmethyl) amino) piperidin-1-yl) ethyl) -1,5-naphthyridin-2 (1H) -one hydrochloride were obtained.
¹ H-NMR (D ₂ O) δ value: 1.87-1.95 (4H, m), 2.01-2.14 (2H, m), 2.51-2.60 (2H, m), 2.92-3.00 (4H, m), 3.19- 3.34 (2H, m), 3.59-3.78 (3H, m), 3.97-4.06 (2H, m), 4.04 (3H, s), 4.47 (2H, s), 4.76-4.79 (2H, m), 6.88 ( 1H, d, J = 9.8Hz), 7.47 (1H, d, J = 2.1Hz), 8.06 (1H, d, J = 9.8Hz), 8.39 (1H, s), 8.41 (1H, d, J = 2.1 Hz)

（１）１−（１，３−ジオキソラン−２−イルメチル）ピリド（３，４−ｂ）ピラジン−２（１Ｈ）−オン95mgに80％トリフルオロ酢酸水溶液4.0mLを加え、室温で2時間攪拌した後、一晩放置した。80％トリフルオロ酢酸水溶液4.0mLを加え、50〜70℃で6時間攪拌した。反応混合物を室温まで冷却し、減圧下で溶媒を留去した。得られた残留物にクロロホルムおよび水を加え、1mol/L水酸化ナトリウム水溶液でpH7.0に調整した。有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、淡褐色油状物の（２−オキソピリド（３，４−ｂ）ピラジン−１（２Ｈ）−イル）アセトアルデヒド40mgを得た。
（２）（２−オキソピリド（３，４−ｂ）ピラジン−１（２Ｈ）−イル）アセトアルデヒド40mgのジクロロメタン2mL懸濁液に、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（ピペリジン−４−イル）カルバマート74mgのジクロロメタン2mL溶液および酢酸12μLを加え、室温で10分間攪拌した。水素化トリアセトキシホウ素ナトリウム67mgを加え、室温で30分間攪拌した。反応混合物に、クロロホルムおよび飽和炭酸水素ナトリウム水溶液を加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をフラッシュ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＝１００：０−９０：１０］で精製し、淡褐色油状物のｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（１−（２−（２−オキソピリド（３，４−ｂ）ピラジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート80mgを得た。
¹H-NMR(CDCl₃)δ値：1.42(9H,s),1.54-1.72(4H,m),2.05-2.23(2H,m),2.59-2.66(2H,m),2.91-3.00(2H,m),3.95-4.14(1H,m),4.20-4.30(8H,m),6.64-6.70(1H,m),6.73(1H,d,J=2.0Hz),6.78(1H,d,J=8.3Hz),7.23(1H,d,J=5.9Hz),8.30(1H,s),8.61(1H,d,J=5.9Hz),9.08(1H,s) Example 41

(1) 1- (1,3-dioxolan-2-ylmethyl) pyrido (3,4-b) pyrazin-2 (1H) -one (95 mL) was added with 80% aqueous trifluoroacetic acid (4.0 mL) and stirred at room temperature for 2 hours. And then left overnight. An 80% aqueous trifluoroacetic acid solution (4.0 mL) was added, and the mixture was stirred at 50 to 70 ° C. for 6 hours. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. Chloroform and water were added to the obtained residue, and the pH was adjusted to 7.0 with a 1 mol / L aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and (2-oxopyrido (3,4-b) pyrazin-1 (2H) -yl) acetaldehyde was obtained as a light brown oil. 40 mg was obtained.
(2) (2-Oxopyrido (3,4-b) pyrazin-1 (2H) -yl) acetaldehyde in a suspension of 40 mg of dichloromethane in 2 mL of tert-butyl = (2,3-dihydro-1,4-benzodioxin A solution of -6-ylmethyl) (piperidin-4-yl) carbamate 74 mg in 2 mL of dichloromethane and 12 μL of acetic acid was added, and the mixture was stirred at room temperature for 10 minutes. 67 mg of sodium triacetoxyborohydride was added and stirred at room temperature for 30 minutes. Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash silica gel column chromatography [gradient elution of chloroform: methanol = 100: 0-90: 10], and tert-butyl = (2,3-dihydro-1,4 -Benzodioxin-6-ylmethyl) (1- (2- (2-oxopyrido (3,4-b) pyrazin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate 80 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.42 (9H, s), 1.54-1.72 (4H, m), 2.05-2.23 (2H, m), 2.59-2.66 (2H, m), 2.91-3.00 (2H , m), 3.95-4.14 (1H, m), 4.20-4.30 (8H, m), 6.64-6.70 (1H, m), 6.73 (1H, d, J = 2.0Hz), 6.78 (1H, d, J = 8.3Hz), 7.23 (1H, d, J = 5.9Hz), 8.30 (1H, s), 8.61 (1H, d, J = 5.9Hz), 9.08 (1H, s)

実施例２と同様の手法により、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（１−（２−（２−オキソピリド（３，４−ｂ）ピラジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートから１−（２−（４−（（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）エチル）ピリド（３，４−ｂ）ピラジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：1.83-1.98(2H,m),2.34-2.45(2H,m),3.09-3.21(2H,m),3.40-3.56(3H,m),3.82-3.90(2H,m),4.10(2H,s),4.21(4H,s),4.50-4.80(2H,m),6.85-6.92(3H,m),7.86(1H,d,J=6.8Hz),8.40(1H,s),8.69(1H,d,J=6.8Hz),9.16(1H,s) Example 42

In the same manner as in Example 2, tert-butyl = (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (1- (2- (2-oxopyrido (3,4-b) pyrazine- 1 (2H) -yl) ethyl) piperidin-4-yl) carbamate to 1- (2- (4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl) amino) piperidine-1- Yl) ethyl) pyrido (3,4-b) pyrazin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.83-1.98 (2H, m), 2.34-2.45 (2H, m), 3.09-3.21 (2H, m), 3.40-3.56 (3H, m), 3.82 3.90 (2H, m), 4.10 (2H, s), 4.21 (4H, s), 4.50-4.80 (2H, m), 6.85-6.92 (3H, m), 7.86 (1H, d, J = 6.8Hz) , 8.40 (1H, s), 8.69 (1H, d, J = 6.8Hz), 9.16 (1H, s)

（７−メトキシ−２−オキソ−１，８−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド0.20gのジクロロメタン20mL溶液にｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（ピペリジン−４−イル）カルバマート0.32gおよび酢酸53μLを加え、室温で15分間攪拌した。反応混合物に水素化トリアセトキシホウ素ナトリウム0.29gを加え、室温で1時間40分間攪拌した。水、飽和炭酸水素ナトリウム水溶液およびクロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［溶離液；クロロホルム：メタノール＝５０：１］で精製し、白色泡状物のｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（１−（２−（７−メトキシ−２−オキソ−１，８−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.50gを得た。
¹H-NMR(CDCl₃)δ値：1.41(9H,s),1.59-1.72(4H,m),2.09-2.25(2H,m),2.64-2.72(2H,m),3.07-3.14(2H,m),3.99(3H,s),4.00-4.15(1H,m),4.20-4.34(6H,m),4.57-4.63(2H,m),6.56(1H,d,J=9.4Hz),6.60(1H,d,J=8.3Hz),6.64-6.69(1H,m),6.71-6.73(1H,m),6.77(1H,d,J=8.3Hz),7.55(1H,d,J=9.4Hz),7.71(1H,d,J=8.3Hz) Example 43

To a solution of 0.20 g of (7-methoxy-2-oxo-1,8-naphthyridin-1 (2H) -yl) acetaldehyde in 20 mL of dichloromethane was added tert-butyl = (2,3-dihydro-1,4-benzodioxin-6 (Ilmethyl) (piperidin-4-yl) carbamate (0.32 g) and acetic acid (53 μL) were added, and the mixture was stirred at room temperature for 15 minutes. To the reaction mixture, 0.29 g of sodium triacetoxyborohydride was added, and stirred at room temperature for 1 hour and 40 minutes. Water, saturated aqueous sodium hydrogen carbonate solution and chloroform were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 50: 1], and tert-butyl = (2,3-dihydro-1,4-benzodioxin-6) as a white foam. 0.50 g of -ylmethyl) (1- (2- (7-methoxy-2-oxo-1,8-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.41 (9H, s), 1.59-1.72 (4H, m), 2.09-2.25 (2H, m), 2.64-2.72 (2H, m), 3.07-3.14 (2H , m), 3.99 (3H, s), 4.00-4.15 (1H, m), 4.20-4.34 (6H, m), 4.57-4.63 (2H, m), 6.56 (1H, d, J = 9.4Hz), 6.60 (1H, d, J = 8.3Hz), 6.64-6.69 (1H, m), 6.71-6.73 (1H, m), 6.77 (1H, d, J = 8.3Hz), 7.55 (1H, d, J = 9.4Hz), 7.71 (1H, d, J = 8.3Hz)

ｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（１−（２−（７−メトキシ−２−オキソ−１，８−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.50gに4mol/L塩化水素／酢酸エチル溶液15mLを加え、室温で43時間攪拌した。減圧下で溶媒を留去し、得られた残留物にメタノールを加え、減圧下で溶媒を留去した後、得られた残留物に酢酸エチルを加え、固形物を濾取し、淡黄色固体の１−（２−（４−（（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，８−ナフチリジン−２（１Ｈ）−オン塩酸塩0.41gを得た。
¹H-NMR(D₂O)δ値：1.92-2.08(2H,m),2.45-2.58(2H,m),3.16-3.31(2H,m),3.56-3.72(3H,m),3.96-4.10(2H,m),4.05(3H,s),4.17-4.28(2H,m),4.33(4H,s),4.82-4.98(2H,m),6.64(1H,d,J=9.3Hz),6.85(1H,d,J=8.4Hz),6.95-7.06(3H,m),7.96(1H,d,J=9.3Hz),8.04(1H,d,J=8.4Hz) Example 44

tert-Butyl = (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (1- (2- (7-methoxy-2-oxo-1,8-naphthyridin-1 (2H) -yl) 15 mL of a 4 mol / L hydrogen chloride / ethyl acetate solution was added to 0.50 g of ethyl) piperidin-4-yl) carbamate, and the mixture was stirred at room temperature for 43 hours. The solvent was distilled off under reduced pressure, methanol was added to the obtained residue, the solvent was distilled off under reduced pressure, ethyl acetate was added to the obtained residue, and the solid was collected by filtration to give a pale yellow solid. 1- (2- (4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl) amino) piperidin-1-yl) ethyl) -7-methoxy-1,8-naphthyridine-2 0.41 g of (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.92-2.08 (2H, m), 2.45-2.58 (2H, m), 3.16-3.31 (2H, m), 3.56-3.72 (3H, m), 3.96- 4.10 (2H, m), 4.05 (3H, s), 4.17-4.28 (2H, m), 4.33 (4H, s), 4.82-4.98 (2H, m), 6.64 (1H, d, J = 9.3Hz) , 6.85 (1H, d, J = 8.4Hz), 6.95-7.06 (3H, m), 7.96 (1H, d, J = 9.3Hz), 8.04 (1H, d, J = 8.4Hz)

１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，８−ナフチリジン−２（１Ｈ）−オン塩酸塩0.20gのメタノール4mL溶液に28％ナトリウムメトキシド0.21g、２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−カルバルデヒド88mg、酢酸30μLおよび水素化シアノホウ素ナトリウム67mgを加え、室温で6時間45分間攪拌した。２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−カルバルデヒド27mgおよび酢酸9μLを加え、1時間30分間攪拌した。一晩放置後、室温で2時間攪拌し、２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−カルバルデヒド27mgおよび酢酸9μLを加え、2時間30分間攪拌した。反応混合物に、水、1mol/L水酸化ナトリウム水溶液およびクロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせて、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、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［溶離液；クロロホルム：メタノール＝５：１］で精製し、得られた油状物を4mol/L塩化水素／酢酸エチル溶液およびメタノールに溶解後、減圧下で溶媒を留去した。得られた残留物に酢酸エチルを加え、固形物を濾取し、白色固体の１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，８−ナフチリジン−２（１Ｈ）−オン塩酸塩0.18gを得た。
¹H-NMR(D₂O)δ値：2.00-2.13(2H,m),2.52-2.62(2H,m),3.21-3.33(2H,m),3.64-3.83(3H,m),3.98-4.15(5H,m),4.49-4.54(2H,m),4.59(2H,s),4.64-4.68(2H,m),4.89-4.94(2H,m),6.65(1H,d,J=9.5Hz),6.86(1H,d,J=8.6Hz),7.56(1H,s),7.97(1H,d,J=9.5Hz),8.05(1H,d,J=8.6Hz),8.43(1H,s) Example 45

1- (2- (4-Aminopiperidin-1-yl) ethyl) -7-methoxy-1,8-naphthyridin-2 (1H) -one hydrochloride 0.20 g in methanol 4 mL solution 28% sodium methoxide 0.21 g , 2,3-dihydro (1,4) dioxino (2,3-c) pyridine-7-carbaldehyde 88 mg, acetic acid 30 μL and sodium cyanoborohydride 67 mg were added, and the mixture was stirred at room temperature for 6 hours 45 minutes. 2,3-Dihydro (1,4) dioxyno (2,3-c) pyridine-7-carbaldehyde 27 mg and acetic acid 9 μL were added and stirred for 1 hour 30 minutes. After standing overnight, the mixture was stirred at room temperature for 2 hours, 27 mg of 2,3-dihydro (1,4) dioxyno (2,3-c) pyridine-7-carbaldehyde and 9 μL of acetic acid were added, and the mixture was stirred for 2 hours and 30 minutes. Water, a 1 mol / L aqueous sodium hydroxide solution and chloroform were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 5: 1]. The obtained oil was dissolved in a 4 mol / L hydrogen chloride / ethyl acetate solution and methanol, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the solid was collected by filtration to give 1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-c) pyridine) as a white solid. 0.18 g of -7-ylmethyl) amino) piperidin-1-yl) ethyl) -7-methoxy-1,8-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 2.00-2.13 (2H, m), 2.52-2.62 (2H, m), 3.21-3.33 (2H, m), 3.64-3.83 (3H, m), 3.98- 4.15 (5H, m), 4.49-4.54 (2H, m), 4.59 (2H, s), 4.64-4.68 (2H, m), 4.89-4.94 (2H, m), 6.65 (1H, d, J = 9.5 Hz), 6.86 (1H, d, J = 8.6Hz), 7.56 (1H, s), 7.97 (1H, d, J = 9.5Hz), 8.05 (1H, d, J = 8.6Hz), 8.43 (1H, s)

（３−オキソピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）アセトアルデヒド0.13gに、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（ピペリジン−４−イル）カルバマート0.23gのジクロロメタン4mL溶液に酢酸38μLおよび水素化トリアセトキシホウ素ナトリウム0.21gを加え、室温で3時間攪拌した。反応混合物にクロロホルムおよび飽和炭酸水素ナトリウム水溶液を加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をフラッシュ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＝１００：０−９０：１０］で精製し、淡褐色油状物のｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（１−（２−（３−オキソピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.24gを得た。
¹H-NMR(CDCl₃)δ値：1.41(9H,s),1.50-1.66(4H,m),1.98-2.20(2H,m),2.64-2.72(2H,m),3.01-3.10(2H,m),3.95-4.14(1H,m),4.18-4.30(6H,m),4.54-4.61(2H,m),6.63-6.68(1H,m),6.69-6.72(1H,m),6.77(1H,d,J=8.3Hz),7.31(1H,dd,J=8.0,4.6Hz),8.16(1H,dd,J=8.0,1.6Hz),8.31(1H,s),8.56(1H,dd,J=4.6,1.6Hz) Example 46

To 0.13 g of (3-oxopyrido (2,3-b) pyrazin-4 (3H) -yl) acetaldehyde, tert-butyl = (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (piperidine- To a solution of 4-yl) carbamate 0.23 g in 4 mL of dichloromethane were added 38 μL of acetic acid and 0.21 g of sodium triacetoxyborohydride, and the mixture was stirred at room temperature for 3 hours. Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by flash silica gel column chromatography [gradient elution of chloroform: methanol = 100: 0-90: 10], and tert-butyl = (2,3-dihydro-1,4 -Benzodioxin-6-ylmethyl) (1- (2- (3-oxopyrido (2,3-b) pyrazin-4 (3H) -yl) ethyl) piperidin-4-yl) carbamate 0.24 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.41 (9H, s), 1.50-1.66 (4H, m), 1.98-2.20 (2H, m), 2.64-2.72 (2H, m), 3.01-3.10 (2H , m), 3.95-4.14 (1H, m), 4.18-4.30 (6H, m), 4.54-4.61 (2H, m), 6.63-6.68 (1H, m), 6.69-6.72 (1H, m), 6.77 (1H, d, J = 8.3Hz), 7.31 (1H, dd, J = 8.0,4.6Hz), 8.16 (1H, dd, J = 8.0,1.6Hz), 8.31 (1H, s), 8.56 (1H, (dd, J = 4.6,1.6Hz)

実施例２と同様の手法により、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（１−（２−（３−オキソピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートから４−（２−（４−（（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）エチル）ピリド（２，３−ｂ）ピラジン−３（４Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：1.90-2.05(2H,m),2.45-2.55(2H,m),3.16-3.32(2H,m),3.55-3.71(3H,m),3.96-4.07(2H,m),4.21(2H,s),4.33(4H,s),4.88-4.93(2H,m),6.95-7.04(3H,m),7.58(1H,dd,J=8.0,4.8Hz),8.35(1H,dd,J=8.0,1.5Hz),8.39(1H,s),8.71(1H,dd,J=4.8,1.5Hz) Example 47

In the same manner as in Example 2, tert-butyl = (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (1- (2- (3-oxopyrido (2,3-b) pyrazine- 4 (3H) -yl) ethyl) piperidin-4-yl) carbamate to 4- (2- (4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl) amino) piperidine-1- Yl) ethyl) pyrido (2,3-b) pyrazin-3 (4H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.90-2.05 (2H, m), 2.45-2.55 (2H, m), 3.16-3.32 (2H, m), 3.55-3.71 (3H, m), 3.96- 4.07 (2H, m), 4.21 (2H, s), 4.33 (4H, s), 4.88-4.93 (2H, m), 6.95-7.04 (3H, m), 7.58 (1H, dd, J = 8.0,4.8 Hz), 8.35 (1H, dd, J = 8.0, 1.5Hz), 8.39 (1H, s), 8.71 (1H, dd, J = 4.8, 1.5Hz)

実施例１と同様の手法により、（２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒドおよびｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（ピペリジン−４−イル）カルバマートからｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートを得た。
¹H-NMR(CDCl₃-D₂O)δ値：1.34-1.52(9H,m),1.60-1.70(4H,m),2.08-2.22(2H,m),2.58-2.63(2H,m),2.95-3.04(2H,m),4.00-4.20(1H,m),4.24-4.40(8H,m),6.74(1H,s),6.91(1H,d,J=9.8Hz),7.46(1H,dd,J=8.6,4.5Hz),7.76(1H,d,J=8.6Hz),7.91(1H,d,J=9.8Hz),8.05(1H,s),8.53-8.56(1H,m) Example 48

In the same manner as in Example 1, (2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde and tert-butyl = (2,3-dihydro (1,4) dioxino (2,3- c) Pyridin-7-ylmethyl) (piperidin-4-yl) carbamate to tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (1- ( 2- (2-Oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ -D ₂ O) δ value: 1.34-1.52 (9H, m), 1.60-1.70 (4H, m), 2.08-2.22 (2H, m), 2.58-2.63 (2H, m) , 2.95-3.04 (2H, m), 4.00-4.20 (1H, m), 4.24-4.40 (8H, m), 6.74 (1H, s), 6.91 (1H, d, J = 9.8Hz), 7.46 (1H , dd, J = 8.6,4.5Hz), 7.76 (1H, d, J = 8.6Hz), 7.91 (1H, d, J = 9.8Hz), 8.05 (1H, s), 8.53-8.56 (1H, m)

実施例２と同様の手法により、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートから１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(DMSO-d₆-D₂O)δ値：2.02-2.18(2H,m),2.36-2.48(2H,m),3.12-3.24(2H,m),3.30-3.50(3H,m),3.72-3.88(2H,m),4.36-4.46(4H,m),4.53(2H,s),4.65-4.73(2H,m),7.00(1H,d,J=9.8Hz),7.62(1H,s),7.76(1H,dd,J=8.6,4.6Hz),8.08(1H,d,J=9.8Hz),8.42(1H,d,J=8.6Hz),8.50(1H,s),8.65(1H,d,J=4.6Hz) Example 49

In the same manner as in Example 2, tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (1- (2- (2-oxo-1 , 5-Naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate to 1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-c)) Pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ -D ₂ O) δ value: 2.02-2.18 (2H, m), 2.36-2.48 (2H, m), 3.12-3.24 (2H, m), 3.30-3.50 (3H, m), 3.72-3.88 (2H, m), 4.36-4.46 (4H, m), 4.53 (2H, s), 4.65-4.73 (2H, m), 7.00 (1H, d, J = 9.8Hz), 7.62 (1H, s), 7.76 (1H, dd, J = 8.6,4.6Hz), 8.08 (1H, d, J = 9.8Hz), 8.42 (1H, d, J = 8.6Hz), 8.50 (1H, s) , 8.65 (1H, d, J = 4.6Hz)

実施例３０と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩および３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド（３，２−ｂ）（１，４）チアジン−６−カルバルデヒドから６−（（（１−（２−（２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）アミノ）メチル）−２Ｈ−ピリド（３，２−ｂ）（１，４）チアジン−３（４Ｈ）−オンを得た。
¹H-NMR(CDCl₃-D₂O)δ値1.36-1.50(2H,m),1.82-1.92(2H,m),2.12-2.20(2H,m),2.44-2.54(1H,m),2.60-2.64(2H,m),2.90-3.00(2H,m),3.44(2H,s),3.79(2H,s),4.34-4.39(2H,m),6.89(1H,d,J=9.6Hz),6.94(1H,d,J=7.8Hz),7.44(1H,dd,J=8.5,4.4Hz),7.54(1H,d,J=7.8Hz),7.78(1H,d,J=8.5Hz),7.89(1H,d,J=9.6Hz),8.52(1H,d,J=4.4Hz) Example 50

In the same manner as in Example 30, 1- (2- (4-aminopiperidin-1-yl) ethyl) -1,5-naphthyridin-2 (1H) -one hydrochloride and 3-oxo-3,4- Dihydro-2H-pyrido (3,2-b) (1,4) thiazine-6-carbaldehyde to 6-(((1- (2- (2-oxo-1,5-naphthyridine-1 (2H)- Yl) ethyl) piperidin-4-yl) amino) methyl) -2H-pyrido (3,2-b) (1,4) thiazin-3 (4H) -one was obtained.
¹ H-NMR (CDCl ₃ -D ₂ O) δ value 1.36-1.50 (2H, m), 1.82-1.92 (2H, m), 2.12-2.20 (2H, m), 2.44-2.54 (1H, m), 2.60-2.64 (2H, m), 2.90-3.00 (2H, m), 3.44 (2H, s), 3.79 (2H, s), 4.34-4.39 (2H, m), 6.89 (1H, d, J = 9.6 Hz), 6.94 (1H, d, J = 7.8Hz), 7.44 (1H, dd, J = 8.5,4.4Hz), 7.54 (1H, d, J = 7.8Hz), 7.78 (1H, d, J = 8.5 Hz), 7.89 (1H, d, J = 9.6Hz), 8.52 (1H, d, J = 4.4Hz)

実施例４１と同様の手法により、１−（１，３−ジオキソラン−２−イルメチル）ピリド（２，３−ｂ）ピラジン−２（１Ｈ）−オンから（２−オキソピリド（２，３−ｂ）ピラジン−１（２Ｈ）−イル）アセトアルデヒドを得た。（２−オキソピリド（２，３−ｂ）ピラジン−１（２Ｈ）−イル）アセトアルデヒドおよびｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（ピペリジン−４−イル）カルバマートからｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（１−（２−（２−オキソピリド（２，３−ｂ）ピラジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.42(9H,s),1.53-1.72(4H,m),2.02-2.23(2H,m),2.49-2.66(2H,m),2.90-3.00(2H,m),3.94-4.13(1H,m),4.20-4.35(8H,m),6.64-6.80(3H,m),7.50(1H,dd,J=8.6,4.5Hz),7.77(1H,dd,J=8.6,1.3Hz),8.53(1H,s),8.66(1H,dd,J=4.5,1.3Hz) Example 51

In the same manner as in Example 41, from 1- (1,3-dioxolan-2-ylmethyl) pyrido (2,3-b) pyrazin-2 (1H) -one to (2-oxopyrido (2,3-b) Pyrazin-1 (2H) -yl) acetaldehyde was obtained. (2-Oxopyrido (2,3-b) pyrazin-1 (2H) -yl) acetaldehyde and tert-butyl = (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (piperidin-4-yl ) Carbamate to tert-butyl = (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (1- (2- (2-oxopyrido (2,3-b) pyrazin-1 (2H) -yl) ) Ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.42 (9H, s), 1.53-1.72 (4H, m), 2.02-2.23 (2H, m), 2.49-2.66 (2H, m), 2.90-3.00 (2H , m), 3.94-4.13 (1H, m), 4.20-4.35 (8H, m), 6.64-6.80 (3H, m), 7.50 (1H, dd, J = 8.6, 4.5Hz), 7.77 (1H, dd , J = 8.6,1.3Hz), 8.53 (1H, s), 8.66 (1H, dd, J = 4.5,1.3Hz)

実施例２と同様の手法により、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（１−（２−（２−オキソピリド（２，３−ｂ）ピラジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートから１−（２−（４−（（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）エチル）ピリド（２，３−ｂ）ピラジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(DMSO-d₆)δ値：1.94-2.12(2H,m),2.27-2.40(2H,m),3.00-3.86(7H,m),4.02-4.13(2H,m),4.25(4H,s),4.60-4.69(2H,m),6.91(1H,d,J=8.3Hz),7.00-7.07(1H,m),7.15(1H,s),7.66-7.79(1H,m),8.32-8.38(1H,m),8.50(1H,s),8.63(1H,d,J=4.4Hz),9.40-9.60(2H,broad),10.65-10.85(1H,broad) Example 52

In the same manner as in Example 2, tert-butyl = (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (1- (2- (2-oxopyrido (2,3-b) pyrazine- 1 (2H) -yl) ethyl) piperidin-4-yl) carbamate to 1- (2- (4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl) amino) piperidine-1- Yl) ethyl) pyrido (2,3-b) pyrazin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.94-21.12 (2H, m), 2.27-2.40 (2H, m), 3.00-3.86 (7H, m), 4.02-4.13 (2H, m), 4.25 (4H, s), 4.60-4.69 (2H, m), 6.91 (1H, d, J = 8.3Hz), 7.00-7.07 (1H, m), 7.15 (1H, s), 7.66-7.79 (1H, m ), 8.32-8.38 (1H, m), 8.50 (1H, s), 8.63 (1H, d, J = 4.4Hz), 9.40-9.60 (2H, broad), 10.65-10.85 (1H, broad)

実施例４１と同様の手法により、４−（１，３−ジオキソラン−２−イルメチル）ピリド（３，４−ｂ）ピラジン−３（４Ｈ）−オンから（３−オキソピリド（３，４−ｂ）ピラジン−４（３Ｈ）−イル）アセトアルデヒドを得た。（３−オキソピリド（３，４−ｂ）ピラジン−４（３Ｈ）−イル）アセトアルデヒドおよびｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（ピペリジン−４−イル）カルバマートからｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（１−（２−（３−オキソピリド（３，４−ｂ）ピラジン−４（３Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.41(9H,s),1.53-1.69(4H,m),2.06-2.26(2H,m),2.65-2.72(2H,m),2.93-3.02(2H,m),3.96-4.12(1H,m),4.12-4.34(6H,m),4.34-4.40(2H,m),6.63-6.80(3H,m),7.74(1H,d,J=5.1Hz),8.45(1H,s),8.58(1H,d,J=5.1Hz),8.87(1H,s) Example 53

In a manner similar to that in Example 41, 4- (1,3-dioxolan-2-ylmethyl) pyrido (3,4-b) pyrazin-3 (4H) -one was converted into (3-oxopyrido (3,4-b). Pyrazin-4 (3H) -yl) acetaldehyde was obtained. (3-Oxopyrido (3,4-b) pyrazin-4 (3H) -yl) acetaldehyde and tert-butyl = (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (piperidin-4-yl ) Carbamate to tert-butyl = (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (1- (2- (3-oxopyrido (3,4-b) pyrazin-4 (3H) -yl ) Ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.41 (9H, s), 1.53-1.69 (4H, m), 2.06-2.26 (2H, m), 2.65-2.72 (2H, m), 2.93-3.02 (2H , m), 3.96-4.12 (1H, m), 4.12-4.34 (6H, m), 4.34-4.40 (2H, m), 6.63-6.80 (3H, m), 7.74 (1H, d, J = 5.1Hz ), 8.45 (1H, s), 8.58 (1H, d, J = 5.1Hz), 8.87 (1H, s)

ｔｅｒｔ−ブチル＝（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）（１−（２−（３−オキソピリド（３，４−ｂ）ピラジン−４（３Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート10mgのジクロロメタン1mL溶液に室温でトリフルオロ酢酸1.0mLを加えた。同温度で4時間攪拌し、減圧下で溶媒を留去した。得られた残留物にクロロホルムおよび水を加え、1mol/L塩酸でpH0.5に調整し、水層を分取した。水層にクロロホルムを加え、1mol/L水酸化ナトリウム水溶液でpH12に調整した。有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、淡褐色油状物の４−（２−（４−（（２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）エチル）ピリド（３，４−ｂ）ピラジン−３（４Ｈ）−オン2mgを得た。
¹H-NMR(CDCl₃)δ値：1.35-1.48(2H,m),1.83-1.95(2H,m),2.13-2.23(2H,m),2.50-2.65(1H,m),2.69-2.75(2H,m),2.91-3.00(2H,m),3.71(2H,s),4.24(4H,s),4.37-4.44(2H,m),6.76-6.86(3H,m),7.74(1H,d,J=5.1Hz),8.45(1H,s),8.58(1H,d,J=5.1Hz),8.90(1H,s) Example 54

tert-Butyl = (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (1- (2- (3-oxopyrido (3,4-b) pyrazin-4 (3H) -yl) ethyl) To a solution of piperidin-4-yl) carbamate 10 mg in 1 mL of dichloromethane was added 1.0 mL of trifluoroacetic acid at room temperature. The mixture was stirred at the same temperature for 4 hours, and the solvent was distilled off under reduced pressure. Chloroform and water were added to the obtained residue, adjusted to pH 0.5 with 1 mol / L hydrochloric acid, and the aqueous layer was separated. Chloroform was added to the aqueous layer, and the pH was adjusted to 12 with a 1 mol / L aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 4- (2- (4-((2,3 2 mg of -dihydro-1,4-benzodioxin-6-ylmethyl) amino) piperidin-1-yl) ethyl) pyrido (3,4-b) pyrazin-3 (4H) -one were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.35-1.48 (2H, m), 1.83-1.95 (2H, m), 2.13-2.23 (2H, m), 2.50-2.65 (1H, m), 2.69-2.75 (2H, m), 2.91-3.00 (2H, m), 3.71 (2H, s), 4.24 (4H, s), 4.37-4.44 (2H, m), 6.76-6.86 (3H, m), 7.74 (1H , d, J = 5.1Hz), 8.45 (1H, s), 8.58 (1H, d, J = 5.1Hz), 8.90 (1H, s)

４−（２−（４−アミノピペリジン−１−イル）エチル）−６−メトキシピリド（２，３−ｂ）ピラジン−３（４Ｈ）−オン塩酸塩0.21gのメタノール5mL懸濁液に室温で28％ナトリウムメトキシド／メタノール溶液0.22g、３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド（３，２−ｂ）（１，４）チアジン−６−カルバルデヒド0.11g、酢酸32μLおよび水素化シアノホウ素ナトリウム70mgを加え、室温で3時間攪拌した。反応混合物にクロロホルムおよび飽和炭酸水素ナトリウム水溶液を加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝１０：１］で精製した。得られた残留物にジエチルエーテルおよびヘキサンを加え、固形物を濾取し、淡褐色固体の６−（（（１−（２−（６−メトキシ−３−オキソピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）エチル）ピペリジン−４−イル）アミノ）メチル）−２Ｈ−ピリド（３，２−ｂ）（１，４）チアジン−３（４Ｈ）−オン0.13gを得た。
¹H-NMR(CDCl₃)δ値：1.34-1.47(2H,m),1.82-1.93(2H,m),2.12-2.22(2H,m),2.46-2.56(1H,m),2.71-2.78(2H,m),3.00-3.08(2H,m),3.46(2H,s),3.83(2H,s),4.03(3H,s),4.54-4.61(2H,m),6.72(1H,d,J=8.7Hz),6.97(1H,d,J=7.8Hz),7.56(1H,d,J=7.8Hz),8.01(1H,d,J=8.7Hz),8.14(1H,s),8.60-8.80(1H,broad) Example 55

4- (2- (4-Aminopiperidin-1-yl) ethyl) -6-methoxypyrido (2,3-b) pyrazin-3 (4H) -one hydrochloride in 0.21 g of methanol in a 5 mL suspension at room temperature 0.22 g% sodium methoxide / methanol solution, 3-oxo-3,4-dihydro-2H-pyrido (3,2-b) (1,4) thiazine-6-carbaldehyde 0.11 g, acetic acid 32 μL and cyanohydride 70 mg of sodium boron was added and stirred at room temperature for 3 hours. Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography [eluent: chloroform: methanol = 10: 1]. Diethyl ether and hexane were added to the obtained residue, and the solid substance was collected by filtration, and a light brown solid 6-(((1- (2- (6-methoxy-3-oxopyrido (2,3-b) pyrazine -4 (3H) -yl) ethyl) piperidin-4-yl) amino) methyl) -2H-pyrido (3,2-b) (1,4) thiazin-3 (4H) -one was obtained in an amount of 0.13 g.
¹ H-NMR (CDCl ₃ ) δ value: 1.34-1.47 (2H, m), 1.82-1.93 (2H, m), 2.12-2.22 (2H, m), 2.46-2.56 (1H, m), 2.71-2.78 (2H, m), 3.00-3.08 (2H, m), 3.46 (2H, s), 3.83 (2H, s), 4.03 (3H, s), 4.54-4.61 (2H, m), 6.72 (1H, d , J = 8.7Hz), 6.97 (1H, d, J = 7.8Hz), 7.56 (1H, d, J = 7.8Hz), 8.01 (1H, d, J = 8.7Hz), 8.14 (1H, s), 8.60-8.80 (1H, broad)

実施例１と同様の手法により、（７−メチル−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒドおよびｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（ピペリジン−４−イル）カルバマートからｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−メチル−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.39(9H,s),1.40-1.72(4H,m),2.08-2.25(2H,m),2.49(3H,s),2.56-2.63(2H,m),2.97-3.06(2H,m),4.02-4.20(1H,m),4.24-4.48(8H,m),6.73(1H,s),6.83(1H,d,J=9.6Hz),7.50-7.54(1H,m),7.86(1H,d,J=9.6Hz),8.05(1H,s),8.36-8.39(1H,m) Example 56

In the same manner as in Example 1, (7-methyl-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde and tert-butyl = (2,3-dihydro (1,4) dioxino ( 2,3-c) pyridin-7-ylmethyl) (piperidin-4-yl) carbamate to tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (1- (2- (7-Methyl-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.39 (9H, s), 1.40-1.72 (4H, m), 2.08-2.25 (2H, m), 2.49 (3H, s), 2.56-2.63 (2H, m ), 2.97-3.06 (2H, m), 4.02-4.20 (1H, m), 4.24-4.48 (8H, m), 6.73 (1H, s), 6.83 (1H, d, J = 9.6Hz), 7.50- 7.54 (1H, m), 7.86 (1H, d, J = 9.6Hz), 8.05 (1H, s), 8.36-8.39 (1H, m)

実施例２と同様の手法により、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−メチル−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートから１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−メチル−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：2.02-2.16(2H,m),2.51-2.63(2H,m),2.65(3H,s),3.25-3.37(2H,m),3.63-3.69(2H,m),3.71-3.82(1H,m),3.99-4.08(2H,m),4.46-4.51(2H,m),4.54(2H,s),4.59-4.63(2H,m),4.76-4.86(2H,m),7.17(1H,d,J=9.9Hz),7.48(1H,s),8.18(1H,d,J=9.9Hz),8.38(1H,s),8.40(1H,s),8.64(1H,m) Example 57

In the same manner as in Example 2, tert-butyl = (2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) (1- (2- (7-methyl-2 1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,4) -oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate 3-c) Pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -7-methyl-1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 2.02-2.16 (2H, m), 2.51-2.63 (2H, m), 2.65 (3H, s), 3.25-3.37 (2H, m), 3.63-3.69 ( 2H, m), 3.71-3.82 (1H, m), 3.99-4.08 (2H, m), 4.46-4.51 (2H, m), 4.54 (2H, s), 4.59-4.63 (2H, m), 4.76- 4.86 (2H, m), 7.17 (1H, d, J = 9.9Hz), 7.48 (1H, s), 8.18 (1H, d, J = 9.9Hz), 8.38 (1H, s), 8.40 (1H, s ), 8.64 (1H, m)

実施例１と同様の手法により、（７−メトキシ−２−オキソピリド（２，３−ｂ）ピラジン−１（２Ｈ）−イル）アセトアルデヒドおよびｔｅｒｔ−ブチル＝（３，４−ジヒドロ−２Ｈ−（１，４）ジオキセピノ（２，３−ｃ）ピリジン−８−イルメチル）（ピペリジン−４−イル）カルバマートからｔｅｒｔ−ブチル＝（３，４−ジヒドロ−２Ｈ−（１，４）ジオキセピノ（２，３−ｃ）ピリジン−８−イルメチル）（１−（２−（７−メトキシ−２−オキソピリド（２，３−ｂ）ピラジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.29-1.72(4H,m),1.37(9H,s),2.06-2.28(4H,m),2.58-2.66(2H,m),2.91-3.01(2H,m),3.99(3H,s),4.06-4.16(1H,m),4.20-4.38(8H,m),6.77(1H,s),7.15-7.21(1H,m),8.13(1H,s),8.33(1H,s),8.36(1H,d,J=2.7Hz) Example 58

In the same manner as in Example 1, (7-methoxy-2-oxopyrido (2,3-b) pyrazin-1 (2H) -yl) acetaldehyde and tert-butyl = (3,4-dihydro-2H- (1 , 4) dioxepino (2,3-c) pyridin-8-ylmethyl) (piperidin-4-yl) carbamate to tert-butyl = (3,4-dihydro-2H- (1,4) dioxepino (2,3- c) Pyridin-8-ylmethyl) (1- (2- (7-methoxy-2-oxopyrido (2,3-b) pyrazin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate was obtained. .
¹ H-NMR (CDCl ₃ ) δ value: 1.29-1.72 (4H, m), 1.37 (9H, s), 2.06-2.28 (4H, m), 2.58-2.66 (2H, m), 2.91-3.01 (2H , m), 3.99 (3H, s), 4.06-4.16 (1H, m), 4.20-4.38 (8H, m), 6.77 (1H, s), 7.15-7.21 (1H, m), 8.13 (1H, s) ), 8.33 (1H, s), 8.36 (1H, d, J = 2.7Hz)

ｔｅｒｔ−ブチル＝（３，４−ジヒドロ−２Ｈ−（１，４）ジオキセピノ（２，３−ｃ）ピリジン−８−イルメチル）（１−（２−（７−メトキシ−２−オキソピリド（２，３−ｂ）ピラジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート87mgのジクロロメタン2mL溶液にトリフルオロ酢酸2mLを加え、室温で1時間攪拌した。減圧下で溶媒を留去し、クロロホルムおよび水を加えた。水層を分取し、20％水酸化ナトリウム水溶液でpH13.1に調整した。クロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、黄褐色油状物の１−（２−（４−（（３，４−ジヒドロ−２Ｈ−（１，４）ジオキセピノ（２，３−ｃ）ピリジン−８−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシピリド（２，３−ｂ）ピラジン−２（１Ｈ）−オン54mgを得た。
¹H-NMR(CDCl₃)δ値：1.36-1.48(2H,m),1.86-1.95(2H,m),2.13-2.28(2H,m),2.25(2H,quint,J=5.8Hz),2.48-2.59(1H,m),2.64-2.70(2H,m),2.91-2.98(2H,m),3.80(2H,s),4.00(3H,s),4.24(2H,t,J=5.8Hz),4.28-4.36(2H,m),4.33(2H,t,J=5.8Hz),6.85(1H,s),7.24-7.28(1H,m),8.18(1H,s),8.34(1H,s),8.36(1H,d,J=2.7Hz) Example 59

tert-butyl = (3,4-dihydro-2H- (1,4) dioxepino (2,3-c) pyridin-8-ylmethyl) (1- (2- (7-methoxy-2-oxopyrido (2,3 -B) Pyrazin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate To a solution of 87 mg of dichloromethane in 2 mL was added 2 mL of trifluoroacetic acid and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and chloroform and water were added. The aqueous layer was separated and adjusted to pH 13.1 with 20% aqueous sodium hydroxide solution. Chloroform was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 1- (2- (4-(( 3,4-dihydro-2H- (1,4) dioxepino (2,3-c) pyridin-8-ylmethyl) amino) piperidin-1-yl) ethyl) -7-methoxypyrido (2,3-b) pyrazine- 54 mg of 2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.36-1.48 (2H, m), 1.86-1.95 (2H, m), 2.13-2.28 (2H, m), 2.25 (2H, quint, J = 5.8Hz), 2.48-2.59 (1H, m), 2.64-2.70 (2H, m), 2.91-2.98 (2H, m), 3.80 (2H, s), 4.00 (3H, s), 4.24 (2H, t, J = 5.8 Hz), 4.28-4.36 (2H, m), 4.33 (2H, t, J = 5.8Hz), 6.85 (1H, s), 7.24-7.28 (1H, m), 8.18 (1H, s), 8.34 (1H , s), 8.36 (1H, d, J = 2.7Hz)

実施例８と同様の手法により、１−（２−（４−（（３，４−ジヒドロ−２Ｈ−（１，４）ジオキセピノ（２，３−ｃ）ピリジン−８−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシピリド（２，３−ｂ）ピラジン−２（１Ｈ）−オンから１−（２−（４−（（３，４−ジヒドロ−２Ｈ−（１，４）ジオキセピノ（２，３−ｃ）ピリジン−８−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシピリド（２，３−ｂ）ピラジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：1.97-2.10(2H,m),2.31(2H,quint,J=5.7Hz),2.49-2.57(2H,m),3.21-3.31(2H,m),3.61-3.71(3H,m),3.95-4.04(2H,m),4.05(3H,s),4.36(2H,t,J=5.9Hz),4.37(2H,s),4.48(2H,t,J=5.9Hz),4.73-4.87(2H,m),7.20(1H,s),7.49(1H,d,J=2.6Hz),8.28(1H,s),8.34(1H,s),8.42(1H,d,J=2.6Hz) Example 60

In the same manner as in Example 8, 1- (2- (4-((3,4-dihydro-2H- (1,4) dioxepino (2,3-c) pyridin-8-ylmethyl) amino) piperidine- 1-yl) ethyl) -7-methoxypyrido (2,3-b) pyrazin-2 (1H) -one to 1- (2- (4-((3,4-dihydro-2H- (1,4) dioxepino) (2,3-c) pyridin-8-ylmethyl) amino) piperidin-1-yl) ethyl) -7-methoxypyrido (2,3-b) pyrazin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.97-2.10 (2H, m), 2.31 (2H, quint, J = 5.7Hz), 2.49-2.57 (2H, m), 3.21-3.31 (2H, m) , 3.61-3.71 (3H, m), 3.95-4.04 (2H, m), 4.05 (3H, s), 4.36 (2H, t, J = 5.9Hz), 4.37 (2H, s), 4.48 (2H, t , J = 5.9Hz), 4.73-4.87 (2H, m), 7.20 (1H, s), 7.49 (1H, d, J = 2.6Hz), 8.28 (1H, s), 8.34 (1H, s), 8.42 (1H, d, J = 2.6Hz)

エチル＝４−（３−（２−オキソ−１，８−ナフチリジン−１（２Ｈ）−イル）プロピル）ピペリジン−４−カルボキシラート0.46gのＮ，Ｎ−ジメチルホルムアミド10mL溶液に炭酸カリウム0.37gおよび２−（（２−ブロモエチル）チオ）チオフェン0.31gを加え、50〜70℃で2時間10分間攪拌した。反応混合物を室温まで冷却後、水および酢酸エチルを加え、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、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［溶離液；クロロホルム：メタノール＝５０：１］で精製し、黄色油状物のエチル＝４−（３−（２−オキソ−１，８−ナフチリジン−１（２Ｈ）−イル）プロピル）−１−（２−（２−チエニルチオ）エチル）ピペリジン−４−カルボキシラート0.39gを得た。
¹H-NMR(CDCl₃)δ値：1.20(3H,t,J=7.1Hz),1.42-1.52(2H,m),1.60-1.69(4H,m),2.00-2.14(4H,m),2.52-2.58(2H,m),2.64-2.71(2H,m),2.85-2.91(2H,m),4.10(2H,q,J=7.1Hz),4.42-4.47(2H,m),6.71(1H,d,J=9.4Hz),6.93-6.97(1H,m),7.08-7.10(1H,m),7.15(1H,dd,J=7.6,4.6Hz),7.30-7.33(1H,m),7.61(1H,d,J=9.4Hz),7.84(1H,dd,J=7.6,1.7Hz),8.55(1H,dd,J=4.6,1.7Hz) Example 61

Ethyl 4- (3- (2-oxo-1,8-naphthyridin-1 (2H) -yl) propyl) piperidine-4-carboxylate in a solution of 0.46 g of N, N-dimethylformamide in 10 mL of potassium carbonate and 2-((2-Bromoethyl) thio) thiophene (0.31 g) was added, and the mixture was stirred at 50 to 70 ° C. for 2 hours and 10 minutes. The reaction mixture was cooled to room temperature, water and ethyl acetate were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 50: 1] Ethyl 4- (3- (2-oxo-1,8-naphthyridin-1 (2H) -yl) propyl) -1- (2- (2-thienylthio) ethyl) piperidine-4-carboxylate as a yellow oil 0.39 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.20 (3H, t, J = 7.1 Hz), 1.42-1.52 (2H, m), 1.60-1.69 (4H, m), 2.00-2.14 (4H, m), 2.52-2.58 (2H, m), 2.64-2.71 (2H, m), 2.85-2.91 (2H, m), 4.10 (2H, q, J = 7.1Hz), 4.42-4.47 (2H, m), 6.71 ( 1H, d, J = 9.4Hz), 6.93-6.97 (1H, m), 7.08-7.10 (1H, m), 7.15 (1H, dd, J = 7.6,4.6Hz), 7.30-7.33 (1H, m) , 7.61 (1H, d, J = 9.4Hz), 7.84 (1H, dd, J = 7.6,1.7Hz), 8.55 (1H, dd, J = 4.6,1.7Hz)

エチル＝４−（３−（２−オキソ−１，８−ナフチリジン−１（２Ｈ）−イル）プロピル）−１−（２−（２−チエニルチオ）エチル）ピペリジン−４−カルボキシラート0.30gのエタノール5mL溶液に室温で20％水酸化ナトリウム水溶液1.7mLを加え、加熱還流下、7時間攪拌した。さらに、20％水酸化ナトリウム水溶液0.3mLを加え、1時間攪拌後、室温まで冷却し、減圧下で溶媒を留去した。得られた残留物に水を加え、1mol/L塩酸でpH6.5に調整した。固形物を濾取し、白色固体の４−（３−（２−オキソ−１，８−ナフチリジン−１（２Ｈ）−イル）プロピル）−１−（２−（２−チエニルチオ）エチル）ピペリジン−４−カルボン酸0.22gを得た。
¹H-NMR(DMSO-d₆)δ値：1.24-1.34(2H,m),1.45-1.59(4H,m),1.86-1.98(4H,m),2.42-2.47(2H,m),2.55-2.62(2H,m),2.87-2.92(2H,m),4.30-4.35(2H,m),6.69(1H,d,J=9.5Hz),7.03(1H,dd,J=5.1,3.6Hz),7.15-7.17(1H,m),7.32(1H,dd,J=7.6,4.8Hz),7.59(1H,d,J=5.1Hz),7.95(1H,d,J=9.5Hz),8.16-8.20(1H,m),8.63-8.66(1H,m) Example 62

Ethyl = 4- (3- (2-oxo-1,8-naphthyridin-1 (2H) -yl) propyl) -1- (2- (2-thienylthio) ethyl) piperidine-4-carboxylate 0.30 g ethanol 1.7 mL of 20% aqueous sodium hydroxide solution was added to the 5 mL solution at room temperature, and the mixture was stirred for 7 hours while heating under reflux. Furthermore, 0.3 mL of a 20% aqueous sodium hydroxide solution was added, stirred for 1 hour, cooled to room temperature, and the solvent was distilled off under reduced pressure. Water was added to the obtained residue, and the pH was adjusted to 6.5 with 1 mol / L hydrochloric acid. The solid was collected by filtration, and white solid 4- (3- (2-oxo-1,8-naphthyridin-1 (2H) -yl) propyl) -1- (2- (2-thienylthio) ethyl) piperidine- 0.22 g of 4-carboxylic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.24-1.34 (2H, m), 1.45-1.59 (4H, m), 1.86-1.98 (4H, m), 2.42-2.47 (2H, m), 2.55 -2.62 (2H, m), 2.87-2.92 (2H, m), 4.30-4.35 (2H, m), 6.69 (1H, d, J = 9.5Hz), 7.03 (1H, dd, J = 5.1,3.6Hz ), 7.15-7.17 (1H, m), 7.32 (1H, dd, J = 7.6, 4.8Hz), 7.59 (1H, d, J = 5.1Hz), 7.95 (1H, d, J = 9.5Hz), 8.16 -8.20 (1H, m), 8.63-8.66 (1H, m)

実施例６１と同様の手法により、エチル＝４−（３−（２−オキソ−１，７−ナフチリジン−１（２Ｈ）−イル）プロピル）ピペリジン−４−カルボキシラ−トおよび２−（２−ブロモエチルチオ）チオフェンからエチル＝４−（３−（２−オキソ−１，７−ナフチリジン−１（２Ｈ）−イル）プロピル）−１−（２−（２−チエニルチオ）エチル）ピペリジン−４−カルボキシラートを得た。
¹H-NMR(CDCl₃)δ値：1.21(3H,t,J=7.2Hz),1.40-1.80(6H,m),2.00-2.18(4H,m),2.50-2.60(2H,m),2.62-2.74(2H,m),2.84-2.92(2H,m),4.12(2H,q,J=7.2Hz),4.24-4.31(2H,m),6.88(1H,d,J=9.5Hz),6.95(1H,dd,J=5.3,3.6Hz),7.10(1H,dd,J=3.6,1.2Hz),7.32(1H,dd,J=5.3,1.2Hz),7.42(1H,d,J=5.0Hz),7.64(1H,d,J=9.5Hz),8.44(1H,d,J=5.0Hz),8.74(1H,s)
実施例６２と同様の手法により、エチル＝４−（３−（２−オキソ−１，７−ナフチリジン−１（２Ｈ）−イル）プロピル）−１−（２−（２−チエニルチオ）エチル）ピペリジン−４−カルボキシラートから４−（３−（２−オキソ−１，７−ナフチリジン−１（２Ｈ）−イル）プロピル）−１−（２−（２−チエニルチオ）エチル）ピペリジン−４−カルボン酸を得た。
¹H-NMR(DMSO-d₆)δ値：1.22-1.36(2H,m),1.48-1.60(4H,m),1.86-2.02(4H,m),2.40-2.63(4H,m),2.86-2.93(2H,m),4.22-4.28(2H,m),6.85(1H,d,J=9.5Hz),7.03(1H,dd,J=5.4,3.5Hz),7.16(1H,dd,J=3.5,1.1Hz),7.58(1H,dd,J=5.4,1.1Hz),7.69(1H,d,J=5.0Hz),7.95(1H,d,J=9.5Hz),8.42(1H,d,J=5.0Hz),8.93(1H,s) Example 63

In the same manner as in Example 61, ethyl = 4- (3- (2-oxo-1,7-naphthyridin-1 (2H) -yl) propyl) piperidine-4-carboxylate and 2- (2- Bromoethylthio) thiophene to ethyl = 4- (3- (2-oxo-1,7-naphthyridin-1 (2H) -yl) propyl) -1- (2- (2-thienylthio) ethyl) piperidine-4- Carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.21 (3H, t, J = 7.2 Hz), 1.40-1.80 (6H, m), 2.00-2.18 (4H, m), 2.50-2.60 (2H, m), 2.62-2.74 (2H, m), 2.84-2.92 (2H, m), 4.12 (2H, q, J = 7.2Hz), 4.24-4.31 (2H, m), 6.88 (1H, d, J = 9.5Hz) , 6.95 (1H, dd, J = 5.3,3.6Hz), 7.10 (1H, dd, J = 3.6,1.2Hz), 7.32 (1H, dd, J = 5.3,1.2Hz), 7.42 (1H, d, J = 5.0Hz), 7.64 (1H, d, J = 9.5Hz), 8.44 (1H, d, J = 5.0Hz), 8.74 (1H, s)
In the same manner as in Example 62, ethyl = 4- (3- (2-oxo-1,7-naphthyridin-1 (2H) -yl) propyl) -1- (2- (2-thienylthio) ethyl) piperidine 4-carboxylate to 4- (3- (2-oxo-1,7-naphthyridin-1 (2H) -yl) propyl) -1- (2- (2-thienylthio) ethyl) piperidine-4-carboxylic acid Got.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.22-1.36 (2H, m), 1.48-1.60 (4H, m), 1.86-2.02 (4H, m), 2.40-2.63 (4H, m), 2.86 -2.93 (2H, m), 4.22-4.28 (2H, m), 6.85 (1H, d, J = 9.5Hz), 7.03 (1H, dd, J = 5.4,3.5Hz), 7.16 (1H, dd, J = 3.5,1.1Hz), 7.58 (1H, dd, J = 5.4,1.1Hz), 7.69 (1H, d, J = 5.0Hz), 7.95 (1H, d, J = 9.5Hz), 8.42 (1H, d , J = 5.0Hz), 8.93 (1H, s)

実施例１と同様の手法により、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（ピペリジン−４−イル）カルバマートおよび（６−フルオロ−３−オキソピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）アセトアルデヒドからｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（６−フルオロ−３−オキソピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.30-1.70(4H,m),1.38(9H,s),2.00-2.15(2H,m),2.64-2.70(2H,m),3.01-3.08(2H,m),4.02-4.16(1H,m),4.25-4.33(6H,m),4.42-4.48(2H,m),6.71(1H,s),6.89(1H,dd,J=8.4,2.8Hz),8.03(1H,s),8.21-8.27(2H,m) Example 64

In the same manner as in Example 1, tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (piperidin-4-yl) carbamate and (6- Fluoro-3-oxopyrido (2,3-b) pyrazin-4 (3H) -yl) acetaldehyde to tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridine-7- (Ilmethyl) (1- (2- (6-fluoro-3-oxopyrido (2,3-b) pyrazin-4 (3H) -yl) ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.30-1.70 (4H, m), 1.38 (9H, s), 2.00-2.15 (2H, m), 2.64-2.70 (2H, m), 3.01-3.08 (2H , m), 4.02-4.16 (1H, m), 4.25-4.33 (6H, m), 4.42-4.48 (2H, m), 6.71 (1H, s), 6.89 (1H, dd, J = 8.4,2.8Hz ), 8.03 (1H, s), 8.21-8.27 (2H, m)

ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（６−フルオロ−３−オキソピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート90mgのメタノール1mL溶液に4mol/L塩化水素／酢酸エチル溶液1mLを加え、室温で1時間攪拌した。固形物を濾取し、白色固体の４−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−６−フルオロピリド（２，３−ｂ）ピラジン−３（４Ｈ）−オン塩酸塩76mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.97-2.09(2H,m),2.28-2.37(2H,m),3.00-3.14(2H,m),3.26-3.36(1H,m),3.39-3.57(2H,m),3.80-4.00(2H,m),4.19-4.27(2H,m),4.33-4.45(4H,m),4.55-4.63(2H,m),7.25(1H,dd,J=8.5,2.2Hz),7.32(1H,s),8.26(1H,s),8.33(1H,s),8.46-8.51(1H,m),9.70-9.90(2H,broad),10.35-10.55(1H,broad) Example 65

tert-butyl = (2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) (1- (2- (6-fluoro-3-oxopyrido (2,3-b) To a solution of pyrazin-4 (3H) -yl) ethyl) piperidin-4-yl) carbamate in 1 mL of methanol was added 1 mL of 4 mol / L hydrogen chloride / ethyl acetate solution, and the mixture was stirred at room temperature for 1 hour. The solid was collected by filtration to give 4- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) piperidine-1- Yl) ethyl) -6-fluoropyrido (2,3-b) pyrazin-3 (4H) -one hydrochloride 76 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.97-2.09 (2H, m), 2.28-2.37 (2H, m), 3.00-3.14 (2H, m), 3.26-3.36 (1H, m), 3.39 -3.57 (2H, m), 3.80-4.00 (2H, m), 4.19-4.27 (2H, m), 4.33-4.45 (4H, m), 4.55-4.63 (2H, m), 7.25 (1H, dd, J = 8.5, 2.2Hz), 7.32 (1H, s), 8.26 (1H, s), 8.33 (1H, s), 8.46-8.51 (1H, m), 9.70-9.90 (2H, broad), 10.35-10.55 (1H, broad)

実施例１と同様の手法により、（７−メトキシ−２−オキソピリド（２，３−ｂ）ピラジン−１（２Ｈ）−イル）アセトアルデヒドおよびｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（ピペリジン−４−イル）カルバマートからｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−メトキシ−２−オキソピリド（２，３−ｂ）ピラジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.34-1.70(4H,m),1.39(9H,s),2.08-2.24(2H,m),2.60-2.66(2H,m),2.92-3.00(2H,m),3.99(3H,s),4.03-4.15(1H,m),4.23-4.37(8H,m),6.73(1H,s),7.18(1H,d,J=2.4Hz),8.05(1H,s),8.33(1H,s),8.36(1H,d,J=2.4Hz) Example 66

In the same manner as in Example 1, (7-methoxy-2-oxopyrido (2,3-b) pyrazin-1 (2H) -yl) acetaldehyde and tert-butyl = (2,3-dihydro (1,4) Dioxyno (2,3-c) pyridin-7-ylmethyl) (piperidin-4-yl) carbamate to tert-butyl = (2,3-dihydro (1,4) dioxino (2,3-c) pyridine-7- (Ilmethyl) (1- (2- (7-methoxy-2-oxopyrido (2,3-b) pyrazin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.34-1.70 (4H, m), 1.39 (9H, s), 2.08-2.24 (2H, m), 2.60-2.66 (2H, m), 2.92-3.00 (2H , m), 3.99 (3H, s), 4.03-4.15 (1H, m), 4.23-4.37 (8H, m), 6.73 (1H, s), 7.18 (1H, d, J = 2.4Hz), 8.05 ( 1H, s), 8.33 (1H, s), 8.36 (1H, d, J = 2.4Hz)

実施例５９と同様の手法により、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−メトキシ−２−オキソピリド（２，３−ｂ）ピラジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートから１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシピリド（２，３−ｂ）ピラジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.37-1.48(2H,m),1.86-1.99(2H,m),2.13-2.23(2H,m),2.48-2.58(1H,m),2.64-2.69(2H,m),2.91-2.98(2H,m),3.78(2H,s),4.00(3H,s),4.25-4.35(6H,m),6.81(1H,s),7.26(1H,d,J=2.6Hz),8.10(1H,s),8.34(1H,s),8.36(1H,d,J=2.6Hz) Example 67

In the same manner as in Example 59, tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (1- (2- (7-methoxy-2 -Oxopyrido (2,3-b) pyrazin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate to 1- (2- (4-((2,3-dihydro (1,4) dioxino ( 2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -7-methoxypyrido (2,3-b) pyrazin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.37-1.48 (2H, m), 1.86-1.99 (2H, m), 2.13-2.23 (2H, m), 2.48-2.58 (1H, m), 2.64-2.69 (2H, m), 2.91-2.98 (2H, m), 3.78 (2H, s), 4.00 (3H, s), 4.25-4.35 (6H, m), 6.81 (1H, s), 7.26 (1H, d , J = 2.6Hz), 8.10 (1H, s), 8.34 (1H, s), 8.36 (1H, d, J = 2.6Hz)

実施例８と同様の手法により、１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシピリド（２，３−ｂ）ピラジン−２（１Ｈ）−オンから１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシピリド（２，３−ｂ）ピラジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：1.96-2.10(2H,m),2.49-2.57(2H,m),3.21-3.32(2H,m),3.61-3.72(3H,m),3.95-4.04(2H,m),4.06(3H,s),4.39(2H,s),4.40-4.54(4H,m),4.75-4.81(2H,m),7.25(1H,s),7.48-7.51(1H,m),8.24(1H,s),8.34(1H,s),8.41-8.44(1H,m) Example 68

In the same manner as in Example 8, 1- (2- (4-((2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) was synthesized. ) Ethyl) -7-methoxypyrido (2,3-b) pyrazin-2 (1H) -one to 1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-c) ) Pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -7-methoxypyrido (2,3-b) pyrazin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.96-2.10 (2H, m), 2.49-2.57 (2H, m), 3.21-3.32 (2H, m), 3.61-3.72 (3H, m), 3.95 4.04 (2H, m), 4.06 (3H, s), 4.39 (2H, s), 4.40-4.54 (4H, m), 4.75-4.81 (2H, m), 7.25 (1H, s), 7.48-7.51 ( 1H, m), 8.24 (1H, s), 8.34 (1H, s), 8.41-8.44 (1H, m)

実施例１と同様の手法により、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（ピペリジン−４−イル）カルバマートおよび（６−クロロ−３−オキソピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）アセトアルデヒドからｔｅｒｔ−ブチル＝（１−（２−（６−クロロ−３−オキソピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）エチル）ピペリジン−４−イル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.38(9H,s),1.40-1.65(4H,m),1.97-2.15(2H,m),2.64-2.70(2H,m),3.03-3.10(2H,m),4.02-4.14(1H,m),4.25-4.34(6H,m),4.46-4.52(2H,m),6.70(1H,s),7.26(1H,d,J=8.2Hz),8.02(1H,s),8.09(1H,d,J=8.2Hz),8.28(1H,s) Example 69

In the same manner as in Example 1, tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (piperidin-4-yl) carbamate and (6- Chloro-3-oxopyrido (2,3-b) pyrazin-4 (3H) -yl) acetaldehyde to tert-butyl = (1- (2- (6-chloro-3-oxopyrido (2,3-b) pyrazine- 4 (3H) -yl) ethyl) piperidin-4-yl) (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.38 (9H, s), 1.40-1.65 (4H, m), 1.97-2.15 (2H, m), 2.64-2.70 (2H, m), 3.03-3.10 (2H , m), 4.02-4.14 (1H, m), 4.25-4.34 (6H, m), 4.46-4.52 (2H, m), 6.70 (1H, s), 7.26 (1H, d, J = 8.2Hz), 8.02 (1H, s), 8.09 (1H, d, J = 8.2Hz), 8.28 (1H, s)

ｔｅｒｔ−ブチル＝（１−（２−（６−クロロ−３−オキソピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）エチル）ピペリジン−４−イル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）カルバマート0.11gのジオキサン3mL溶液にｔｅｒｔ−ブチルカルバマート25mgおよび炭酸セシウム82mgを加えた。アルゴン雰囲気下、トリス（ジベンジリデンアセタート）ジパラジウム（０）2.5mgおよび４，５−ビス（ジフェニルホスフィノ）−９，９−ジメチルキサンテン3.1mgを加えた。アルゴン雰囲気下、80〜90℃で2時間攪拌した。不溶物を濾去し、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝２０：１］で精製し、淡褐色油状物のｔｅｒｔ−ブチル＝（１−（２−（６−（（ｔｅｒｔ−ブトキシカルボニル）アミノ）−３−オキソピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）エチル）ピペリジン−４−イル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）カルバマート78mgを得た。
¹H-NMR(CDCl₃)δ値：1.35-1.70(4H,m),1.38(9H,s),1.56(9H,s),2.03-2.19(2H,m),2.58-2.64(2H,m),3.00-3.04(2H,m),4.06-4.19(1H,m),4.24-4.38(6H,m),4.40-4.48(2H,m),6.72(1H,s),7.37(1H,s),7.96(1H,d,J=8.8Hz),8.05(1H,s),8.09(1H,d,J=8.8Hz),8.15(1H,s) Example 70

tert-butyl = (1- (2- (6-chloro-3-oxopyrido (2,3-b) pyrazin-4 (3H) -yl) ethyl) piperidin-4-yl) (2,3-dihydro (1 , 4) Dioxino (2,3-c) pyridin-7-ylmethyl) carbamate 0.11 g of dioxane 3 mL was added with 25 mg of tert-butylcarbamate and 82 mg of cesium carbonate. Under an argon atmosphere, 2.5 mg of tris (dibenzylidene acetate) dipalladium (0) and 3.1 mg of 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene were added. The mixture was stirred at 80 to 90 ° C. for 2 hours under an argon atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography [eluent: chloroform: methanol = 20: 1], and tert-butyl = (1- (2- (6-((tert- Butoxycarbonyl) amino) -3-oxopyrido (2,3-b) pyrazin-4 (3H) -yl) ethyl) piperidin-4-yl) (2,3-dihydro (1,4) dioxyno (2,3- c) 78 mg of pyridin-7-ylmethyl) carbamate were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.35-1.70 (4H, m), 1.38 (9H, s), 1.56 (9H, s), 2.03-2.19 (2H, m), 2.58-2.64 (2H, m ), 3.00-3.04 (2H, m), 4.06-4.19 (1H, m), 4.24-4.38 (6H, m), 4.40-4.48 (2H, m), 6.72 (1H, s), 7.37 (1H, s) ), 7.96 (1H, d, J = 8.8Hz), 8.05 (1H, s), 8.09 (1H, d, J = 8.8Hz), 8.15 (1H, s)

実施例６５と同様の手法により、ｔｅｒｔ−ブチル＝（１−（２−（６−（（ｔｅｒｔ−ブトキシカルボニル）アミノ）−３−オキソピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）エチル）ピペリジン−４−イル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）カルバマートから６−アミノ−４−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）ピリド（２，３−ｂ）ピラジン−３（４Ｈ）−オン塩酸塩を得た。
¹H-NMR(DMSO-d₆-D₂O)δ値：1.85-1.97(2H,m),2.32-2.41(2H,m),3.04-3.14(2H,m),3.33-3.48(3H,m),3.92-4.00(2H,m),4.26(2H,s),4.35-4.46(4H,m),4.54-4.60(2H,m),6.56(1H,d,J=8.8Hz),7.31(1H,s),7.83(1H,d,J=8.8Hz),7.87(1H,s),8.30(1H,s) Example 71

In the same manner as in Example 65, tert-butyl = (1- (2- (6-((tert-butoxycarbonyl) amino) -3-oxopyrido (2,3-b) pyrazin-4 (3H) -yl ) Ethyl) piperidin-4-yl) (2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) carbamate to 6-amino-4- (2- (4-(( 2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) pyrido (2,3-b) pyrazin-3 (4H) -one The hydrochloride salt was obtained.
¹ H-NMR (DMSO-d ₆ -D ₂ O) δ value: 1.85-1.97 (2H, m), 2.32-2.41 (2H, m), 3.04-3.14 (2H, m), 3.33-3.48 (3H, m), 3.92-4.00 (2H, m), 4.26 (2H, s), 4.35-4.46 (4H, m), 4.54-4.60 (2H, m), 6.56 (1H, d, J = 8.8Hz), 7.31 (1H, s), 7.83 (1H, d, J = 8.8Hz), 7.87 (1H, s), 8.30 (1H, s)

（１）４−（１，３−ジオキソラン−２−イルメチル）−６−（１Ｈ−１，２，４−トリアゾール−１−イル）ピリド（２，３−ｂ）ピラジン−３（４Ｈ）−オン98mgに80％トリフルオロ酢酸水溶液3mLを加え、室温で6時間30分間攪拌した。水および酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液および水酸化ナトリウム水溶液で中和した。有機層を分取し、水層に塩化ナトリウムを加え、クロロホルムで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、淡赤色固体の（３−オキソ−６−（１Ｈ−１，２，４−トリアゾール−１−イル）ピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）アセトアルデヒド0.12gを得た。
（２）ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（ピペリジン−４−イル）カルバマート48mgのメタノール2mL溶液に（３−オキソ−６−（１Ｈ−１，２，４−トリアゾール−１−イル）ピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）アセトアルデヒド50mg、ジクロロメタン2.5mLおよび酢酸20μLを加え、室温で40分間攪拌した。反応混合物に水素化シアノホウ素ナトリウム9.0mgを加え、室温で1時間30分間攪拌した。飽和炭酸水素ナトリウム水溶液およびクロロホルムを加え、有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［溶離液；クロロホルム：メタノール＝５０：１］で精製し、淡黄色油状物のｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（３−オキソ−６−（１Ｈ−１，２，４−トリアゾール−１−イル）ピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート35mgを得た。
¹H-NMR(CDCl₃)δ値：1.38(9H,s),1.30-1.70(4H,m),2.05-2.21(2H,m),2.69-2.75(2H,m),3.00-3.08(2H,m),4.04-4.16(1H,m),4.25-4.34(6H,m),4.52-4.58(2H,m),6.70(1H,s),7.92(1H,d,J=8.6Hz),8.02(1H,s),8.14(1H,s),8.31(1H,s),8.35(1H,d,J=8.6Hz),9.09(1H,s) Example 72

(1) 4- (1,3-Dioxolan-2-ylmethyl) -6- (1H-1,2,4-triazol-1-yl) pyrido (2,3-b) pyrazin-3 (4H) -one To 80 mg, 3 mL of 80% aqueous trifluoroacetic acid solution was added, and the mixture was stirred at room temperature for 6 hours and 30 minutes. Water and ethyl acetate were added, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and aqueous sodium hydroxide solution. The organic layer was separated, sodium chloride was added to the aqueous layer, and the mixture was extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give (3-oxo-6- (1H-1,2,4-triazol-1-yl) as a pale red solid. 0.12 g of pyrido (2,3-b) pyrazin-4 (3H) -yl) acetaldehyde was obtained.
(2) tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (piperidin-4-yl) carbamate 48 mg -6- (1H-1,2,4-triazol-1-yl) pyrido (2,3-b) pyrazin-4 (3H) -yl) acetaldehyde (50 mg), dichloromethane (2.5 mL) and acetic acid (20 μL) were added. Stir for minutes. To the reaction mixture, 9.0 mg of sodium cyanoborohydride was added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added, the organic layer was separated, washed successively with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 50: 1], and tert-butyl = (2,3-dihydro (1,4) dioxyno (2, 3-c) Pyridin-7-ylmethyl) (1- (2- (3-oxo-6- (1H-1,2,4-triazol-1-yl) pyrido (2,3-b) pyrazine-4 ( 35 mg of 3H) -yl) ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.38 (9H, s), 1.30-1.70 (4H, m), 2.05-2.21 (2H, m), 2.69-2.75 (2H, m), 3.00-3.08 (2H , m), 4.04-4.16 (1H, m), 4.25-4.34 (6H, m), 4.52-4.58 (2H, m), 6.70 (1H, s), 7.92 (1H, d, J = 8.6Hz), 8.02 (1H, s), 8.14 (1H, s), 8.31 (1H, s), 8.35 (1H, d, J = 8.6Hz), 9.09 (1H, s)

実施例６５と同様の手法により、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（３−オキソ−６−（１Ｈ−１，２，４−トリアゾール−１−イル）ピリド（２，３−ｂ）ピラジン−４（３Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートから４−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−６−（１Ｈ−１，２，４−トリアゾール−１−イル）ピリド（２，３−ｂ）ピラジン−３（４Ｈ）−オン塩酸塩を得た。
¹H-NMR(DMSO-d₆)δ値：1.97-2.34(4H,m),3.02-3.14(2H,m),3.24-3.36(1H,m),3.40-3.50(2H,m),3.80-4.00(2H,m),4.19-4.26(2H,m),4.30-4.45(4H,m),4.80-4.83(2H,m),7.27(1H,s),7.90(1H,d,J=8.4Hz),8.25(1H,s),8.35(1H,s),8.41(1H,s),8.52(1H,d,J=8.4Hz),9.55-9.80(2H,broad),9.94(1H,s),10.95-11.00(1H,m) Example 73

In the same manner as in Example 65, tert-butyl = (2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) (1- (2- (3-oxo-6 -(1H-1,2,4-triazol-1-yl) pyrido (2,3-b) pyrazin-4 (3H) -yl) ethyl) piperidin-4-yl) carbamate to 4- (2- (4 -((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -6- (1H-1,2,4-triazole -1-yl) pyrido (2,3-b) pyrazin-3 (4H) -one hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.97-2.34 (4H, m), 3.02-3.14 (2H, m), 3.24-3.36 (1H, m), 3.40-3.50 (2H, m), 3.80 -4.00 (2H, m), 4.19-4.26 (2H, m), 4.30-4.45 (4H, m), 4.80-4.83 (2H, m), 7.27 (1H, s), 7.90 (1H, d, J = 8.4Hz), 8.25 (1H, s), 8.35 (1H, s), 8.41 (1H, s), 8.52 (1H, d, J = 8.4Hz), 9.55-9.80 (2H, broad), 9.94 (1H, s), 10.95-11.00 (1H, m)

実施例１と同様の手法により、エチル＝（２Ｅ）−３−（６−オキソ−５−（２−オキソエチル）−５，６−ジヒドロ−１，５−ナフチリジン−３−イル）アクリラートおよびｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（ピペリジン−４−イル）カルバマートからエチル＝（２Ｅ）−３−（５−（２−（４−（（ｔｅｒｔ−ブトキシカルボニル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−６−オキソ−５，６−ジヒドロ−１，５−ナフチリジン−３−イル）アクリラートを得た。
¹H-NMR(CDCl₃)δ値：1.30-1.75(13H,m),1.38(3H,t,J=7.2Hz),2.10-2.27(2H,m),2.58-2.65(2H,m),2.98-3.06(2H,m),4.04-4.20(1H,m),4.24-4.46(10H,m),6.62(1H,d,J=16.2Hz),6.72-6.74(1H,broad),6.93(1H,d,J=9.8Hz),7.75(1H,d,J=16.2Hz),7.78(1H,s),7.89(1H,d,J=9.8Hz),8.05(1H,s),8.68(1H,d,J=1.2Hz) Example 74

In the same manner as in Example 1, ethyl = (2E) -3- (6-oxo-5- (2-oxoethyl) -5,6-dihydro-1,5-naphthyridin-3-yl) acrylate and tert- Butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (piperidin-4-yl) carbamate to ethyl = (2E) -3- (5- (2- (4-((tert-butoxycarbonyl) (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -6-oxo- 5,6-Dihydro-1,5-naphthyridin-3-yl) acrylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.30-1.75 (13H, m), 1.38 (3H, t, J = 7.2 Hz), 2.10-2.27 (2H, m), 2.58-2.65 (2H, m), 2.98-3.06 (2H, m), 4.04-4.20 (1H, m), 4.24-4.46 (10H, m), 6.62 (1H, d, J = 16.2Hz), 6.72-6.74 (1H, broad), 6.93 ( 1H, d, J = 9.8Hz), 7.75 (1H, d, J = 16.2Hz), 7.78 (1H, s), 7.89 (1H, d, J = 9.8Hz), 8.05 (1H, s), 8.68 ( (1H, d, J = 1.2Hz)

実施例５４と同様の手法により、エチル＝（２Ｅ）−３−（５−（２−（４−（（ｔｅｒｔ−ブトキシカルボニル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−６−オキソ−５，６−ジヒドロ−１，５−ナフチリジン−３−イル）アクリラートからエチル＝（２Ｅ）−３−（５−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−６−オキソ−５，６−ジヒドロ−１，５−ナフチリジン−３−イル）アクリラートを得た。
¹H-NMR(CDCl₃)δ値：1.35-1.54(2H,m),1.37(3H,t,J=7.2Hz),1.85-2.00(2H,m),2.12-2.28(2H,m),2.46-2.74(3H,m),2.93-3.04(2H,m),3.80(2H,s),4.24-4.44(8H,m),6.65(1H,d,J=16.1Hz),6.82(1H,s),6.93(1H,d,J=9.8Hz),7.76(1H,d,J=16.1Hz),7.87-7.92(1H,broad),7.89(1H,d,J=9.8Hz),8.10(1H,s),8.68(1H,d,J=1.7Hz) Example 75

In the same manner as in Example 54, ethyl = (2E) -3- (5- (2- (4-((tert-butoxycarbonyl) (2,3-dihydro (1,4) dioxyno (2,3- c) Pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl) acrylate to ethyl = (2E) -3- ( 5- (2- (4-((2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -6-oxo-5 , 6-Dihydro-1,5-naphthyridin-3-yl) acrylate.
¹ H-NMR (CDCl ₃ ) δ value: 1.35-1.54 (2H, m), 1.37 (3H, t, J = 7.2 Hz), 1.85-2.00 (2H, m), 2.12-2.28 (2H, m), 2.46-2.74 (3H, m), 2.93-3.04 (2H, m), 3.80 (2H, s), 4.24-4.44 (8H, m), 6.65 (1H, d, J = 16.1Hz), 6.82 (1H, s), 6.93 (1H, d, J = 9.8Hz), 7.76 (1H, d, J = 16.1Hz), 7.87-7.92 (1H, broad), 7.89 (1H, d, J = 9.8Hz), 8.10 ( 1H, s), 8.68 (1H, d, J = 1.7Hz)

実施例１と同様の手法により、（７−クロロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒドおよびｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（ピペリジン−４−イル）カルバマートからｔｅｒｔ−ブチル＝（１−（２−（７−クロロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.35-1.55(13H,m),2.08-2.27(2H,m),2.58-2.65(2H,m),2.93-3.02(2H,m),4.05-4.20(1H,m),4.22-4.50(8H,m),6.72(1H,s),6.88(1H,d,J=9.8Hz),7.78-7.82(1H,m),7.86(1H,d,J=9.8Hz),8.05(1H,s),8.46(1H,d,J=2.0Hz) Example 76

In the same manner as in Example 1, (7-chloro-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde and tert-butyl = (2,3-dihydro (1,4) dioxino ( 2,3-c) pyridin-7-ylmethyl) (piperidin-4-yl) carbamate to tert-butyl = (1- (2- (7-chloro-2-oxo-1,5-naphthyridine-1 (2H) -Yl) ethyl) piperidin-4-yl) (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.35-1.55 (13H, m), 2.08-2.27 (2H, m), 2.58-2.65 (2H, m), 2.93-3.02 (2H, m), 4.05-4.20 (1H, m), 4.22-4.50 (8H, m), 6.72 (1H, s), 6.88 (1H, d, J = 9.8Hz), 7.78-7.82 (1H, m), 7.86 (1H, d, J = 9.8Hz), 8.05 (1H, s), 8.46 (1H, d, J = 2.0Hz)

実施例２と同様の手法により、ｔｅｒｔ−ブチル＝（１−（２−（７−クロロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）カルバマートから７−クロロ−１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：2.00-2.14(2H,m),2.51-2.61(2H,m),3.22-3.36(2H,m),3.60-3.80(3H,m),3.97-4.07(2H,m),4.45-4.50(2H,m),4.52(2H,s),4.57-4.62(2H,m),4.72-4.82(2H,m),7.03(1H,d,J=9.8Hz),7.44(1H,s),8.08(1H,d,J=9.8Hz),8.19-8.22(1H,m),8.36(1H,s),8.61(1H,d,J=1.7Hz) Example 77

In the same manner as in Example 2, tert-butyl = (1- (2- (7-chloro-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) ( 2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) carbamate to 7-chloro-1- (2- (4-((2,3-dihydro (1,4) Dioxino (2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 2.00-2.14 (2H, m), 2.51-2.61 (2H, m), 3.22-3.36 (2H, m), 3.60-3.80 (3H, m), 3.97- 4.07 (2H, m), 4.45-4.50 (2H, m), 4.52 (2H, s), 4.57-4.62 (2H, m), 4.72-4.82 (2H, m), 7.03 (1H, d, J = 9.8 Hz), 7.44 (1H, s), 8.08 (1H, d, J = 9.8Hz), 8.19-8.22 (1H, m), 8.36 (1H, s), 8.61 (1H, d, J = 1.7Hz)

１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.22gのメタノール7mL懸濁液に水素化シアノホウ素ナトリウム66mg、３−フルオロ−４−メチルベンズアルデヒド64μL、28％ナトリウムメトキシド／メタノール溶液0.30gおよび酢酸30μLを加え、室温で3時間攪拌した。３−フルオロ−４−メチルベンズアルデヒド22mgを加え、同温度で1時間攪拌した。さらに水素化シアノホウ素ナトリウム33mgを加え、同温度で1時間攪拌した。飽和炭酸水素ナトリウム水溶液を加え、減圧下で溶媒を留去した。クロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝９：１］で精製し、無色油状物の１−（２−（４−（（３−フルオロ−４−メチルベンジル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン20mgを得た。
¹H-NMR(CDCl₃)δ値：1.36-1.57(2H,m),1.86-1.94(2H,m),2.13-2.22(2H,m),2.25(3H,s),2.48-2.56(1H,m),2.61-2.68(2H,m),2.94-3.01(2H,m),3.77(2H,s),3.97(3H,s),4.33-4.39(2H,m),6.74(1H,d,J=9.6Hz),6.95-7.01(2H,m),7.11(1H,t,J=8.0Hz),7.23(1H,d,J=2.3Hz),7.84(1H,d,J=9.6Hz),8.28(1H,d,J=2.3Hz) Example 78

Sodium cyanoborohydride in a suspension of 0.22 g of 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride in 7 mL of methanol 66 mg, 3-fluoro-4-methylbenzaldehyde 64 μL, 28% sodium methoxide / methanol solution 0.30 g and acetic acid 30 μL were added, and the mixture was stirred at room temperature for 3 hours. 22 mg of 3-fluoro-4-methylbenzaldehyde was added and stirred at the same temperature for 1 hour. Further, 33 mg of sodium cyanoborohydride was added and stirred at the same temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added, and the solvent was distilled off under reduced pressure. Chloroform was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography [eluent: chloroform: methanol = 9: 1] to give 1- (2- (4-((3-fluoro-4-methylbenzyl) as a colorless oil. 20) Amino) piperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.36-1.57 (2H, m), 1.86-1.94 (2H, m), 2.13-2.22 (2H, m), 2.25 (3H, s), 2.48-2.56 (1H , m), 2.61-2.68 (2H, m), 2.94-3.01 (2H, m), 3.77 (2H, s), 3.97 (3H, s), 4.33-4.39 (2H, m), 6.74 (1H, d , J = 9.6Hz), 6.95-7.01 (2H, m), 7.11 (1H, t, J = 8.0Hz), 7.23 (1H, d, J = 2.3Hz), 7.84 (1H, d, J = 9.6Hz ), 8.28 (1H, d, J = 2.3Hz)

１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン297mgおよび３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド（３，２−ｂ）（１，４）オキサジン−６−カルバルデヒド159mgのクロロホルム4mLおよびメタノール1mL溶液に酢酸0.11mLを加え、室温で16時間攪拌した。反応混合物に水素化トリアセトキシホウ素ナトリウム299mgを加え、1.5時間攪拌した。飽和炭酸水素ナトリウム水溶液を加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［シリカゲル；関東化学株式会社、シリカゲル６０、溶離液；クロロホルム：メタノール（28％アンモニア水、5％混合）＝８７：１３］で精製し、黄色泡状物の１−（２−（４−（（３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド（３，２−ｂ）（１，４）オキサジン−６−イル）メチルアミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン275mgを得た。
１−（２−（４−（（３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド（３，２−ｂ）（１，４）オキサジン−６−イル）メチルアミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン260mgの酢酸エチル4mLおよびメタノール2mL溶液に4mol/L塩化水素／酢酸エチル3mLを加え、室温で12分間攪拌した。減圧下で溶媒を留去し、ジエチルエーテルを加え、固形物を濾取し、白色固体の１−（２−（４−（（３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド（３，２−ｂ）（１，４）オキサジン−６−イル）メチルアミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩304mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.03-2.12(2H,m),2.37-2.44(2H,m),3.08-3.16(2H,m),3.27-3.33(2H,m),3.35-3.43(1H,m),3.78-3.82(2H,m),4.07(3H,s),4.19(2H,t,J=5.5Hz),4.70-4.73(4H,m),6.72(1H,d,J=9.6Hz),7.23(1H,d,J=8.3Hz),7.46(1H,d,J=8.3Hz),7.72(1H,d,J=2.3Hz),7.94(1H,d,J=9.6Hz),8.34(1H,d,J=2.3Hz),9.54-9.68(2H,m),11.30-11.63(2H,m) Example 79

1- (2- (4-Aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one 297 mg and 3-oxo-3,4-dihydro-2H-pyrido ( Acetic acid (0.11 mL) was added to chloroform (4 mL) and methanol (1 mL) solution of 3,2-b) (1,4) oxazine-6-carbaldehyde (159 mg), and the mixture was stirred at room temperature for 16 hours. To the reaction mixture, 299 mg of sodium triacetoxyborohydride was added and stirred for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent; chloroform: methanol (28% aqueous ammonia, 5% mixed) = 87: 13] to give a yellow foam 1- (2- (4-((3-oxo-3,4-dihydro-2H-pyrido (3,2-b) (1,4) oxazin-6-yl) methylamino) piperidin-1-yl) ) Ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one 275 mg was obtained.
1- (2- (4-((3-oxo-3,4-dihydro-2H-pyrido (3,2-b) (1,4) oxazin-6-yl) methylamino) piperidin-1-yl) Ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one 260 mL of ethyl acetate 4 mL and methanol 2 mL were added with 4 mol / L hydrogen chloride / ethyl acetate 3 mL and stirred at room temperature for 12 minutes. The solvent was distilled off under reduced pressure, diethyl ether was added, the solid was collected by filtration, and the white solid 1- (2- (4-((3-oxo-3,4-dihydro-2H-pyrido (3, 2-b) (1,4) oxazin-6-yl) methylamino) piperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride 304 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.03-2.12 (2H, m), 2.37-2.44 (2H, m), 3.08-3.16 (2H, m), 3.27-3.33 (2H, m), 3.35 -3.43 (1H, m), 3.78-3.82 (2H, m), 4.07 (3H, s), 4.19 (2H, t, J = 5.5Hz), 4.70-4.73 (4H, m), 6.72 (1H, d , J = 9.6Hz), 7.23 (1H, d, J = 8.3Hz), 7.46 (1H, d, J = 8.3Hz), 7.72 (1H, d, J = 2.3Hz), 7.94 (1H, d, J = 9.6Hz), 8.34 (1H, d, J = 2.3Hz), 9.54-9.68 (2H, m), 11.30-11.63 (2H, m)

１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン150mgおよび２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｂ）ピリジン−７−カルバルデヒド82mgのクロロホルム15mL溶液に酢酸60mgを加え、室温で16.5時間攪拌した。反応混合物に水素化トリアセトキシホウ素ナトリウム158mgを加え、2時間攪拌した。飽和炭酸水素ナトリウム水溶液を加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［シリカゲル；関東化学株式会社、シリカゲル６０Ｎ、溶離液；クロロホルム：メタノール＝１０：１］で精製し、無色粘性油状物の１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｂ）ピリジン−７−イル）メチルアミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン103mgを得た。
１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｂ）ピリジン−７−イル）メチルアミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン134mgのメタノール1mLおよび酢酸エチル5mL溶液に4mol/L塩化水素／酢酸エチル2mLを加え、室温で攪拌した。固形物を濾取し、淡黄色固体の１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｂ）ピリジン−７−イル）メチルアミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩159mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.02-2.11(2H,m),2.35-2.42(2H,m),3.07-3.17(2H,m),3.24-3.32(3H,m),3.75-3.82(2H,m),4.07(3H,s),4.09-4.19(2H,m),4.25-4.31(2H,m),4.41-4.44(2H,m),4.67-4.74(2H,m),6.72(1H,d,J=9.6Hz),7.64(1H,d,J=2.3Hz),7.70(1H,d,J=2.3Hz),7.92(1H,d,J=2.3Hz),7.94(1H,d,J=9.6Hz),8.33(1H,d,J=2.3Hz),9.59-9.78(3H,m),11.26-11.52(1H,m) Example 80

1- (2- (4-Aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one 150 mg and 2,3-dihydro (1,4) dioxino (2, 3-b) To a solution of 82 mg of pyridine-7-carbaldehyde in 15 mL of chloroform was added 60 mg of acetic acid, and the mixture was stirred at room temperature for 16.5 hours. To the reaction mixture, 158 mg of sodium triacetoxyborohydride was added and stirred for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60N, eluent; chloroform: methanol = 10: 1] to give 1- (2- (4- ( (2,3-dihydro (1,4) dioxyno (2,3-b) pyridin-7-yl) methylamino) piperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridine-2 (1H ) -On 103 mg was obtained.
1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-b) pyridin-7-yl) methylamino) piperidin-1-yl) ethyl) -7-methoxy- To a solution of 134 mg of 1,5-naphthyridin-2 (1H) -one in 1 mL of methanol and 5 mL of ethyl acetate, 2 mL of 4 mol / L hydrogen chloride / ethyl acetate was added and stirred at room temperature. The solid was collected by filtration to give 1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-b) pyridin-7-yl) methylamino) piperidine- 159 mg of 1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.02-2.11 (2H, m), 2.35-2.42 (2H, m), 3.07-3.17 (2H, m), 3.24-3.32 (3H, m), 3.75 -3.82 (2H, m), 4.07 (3H, s), 4.09-4.19 (2H, m), 4.25-4.31 (2H, m), 4.41-4.44 (2H, m), 4.67-4.74 (2H, m) , 6.72 (1H, d, J = 9.6Hz), 7.64 (1H, d, J = 2.3Hz), 7.70 (1H, d, J = 2.3Hz), 7.92 (1H, d, J = 2.3Hz), 7.94 (1H, d, J = 9.6Hz), 8.33 (1H, d, J = 2.3Hz), 9.59-9.78 (3H, m), 11.26-11.52 (1H, m)

１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イル）メチルアミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン150mgおよびブロモ＝アセタート85mgのアセトニトリル15mL溶液に炭酸カリウム100mgを加え、室温で18時間、40℃で4時間攪拌した。減圧下で溶媒を留去し、クロロホルムおよび水を加え、有機層を分取した。有機層を無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［シリカゲル；関東化学株式会社、シリカゲル６０Ｎ、溶離液；クロロホルム：メタノール＝２０：１］で精製し、褐色油状物のエチル＝（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）アミノ）アセタート90mgを得た。
¹H-NMR(CDCl₃)δ値：1.26(3H,m),1.52-1.60(2H,m),1.84-1.89(2H,m),2.08-2.15(2H,m),2.59-2.64(2H,m),2.65-2.71(1H,m),3.01-3.07(2H,m),3.40-3.43(2H,m),3.84-3.87(2H,m),3.97(3H,s),4.12-4.17(2H,m),4.26-4.29(2H,m),4.31-4.37(4H,m),6.72-6.75(1H,m),7.13-7.15(1H,m),7.19-7.21(1H,m),7.82-7.85(1H,m),8.05-8.07(1H,m),8.27-8.29(1H,m) Example 81

1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-yl) methylamino) piperidin-1-yl) ethyl) -7-methoxy- To a solution of 150 mg of 1,5-naphthyridin-2 (1H) -one and 85 mg of bromoacetate in 15 mL of acetonitrile was added 100 mg of potassium carbonate, and the mixture was stirred at room temperature for 18 hours and at 40 ° C. for 4 hours. The solvent was distilled off under reduced pressure, chloroform and water were added, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60N, eluent: chloroform: methanol = 20: 1], and the brown oil ethyl = ((2,3-dihydro ( 1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (1- (2- (7-methoxy-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidine- 90 mg of 4-yl) amino) acetate were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.26 (3H, m), 1.52-1.60 (2H, m), 1.84-1.89 (2H, m), 2.08-2.15 (2H, m), 2.59-2.64 (2H , m), 2.65-2.71 (1H, m), 3.01-3.07 (2H, m), 3.40-3.43 (2H, m), 3.84-3.87 (2H, m), 3.97 (3H, s), 4.12-4.17 (2H, m), 4.26-4.29 (2H, m), 4.31-4.37 (4H, m), 6.72-6.75 (1H, m), 7.13-7.15 (1H, m), 7.19-7.21 (1H, m) , 7.82-7.85 (1H, m), 8.05-8.07 (1H, m), 8.27-8.29 (1H, m)

エチル＝（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）アミノ）アセタート90mgのメタノール0.2mLおよびテトラヒドロフラン1mL溶液に10％水酸化ナトリウム水溶液0.2mLを加え、室温で2時間攪拌した。反応混合物に1mol/L塩酸水溶液を加え、中和し、減圧下で溶媒を留去した。得られた残留物を樹脂［樹脂；三菱化学株式会社、ＨＰ−２０、溶離液；アセトン］で精製し、淡黄色固体の（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）アミノ）酢酸54mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.26-1.34(2H,m),1.66-1.71(2H,m),1.74-1.78(2H,m),1.90-1.97(2H,m),2.94-3.01(3H,m),3.58-3.62(2H,m),3.66-3.69(2H,m),3.96(3H,s),4.25-4.28(2H,m),4.31-4.35(4H,m),6.65(1H,d,J=9.6Hz),7.08(1H,s),7.40(1H,d,J=2.3Hz),7.86(1H,d,J=9.6Hz),7.96(1H,s),8.27(1H,d,J=2.3Hz) Example 82

Ethyl = ((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (1- (2- (7-methoxy-2-oxo-1,5-naphthyridine-1 To a solution of (2H) -yl) ethyl) piperidin-4-yl) amino) acetate 90 mg in methanol 0.2 mL and tetrahydrofuran 1 mL was added 10% aqueous sodium hydroxide solution 0.2 mL, and the mixture was stirred at room temperature for 2 hours. A 1 mol / L aqueous hydrochloric acid solution was added to the reaction mixture for neutralization, and the solvent was distilled off under reduced pressure. The obtained residue was purified with a resin [resin; Mitsubishi Chemical Corporation, HP-20, eluent: acetone] to give a pale yellow solid (((2,3-dihydro (1,4) dioxyno (2,3- c) 54 mg of pyridin-7-ylmethyl) (1- (2- (7-methoxy-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) amino) acetic acid is obtained. It was.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.26-1.34 (2H, m), 1.66-1.71 (2H, m), 1.74-1.78 (2H, m), 1.90-1.97 (2H, m), 2.94 -3.01 (3H, m), 3.58-3.62 (2H, m), 3.66-3.69 (2H, m), 3.96 (3H, s), 4.25-4.28 (2H, m), 4.31-4.35 (4H, m) , 6.65 (1H, d, J = 9.6Hz), 7.08 (1H, s), 7.40 (1H, d, J = 2.3Hz), 7.86 (1H, d, J = 9.6Hz), 7.96 (1H, s) , 8.27 (1H, d, J = 2.3Hz)

ｔｅｒｔ−ブチル＝（１−（２−（７−シアノ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート75mgの酢酸エチル5mL溶液に4mol/L塩化水素／酢酸エチル7mLを加え、室温で2時間攪拌した。反応混合物を飽和炭酸水素ナトリウムでアルカリ性とし、減圧下で溶媒留去した後、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［シリカゲル；富士シリシア社、Chromatorex-NH、溶離液；クロロホルム］で精製し、淡黄色固体の１−（２−（４−アミノピペリジン−１−イル）エチル）−７−シアノ−１，５−ナフチリジン−２（１Ｈ）−オン34mgを得た。
１−（２−（４−アミノピペリジン−１−イル）エチル）−７−シアノ−（１，５−ナフチリジン）−２（１Ｈ）−オン32mg、２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−カルバルデヒド16mgのクロロホルム5mL溶液に酢酸9μLを加え、室温で一晩攪拌した。反応混合物に水素化トリアセトキシホウ素ナトリウム34mgを加え、9時間攪拌した。飽和炭酸水素ナトリウム水溶液を加え、減圧下で溶媒を留去した。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［シリカゲル；富士シリシア社、Chromatorex-NH、溶離液；クロロホルム］で精製し、淡黄色固体の１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−シアノ−１，５−ナフチリジン−２（１Ｈ）−オン39mgを得た。
１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−シアノ−１，５−ナフチリジン−２（１Ｈ）−オン36mgの酢酸エチル5mL溶液に4mol/L塩化水素／酢酸エチル0.5mLおよび酢酸エチル5mLを加え、室温で10分間攪拌した。減圧下で溶媒を留去して白色固体の１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−シアノ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩44mgを得た。
¹H-NMR(CDCl₃)δ値：2.03-2.09(2H,m),2.33-2.38(2H,m),3.07-3.15(2H,m),3.28-3.36(3H,m),3.76-3.81(2H,m),4.21-4.24(2H,m),4.34-4.36(2H,m),4.40-4.43(2H,m),4.62-4.66(2H,m),7.09(1H,d,J=9.6Hz),7.26(1H,s),8.07(1H,d,J=9.6Hz),8.23(1H,s),8.84-8.85(1H,m),8.96(1H,d,J=1.8Hz),9.65-9.70(2H,m),10.74-10.78(1H,m) Example 83

tert-Butyl = (1- (2- (7-cyano-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate 4 mol / ml in 75 mL of ethyl acetate 7 mL of L hydrogen chloride / ethyl acetate was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was made alkaline with saturated sodium bicarbonate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [silica gel; Fuji Silysia, Chromatorex-NH, eluent: chloroform] A pale yellow solid 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-cyano-1,5-naphthyridin-2 (1H) -one 34 mg was obtained.
1- (2- (4-aminopiperidin-1-yl) ethyl) -7-cyano- (1,5-naphthyridin) -2 (1H) -one 32 mg, 2,3-dihydro (1,4) dioxino ( To a solution of 2,3-c) pyridine-7-carbaldehyde 16 mg in chloroform 5 mL was added 9 μL of acetic acid and stirred at room temperature overnight. 34 mg of sodium triacetoxyborohydride was added to the reaction mixture and stirred for 9 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Fuji Silysia Co., Ltd., Chromatorex-NH, eluent: chloroform], and 1- (2- (4-((2,3-dihydro ( 1,4) Dioxino (2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -7-cyano-1,5-naphthyridin-2 (1H) -one 39 mg was obtained.
1- (2- (4-((2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -7-cyano-1 , 5-naphthyridin-2 (1H) -one 36 mL of ethyl acetate in 5 mL solution was added 4 mol / L hydrogen chloride / ethyl acetate 0.5 mL and ethyl acetate 5 mL, and the mixture was stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure to give 1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) piperidine- 44 mg of 1-yl) ethyl) -7-cyano-1,5-naphthyridin-2 (1H) -one hydrochloride were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.03-2.09 (2H, m), 2.33-2.38 (2H, m), 3.07-3.15 (2H, m), 3.28-3.36 (3H, m), 3.76-3.81 (2H, m), 4.21-4.24 (2H, m), 4.34-4.36 (2H, m), 4.40-4.43 (2H, m), 4.62-4.66 (2H, m), 7.09 (1H, d, J = 9.6Hz), 7.26 (1H, s), 8.07 (1H, d, J = 9.6Hz), 8.23 (1H, s), 8.84-8.85 (1H, m), 8.96 (1H, d, J = 1.8Hz) , 9.65-9.70 (2H, m), 10.74-10.78 (1H, m)

（３−メトキシ−６−オキソピリド（２，３−ｂ）ピラジン−５（６Ｈ）−イル）アセトアルデヒド0.12gの塩化メチレン5mL溶液にｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（ピペリジン−４−イル）カルバマート0.18g、酢酸26μLおよび水素化トリアセトキシホウ素ナトリウム0.12gを加え、室温で2時間30分間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液およびクロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［溶離液；クロロホルム：メタノール＝２０：１］で精製し、無色油状物のｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（３−メトキシ−６−オキソピリド（２，３−ｂ）ピラジン−５（６Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.32gを得た。
¹H-NMR(CDCl₃)δ値：1.27-1.72(13H,m),2.01-2.23(2H,m),2.59-2.69(2H,m),3.01-3.11(2H,m),3.98-4.18(1H,m),4.03(3H,s),4.19-4.39(6H,m),4.46-4.56(2H,m),6.71(1H,s),6.74(1H,d,J=9.8Hz),7.83(1H,d,J=9.8Hz),8.04(1H,s),8.10(1H,s) Example 84

(3-Methoxy-6-oxopyrido (2,3-b) pyrazin-5 (6H) -yl) acetaldehyde 0.12 g in methylene chloride 5 mL solution was added tert-butyl = (2,3-dihydro (1,4) dioxyno ( 2,3-c) pyridin-7-ylmethyl) (piperidin-4-yl) carbamate 0.18 g, acetic acid 26 μL and sodium triacetoxyborohydride 0.12 g were added, and the mixture was stirred at room temperature for 2 hours 30 minutes. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 20: 1], and tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3 -C) pyridin-7-ylmethyl) (1- (2- (3-methoxy-6-oxopyrido (2,3-b) pyrazin-5 (6H) -yl) ethyl) piperidin-4-yl) carbamate 0.32 g Got.
¹ H-NMR (CDCl ₃ ) δ value: 1.27-1.72 (13H, m), 2.01-2.23 (2H, m), 2.59-2.69 (2H, m), 3.01-3.11 (2H, m), 3.98-4.18 (1H, m), 4.03 (3H, s), 4.19-4.39 (6H, m), 4.46-4.56 (2H, m), 6.71 (1H, s), 6.74 (1H, d, J = 9.8Hz), 7.83 (1H, d, J = 9.8Hz), 8.04 (1H, s), 8.10 (1H, s)

ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（３−メトキシ−６−オキソピリド（２，３−ｂ）ピラジン−５（６Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.32gに4mol/L塩化水素/酢酸エチル溶液15mLを加え、室温で2.5日間攪拌した。減圧下で溶媒を留去し、得られた残留物に酢酸エチル5mLを加え、固形物を濾取し、黄色固体の５−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−３−メトキシピリド（２，３−ｂ）ピラジン−６（５Ｈ）−オン塩酸塩0.24gを得た。
¹H-NMR(D₂O)δ値：1.98-2.13(2H,m),2.50-2.59(2H,m),3.19-3.35(2H,m),3.64-3.77(3H,m),3.97-4.09(2H,m),4.13(3H,s),4.45-4.52(4H,m),4.55-4.61(2H,m),4.90-4.94(1H,m),6.88(1H,d,J=9.8Hz),7.40(1H,s),8.08(1H,d,J=9.8Hz),8.26(1H,s),8.33(1H,s) Example 85

tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (1- (2- (3-methoxy-6-oxopyrido (2,3-b) 15 mL of 4 mol / L hydrogen chloride / ethyl acetate solution was added to 0.32 g of pyrazin-5 (6H) -yl) ethyl) piperidin-4-yl) carbamate and stirred at room temperature for 2.5 days. The solvent was distilled off under reduced pressure, 5 mL of ethyl acetate was added to the obtained residue, the solid was collected by filtration, and a yellow solid 5- (2- (4-((2,3-dihydro (1,4 ) Dioxino (2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -3-methoxypyrido (2,3-b) pyrazin-6 (5H) -one hydrochloride 0.24 g is obtained. It was.
¹ H-NMR (D ₂ O) δ value: 1.98-2.13 (2H, m), 2.50-2.59 (2H, m), 3.19-3.35 (2H, m), 3.64-3.77 (3H, m), 3.97- 4.09 (2H, m), 4.13 (3H, s), 4.45-4.52 (4H, m), 4.55-4.61 (2H, m), 4.90-4.94 (1H, m), 6.88 (1H, d, J = 9.8 Hz), 7.40 (1H, s), 8.08 (1H, d, J = 9.8Hz), 8.26 (1H, s), 8.33 (1H, s)

実施例１と同様の手法により、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（モルホリン−２−イルメチル）カルバマートおよび（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒドからｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（４−（２−（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）モルホリン−２−イルメチル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.35-1.55(9H,m),1.95-2.10(1H,m),2.23-2.33(1H,m),2.58-2.71(2H,m),2.75-2.88(2H,m),3.17-3.50(2H,m),3.53-3.62(1H,m),3.65-3.79(1H,m),3.82-3.89(1H,m),3.98(3H,s),4.22-4.46(7H,m),4.52-4.68(1H,m),6.69-6.77(1H,m),6.74(1H,d,J=9.6Hz),7.18(1H,d,J=2.2Hz),7.85(1H,d,J=9.6Hz),8.08(1H,s),8.26-8.31(1H,m) Example 86

In the same manner as in Example 1, tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (morpholin-2-ylmethyl) carbamate and (7- Methoxy-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde to tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (4- (2- (7-methoxy-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) morpholin-2-ylmethyl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.35-1.55 (9H, m), 1.95-2.10 (1H, m), 2.23-2.33 (1H, m), 2.58-2.71 (2H, m), 2.75-2.88 (2H, m), 3.17-3.50 (2H, m), 3.53-3.62 (1H, m), 3.65-3.79 (1H, m), 3.82-3.89 (1H, m), 3.98 (3H, s), 4.22 -4.46 (7H, m), 4.52-4.68 (1H, m), 6.69-6.77 (1H, m), 6.74 (1H, d, J = 9.6Hz), 7.18 (1H, d, J = 2.2Hz), 7.85 (1H, d, J = 9.6Hz), 8.08 (1H, s), 8.26-8.31 (1H, m)

実施例２と同様の手法により、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（４−（２−（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）モルホリン−２−イルメチル）カルバマートから１−（２−（２−（（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）メチル）モルホリン−４−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：3.11-3.20(1H,m),3.27-3.39(2H,m),3.43-3.50(1H,m),3.65-3.74(2H,m),3.78-3.86(1H,m),3.87-3.97(2H,m),4.05(3H,s),4.21-4.32(2H,m),4.44-4.51(4H,m),4.56-4.61(2H,m),4.70-4.83(2H,m),6.89(1H,d,J=9.8Hz),7.42(1H,s),7.49-7.53(1H,m),8.07(1H,d,J=9.8Hz),8.35(1H,s),8.42(1H,d,J=2.2Hz) Example 87

In the same manner as in Example 2, tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (4- (2- (7-methoxy-2 -Oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) morpholin-2-ylmethyl) carbamate to 1- (2- (2-(((2,3-dihydro (1,4) dioxino (2 , 3-c) pyridin-7-ylmethyl) amino) methyl) morpholin-4-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 3.11-3.20 (1H, m), 3.27-3.39 (2H, m), 3.43-3.50 (1H, m), 3.65-3.74 (2H, m), 3.78- 3.86 (1H, m), 3.87-3.97 (2H, m), 4.05 (3H, s), 4.21-4.32 (2H, m), 4.44-4.51 (4H, m), 4.56-4.61 (2H, m), 4.70-4.83 (2H, m), 6.89 (1H, d, J = 9.8Hz), 7.42 (1H, s), 7.49-7.53 (1H, m), 8.07 (1H, d, J = 9.8Hz), 8.35 (1H, s), 8.42 (1H, d, J = 2.2Hz)

実施例７８と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩および５−フルオロ−２−メチルニコチンアルデヒドから１−（２−（４−（（（５−フルオロ−２−メチルピリジン−３−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.39-1.51(2H,m),1.90-1.99(2H,m),2.17-2.28(2H,m),2.44-2.61(1H,m),2.51(3H,s),2.63-2.71(2H,m),2.96-3.05(2H,m),3.79(2H,s),3.98(3H,s),4.33-4.42(2H,m),6.75(1H,d,J=9.8Hz),7.23(1H,s),7.47(1H,dd,J=9.0,2.6Hz),7.85(1H,d,J=9.8Hz),8.23(1H,d,J=2.6Hz),8.28(1H,d,J=2.2Hz) Example 88

In a manner similar to that of Example 78, 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride and 5-fluoro- 2-Methylnicotinaldehyde to 1- (2- (4-(((5-fluoro-2-methylpyridin-3-yl) methyl) amino) piperidin-1-yl) ethyl) -7-methoxy-1,5 -Naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.39-1.51 (2H, m), 1.90-1.99 (2H, m), 2.17-2.28 (2H, m), 2.44-2.61 (1H, m), 2.51 (3H , s), 2.63-2.71 (2H, m), 2.96-3.05 (2H, m), 3.79 (2H, s), 3.98 (3H, s), 4.33-4.42 (2H, m), 6.75 (1H, d , J = 9.8Hz), 7.23 (1H, s), 7.47 (1H, dd, J = 9.0,2.6Hz), 7.85 (1H, d, J = 9.8Hz), 8.23 (1H, d, J = 2.6Hz ), 8.28 (1H, d, J = 2.2Hz)

１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.10gのメタノール4mL懸濁液に水素化シアノホウ素ナトリウム31mg、４−フルオロ−３−メチルベンズアルデヒド44μL、28％ナトリウムメトキシド／メタノール溶液39mgおよび酢酸42μLを加え、室温で1時間15分間攪拌した。４−フルオロ−３−メチルベンズアルデヒド44μLおよび水素化シアノホウ素ナトリウム31mgを加え、同温度で45分間攪拌した。さらに４−フルオロ−３−メチルベンズアルデヒド44μLおよび水素化シアノホウ素ナトリウム31mgを加え、同温度で30分間攪拌した。飽和炭酸水素ナトリウム水溶液および酢酸エチルを加え、有機層を分取し、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝１０：１］で精製した。酢酸エチル2mLに溶解し、室温で4.0mol/L塩化水素／酢酸エチル溶液1mLを加えた。減圧下で溶媒を留去し、得られた残留物に酢酸エチルを加え、固形物を濾取し、淡黄色固体の１−（２−（４−（（４−フルオロ−３−メチルベンジル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩54mgを得た。
¹H-NMR(D₂O)δ値：1.95-2.09(2H,m),2.28(3H,d,J=1.5Hz),2.47-2.56(2H,m),3.16-3.26(2H,m),3.55-3.64(3H,m),3.92-4.00(2H,m),4.04(3H,s),4.27(2H,s),4.70-4.90(2H,m),6.87(1H,d,J=9.8Hz),7.12-7.18(1H,m),7.28-7.39(2H,m),7.44(1H,d,J=2.2Hz),8.06(1H,d,J=9.8Hz),8.40(1H,d,J=2.3Hz) Example 89

Sodium cyanoborohydride in a suspension of 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride 0.10 g in methanol 4 mL 31 mg, 44 μL of 4-fluoro-3-methylbenzaldehyde, 39 mg of 28% sodium methoxide / methanol solution and 42 μL of acetic acid were added, and the mixture was stirred at room temperature for 1 hour and 15 minutes. 4-Fluoro-3-methylbenzaldehyde (44 μL) and sodium cyanoborohydride (31 mg) were added, and the mixture was stirred at the same temperature for 45 minutes. Further, 44 μL of 4-fluoro-3-methylbenzaldehyde and 31 mg of sodium cyanoborohydride were added and stirred at the same temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added, and the organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography [eluent: chloroform: methanol = 10: 1]. Dissolved in 2 mL of ethyl acetate, 1 mL of 4.0 mol / L hydrogen chloride / ethyl acetate solution was added at room temperature. The solvent was distilled off under reduced pressure, ethyl acetate was added to the obtained residue, and the solid was collected by filtration to give 1- (2- (4-((4-fluoro-3-methylbenzyl)) as a pale yellow solid. 54 mg of amino) piperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.95-2.09 (2H, m), 2.28 (3H, d, J = 1.5Hz), 2.47-2.56 (2H, m), 3.16-3.26 (2H, m) , 3.55-3.64 (3H, m), 3.92-4.00 (2H, m), 4.04 (3H, s), 4.27 (2H, s), 4.70-4.90 (2H, m), 6.87 (1H, d, J = 9.8Hz), 7.12-7.18 (1H, m), 7.28-7.39 (2H, m), 7.44 (1H, d, J = 2.2Hz), 8.06 (1H, d, J = 9.8Hz), 8.40 (1H, d, J = 2.3Hz)

実施例３０と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩および３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド（３，２−ｂ）（１，４）チアジン−６−カルバルデヒドから６−（（（１−（２−（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）アミノ）メチル）−２Ｈ−ピリド（３，２−ｂ）（１，４）チアジン−３（４Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.40-1.53(2H,m),1.87-1.96(2H,m),2.14-2.24(2H,m),2.47-2.58(1H,m),2.62-2.69(2H,m),2.95-3.04(2H,m),3.48(2H,s),3.83(2H,s),3.98(3H,s),4.33-4.41(2H,m),6.74(1H,d,J=9.6Hz),6.97(1H,d,J=7.7Hz),7.24(1H,d,J=2.2Hz),7.57(1H,d,J=7.7Hz),7.85(1H,d,J=9.6Hz),8.13-8.23(1H,broad),8.28(1H,d,J=2.2Hz) Example 90

In a manner similar to that in Example 30, 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride and 3-oxo- From 3,4-dihydro-2H-pyrido (3,2-b) (1,4) thiazine-6-carbaldehyde to 6-(((1- (2- (7-methoxy-2-oxo-1,5 -Naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) amino) methyl) -2H-pyrido (3,2-b) (1,4) thiazin-3 (4H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.40-1.53 (2H, m), 1.87-1.96 (2H, m), 2.14-2.24 (2H, m), 2.47-2.58 (1H, m), 2.62-2.69 (2H, m), 2.95-3.04 (2H, m), 3.48 (2H, s), 3.83 (2H, s), 3.98 (3H, s), 4.33-4.41 (2H, m), 6.74 (1H, d , J = 9.6Hz), 6.97 (1H, d, J = 7.7Hz), 7.24 (1H, d, J = 2.2Hz), 7.57 (1H, d, J = 7.7Hz), 7.85 (1H, d, J = 9.6Hz), 8.13-8.23 (1H, broad), 8.28 (1H, d, J = 2.2Hz)

（７−（１Ｈ−イミダゾール−１−イル）−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド0.12gのジクロロメタン1mL溶液にｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（ピペリジン−４−イル）カルバマート0.14gのジクロロメタン1.4mL溶液、酢酸23μLおよび水素化トリアセトキシホウ素ナトリウム0.13gを加え室温で1時間40分間攪拌した。反応混合物にクロロホルムおよび飽和炭酸水素ナトリウム水溶液を加え、pH8.6に調整し、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を塩基性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＝１９：１−９３：７］で精製し、淡黄色固形物のｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−（１Ｈ−イミダゾール−１−イル）−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.12gを得た。
¹H-NMR(CDCl₃)δ値：1.32-1.72(13H,m),2.10-2.27(2H,m),2.60-2.69(2H,m),2.94-3.03(2H,m),4.05-4.15(1H,m),4.24-4.40(8H,m),6.72(1H,s),6.93(1H,d,J=9.8Hz),7.32(1H,s),7.39(1H,s),7.75(1H,s),7.93(1H,d,J=9.8Hz),7.97(1H,s),8.04(1H,s),8.65(1H,d,J=1.9Hz) Example 91

(7- (1H-imidazol-1-yl) -2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde 0.12 g in dichloromethane 1 mL solution was added tert-butyl = (2,3-dihydro (1 , 4) Dioxino (2,3-c) pyridin-7-ylmethyl) (piperidin-4-yl) carbamate 0.14 g in 1.4 mL dichloromethane, 23 μL acetic acid and 0.13 g sodium triacetoxyborohydride were added for 1 hour at room temperature Stir for 40 minutes. Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture to adjust to pH 8.6, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography [gradient elution of chloroform: methanol = 19: 1-93: 7], and tert-butyl = (2,3-dihydro (1, 4) Dioxino (2,3-c) pyridin-7-ylmethyl) (1- (2- (7- (1H-imidazol-1-yl) -2-oxo-1,5-naphthyridine-1 (2H)- 0.12 g of yl) ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.32-1.72 (13H, m), 2.10-2.27 (2H, m), 2.60-2.69 (2H, m), 2.94-3.03 (2H, m), 4.05-4.15 (1H, m), 4.24-4.40 (8H, m), 6.72 (1H, s), 6.93 (1H, d, J = 9.8Hz), 7.32 (1H, s), 7.39 (1H, s), 7.75 ( 1H, s), 7.93 (1H, d, J = 9.8Hz), 7.97 (1H, s), 8.04 (1H, s), 8.65 (1H, d, J = 1.9Hz)

実施例４と同様の手法により、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−（１Ｈ−イミダゾール−１−イル）−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートから１−（２−（４−（（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−７−（１Ｈ−イミダゾール−１−イル）−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：1.90-2.15(2H,m),2.52-2.61(2H,m),3.24-3.36(2H,m),3.66-3.80(3H,m),4.00-4.09(2H,m),4.40-4.50(2H,m),4.50-4.54(2H,m),4.57-4.88(4H,m),7.16(1H,d,J=9.9Hz),7.45(1H,s),7.77(1H,t,J=2.0Hz),8.09(1H,t,J=1.6Hz),8.19(1H,d,J=9.9Hz),8.36(1H,s),8.44(1H,d,J=1.6Hz),8.93(1H,d,J=2.0Hz),9.46(1H,t,J=1.4Hz) Example 92

In the same manner as in Example 4, tert-butyl = (2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) (1- (2- (7- (1H- Imidazol-1-yl) -2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate to 1- (2- (4-(((2,3-dihydro (1,4) Dioxyno (2,3-c) pyridin-7-yl) methyl) amino) piperidin-1-yl) ethyl) -7- (1H-imidazol-1-yl) -1,5-naphthyridine 2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.90-2.15 (2H, m), 2.52-2.61 (2H, m), 3.24-3.36 (2H, m), 3.66-3.80 (3H, m), 4.00- 4.09 (2H, m), 4.40-4.50 (2H, m), 4.50-4.54 (2H, m), 4.57-4.88 (4H, m), 7.16 (1H, d, J = 9.9Hz), 7.45 (1H, s), 7.77 (1H, t, J = 2.0Hz), 8.09 (1H, t, J = 1.6Hz), 8.19 (1H, d, J = 9.9Hz), 8.36 (1H, s), 8.44 (1H, d, J = 1.6Hz), 8.93 (1H, d, J = 2.0Hz), 9.46 (1H, t, J = 1.4Hz)

実施例７８と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩および５−フルオロ−６−メチルニコチンアルデヒドから１−（２−（４−（（（５−フルオロ−６−メチルピリジン−３−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.35-1.47(2H,m),1.86-1.95(2H,m),2.14-2.24(2H,m),2.47-2.56(1H,m),2.51(3H,d,J=2.9Hz),2.62-2.68(2H,m),2.94-3.02(2H,m),3.82(2H,s),3.98(3H,s),4.33-4.40(2H,m),6.74(1H,d,J=9.8Hz),7.21(1H,d,J=2.3Hz),7.36(1H,dd,J=9.9,1.4Hz),7.84(1H,d,J=9.8Hz),8.23(1H,s),8.28(1H,d,J=2.3Hz) Example 93

In a manner similar to that of Example 78, 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride and 5-fluoro- 1- (2- (4-(((5-fluoro-6-methylpyridin-3-yl) methyl) amino) piperidin-1-yl) ethyl) -7-methoxy-1,5 from 6-methylnicotinaldehyde -Naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.35-1.47 (2H, m), 1.86-1.95 (2H, m), 2.14-2.24 (2H, m), 2.47-2.56 (1H, m), 2.51 (3H , d, J = 2.9Hz), 2.62-2.68 (2H, m), 2.94-3.02 (2H, m), 3.82 (2H, s), 3.98 (3H, s), 4.33-4.40 (2H, m), 6.74 (1H, d, J = 9.8Hz), 7.21 (1H, d, J = 2.3Hz), 7.36 (1H, dd, J = 9.9,1.4Hz), 7.84 (1H, d, J = 9.8Hz), 8.23 (1H, s), 8.28 (1H, d, J = 2.3Hz)

実施例１と同様の手法により、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（（３Ｒ，４Ｒ）−３−ヒドロキシピペリジン−４−イル）カルバマートおよび（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒドからｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（（３Ｒ，４Ｒ）−３−ヒドロキシ−１−（２−（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.22-1.42(9H,m),1.55-1.85(3H,m),2.18-2.36(2H,m),2.67-2.79(2H,m),2.98-3.07(1H,m),3.26-3.36(1H,m),3.62-3.73(1H,m),3.94(3H,s),4.00-4.52(8H,m),6.70-6.84(2H,m),7.13-7.17(1H,m),7.81-8.05(2H,m),8.24-8.32(1H,m) Example 94

In the same manner as in Example 1, tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) ((3R, 4R) -3-hydroxypiperidine- 4-yl) carbamate and (7-methoxy-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde to tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3 -C) pyridin-7-ylmethyl) ((3R, 4R) -3-hydroxy-1- (2- (7-methoxy-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidine -4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.22-1.42 (9H, m), 1.55-1.85 (3H, m), 2.18-2.36 (2H, m), 2.67-2.79 (2H, m), 2.98-3.07 (1H, m), 3.26-3.36 (1H, m), 3.62-3.73 (1H, m), 3.94 (3H, s), 4.00-4.52 (8H, m), 6.70-6.84 (2H, m), 7.13 -7.17 (1H, m), 7.81-8.05 (2H, m), 8.24-8.32 (1H, m)

ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（（３Ｒ，４Ｒ）−３−ヒドロキシ−１−（２−（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート75mgのエタノール3mL溶液に室温で塩化水素／エタノール溶液3.0mLを加えた。同温度で1時間攪拌し、減圧下で溶媒を留去した。得られた残留物にジエチルエーテルを加え、固形物を濾取した。その固形物にクロロホルムおよび水を加え、水層を分取した。水層にクロロホルムを加え、1mol/L水酸化ナトリウム水溶液でpH12に調整した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、淡褐色油状物の１−（２−（（３Ｒ，４Ｒ）−４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）−３−ヒドロキシピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン45mgを得た。
¹H-NMR(CDCl₃)δ値：1.35-1.47(1H,m),1.92-2.02(1H,m),2.07-2.23(2H,m),2.33-2.42(1H,m),2.65-2.73(2H,m),2.91-2.99(1H,m),3.14-3.22(1H,m),3.44-3.52(1H,m),3.72-3.84(1H,m),3.92-4.01(1H,m),3.97(3H,s),4.25-4.42(6H,m),6.73(1H,d,J=9.8Hz),6.76(1H,s),7.18(1H,d,J=2.4Hz),7.84(1H,d,J=9.8Hz),8.09(1H,s),8.27(1H,d,J=2.4Hz) Example 95

tert-Butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) ((3R, 4R) -3-hydroxy-1- (2- (7-methoxy- To a solution of 2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate in 75 mL of ethanol was added 3.0 mL of a hydrogen chloride / ethanol solution at room temperature. The mixture was stirred at the same temperature for 1 hour, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the obtained residue, and the solid was collected by filtration. Chloroform and water were added to the solid, and the aqueous layer was separated. Chloroform was added to the aqueous layer, and the pH was adjusted to 12 with a 1 mol / L aqueous sodium hydroxide solution. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 1- (2-((3R, 4R) -4- ((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) -3-hydroxypiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridine -2 (1H) -one 45 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.35-1.47 (1H, m), 1.92-2.02 (1H, m), 2.07-2.23 (2H, m), 2.33-2.42 (1H, m), 2.65-2.73 (2H, m), 2.91-2.99 (1H, m), 3.14-3.22 (1H, m), 3.44-3.52 (1H, m), 3.72-3.84 (1H, m), 3.92-4.01 (1H, m) , 3.97 (3H, s), 4.25-4.42 (6H, m), 6.73 (1H, d, J = 9.8Hz), 6.76 (1H, s), 7.18 (1H, d, J = 2.4Hz), 7.84 ( 1H, d, J = 9.8Hz), 8.09 (1H, s), 8.27 (1H, d, J = 2.4Hz)

実施例７８と同様の手法により、５−（２−（４−アミノピペリジン−１−イル）エチル）−３−メトキシピリド（２，３−ｂ）ピラジン−６（５Ｈ）−オン塩酸塩および５−フルオロ−６−メチルニコチンアルデヒドから５−（２−（４−（（（５−フルオロ−６−メチルピリジン−３−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−３−メトキシピリド（２，３−ｂ）ピラジン−６（５Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.31-1.43(2H,m),1.83-1.92(2H,m),2.12-2.22(2H,m),2.44-2.55(1H,m),2.50(3H,d,J=2.7Hz),2.67-2.74(2H,m),2.99-3.08(2H,m),3.81(2H,s),4.06(3H,s),4.55-4.62(2H,m),6.76(1H,d,J=9.8Hz),7.36(1H,d,J=9.8Hz),7.84(1H,d,J=9.8Hz),8.11(1H,s),8.22(1H,s) Example 96

In a manner similar to that in Example 78, 5- (2- (4-aminopiperidin-1-yl) ethyl) -3-methoxypyrido (2,3-b) pyrazin-6 (5H) -one hydrochloride and 5- From fluoro-6-methylnicotinaldehyde to 5- (2- (4-(((5-fluoro-6-methylpyridin-3-yl) methyl) amino) piperidin-1-yl) ethyl) -3-methoxypyrido (2 , 3-b) Pyrazin-6 (5H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.31-1.43 (2H, m), 1.83-1.92 (2H, m), 2.12-2.22 (2H, m), 2.44-2.55 (1H, m), 2.50 (3H , d, J = 2.7Hz), 2.67-2.74 (2H, m), 2.99-3.08 (2H, m), 3.81 (2H, s), 4.06 (3H, s), 4.55-4.62 (2H, m), 6.76 (1H, d, J = 9.8Hz), 7.36 (1H, d, J = 9.8Hz), 7.84 (1H, d, J = 9.8Hz), 8.11 (1H, s), 8.22 (1H, s)

（２−メトキシ−７−オキソピリド（２，３−ｄ）ピリミジン−８（７Ｈ）−イル）アセトアルデヒド0.33gのジクロロメタン15mL溶液にｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（ピペリジン−４−イル）カルバマート0.53gのジクロロメタン5.3mL溶液および酢酸87μLを加え、室温で1時間30分間攪拌した。反応混合物に水素化トリアセトキシホウ素ナトリウム0.40gを加え、2時間30分間攪拌した。一晩放置後、室温で4時間攪拌した。反応混合物にクロロホルムおよび飽和炭酸水素ナトリウム水溶液を加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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：メタノールの勾配溶離＝５０：１−１０：１］で精製し、淡黄色泡状物のｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（２−メトキシ−７−オキソピリド（２，３−ｄ）ピリミジン−８（７Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.55gを得た。
¹H-NMR(CDCl₃)δ値：1.25-1.69(13H),2.01-2.23(2H,m),2.61-2.69(2H,m),3.02-3.11(2H,m),3.63-3.84(1H,m),4.06(3H,s),4.22-4.43(6H,m),4.45-4.53(2H,m),6.57(1H,d,J=9.4Hz),6.71(1H,s),7.60(1H,d,J=9.4Hz),8.04(1H,s),8.64(1H,s) Example 97

To a solution of 0.33 g of (2-methoxy-7-oxopyrido (2,3-d) pyrimidin-8 (7H) -yl) acetaldehyde in 15 mL of dichloromethane was added tert-butyl = (2,3-dihydro (1,4) dioxyno (2 , 3-c) Pyridin-7-ylmethyl) (piperidin-4-yl) carbamate 0.53 g in dichloromethane 5.3 mL and acetic acid 87 μL were added and stirred at room temperature for 1 hour 30 minutes. To the reaction mixture, 0.40 g of sodium triacetoxyborohydride was added and stirred for 2 hours and 30 minutes. After standing overnight, the mixture was stirred at room temperature for 4 hours. Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [gradient elution of chloroform: methanol = 50: 1-10: 1], and tert-butyl = (2,3-dihydro (1,4 ) Dioxino (2,3-c) pyridin-7-ylmethyl) (1- (2- (2-methoxy-7-oxopyrido (2,3-d) pyrimidin-8 (7H) -yl) ethyl) piperidine-4 -Yl) Carbamate 0.55g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.25-1.69 (13H), 2.01-2.23 (2H, m), 2.61-2.69 (2H, m), 3.02-3.11 (2H, m), 3.63-3.84 (1H , m), 4.06 (3H, s), 4.22-4.43 (6H, m), 4.45-4.53 (2H, m), 6.57 (1H, d, J = 9.4Hz), 6.71 (1H, s), 7.60 ( 1H, d, J = 9.4Hz), 8.04 (1H, s), 8.64 (1H, s)

ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（２−メトキシ−７−オキソピリド（２，３−ｄ）ピリミジン−８（７Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.54gのジクロロメタン15mL溶液にトリフルオロ酢酸5mLを加え、室温で2時間攪拌した。氷冷下２mol/L水酸化ナトリウム水溶液でpH13に調整し、ジクロロメタンを加え、有機層を分取し、水層をジクロロメタンで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝１０：１］で精製し、黄色油状物の８−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−２−メトキシピリド（２，３−ｄ）ピリミジン−７（８Ｈ）−オン0.34gを得た。
¹H-NMR(CDCl₃)δ値：1.31-1.43(2H,m),1.81-1.90(2H,m),2.08-2.19(2H,m),2.41-2.55(1H,m),2.64-2.72(2H,m),2.97-3.06(2H,m),3.77(2H,s),4.07(3H,s),4.23-4.34(4H,m),4.50-4.58(2H,m),6.56(1H,d,J=9.5Hz),6.80(1H,s),7.59(1H,d,J=9.5Hz),8.08(1H,s),8.63(1H,s) Example 98

tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (1- (2- (2-methoxy-7-oxopyrido (2,3-d) 5 mL of trifluoroacetic acid was added to a solution of pyrimidine-8 (7H) -yl) ethyl) piperidin-4-yl) carbamate 0.54 g in dichloromethane 15 mL and stirred at room temperature for 2 hours. Under ice cooling, the pH was adjusted to 13 with a 2 mol / L aqueous sodium hydroxide solution, dichloromethane was added, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography [eluent: chloroform: methanol = 10: 1] to give 8- (2- (4-((2,3-dihydro (1, 4) Dioxino (2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -2-methoxypyrido (2,3-d) pyrimidin-7 (8H) -one 0.34 g was obtained. .
¹ H-NMR (CDCl ₃ ) δ value: 1.31-1.43 (2H, m), 1.81-1.90 (2H, m), 2.08-2.19 (2H, m), 2.41-2.55 (1H, m), 2.64-2.72 (2H, m), 2.97-3.06 (2H, m), 3.77 (2H, s), 4.07 (3H, s), 4.23-4.34 (4H, m), 4.50-4.58 (2H, m), 6.56 (1H , d, J = 9.5Hz), 6.80 (1H, s), 7.59 (1H, d, J = 9.5Hz), 8.08 (1H, s), 8.63 (1H, s)

Ｎ−（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）−２，２，２−トリフルオロ−Ｎ−（ピペリジン−３−イルメチル）アセトアミド0.15gのジクロロメタン2mL溶液に（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド85mgおよび酢酸24μLを加え、続いて水素化トリアセトキシホウ素ナトリウム0.13gを加え、室温で2時間攪拌した。反応混合物にクロロホルムを加え、氷冷下、飽和炭酸水素ナトリウム水溶液を加えてpH8.0に調整した。有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、黄色固体のＮ−（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）−２，２，２−トリフルオロ−Ｎ−（１−（２−（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−３−イルメチル）アセトアミド0.21gを得た。
Ｎ−（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）−２，２，２−トリフルオロ−Ｎ−（１−（２−（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−３−イルメチル）アセトアミド0.21gにメタノール3mLおよび水0.7mLを加え、炭酸カリウム62mgを加えた。室温で1時間15分間攪拌した後、40〜50℃で1時間攪拌し、50〜60℃で1時間30分間攪拌した。減圧下で溶媒を留去し、得られた残留物にクロロホルムおよび水を加え有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を塩基性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＝９２：８−８８：１２］で精製し、淡黄色油状物の１−（２−（３−（（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）メチル）ピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン0.18gを得た。
¹H-NMR(CDCl₃)δ値：0.90-1.10(1H,m),1.45-1.92(5H,m),2.05-2.14(1H,m),2.46-2.52(2H,m),2.60-2.66(2H,m),2.85-2.92(1H,m),2.98-3.05(1H,m),3.74(2H,s),4.25-4.35(6H,m),6.81(1H,s),6.86(1H,d,J=9.8Hz),7.60(1H,dd,J=10.4,2.2Hz),7.88(1H,d,J=9.8Hz),8.10(1H,s),8.41(1H,d,J=2.4Hz) Example 99

0.15 g of N- (2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) -2,2,2-trifluoro-N- (piperidin-3-ylmethyl) acetamide To a 2 mL solution of dichloromethane was added 85 mg of (7-fluoro-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde and 24 μL of acetic acid, followed by 0.13 g of sodium triacetoxyborohydride, Stir for hours. Chloroform was added to the reaction mixture, and the mixture was adjusted to pH 8.0 by adding saturated aqueous sodium hydrogen carbonate solution under ice cooling. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give N- (2,3-dihydro (1,4) as a yellow solid. Dioxino (2,3-c) pyridin-7-ylmethyl) -2,2,2-trifluoro-N- (1- (2- (7-fluoro-2-oxo-1,5-naphthyridine-1 (2H 0.21 g of) -yl) ethyl) piperidin-3-ylmethyl) acetamide was obtained.
N- (2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) -2,2,2-trifluoro-N- (1- (2- (7-fluoro- To 0.21 g of 2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-3-ylmethyl) acetamide was added 3 mL of methanol and 0.7 mL of water, and 62 mg of potassium carbonate was added. After stirring at room temperature for 1 hour and 15 minutes, the mixture was stirred at 40 to 50 ° C for 1 hour, and stirred at 50 to 60 ° C for 1 hour and 30 minutes. The solvent was distilled off under reduced pressure, chloroform and water were added to the resulting residue, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography [gradient elution of hexane: ethyl acetate = 92: 8-88: 12] to give 1- (2- (3-(((2 , 3-Dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) methyl) piperidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridine-2 (1H) -Obtained 0.18 g of ON.
¹ H-NMR (CDCl ₃ ) δ value: 0.90-1.10 (1H, m), 1.45-1.92 (5H, m), 2.05-2.14 (1H, m), 2.46-2.52 (2H, m), 2.60-2.66 (2H, m), 2.85-2.92 (1H, m), 2.98-3.05 (1H, m), 3.74 (2H, s), 4.25-4.35 (6H, m), 6.81 (1H, s), 6.86 (1H , d, J = 9.8Hz), 7.60 (1H, dd, J = 10.4,2.2Hz), 7.88 (1H, d, J = 9.8Hz), 8.10 (1H, s), 8.41 (1H, d, J = 2.4Hz)

１−（２−（３−（（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）メチル）ピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン0.14gの酢酸エチル4mL溶液に４mol/L塩化水素/酢酸エチル溶液1mLを加え、室温で20分間攪拌した。減圧下で溶媒を留去し、得られた残留物にジエチルエーテルを加え、固形物を濾取し、淡黄色固体の１−（２−（３−（（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）メチル）ピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.10gを得た。
¹H-NMR(D₂O)δ値：1.31-1.48(1H,m),1.76-1.90(1H,m),2.00-2.14(2H,m),2.32-2.44(1H,m),2.86-3.26(4H,m),3.56-4.00(4H,m),4.38-4.46(4H,m),4.52-4.56(2H,m),4.74-4.84(2H,m),6.99(1H,d,J=10.4Hz),7.33(1H,s),7.94(1H,dd,J=10.4,2.1Hz),8.10(1H,d,J=10.2Hz),8.29(1H,s),8.56(1H,d,J=2.1Hz) Example 100

1- (2- (3-(((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) methyl) piperidin-1-yl) ethyl) -7- 1 mL of 4 mol / L hydrogen chloride / ethyl acetate solution was added to 4 mL of ethyl acetate in 0.14 g of fluoro-1,5-naphthyridin-2 (1H) -one and stirred at room temperature for 20 minutes. The solvent was distilled off under reduced pressure, diethyl ether was added to the obtained residue, the solid was collected by filtration, and 1- (2- (3-(((2,3-dihydro (1, 4) 0.10 g of dioxino (2,3-c) pyridin-7-ylmethyl) amino) methyl) piperidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one hydrochloride Obtained.
¹ H-NMR (D ₂ O) δ value: 1.31-1.48 (1H, m), 1.76-1.90 (1H, m), 2.00-2.14 (2H, m), 2.32-2.44 (1H, m), 2.86 3.26 (4H, m), 3.56-4.00 (4H, m), 4.38-4.46 (4H, m), 4.52-4.56 (2H, m), 4.74-4.84 (2H, m), 6.99 (1H, d, J = 10.4Hz), 7.33 (1H, s), 7.94 (1H, dd, J = 10.4, 2.1Hz), 8.10 (1H, d, J = 10.2Hz), 8.29 (1H, s), 8.56 (1H, d , J = 2.1Hz)

１−（２−（４−アミノピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.10gのメタノール2mL懸濁液に28％ナトリウムメトキシド／メタノール溶液0.15g、（５−フルオロ−６−メトキシ）ニコチンアルデヒド39mgおよび酢酸14μLを加えた。水素化シアノホウ素ナトリウム31mgを加え、室温で3時間攪拌した。一晩放置後、室温で35分間攪拌し、水素化シアノホウ素ナトリウム31mgを加え、同温度で1時間40分間攪拌した。反応混合物にクロロホルムおよび飽和炭酸水素ナトリウム水溶液を加え、有機層を分取し、水および飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、得られた残留物を塩基性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＝９５：５−９２：８］で精製し、白色固体の７−フルオロ−１−（２−（４−（（（５−フルオロ−６−メトキシピリジン−３−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オン43mgを得た。
¹H-NMR(CDCl₃)δ値：1.32-1.46(2H,m),1.85-1.94(2H,m),2.13-2.22(2H,m),2.45-2.55(1H,m),2.62-2.68(2H,m),2.91-2.99(2H,m),3.75(2H,s),4.01(3H,m),4.28-4.34(2H,m),6.86(1H,d,J=9.8Hz),7.38(1H,dd,J=10.9,2.0Hz),7.50-7.55(1H,m),7.83(1H,d,J=2.0Hz),7.88(1H,d,J=9.8Hz),8.42(1H,d,2.4Hz) Example 101

1- (2- (4-Aminopiperidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one hydrochloride 0.10 g of methanol in 2 mL suspension of 28% sodium methoxide /0.15 g of methanol solution, 39 mg of (5-fluoro-6-methoxy) nicotinaldehyde and 14 μL of acetic acid were added. 31 mg of sodium cyanoborohydride was added and stirred at room temperature for 3 hours. After standing overnight, the mixture was stirred at room temperature for 35 minutes, 31 mg of sodium cyanoborohydride was added, and the mixture was stirred at the same temperature for 1 hour and 40 minutes. Chloroform and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the organic layer was separated and washed with water and a saturated aqueous sodium chloride solution. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography [gradient elution of chloroform: methanol = 95: 5-92: 8] to give a white solid. 7-fluoro-1- (2- (4-(((5-fluoro-6-methoxypyridin-3-yl) methyl) amino) piperidin-1-yl) ethyl) -1,5-naphthyridine-2 ( 43 mg of 1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.32-1.46 (2H, m), 1.85-1.94 (2H, m), 2.13-2.22 (2H, m), 2.45-2.55 (1H, m), 2.62-2.68 (2H, m), 2.91-2.99 (2H, m), 3.75 (2H, s), 4.01 (3H, m), 4.28-4.34 (2H, m), 6.86 (1H, d, J = 9.8Hz), 7.38 (1H, dd, J = 10.9,2.0Hz), 7.50-7.55 (1H, m), 7.83 (1H, d, J = 2.0Hz), 7.88 (1H, d, J = 9.8Hz), 8.42 (1H , d, 2.4Hz)

実施例７８と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩および５−フルオロ−２，６−ジメチルニコチンアルデヒドから７−フルオロ−１−（２−（４−（（（５−フルオロ−２，６−ジメチルピリジン−３−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.36-1.48(2H,m),1.87-1.97(2H,m),2.16-2.26(2H,m),2.42-2.59(7H,m),2.62-2.70(2H,m),2.92-3.01(2H,m),3.74(2H,s),4.29-4.37(2H,m),6.86(1H,d,J=9.5Hz),7.34(1H,d,J=10.0Hz),7.54(1H,dd,J=10.2,2.0Hz),7.89(1H,d,J=10.0Hz),8.42(1H,d,J=2.2Hz) Example 102

In a manner similar to that of Example 78, 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one hydrochloride and 5-fluoro- 2,6-Dimethylnicotinaldehyde to 7-fluoro-1- (2- (4-(((5-fluoro-2,6-dimethylpyridin-3-yl) methyl) amino) piperidin-1-yl) ethyl) -1,5-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.36-1.48 (2H, m), 1.87-1.97 (2H, m), 2.16-2.26 (2H, m), 2.42-2.59 (7H, m), 2.62-2.70 (2H, m), 2.92-3.01 (2H, m), 3.74 (2H, s), 4.29-4.37 (2H, m), 6.86 (1H, d, J = 9.5Hz), 7.34 (1H, d, J = 10.0Hz), 7.54 (1H, dd, J = 10.2,2.0Hz), 7.89 (1H, d, J = 10.0Hz), 8.42 (1H, d, J = 2.2Hz)

１−（２−（４−アミノピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.10gおよび３，４−ジヒドロ−２Ｈ−ピラノ（２，３−ｃ）ピリジン−６−カルバルデヒド61mgのメタノール2.5mL懸濁液に水素化シアノホウ素ナトリウム62mg、28％ナトリウムメトキシド／メタノール溶液0.14gおよび酢酸86μLを加え、室温で1時間50分間攪拌した。酢酸エチル、飽和炭酸水素ナトリウム水溶液および2mol/L水酸化ナトリウム水溶液を加え、有機層を分取し、水層を酢酸エチルで２回抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝１０：１］で精製した。メタノール1mLおよび酢酸エチル１mLに溶解し、室温で4mol/L塩化水素／酢酸エチル溶液0.5mLを加えた。減圧下で溶媒を留去し、得られた残留物にジエチルエーテルを加え、固形物を濾取し、淡黄色固体の１−（２−（４−（（３，４−ジヒドロ−２Ｈ−ピラノ（２，３−ｃ）ピリジン−６−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.11gを得た。
¹H-NMR(D₂O)δ値：2.00-2.12(4H,m),2.50-2.59(2H,m),2.93(2H,t,J=6.3Hz),3.22-3.32(2H,m),3.60-3.75(1H,m),3.63(2H,t,J=5.9Hz),3.95-4.06(2H,m),4.33-4.36(2H,m),4.44(2H,s),4.72-4.92(2H,m),6.99(1H,d,J=9.9Hz),7.52(1H,s),7.95(1H,dd,J=10.3,2.1Hz),8.10(1H,d,J=9.9Hz),8.20(1H,s),8.57(1H,d,J=2.1Hz) Example 103

1- (2- (4-Aminopiperidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one hydrochloride 0.10 g and 3,4-dihydro-2H-pyrano (2 , 3-c) 62 mg of sodium cyanoborohydride, 0.14 g of 28% sodium methoxide / methanol solution and 86 μL of acetic acid were added to a suspension of 61 mg of pyridine-6-carbaldehyde in 2.5 mL of methanol and stirred at room temperature for 1 hour and 50 minutes. did. Ethyl acetate, saturated aqueous sodium hydrogen carbonate solution and 2 mol / L aqueous sodium hydroxide solution were added, the organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography [eluent: chloroform: methanol = 10: 1]. Dissolved in 1 mL of methanol and 1 mL of ethyl acetate, 0.5 mL of 4 mol / L hydrogen chloride / ethyl acetate solution was added at room temperature. The solvent was distilled off under reduced pressure, diethyl ether was added to the obtained residue, and the solid was collected by filtration to give 1- (2- (4-((3,4-dihydro-2H-pyrano) as a pale yellow solid. 0.12 g of (2,3-c) pyridin-6-ylmethyl) amino) piperidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 2.00-2.12 (4H, m), 2.50-2.59 (2H, m), 2.93 (2H, t, J = 6.3Hz), 3.22-3.32 (2H, m) , 3.60-3.75 (1H, m), 3.63 (2H, t, J = 5.9Hz), 3.95-4.06 (2H, m), 4.33-4.36 (2H, m), 4.44 (2H, s), 4.72-4.92 (2H, m), 6.99 (1H, d, J = 9.9Hz), 7.52 (1H, s), 7.95 (1H, dd, J = 10.3,2.1Hz), 8.10 (1H, d, J = 9.9Hz) , 8.20 (1H, s), 8.57 (1H, d, J = 2.1Hz)

（３Ｓ）−Ｎ−（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）ピロリジン−３−アミン塩酸塩62mgのメタノール3mL溶液に室温で28％ナトリウムメトキシド／メタノール溶液0.10g、（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド37mg、酢酸60μL、モレキュラーシーブス３Ａ0.12gおよび水素化シアノホウ素ナトリウム11mgを加え、同温度で1時間10分間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液および酢酸エチルを加え、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝３０：１］で精製し、酢酸エチルおよび4mol/L塩化水素／酢酸エチル溶液を加え、固形物を濾取し、黄色固体の１−（２−（（３Ｓ）−３−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピロリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩33mgを得た。
¹H-NMR(D₂O)δ値：2.16-2.34(1H,m),2.55-2.70(1H,m),3.35-3.95(6H,m),4.16-4.26(1H,m),4.45-4.85(8H,m),6.98(1H,d,J=10.0Hz),7.47(1H,s),7.94-7.98(1H,m),8.08(1H,d,J=10.0Hz),8.36(1H,s),8.56(1H,s) Example 104

(3S) -N- (2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) pyrrolidin-3-amine hydrochloride in 62 mL of methanol at room temperature with 28% sodium methoxy 0.10 g of a solution of methanol / methanol, 37 mg of (7-fluoro-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde, 60 μL of acetic acid, 0.12 g of molecular sieves 3A and 11 mg of sodium cyanoborohydride were added. The mixture was stirred at the same temperature for 1 hour and 10 minutes. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography [eluent: chloroform: methanol = 30: 1], ethyl acetate and 4 mol / L hydrogen chloride / ethyl acetate solution were added, and the solid was collected by filtration. 1- (2-((3S) -3-((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) pyrrolidin-1-yl) ethyl as a yellow solid ) -7-fluoro-1,5-naphthyridin-2 (1H) -one hydrochloride 33 mg was obtained.
¹ H-NMR (D ₂ O) δ value: 2.16-2.34 (1H, m), 2.55-2.70 (1H, m), 3.35-3.95 (6H, m), 4.16-4.26 (1H, m), 4.45 4.85 (8H, m), 6.98 (1H, d, J = 10.0Hz), 7.47 (1H, s), 7.94-7.98 (1H, m), 8.08 (1H, d, J = 10.0Hz), 8.36 (1H , s), 8.56 (1H, s)

実施例７８と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩および５−フルオロ−６−メチルニコチンアルデヒドから７−フルオロ−１−（２−（４−（（（５−フルオロ−６−メチルピリジン−３−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.33-1.45(2H,m),1.85-1.94(2H,m),2.14-2.23(2H,m),2.46-2.55(1H,m),2.51(3H,d,J=2.7Hz),2.61-2.68(2H,m),2.91-3.00(2H,m),3.81(2H,s),4.28-4.35(2H,m),6.86(1H,d,J=9.8Hz),7.36(1H,dd,J=10.1,1.6Hz),7.53(1H,dd,J=10.2,2.3Hz),7.88(1H,d,J=9.8Hz),8.23(1H,s),8.42(1H,d,J=2.3Hz) Example 105

In a manner similar to that of Example 78, 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one hydrochloride and 5-fluoro- 6-methylnicotinaldehyde to 7-fluoro-1- (2- (4-(((5-fluoro-6-methylpyridin-3-yl) methyl) amino) piperidin-1-yl) ethyl) -1,5 -Naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.33-1.45 (2H, m), 1.85-1.94 (2H, m), 2.14-2.23 (2H, m), 2.46-2.55 (1H, m), 2.51 (3H , d, J = 2.7Hz), 2.61-2.68 (2H, m), 2.91-3.00 (2H, m), 3.81 (2H, s), 4.28-4.35 (2H, m), 6.86 (1H, d, J = 9.8Hz), 7.36 (1H, dd, J = 10.1,1.6Hz), 7.53 (1H, dd, J = 10.2,2.3Hz), 7.88 (1H, d, J = 9.8Hz), 8.23 (1H, s ), 8.42 (1H, d, J = 2.3Hz)

実施例１と同様の手法により、ｔｅｒｔ−ブチル＝（３，４−ジヒドロ−２Ｈ−（１，４）ジオキセピノ（２，３−ｃ）ピリジン−８−イルメチル）（ピペリジン−４−イル）カルバマートおよび（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒドからｔｅｒｔ−ブチル＝（３，４−ジヒドロ−２Ｈ−（１，４）ジオキセピノ（２，３−ｃ）ピリジン−８−イルメチル）（１−（２−（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.28-1.74(13H,m),2.07-2.30(4H,m),2.57-2.65(2H,m),2.94-3.03(2H,m),4.06-4.18(1H,m),4.20-4.40(8H,m),6.77(1H,s),6.85(1H,d,J=9.8Hz),7.47(1H,dd,J=10.4,2.3Hz),7.87(1H,d,J=9.8Hz),8.14(1H,s),8.41(1H,d,J=2.3Hz) Example 106

In the same manner as in Example 1, tert-butyl = (3,4-dihydro-2H- (1,4) dioxepino (2,3-c) pyridin-8-ylmethyl) (piperidin-4-yl) carbamate and (7-Fluoro-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde to tert-butyl = (3,4-dihydro-2H- (1,4) dioxepino (2,3-c) Pyridin-8-ylmethyl) (1- (2- (7-fluoro-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.28-1.74 (13H, m), 2.07-2.30 (4H, m), 2.57-2.65 (2H, m), 2.94-3.03 (2H, m), 4.06-4.18 (1H, m), 4.20-4.40 (8H, m), 6.77 (1H, s), 6.85 (1H, d, J = 9.8Hz), 7.47 (1H, dd, J = 10.4,2.3Hz), 7.87 ( 1H, d, J = 9.8Hz), 8.14 (1H, s), 8.41 (1H, d, J = 2.3Hz)

実施例２と同様の手法により、ｔｅｒｔ−ブチル＝（３，４−ジヒドロ−２Ｈ−（１，４）ジオキセピノ（２，３−ｃ）ピリジン−８−イルメチル）（１−（２−（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートから１−（２−（４−（（３，４−ジヒドロ−２Ｈ−（１，４）ジオキセピノ（２，３−ｃ）ピリジン−８−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：2.00-2.15(2H,m),2.37(2H,quint,J=5.9Hz),2.51-2.60(2H,m),3.20-3.35(2H,m),3.60-3.78(3H,m),3.97-4.07(2H,m),4.42(2H,t,J=5.9Hz),4.48(2H,s),4.60(2H,t,J=5.9Hz),4.71-4.87(2H,m),6.99(1H,d,J=10.0Hz),7.37(1H,S),7.96(1H,dd,J=10.1,2.1Hz),8.10(1H,d,J=10.0Hz),8.37(1H,s),8.57(1H,d,J=2.1Hz) Example 107

In the same manner as in Example 2, tert-butyl = (3,4-dihydro-2H- (1,4) dioxepino (2,3-c) pyridin-8-ylmethyl) (1- (2- (7- Fluoro-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate to 1- (2- (4-((3,4-dihydro-2H- (1, 4) Dioxepino (2,3-c) pyridin-8-ylmethyl) amino) piperidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 2.00-2.15 (2H, m), 2.37 (2H, quint, J = 5.9Hz), 2.51-2.60 (2H, m), 3.20-3.35 (2H, m) , 3.60-3.78 (3H, m), 3.97-4.07 (2H, m), 4.42 (2H, t, J = 5.9Hz), 4.48 (2H, s), 4.60 (2H, t, J = 5.9Hz), 4.71-4.87 (2H, m), 6.99 (1H, d, J = 10.0Hz), 7.37 (1H, S), 7.96 (1H, dd, J = 10.1,2.1Hz), 8.10 (1H, d, J = 10.0Hz), 8.37 (1H, s), 8.57 (1H, d, J = 2.1Hz)

実施例３０と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩および（１，３）ジオキソロ（４，５−ｃ）ピリジン−６−カルバルデヒドから１−（２−（４−（（（１，３）ジオキソロ（４，５−ｃ）ピリジン−６−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.36-1.50(2H,m),1.80-1.97(2H,m),2.13-2.24(2H,m),2.47-2.57(1H,m),2.61-2.68(2H,m),2.91-3.00(2H,m),3.83(2H,s),4.28-4.36(2H,m),6.03(2H,s),6.86(1H,d,J=9.8Hz),6.88(1H,s),7.56(1H,dd,J=10.2,2.1Hz),7.88(1H,dd,J=9.8,0.5Hz),8.00(1H,s),8.41(1H,d,J=2.1Hz) Example 108

In a manner similar to that in Example 30, 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one hydrochloride and (1,3 ) Dioxolo (4,5-c) pyridine-6-carbaldehyde to 1- (2- (4-(((1,3) dioxolo (4,5-c) pyridin-6-ylmethyl) amino) piperidine-1) -Yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.36-1.50 (2H, m), 1.80-1.97 (2H, m), 2.13-2.24 (2H, m), 2.47-2.57 (1H, m), 2.61-2.68 (2H, m), 2.91-3.00 (2H, m), 3.83 (2H, s), 4.28-4.36 (2H, m), 6.03 (2H, s), 6.86 (1H, d, J = 9.8Hz), 6.88 (1H, s), 7.56 (1H, dd, J = 10.2,2.1Hz), 7.88 (1H, dd, J = 9.8,0.5Hz), 8.00 (1H, s), 8.41 (1H, d, J = 2.1Hz)

実施例８と同様の手法により、１−（２−（４−（（（１，３）ジオキソロ（４，５−ｃ）ピリジン−６−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オンから１−（２−（４−（（（１，３）ジオキソロ（４，５−ｃ）ピリジン−６−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：2.00-2.14(2H,m),2.50-2.60(2H,m),3.20-3.35(2H,m),3.60-3.78(3H,m),3.96-4.07(2H,m),4.48(2H,s),4.70-4.88(2H,m),6.34(2H,s),7.00(1H,d,J=9.9Hz),7.32(1H,S),7.93-7.99(1H,m),8.10(1H,d,J=9.9Hz),8.16(1H,s),8.57(1H,d,J=2.2Hz) Example 109

In the same manner as in Example 8, 1- (2- (4-(((1,3) dioxolo (4,5-c) pyridin-6-ylmethyl) amino) piperidin-1-yl) ethyl) -7 1- (2- (4-(((1,3) dioxolo (4,5-c) pyridin-6-ylmethyl) amino) piperidine-1 from -fluoro-1,5-naphthyridin-2 (1H) -one -Yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 2.00-2.14 (2H, m), 2.50-2.60 (2H, m), 3.20-3.35 (2H, m), 3.60-3.78 (3H, m), 3.96- 4.07 (2H, m), 4.48 (2H, s), 4.70-4.88 (2H, m), 6.34 (2H, s), 7.00 (1H, d, J = 9.9Hz), 7.32 (1H, S), 7.93 -7.99 (1H, m), 8.10 (1H, d, J = 9.9Hz), 8.16 (1H, s), 8.57 (1H, d, J = 2.2Hz)

ｔｅｒｔ−ブチル＝（（５−（１，３−ジオキソラン−２−イル）メチル）−６−オキソ−５，６−ジヒドロ−１，５−ナフチリジン−３−イル）（メチル）カルバマート0.12gに80％トリフルオロ酢酸水溶液2mLを加え、室温で2時間攪拌した。一晩放置後、80％トリフルオロ酢酸水溶液2mLを加え、室温で1時間30分間攪拌し、40〜50℃で35分間攪拌した。反応混合物に20％水酸化ナトリウム水溶液およびクロロホルムを加えpH6.3に調整した。有機層を分取し、水層をクロロホルムで抽出した。さらに水層を中性付近に保ちながら、クロロホルム：メタノール（５：９５）の混合溶媒で抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、黄色固体の（７−（メチルアミノ）−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド76mgを得た。
（７−（メチルアミノ）−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド76mgにｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（ピペリジン−４−イル）カルバマート0.11gのジクロロメタン2.5mL溶液および酢酸19μLを加え、室温で5分間攪拌した。反応混合物に水素化トリアセトキシホウ素ナトリウム0.10gを加え、同温度で2時間20分間攪拌した。反応混合物にクロロホルムを加え、飽和炭酸水素ナトリウム水溶液でpH8.3に調整した。有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、水および飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝１９：１］で精製し、淡黄色油状物のｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−（メチルアミノ）−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート55mgを得た。
¹H-NMR(CDCl₃)δ値：1.34-1.73(13H,m),2.10-2.26(2H,m),2.58-2.64(2H,m),2.96(3H,d,J=5.1Hz),2.98-3.05(2H,m),4.03-4.17(1H,m),4.25-4.45(8H,m),6.57(1H,d,J=9.8Hz),6.70-6.76(2H,m),7.74(1H,d,J=9.8Hz),7.98(1H,d,J=2.2Hz),8.05(1H,s) Example 110

tert-butyl = ((5- (1,3-dioxolan-2-yl) methyl) -6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl) (methyl) carbamate A 2% aqueous solution of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. After leaving overnight, 2 mL of 80% aqueous trifluoroacetic acid solution was added, and the mixture was stirred at room temperature for 1 hour and 30 minutes, and stirred at 40 to 50 ° C. for 35 minutes. The reaction mixture was adjusted to pH 6.3 by adding 20% aqueous sodium hydroxide and chloroform. The organic layer was separated and the aqueous layer was extracted with chloroform. Further, the mixture was extracted with a mixed solvent of chloroform: methanol (5:95) while keeping the aqueous layer near neutral. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give (7- (methylamino) -2-oxo-1,5-naphthyridine-1 (2H)- Yl) 76 mg of acetaldehyde was obtained.
(7- (Methylamino) -2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde was added to 76 mg of tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c ) A solution of 0.11 g of pyridin-7-ylmethyl) (piperidin-4-yl) carbamate in 2.5 mL of dichloromethane and 19 μL of acetic acid were added and stirred at room temperature for 5 minutes. To the reaction mixture was added 0.10 g of sodium triacetoxyborohydride, and the mixture was stirred at the same temperature for 2 hours and 20 minutes. Chloroform was added to the reaction mixture, and the pH was adjusted to 8.3 with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography [eluent: chloroform: methanol = 19: 1], and tert-butyl = (2,3-dihydro (1,4) dioxino ( 2,3-c) pyridin-7-ylmethyl) (1- (2- (7- (methylamino) -2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl ) 55 mg carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.34-1.73 (13H, m), 2.10-2.26 (2H, m), 2.58-2.64 (2H, m), 2.96 (3H, d, J = 5.1Hz), 2.98-3.05 (2H, m), 4.03-4.17 (1H, m), 4.25-4.45 (8H, m), 6.57 (1H, d, J = 9.8Hz), 6.70-6.76 (2H, m), 7.74 ( 1H, d, J = 9.8Hz), 7.98 (1H, d, J = 2.2Hz), 8.05 (1H, s)

実施例４と同様の手法により、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−（メチルアミノ）−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートから１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−（メチルアミノ）−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：1.96-2.12(2H,m),2.48-2.57(2H,m),2.95(3H,s),3.20-3.32(2H,m),3.60-3.72(3H,m),3.95-4.04(2H,m),4.37-4.44(4H,m),4.47-4.52(2H,m),4.77-4.83(2H,m),6.75(1H,d,J=9.8Hz),7.05-7.08(1H,m),7.23(1H,s),7.97(1H,d,J=9.8Hz),8.16(1H,d,J=2.2Hz),8.24(1H,s) Example 111

In the same manner as in Example 4, tert-butyl = (2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) (1- (2- (7- (methylamino ) -2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate to 1- (2- (4-((2,3-dihydro (1,4) dioxino) (2,3-c) Pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -7- (methylamino) -1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.96-2.12 (2H, m), 2.48-2.57 (2H, m), 2.95 (3H, s), 3.20-3.32 (2H, m), 3.60-3.72 ( 3H, m), 3.95-4.04 (2H, m), 4.37-4.44 (4H, m), 4.47-4.52 (2H, m), 4.77-4.83 (2H, m), 6.75 (1H, d, J = 9.8 Hz), 7.05-7.08 (1H, m), 7.23 (1H, s), 7.97 (1H, d, J = 9.8Hz), 8.16 (1H, d, J = 2.2Hz), 8.24 (1H, s)

実施例７８と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩およびｔｅｒｔ−ブチル＝７−ホルミル−２，３−ジヒドロ−４Ｈ−ピリド（４，３−ｂ）（１，４）オキサジン−４−カルボキシラートから、ｔｅｒｔ−ブチル＝７−（（（１−（２−（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）アミノ）メチル）−２，３−ジヒドロ−４Ｈ−ピリド（４，３−ｂ）（１，４）オキサジン−４−カルボキシラートを得た。
¹H-NMR(CDCl₃)δ値：1.38-1.49(2H,m),1.59(9H,s),1.87-1.95(2H,m),2.13-2.23(2H,m),2.48-2.57(1H,m),2.61-2.66(2H,m),2.92-2.98(2H,m),3.81(2H,s),3.84-3.87(2H,m),4.28-4.34(4H,m),6.82(1H,s),6.86(1H,d,J=9.9Hz),7.55(1H,dd,J=10.5,2.2Hz),7.88(1H,d,J=9.9Hz),8.41(1H,d,J=2.2Hz),8.79-8.87(1H,m) Example 112

In the same manner as in Example 78, 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one hydrochloride and tert-butyl = From 7-formyl-2,3-dihydro-4H-pyrido (4,3-b) (1,4) oxazine-4-carboxylate, tert-butyl = 7-(((1- (2- (7- Fluoro-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) amino) methyl) -2,3-dihydro-4H-pyrido (4,3-b) (1 4) Oxazine-4-carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.38-1.49 (2H, m), 1.59 (9H, s), 1.87-1.95 (2H, m), 2.13-2.23 (2H, m), 2.48-2.57 (1H , m), 2.61-2.66 (2H, m), 2.92-2.98 (2H, m), 3.81 (2H, s), 3.84-3.87 (2H, m), 4.28-4.34 (4H, m), 6.82 (1H , s), 6.86 (1H, d, J = 9.9Hz), 7.55 (1H, dd, J = 10.5, 2.2Hz), 7.88 (1H, d, J = 9.9Hz), 8.41 (1H, d, J = 2.2Hz), 8.79-8.87 (1H, m)

実施例２と同様の手法により、ｔｅｒｔ−ブチル＝７−（（（１−（２−（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）アミノ）メチル）−２，３−ジヒドロ−４Ｈ−ピリド（４，３−ｂ）（１，４）オキサジン−４−カルボキシラートから１−（２−（４−（（３，４−ジヒドロ−２Ｈ−ピリド（４，３−ｂ）（１，４）オキサジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：2.00-2.12(2H,m),2.52-2.60(2H,m),3.23-3.36(2H,m),3.51(2H,t,J=4.4Hz),3.64(2H,t,J=6.0Hz),3.68-3.78(1H,m),3.98-4.06(2H,m),4.48-4.54(4H,m),4.66-4.92(2H,m),6.99(1H,d,J=9.8Hz),7.30-7.36(1H,m),7.92-7.98(1H,m),8.01(1H,s),8.11(1H,d,J=9.8Hz),8.57(1H,s) Example 113

In the same manner as in Example 2, tert-butyl = 7-(((1- (2- (7-fluoro-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidine-4 -Yl) amino) methyl) -2,3-dihydro-4H-pyrido (4,3-b) (1,4) oxazine-4-carboxylate to 1- (2- (4-((3,4-) Dihydro-2H-pyrido (4,3-b) (1,4) oxazin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one The hydrochloride salt was obtained.
¹ H-NMR (D ₂ O) δ value: 2.00-2.12 (2H, m), 2.52-2.60 (2H, m), 3.23-3.36 (2H, m), 3.51 (2H, t, J = 4.4Hz) , 3.64 (2H, t, J = 6.0Hz), 3.68-3.78 (1H, m), 3.98-4.06 (2H, m), 4.48-4.54 (4H, m), 4.66-4.92 (2H, m), 6.99 (1H, d, J = 9.8Hz), 7.30-7.36 (1H, m), 7.92-7.98 (1H, m), 8.01 (1H, s), 8.11 (1H, d, J = 9.8Hz), 8.57 ( 1H, s)

１−（２−（１−ヒドロキシ−４−オキソシクロヘキシル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン40mgのジクロロメタン溶液5mLに室温で１−（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イル）メタンアミン25mgおよび酢酸11μLを加え、2時間攪拌した後、反応混合物に水素化トリアセトキシホウ素ナトリウム27mgを加え、室温で1時間攪拌した。飽和炭酸水素ナトリウム水溶液およびクロロホルムを加え、有機層を分取し、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝３０：１］で精製し、（Ａ）淡黄色固体の１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）−１−ヒドロキシシクロヘキシル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン10mgおよび（Ｂ）淡黄色固体の１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）−１−ヒドロキシシクロヘキシル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン9mgを得た。
（Ａ）¹H-NMR(CDCl₃)δ値：1.35-1.55(4H,m),1.80-2.20(6H,m),2.65-2.75(1H,m),3.77(2H,s),3.97(3H,s),4.25-4.46(6H,m),6.75(1H,d,J=9.6Hz),6.80(1H,s),7.32(1H,d,J=2.4Hz),7.86(1H,d,J=9.6Hz),8.10(1H,s),8.29(1H,d,J=2.4Hz)
（Ｂ）¹H-NMR(CDCl₃)δ値：1.40-1.60(4H,m),1.70-1.90(6H,m),2.48-2.58(1H,m),3.82(2H,s),3.96(3H,s),4.26-4.44(6H,m),6.74(1H,d,J=9.6Hz),6.82(1H,s),7.38(1H,d,J=2.4Hz),7.85(1H,d,J=9.6Hz),8.11(1H,s),8.28(1H,d,J=2.4Hz) Example 114

1- (2- (1-Hydroxy-4-oxocyclohexyl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one 40 mL of a solution of 40 mg of dichloromethane in 1 mL of 1- (2,3-dihydro (1,4) Dioxino (2,3-c) pyridin-7-yl) methanamine (25 mg) and acetic acid (11 μL) were added and stirred for 2 hours. Then, sodium triacetoxyborohydride (27 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Stir. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added, the organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography [eluent: chloroform: methanol = 30: 1], and (A) 1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) -1-hydroxycyclohexyl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one 10 mg and (B ) 1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) -1-hydroxycyclohexyl) ethyl)- 9 mg of 7-methoxy-1,5-naphthyridin-2 (1H) -one was obtained.
(A) ¹ H-NMR (CDCl ₃ ) δ value: 1.35-1.55 (4H, m), 1.80-2.20 (6H, m), 2.65-2.75 (1H, m), 3.77 (2H, s), 3.97 ( 3H, s), 4.25-4.46 (6H, m), 6.75 (1H, d, J = 9.6Hz), 6.80 (1H, s), 7.32 (1H, d, J = 2.4Hz), 7.86 (1H, d , J = 9.6Hz), 8.10 (1H, s), 8.29 (1H, d, J = 2.4Hz)
(B) ¹ H-NMR (CDCl ₃ ) δ value: 1.40-1.60 (4H, m), 1.70-1.90 (6H, m), 2.48-2.58 (1H, m), 3.82 (2H, s), 3.96 ( 3H, s), 4.26-4.44 (6H, m), 6.74 (1H, d, J = 9.6Hz), 6.82 (1H, s), 7.38 (1H, d, J = 2.4Hz), 7.85 (1H, d , J = 9.6Hz), 8.11 (1H, s), 8.28 (1H, d, J = 2.4Hz)

実施例３と同様の手法により、７−フルオロ−１−（２−ヒドロキシ−２−メトキシエチル）−１，５−ナフチリジン−２（１Ｈ）−オンおよびｔｅｒｔ−ブチル＝（ピペリジン−４−イル）（３−（ピラジン−２−イル）−２−プロピン−１−イル）カルバマートからｔｅｒｔ−ブチル＝（１−（２−（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）（３−（ピラジン−２−イル）−２−プロピン−１−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.50(9H,s),1.78-1.88(4H,m),2.16-2.28(2H,m),2.66(2H,t,J=7.1Hz),3.03-3.12(2H,m),4.04-4.25(3H,m),4.32(2H,t,J=7.1Hz),6.86(1H,d,J=9.8Hz),7.48-7.54(1H,m),7.88(1H,d,J=9.8Hz),8.41(1H,d,J=2.4Hz),8.48(1H,d,J=2.7Hz),8.51-8.54(1H,m),8.62(1H,d,J=1.2Hz) Example 115

In the same manner as in Example 3, 7-fluoro-1- (2-hydroxy-2-methoxyethyl) -1,5-naphthyridin-2 (1H) -one and tert-butyl = (piperidin-4-yl) (3- (pyrazin-2-yl) -2-propin-1-yl) carbamate to tert-butyl = (1- (2- (7-fluoro-2-oxo-1,5-naphthyridine-1 (2H) -Yl) ethyl) piperidin-4-yl) (3- (pyrazin-2-yl) -2-propyn-1-yl) carbamate was obtained.
¹ H-NMR (CDCl _Three ) δ value: 1.50 (9H, s), 1.78-1.88 (4H, m), 2.16-2.28 (2H, m), 2.66 (2H, t, J = 7.1Hz), 3.03-3.12 (2H, m), 4.04-4.25 (3H, m), 4.32 (2H, t, J = 7.1Hz), 6.86 (1H, d, J = 9.8Hz), 7.48-7.54 (1H, m), 7.88 (1H, d, J = 9.8Hz), 8.41 (1H, d, J = 2.4Hz), 8.48 (1H, d, J = 2.7Hz), 8.51-8.54 (1H, m), 8.62 (1H, d, J = 1.2Hz)

ｔｅｒｔ−ブチル＝（１−（２−（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）（３−（ピラジン−２−イル）−２−プロピン−１−イル）カルバマート96mgのクロロホルム2mL溶液に室温でトリフルオロ酢酸1mLを加え、1時間30分間攪拌した。飽和炭酸水素ナトリウム水溶液を加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝２０：１］で精製し、黄色油状物の７−フルオロ−１−（２−（４−（（３−（ピラジン−２−イル）プロプ−２−イン−１−イル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オン20mgを得た。
¹H-NMR(CDCl₃)δ値：1.38-1.49(2H,m),1.86-1.95(2H,m),2.21-2.30(2H,m),2.67(2H,t,J=7.1Hz),2.76-2.86(1H,m),2.93-3.01(2H,m),3.76(2H,s),4.33(2H,t,J=7.1Hz),6.86(1H,d,J=9.8Hz),7.56(1H,dd,J=10.3,2.2Hz),7.89(1H,d,J=9.8Hz),8.42(1H,d,J=2.2Hz),8.48(1H,d,J=2.4Hz),8.52-8.55(1H,m),8.65(1H,d,J=1.4Hz) Example 116

tert-butyl = (1- (2- (7-fluoro-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) (3- (pyrazin-2-yl) To a solution of 2-propyn-1-yl) carbamate 96 mg in 2 mL of chloroform was added 1 mL of trifluoroacetic acid at room temperature, and the mixture was stirred for 1 hour 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography [eluent: chloroform: methanol = 20: 1], and 7-fluoro-1- (2- (4-((3- (pyrazine There was obtained 20 mg of 2-yl) prop-2-yn-1-yl) amino) piperidin-1-yl) ethyl) -1,5-naphthyridin-2 (1H) -one.
¹ H-NMR (CDCl ₃ ) δ value: 1.38-1.49 (2H, m), 1.86-1.95 (2H, m), 2.21-2.30 (2H, m), 2.67 (2H, t, J = 7.1 Hz), 2.76-2.86 (1H, m), 2.93-3.01 (2H, m), 3.76 (2H, s), 4.33 (2H, t, J = 7.1Hz), 6.86 (1H, d, J = 9.8Hz), 7.56 (1H, dd, J = 10.3,2.2Hz), 7.89 (1H, d, J = 9.8Hz), 8.42 (1H, d, J = 2.2Hz), 8.48 (1H, d, J = 2.4Hz), 8.52 -8.55 (1H, m), 8.65 (1H, d, J = 1.4Hz)

１−（２−（４−（（３，４−ジヒドロ−２Ｈ−（１，４）ジオキセピノ（２，３−ｃ）ピリジン−８−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩85mgにクロロホルムおよび飽和炭酸水素ナトリウム水溶液を加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた油状物にメタノール2mLおよび28％ナトリウムメトキシド／メタノール溶液83mgを室温で加え、加熱還流下、4時間攪拌した。室温まで冷却した後、反応混合物に水およびクロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、淡褐色油状物の１−（２−（４−（（３，４−ジヒドロ−２Ｈ−（１，４）ジオキセピノ（２，３−ｃ）ピリジン−８−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン53mgを得た。
¹H-NMR(CDCl₃)δ値：1.38-1.52(2H,m),1.86-1.97(2H,m),2.13-2.28(4H,m),2.46-2.59(1H,m),2.61-2.68(2H,m),2.94-3.02(2H,m),3.78-3.84(2H,m),3.97(3H,s),4.24(2H,t,J=5.8Hz),4.31-4.40(4H,m),6.74(1H,d,J=9.8Hz),6.86(1H,s),7.23-7.32(1H,m),7.84(1H,d,J=9.8Hz),8.18(1H,s),8.27(1H,d,J=2.4Hz) Example 117

1- (2- (4-((3,4-dihydro-2H- (1,4) dioxepino (2,3-c) pyridin-8-ylmethyl) amino) piperidin-1-yl) ethyl) -7- Chloroform and a saturated aqueous sodium hydrogen carbonate solution were added to 85 mg of fluoro-1,5-naphthyridin-2 (1H) -one hydrochloride, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the obtained oil, 2 mL of methanol and 83 mg of 28% sodium methoxide / methanol solution were added at room temperature, and the mixture was stirred for 4 hours with heating under reflux. After cooling to room temperature, water and chloroform were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 1- (2- (4-((3,4 -Dihydro-2H- (1,4) dioxepino (2,3-c) pyridin-8-ylmethyl) amino) piperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridine-2 (1H)- On 53 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.38-1.52 (2H, m), 1.86-1.97 (2H, m), 2.13-2.28 (4H, m), 2.46-2.59 (1H, m), 2.61-2.68 (2H, m), 2.94-3.02 (2H, m), 3.78-3.84 (2H, m), 3.97 (3H, s), 4.24 (2H, t, J = 5.8Hz), 4.31-4.40 (4H, m ), 6.74 (1H, d, J = 9.8Hz), 6.86 (1H, s), 7.23-7.32 (1H, m), 7.84 (1H, d, J = 9.8Hz), 8.18 (1H, s), 8.27 (1H, d, J = 2.4Hz)

実施例８と同様の手法により、１−（２−（４−（（３，４−ジヒドロ−２Ｈ−（１，４）ジオキセピノ（２，３−ｃ）ピリジン−８−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オンから１−（２−（４−（（３，４−ジヒドロ−２Ｈ−（１，４）ジオキセピノ（２，３−ｃ）ピリジン−８−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：1.99-2.14(2H,m),2.35(2H,quint,J=5.9Hz),2.50-2.60(2H,m),3.20-3.34(2H,m),3.60-3.76(3H,m),3.96-4.07(2H,m),4.06(3H,s),4.40(2H,t,J=5.9Hz),4.44(2H,s),4.56(2H,t,J=5.9Hz),4.71-4.87(2H,m),6.90(1H,d,J=9.8Hz),7.31(1H,s),7.53(1H,d,J=2.1Hz),8.07(1H,d,J=9.8Hz),8.34(1H,s),8.43(1H,d,J=2.1Hz) Example 118

In the same manner as in Example 8, 1- (2- (4-((3,4-dihydro-2H- (1,4) dioxepino (2,3-c) pyridin-8-ylmethyl) amino) piperidine- 1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one to 1- (2- (4-((3,4-dihydro-2H- (1,4) dioxepino (2 , 3-c) pyridin-8-ylmethyl) amino) piperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.99-2.14 (2H, m), 2.35 (2H, quint, J = 5.9Hz), 2.50-2.60 (2H, m), 3.20-3.34 (2H, m) , 3.60-3.76 (3H, m), 3.96-4.07 (2H, m), 4.06 (3H, s), 4.40 (2H, t, J = 5.9Hz), 4.44 (2H, s), 4.56 (2H, t , J = 5.9Hz), 4.71-4.87 (2H, m), 6.90 (1H, d, J = 9.8Hz), 7.31 (1H, s), 7.53 (1H, d, J = 2.1Hz), 8.07 (1H , d, J = 9.8Hz), 8.34 (1H, s), 8.43 (1H, d, J = 2.1Hz)

実施例１１４と同様の手法により、５−（２−（１−ヒドロキシ−４−オキソシクロヘキシル）エチル）−３−メトキシピリド（２，３−ｂ）ピラジン−６（５Ｈ）−オンおよび１−（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イル）メタンアミンから（Ａ）黄色油状物の５−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）−１−ヒドロキシシクロヘキシル）エチル）−３−メトキシピリド（２，３−ｂ）ピラジン−６（５Ｈ）−オンおよび（Ｂ）淡黄色固体の５−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）−１−ヒドロキシシクロヘキシル）エチル）−３−メトキシピリド（２，３−ｂ）ピラジン−６（５Ｈ）−オンを得た。
（Ａ）¹H-NMR(CDCl₃)δ値：1.33-1.56(4H,m),1.70-1.95(4H,m),1.99(2H,t,J=7.3Hz),2.62-2.71(1H,m),3.75(2H,s),4.08(3H,s),4.25-4.35(4H,m),4.59(2H,t,J=7.3Hz),6.77(1H,d,J=9.6Hz),6.78(1H,s),7.86(1H,d,J=9.6Hz),8.10(1H,s),8.13(1H,s)
（Ｂ）¹H-NMR(CDCl₃)δ値：1.38-1.48(2H,m),1.50-1.90(8H,m),2.42-2.54(1H,m),3.82(2H,s),4.08(3H,s),4.24-4.35(4H,m),4.57-4.62(2H,m),6.77(1H,d,J=10.0Hz),6.83(1H,s),7.85(1H,d,J=10.0Hz),8.10(1H,s),8.13(1H,s) Example 119

In a manner similar to that in Example 114, 5- (2- (1-hydroxy-4-oxocyclohexyl) ethyl) -3-methoxypyrido (2,3-b) pyrazin-6 (5H) -one and 1- (2 , 3-Dihydro (1,4) dioxino (2,3-c) pyridin-7-yl) methanamine to (A) yellow oil 5- (2- (4-((2,3-dihydro (1, 4) Dioxino (2,3-c) pyridin-7-ylmethyl) amino) -1-hydroxycyclohexyl) ethyl) -3-methoxypyrido (2,3-b) pyrazin-6 (5H) -one and (B) light 5- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) -1-hydroxycyclohexyl) ethyl) -3- Methoxypyrido (2 3-b) pyrazine -6 (5H) - was obtained on.
(A) ¹ H-NMR (CDCl ₃ ) δ value: 1.33-1.56 (4H, m), 1.70-1.95 (4H, m), 1.99 (2H, t, J = 7.3 Hz), 2.62-2.71 (1H, m), 3.75 (2H, s), 4.08 (3H, s), 4.25-4.35 (4H, m), 4.59 (2H, t, J = 7.3Hz), 6.77 (1H, d, J = 9.6Hz), 6.78 (1H, s), 7.86 (1H, d, J = 9.6Hz), 8.10 (1H, s), 8.13 (1H, s)
(B) ¹ H-NMR (CDCl ₃ ) δ value: 1.38-1.48 (2H, m), 1.50-1.90 (8H, m), 2.42-2.54 (1H, m), 3.82 (2H, s), 4.08 ( 3H, s), 4.24-4.35 (4H, m), 4.57-4.62 (2H, m), 6.77 (1H, d, J = 10.0Hz), 6.83 (1H, s), 7.85 (1H, d, J = 10.0Hz), 8.10 (1H, s), 8.13 (1H, s)

１−（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イル）−Ｎ−（ピロリジン−３−イルメチル）メタンアミン塩酸塩0.10gのメタノール5mL懸濁液に室温で28％ナトリウムメトキシド／メタノール溶液0.17g、（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド66mg、モレキュラーシーブス３Ａ0.10g、酢酸33μLおよび水素化シアノホウ素ナトリウム18mgを加え、同温度で2時間30分間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液および酢酸エチルを加え、有機層を分取し、水層を酢酸エチルで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝３０：１］で精製し、黄色油状物の１−（２−（３−（（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）メチル）ピロリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン20mgを得た。
¹H-NMR(CDCl₃)δ値：1.45-1.55(1H,m),1.96-2.07(1H,m),2.32-2.47(2H,m),2.59-2.88(7H,m),3.77(2H,s),4.25-4.37(6H,m),6.81(1H,s),6.86(1H,d,J=9.8Hz),7.54(1H,dd,J=10.2,2.1Hz),7.88(1H,d,J=9.8Hz),8.10(1H,s),8.41(1H,d,J=2.1Hz) Example 120

1- (2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-yl) -N- (pyrrolidin-3-ylmethyl) methanamine hydrochloride 0.10 g in a 5 mL methanol suspension at room temperature 0.17 g of 28% sodium methoxide / methanol solution, 66 mg of (7-fluoro-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde, 0.10 g of molecular sieves 3A, 33 μL of acetic acid and cyanoborohydride Sodium (18 mg) was added, and the mixture was stirred at the same temperature for 2 hours and 30 minutes. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography [eluent: chloroform: methanol = 30: 1] to give 1- (2- (3-(((2,3-dihydro (1 , 4) Dioxyno (2,3-c) pyridin-7-ylmethyl) amino) methyl) pyrrolidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one 20 mg was obtained. .
¹ H-NMR (CDCl ₃ ) δ value: 1.45-1.55 (1H, m), 1.96-2.07 (1H, m), 2.32-2.47 (2H, m), 2.59-2.88 (7H, m), 3.77 (2H , s), 4.25-4.37 (6H, m), 6.81 (1H, s), 6.86 (1H, d, J = 9.8Hz), 7.54 (1H, dd, J = 10.2, 2.1Hz), 7.88 (1H, d, J = 9.8Hz), 8.10 (1H, s), 8.41 (1H, d, J = 2.1Hz)

実施例５５と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩および２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−カルバルデヒド＝６−オキシドから７−メトキシ−１−（２−（４−（（（６−オキシド−２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.38-1.50(2H,m),1.85-1.96(2H,m),2.13-2.23(2H,m),2.44-2.54(1H,m),2.61-2.68(2H,m),2.93-3.02(2H,m),3.93(2H,s),3.98(3H,s),4.28-4.40(6H,m),6.74(1H,d,J=9.8Hz),6.94(1H,s),7.23(1H,d,J=2.2Hz),7.84(1H,d,J=9.8Hz),7.97(1H,s),8.28(1H,d,J=2.2Hz) Example 121

In a manner similar to Example 55, 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride and 2,3- Dihydro (1,4) dioxino (2,3-c) pyridine-7-carbaldehyde = 6-oxide to 7-methoxy-1- (2- (4-(((6-oxide-2,3-dihydro ( 1,4) Dioxino (2,3-c) pyridin-7-yl) methyl) amino) piperidin-1-yl) ethyl) -1,5-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.38-1.50 (2H, m), 1.85-1.96 (2H, m), 2.13-2.23 (2H, m), 2.44-2.54 (1H, m), 2.61-2.68 (2H, m), 2.93-3.02 (2H, m), 3.93 (2H, s), 3.98 (3H, s), 4.28-4.40 (6H, m), 6.74 (1H, d, J = 9.8Hz), 6.94 (1H, s), 7.23 (1H, d, J = 2.2Hz), 7.84 (1H, d, J = 9.8Hz), 7.97 (1H, s), 8.28 (1H, d, J = 2.2Hz)

１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.20gのメタノール2mL懸濁液に28％ナトリウムメトキシド／メタノール溶液0.28g、５−エチルピリジン−２−カルバルデヒド66mgおよび酢酸28μLを加えた。次いで水素化シアノホウ素ナトリウム61mgを加え、室温で3時間攪拌した。さらに水素化シアノホウ素ナトリウム31mgを追加し、室温で1時間30分間攪拌した。反応混合物にクロロホルムおよび飽和炭酸水素ナトリウム水溶液を加えた。有機層を分取し、水および飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、得られた残留物を塩基性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＝９３：７−９：１］で精製し、淡黄色油状物の１−（２−（４−（（（５−エチルピリジン−２−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン0.15gを得た。
¹H-NMR(CDCl₃)δ値：1.24(3H,t,J=6.6Hz),1.40-1.52(2H,m),1.89-1.97(2H,m),2.15-2.23(2H,m),2.50-2.59(1H,m),2.60-2.67(4H,m),2.95-3.02(2H,m),3.90(2H,s),3.97(3H,s),4.34-4.39(2H,m),6.74(1H,d,J=9.6Hz),7.21(1H,d,J=7.9Hz),7.25(1H,d,J=2.2Hz),7.47(1H,dd,J=7.9,2.4Hz),7.84(1H,d,J=9.7Hz),8.27(1H,d,J=2.4Hz),8.39(1H,d,J=2.2Hz) Example 122

1- (2- (4-Aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride 28% sodium methoxide in 2 mL of methanol suspension / 0.28 g of methanol solution, 66 mg of 5-ethylpyridine-2-carbaldehyde and 28 μL of acetic acid were added. Next, 61 mg of sodium cyanoborohydride was added and stirred at room temperature for 3 hours. Further, 31 mg of sodium cyanoborohydride was added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was separated and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography [gradient elution of chloroform: methanol = 93: 7-9: 1] to give pale yellow 1- (2- (4-(((5-Ethylpyridin-2-yl) methyl) amino) piperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridine-2 (1H) as oil -0.15 g of ON was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.24 (3H, t, J = 6.6 Hz), 1.40-1.52 (2H, m), 1.89-1.97 (2H, m), 2.15-2.23 (2H, m), 2.50-2.59 (1H, m), 2.60-2.67 (4H, m), 2.95-3.02 (2H, m), 3.90 (2H, s), 3.97 (3H, s), 4.34-4.39 (2H, m), 6.74 (1H, d, J = 9.6Hz), 7.21 (1H, d, J = 7.9Hz), 7.25 (1H, d, J = 2.2Hz), 7.47 (1H, dd, J = 7.9,2.4Hz), 7.84 (1H, d, J = 9.7Hz), 8.27 (1H, d, J = 2.4Hz), 8.39 (1H, d, J = 2.2Hz)

実施例１００と同様の手法により、１−（２−（４−（（（５−エチルピリジン−２−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オンから１−（２−（４−（（（５−エチルピリジン−２−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：1.28(3H,t,J=7.6Hz),2.02-2.17(2H,m),2.53-2.62(2H,m),2.83(2H,t,J=7.6Hz),3.22-3.35(2H,m),3.62-3.82(3H,m),3.98-4.10(2H,m),4.06(3H,s),4.61(2H,s),4.70-4.92(2H,m),6.92(1H,d,J=9.9Hz),7.56(1H,d,J=2.1Hz),7.84(1H,d,J=8.2Hz),8.08(1H,d,J=9.9Hz),8.24(1H,dd,J=8.2,1.5Hz),8.44(1H,d,J=2.1Hz),8.65(1H,d,J=1.5Hz) Example 123

In the same manner as in Example 100, 1- (2- (4-(((5-ethylpyridin-2-yl) methyl) amino) piperidin-1-yl) ethyl) -7-methoxy-1,5- Naphthyridin-2 (1H) -one to 1- (2- (4-(((5-ethylpyridin-2-yl) methyl) amino) piperidin-1-yl) ethyl) -7-methoxy-1,5- Naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.28 (3H, t, J = 7.6 Hz), 2.02-2.17 (2H, m), 2.53-2.62 (2H, m), 2.83 (2H, t, J = 7.6Hz), 3.22-3.35 (2H, m), 3.62-3.82 (3H, m), 3.98-4.10 (2H, m), 4.06 (3H, s), 4.61 (2H, s), 4.70-4.92 (2H , m), 6.92 (1H, d, J = 9.9Hz), 7.56 (1H, d, J = 2.1Hz), 7.84 (1H, d, J = 8.2Hz), 8.08 (1H, d, J = 9.9Hz) ), 8.24 (1H, dd, J = 8.2,1.5Hz), 8.44 (1H, d, J = 2.1Hz), 8.65 (1H, d, J = 1.5Hz)

３−フルオロ−４−メチル安息香酸50mgの塩化チオニル0.64mL溶液にＮ，Ｎ−ジメチルホルムアミド50μL加え、加熱還流下で1時間攪拌した。減圧下で溶媒を留去し、ジクロロメタン4.0mLに溶解し、氷冷下、トリエチルアミン0.13mLおよび１−（２−（４−アミノピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩64mgを加え、2時間攪拌した。クロロホルムおよび水を加え、6mol/L塩酸でpH1に調整した。固形物を濾取し、白色固体の３−フルオロ−Ｎ−（１−（２−（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）−４−メチルベンズアミド塩酸塩51mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.83-1.96(2H,m),2.00-2.11(2H,m),2.29(3H,s),3.00-3.50(4H,m),3.70-3.79(2H,m),3.99-4.11(1H,m),4.58-4.66(2H,m),6.90(1H,d,J=9.9Hz),7.37-7.42(1H,m),7.62-7.68(2H,m),8.02(1H,d,J=9.9Hz),8.27-8.36(1H,m),8.52-8.57(1H,m),8.61-8.65(1H,m),9.95-10.07(1H,m) Example 124

To a solution of 50 mg of 3-fluoro-4-methylbenzoic acid in 0.64 mL of thionyl chloride, 50 μL of N, N-dimethylformamide was added, and the mixture was stirred for 1 hour under heating and reflux. The solvent was distilled off under reduced pressure, and the residue was dissolved in 4.0 mL of dichloromethane. Under ice cooling, 0.13 mL of triethylamine and 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-fluoro-1,5- Naphthyridin-2 (1H) -one hydrochloride (64 mg) was added, and the mixture was stirred for 2 hours. Chloroform and water were added, and the pH was adjusted to 1 with 6 mol / L hydrochloric acid. The solid was collected by filtration and white solid 3-fluoro-N- (1- (2- (7-fluoro-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidine-4- Yl) -4-methylbenzamide hydrochloride 51 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.83-1.96 (2H, m), 2.00-2.11 (2H, m), 2.29 (3H, s), 3.00-3.50 (4H, m), 3.70-3.79 (2H, m), 3.99-4.11 (1H, m), 4.58-4.66 (2H, m), 6.90 (1H, d, J = 9.9Hz), 7.37-7.42 (1H, m), 7.62-7.68 (2H , m), 8.02 (1H, d, J = 9.9Hz), 8.27-8.36 (1H, m), 8.52-8.57 (1H, m), 8.61-8.65 (1H, m), 9.95-10.07 (1H, m )

２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−カルボン酸50mgの塩化チオニル2.0mL溶液にＮ，Ｎ−ジメチルホルムアミド1滴を加え、加熱還流下で1時間30分間攪拌した。減圧下で溶媒を留去し、ジクロロメタン2.0mLに溶解し、トリエチルアミン0.14mLおよび１−（２−（４−アミノピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩53mgを加え、1時間攪拌した。クロロホルムおよび水を加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、水酸化ナトリウム水溶液、ついで飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去た。得られた残留物に酢酸エチル：ジエチルエーテルの混合溶媒を加え、淡褐色固体のＮ−（１−（２−（７−フルオロ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）−２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−カルボキサミド48mgを得た。
¹H-NMR(CDCl₃)δ値：1.50-3.20(10H,m),3.94-4.13(1H,m),4.30-4.40(6H,m),6.86(1H,d,J=9.9Hz),7.70(1H,s),7.77-7.95(1H,m),7.91(1H,d,J=9.9Hz),8.07(1H,s),8.43(1H,d,J=2.2Hz) Example 125

To a 2.0 mL solution of thionyl chloride in 50 mg of 2,3-dihydro (1,4) dioxino (2,3-c) pyridine-7-carboxylic acid was added 1 drop of N, N-dimethylformamide, and the mixture was heated under reflux for 1 hour 30 Stir for minutes. The solvent was distilled off under reduced pressure, dissolved in 2.0 mL of dichloromethane, 0.14 mL of triethylamine and 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridine-2 ( 1H) -one hydrochloride 53 mg was added and stirred for 1 hour. Chloroform and water were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with an aqueous sodium hydroxide solution and then with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. A mixed solvent of ethyl acetate: diethyl ether was added to the obtained residue, and N- (1- (2- (7-fluoro-2-oxo-1,5-naphthyridin-1 (2H) -yl) was obtained as a light brown solid. 48 mg of ethyl) piperidin-4-yl) -2,3-dihydro (1,4) dioxino (2,3-c) pyridine-7-carboxamide was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.50-3.20 (10H, m), 3.94-4.13 (1H, m), 4.30-4.40 (6H, m), 6.86 (1H, d, J = 9.9Hz), 7.70 (1H, s), 7.77-7.95 (1H, m), 7.91 (1H, d, J = 9.9Hz), 8.07 (1H, s), 8.43 (1H, d, J = 2.2Hz)

（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド0.14gのジクロロメタン12mL溶液にｔｅｒｔ−ブチル＝（（７−オキソ−５，６，７，８−テトラヒドロ−１，８−ナフチリジン−２−イル）メチル）（ピペリジン−４−イル）カルバマート0.23g、酢酸37μLを加え、室温で30分間攪拌した後、反応混合物に水素化トリアセトキシホウ素ナトリウム0.17gを加え、室温で30分間攪拌した後、一晩放置し、さらに5時間攪拌した。反応混合物に、水、飽和炭酸水素ナトリウム水溶液およびクロロホルムおよびを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［溶離液；クロロホルム：メタノール＝５０：１］で精製し、淡黄色泡状物のｔｅｒｔ−ブチル＝（１−（２−（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）（（７−オキソ−５，６，７，８−テトラヒドロ−１，８−ナフチリジン−２−イル）メチル）カルバマート0.23gを得た。
¹H-NMR(CDCl₃)δ値：1.28-1.88(13H,m),2.10-2.28(2H,m),2.58-2.72(4H,m),2.87-3.09(4H,m),3.97(3H,s),4.06-4.23(1H,m),4.27-4.47(4H,m),6.73(1H,d,J=9.6Hz),6.80-6.91(1H,m),7.18(1H,s),7.42(1H,d,J=7.3Hz),7.84(1H,d,J=9.6Hz),8.21(1H,s),8.28(1H,d,J=2.2Hz) Example 126

To a solution of 0.17 g of (7-methoxy-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde in 12 mL of dichloromethane was added tert-butyl = ((7-oxo-5,6,7,8-tetrahydro- 1,8-naphthyridin-2-yl) methyl) (piperidin-4-yl) carbamate 0.23 g and acetic acid 37 μL were added and stirred at room temperature for 30 minutes, then 0.17 g of sodium triacetoxyborohydride was added to the reaction mixture, The mixture was stirred at room temperature for 30 minutes, then allowed to stand overnight, and further stirred for 5 hours. Water, saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 50: 1], and tert-butyl = (1- (2- (7-methoxy-2-oxo) was obtained as a pale yellow foam. -1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) ((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) methyl) 0.23 g of carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.28-1.88 (13H, m), 2.10-2.28 (2H, m), 2.58-2.72 (4H, m), 2.87-3.09 (4H, m), 3.97 (3H , s), 4.06-4.23 (1H, m), 4.27-4.47 (4H, m), 6.73 (1H, d, J = 9.6Hz), 6.80-6.91 (1H, m), 7.18 (1H, s), 7.42 (1H, d, J = 7.3Hz), 7.84 (1H, d, J = 9.6Hz), 8.21 (1H, s), 8.28 (1H, d, J = 2.2Hz)

実施例２と同様の手法により、ｔｅｒｔ−ブチル＝（１−（２−（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）（（７−オキソ−５，６，７，８−テトラヒドロ−１，８−ナフチリジン−２−イル）メチル）カルバマートから７−メトキシ−１−（２−（４−（（（７−オキソ−５，６，７，８−テトラヒドロ−１，８−ナフチリジン−２−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：2.01-2.21(2H,m),2.48-2.63(2H,m),2.65-2.75(2H,m),2.97-3.07(2H,m),3.19-3.41(2H,m),3.59-3.77(3H,m),3.97-4.11(2H,m),4.09(3H,s),4.40(2H,s),4.52-5.18(2H,m),6.95(1H,d,J=9.5Hz),7.15(1H,d,J=7.4Hz),7.66(1H,s),7.72(1H,d,J=7.4Hz),8.07(1H,d,J=9.5Hz),8.46(1H,s) Example 127

In the same manner as in Example 2, tert-butyl = (1- (2- (7-methoxy-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) ( From (7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) methyl) carbamate to 7-methoxy-1- (2- (4-(((7-oxo-5,5 6,7,8-Tetrahydro-1,8-naphthyridin-2-yl) methyl) amino) piperidin-1-yl) ethyl) -1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 2.01-2.21 (2H, m), 2.48-2.63 (2H, m), 2.65-2.75 (2H, m), 2.97-3.07 (2H, m), 3.19- 3.41 (2H, m), 3.59-3.77 (3H, m), 3.97-4.11 (2H, m), 4.09 (3H, s), 4.40 (2H, s), 4.52-5.18 (2H, m), 6.95 ( 1H, d, J = 9.5Hz), 7.15 (1H, d, J = 7.4Hz), 7.66 (1H, s), 7.72 (1H, d, J = 7.4Hz), 8.07 (1H, d, J = 9.5 Hz), 8.46 (1H, s)

４−メトキシ−５−メチルピリジン−２−カルバルデヒド71mgのメタノール2mL溶液に28％ナトリウムメトキシド/メタノール溶液0.27g、１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.19gおよび酢酸27μLを加えた。次いで水素化シアノホウ素ナトリウム59mgを加え、室温で4時間攪拌した。反応混合物にクロロホルムおよび飽和炭酸水素ナトリウム水溶液を加えた。有機層を分取し、水および飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、得られた残留物を塩基性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＝１９：１−８６：１４］で精製し黄色油状物の７−メトキシ−１−（２−（４−（（（４−メトキシ−５−メチルピリジン−２−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オン0.13gを得た。
¹H-NMR(CDCl₃)δ値：1.40-1.52(2H,m),1.88-1.97(2H,m),2.14(3H,s),2.14-2.23(2H,m),2.50-2.60(1H,m),2.62-2.68(2H,m),2.94-3.03(2H,m),3.86(2H,s),3.88(3H,s),3.97(3H,s),4.34-4.40(2H,m),6.74(1H,d,J=9.8Hz),6.79(1H,s),7.25(1H,d,J=2.4Hz),7.84(1H,d,J=9.8Hz),8.16(1H,s),8.28(1H,d,J=2.4Hz) Example 128

4-methoxy-5-methylpyridine-2-carbaldehyde 71 mg of methanol in 2 mL solution was added 0.27 g of 28% sodium methoxide / methanol solution, 1- (2- (4-aminopiperidin-1-yl) ethyl) -7- 0.19 g of methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride and 27 μL of acetic acid were added. Next, 59 mg of sodium cyanoborohydride was added, and the mixture was stirred at room temperature for 4 hours. Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was separated and washed with water and saturated aqueous sodium chloride solution. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography [gradient elution of chloroform: methanol = 19: 1-86: 14] to give a yellow oil 7-methoxy-1- (2- (4-(((4-methoxy-5-methylpyridin-2-yl) methyl) amino) piperidin-1-yl) ethyl) -1,5-naphthyridine-2 ( 0.13 g of 1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.40-1.52 (2H, m), 1.88-1.97 (2H, m), 2.14 (3H, s), 2.14-2.23 (2H, m), 2.50-2.60 (1H , m), 2.62-2.68 (2H, m), 2.94-3.03 (2H, m), 3.86 (2H, s), 3.88 (3H, s), 3.97 (3H, s), 4.34-4.40 (2H, m ), 6.74 (1H, d, J = 9.8Hz), 6.79 (1H, s), 7.25 (1H, d, J = 2.4Hz), 7.84 (1H, d, J = 9.8Hz), 8.16 (1H, s) ), 8.28 (1H, d, J = 2.4Hz)

実施例８と同様の手法により、７−メトキシ−１−（２−（４−（（（４−メトキシ−５−メチルピリジン−２−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オンから７−メトキシ−１−（２−（４−（（（４−メトキシ−５−メチルピリジン−２−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：1.79-1.92(2H,m),2.22(3H,s),2.30-2.40(2H,m),3.02-3.17(2H,m),3.23-3.35(1H,m),3.42-3.53(2H,m),3.74-3.86(2H,m),4.03(3H,s),4.05(3H,s),4.26(2H,s),4.67-4.80(2H,m),6.87(1H,d,J=9.8Hz),7.23-7.25(1H,m),7.44(1H,d,J=2.2Hz),8.05(1H,d,J=9.8Hz),8.25(1H,s),8.40(1H,d,J=2.2Hz) Example 129

In the same manner as in Example 8, 7-methoxy-1- (2- (4-(((4-methoxy-5-methylpyridin-2-yl) methyl) amino) piperidin-1-yl) ethyl)- 1,5-naphthyridin-2 (1H) -one to 7-methoxy-1- (2- (4-(((4-methoxy-5-methylpyridin-2-yl) methyl) amino) piperidin-1-yl ) Ethyl) -1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.79-1.92 (2H, m), 2.22 (3H, s), 2.30-2.40 (2H, m), 3.02-3.17 (2H, m), 3.23-3.35 ( 1H, m), 3.42-3.53 (2H, m), 3.74-3.86 (2H, m), 4.03 (3H, s), 4.05 (3H, s), 4.26 (2H, s), 4.67-4.80 (2H, m), 6.87 (1H, d, J = 9.8Hz), 7.23-7.25 (1H, m), 7.44 (1H, d, J = 2.2Hz), 8.05 (1H, d, J = 9.8Hz), 8.25 ( 1H, s), 8.40 (1H, d, J = 2.2Hz)

１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.10gのメタノール2mL懸濁液に28％ナトリウムメトキシド/メタノール溶液0.14g、５−エチル−４−メトキシピリジン−２−カルバルデヒド40mgおよび酢酸14μLを加えた。次いで水素化シアノホウ素ナトリウム30mgを加え、室温で5時間攪拌した。反応混合物にクロロホルムおよび飽和炭酸水素ナトリウム水溶液を加えた。有機層を分取し、水および飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、得られた残留物を塩基性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＝９：１−８６：１４］で精製し黄色油状物の１−（２−（４−（（（５−エチル−４−メトキシピリジン−２−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン51mgを得た。
¹H-NMR(CDCl₃)δ値：1.18(3H,t,7.6Hz),1.41-1.55(2H,m),1.89-1.98(2H,m),2.12-2.24(2H,m),2.51-2.68(5H,m),2.93-3.03(2H,m),3.83-3.90(5H,m),3.97(3H,s),4.33-4.40(2H,m),6.74(1H,d,J=9.6Hz),6.79(1H,s),7.24-7.30(1H,m),7.84(1H,d,J=9.6Hz),8.17(1H,s),8.28(1H,d,J=2.4Hz) Example 130

1- (2- (4-Aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride 0.10 g of methanol in 2 mL suspension of 28% sodium methoxide 0.14 g of methanol / methanol solution, 40 mg of 5-ethyl-4-methoxypyridine-2-carbaldehyde and 14 μL of acetic acid were added. Next, 30 mg of sodium cyanoborohydride was added and stirred at room temperature for 5 hours. Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was separated and washed with water and saturated aqueous sodium chloride solution. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography [gradient elution of chloroform: methanol = 9: 1-86: 14] to give a yellow oil 1- (2- (4-(((5-ethyl-4-methoxypyridin-2-yl) methyl) amino) piperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridine-2 ( 51 mg of 1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.18 (3H, t, 7.6 Hz), 1.41-1.55 (2H, m), 1.89-1.98 (2H, m), 2.12-2.24 (2H, m), 2.51- 2.68 (5H, m), 2.93-3.03 (2H, m), 3.83-3.90 (5H, m), 3.97 (3H, s), 4.33-4.40 (2H, m), 6.74 (1H, d, J = 9.6 Hz), 6.79 (1H, s), 7.24-7.30 (1H, m), 7.84 (1H, d, J = 9.6Hz), 8.17 (1H, s), 8.28 (1H, d, J = 2.4Hz)

実施例８と同様の手法により、１−（２−（４−（（（５−エチル−４−メトキシピリジン−２−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オンから１−（２−（４−（（（５−エチル−４−メトキシピリジン−２−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：1.20(3H,t,J=7.6Hz),1.79-1.94(2H,m),2.32-2.40(2H,m),2.68(2H,q,J=7.6Hz),3.12-3.32(3H,m),3.51-3.57(2H,m),3.80-3.89(2H,m),4.04(6H,s),4.26(2H,s),4.70-4.90(2H,m),6.86(1H,d,J=9.9Hz),7.28(1H,s),7.42-7.45(1H,m),8.05(1H,d,J=9.9Hz),8.26(1H,s),8.39(1H,d,J=2.2Hz) Example 131

In the same manner as in Example 8, 1- (2- (4-(((5-ethyl-4-methoxypyridin-2-yl) methyl) amino) piperidin-1-yl) ethyl) -7-methoxy- 1,5-Naphthyridin-2 (1H) -one to 1- (2- (4-(((5-ethyl-4-methoxypyridin-2-yl) methyl) amino) piperidin-1-yl) ethyl)- 7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.20 (3H, t, J = 7.6 Hz), 1.79-1.94 (2H, m), 2.32-2.40 (2H, m), 2.68 (2H, q, J = 7.6Hz), 3.12-3.32 (3H, m), 3.51-3.57 (2H, m), 3.80-3.89 (2H, m), 4.04 (6H, s), 4.26 (2H, s), 4.70-4.90 (2H) , m), 6.86 (1H, d, J = 9.9Hz), 7.28 (1H, s), 7.42-7.45 (1H, m), 8.05 (1H, d, J = 9.9Hz), 8.26 (1H, s) , 8.39 (1H, d, J = 2.2Hz)

１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.20gのメタノール2mL懸濁液に28％ナトリウムメトキシド/メタノール溶液0.28g、５−メトキシ−４−メチルピリジン−２−カルバルデヒド73mgおよび酢酸28μLを加えた。次いで水素化シアノホウ素ナトリウム61mgを加え、室温で1時間30分間攪拌した。反応混合物にクロロホルム、飽和炭酸水素ナトリウム水溶液および水を加えた。有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせて、水および飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、得られた残留物を塩基性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＝９３：７−８６：１４］で精製し、淡黄色固体の７−メトキシ−１−（２−（４−（（（５−メトキシ−４−メチルピリジン−２−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オン82mgを得た。
¹H-NMR(CDCl₃)δ値：1.40-1.53(2H,m),1.89-1.98(2H,m),2.13-2.23(2H,m),2.22(3H,s),2.50-2.60(1H,m),2.62-2.68(2H,m),2.93-3.03(2H,m),3.83(2H,s),3.90(3H,s),3.97(3H,s),4.34-4.39(2H,m),6.74(1H,d,J=9.8Hz),7.08(1H,s),7.24-7.28(1H,m),7.84(1H,d,J=9.8Hz),8.08(1H,s),8.27(1H,d,J=2.2Hz) Example 132

1- (2- (4-Aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride 28% sodium methoxide in 2 mL of methanol suspension 0.28 g of methanol / methanol solution, 73 mg of 5-methoxy-4-methylpyridine-2-carbaldehyde and 28 μL of acetic acid were added. Next, 61 mg of sodium cyanoborohydride was added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Chloroform, saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography [gradient elution of chloroform: methanol = 93: 7-86: 14] to give pale yellow Solid 7-methoxy-1- (2- (4-(((5-methoxy-4-methylpyridin-2-yl) methyl) amino) piperidin-1-yl) ethyl) -1,5-naphthyridine-2 82 mg of (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.40-1.53 (2H, m), 1.89-1.98 (2H, m), 2.13-2.23 (2H, m), 2.22 (3H, s), 2.50-2.60 (1H , m), 2.62-2.68 (2H, m), 2.93-3.03 (2H, m), 3.83 (2H, s), 3.90 (3H, s), 3.97 (3H, s), 4.34-4.39 (2H, m ), 6.74 (1H, d, J = 9.8Hz), 7.08 (1H, s), 7.24-7.28 (1H, m), 7.84 (1H, d, J = 9.8Hz), 8.08 (1H, s), 8.27 (1H, d, J = 2.2Hz)

実施例３０と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩および５−（３−チエニル）イソオキサゾール−３−カルバルデヒドから７−メトキシ−１−（２−（４−（（（５−（３−チエニル）イソオキサゾール−３−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.38-1.50(2H,m),1.89-1.97(2H,m),2.15-2.25(2H,m),2.54-2.68(3H,m),2.95-3.03(2H,m),3.93(2H,s),3.98(3H,s),4.35-4.39(2H,m),6.39(1H,s),6.74(1H,d,J=9.6Hz),7.23(1H,d,J=2.2Hz),7.38-7.43(2H,m),7.77(1H,dd,J=2.8,1.4Hz),7.84(1H,d,J=9.6Hz),8.28(1H,d,J=2.2Hz) Example 133

In a manner similar to that in Example 30, 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride and 5- (3 -Thienyl) isoxazole-3-carbaldehyde to 7-methoxy-1- (2- (4-(((5- (3-thienyl) isoxazol-3-yl) methyl) amino) piperidin-1-yl) Ethyl) -1,5-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.38-1.50 (2H, m), 1.89-1.97 (2H, m), 2.15-2.25 (2H, m), 2.54-2.68 (3H, m), 2.95-3.03 (2H, m), 3.93 (2H, s), 3.98 (3H, s), 4.35-4.39 (2H, m), 6.39 (1H, s), 6.74 (1H, d, J = 9.6Hz), 7.23 ( 1H, d, J = 2.2Hz), 7.38-7.43 (2H, m), 7.77 (1H, dd, J = 2.8,1.4Hz), 7.84 (1H, d, J = 9.6Hz), 8.28 (1H, d , J = 2.2Hz)

１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.14gのメタノール5mL懸濁液に、室温で28％ナトリウムメトキシド／メタノール溶液0.14g、６−（３−チエニル）ピリジン−２−カルバルデヒド46mg、モレキュラーシーブス３Ａ0.10g、酢酸28μLおよび水素化シアノホウ素ナトリウム15mgを加え、同温度で3時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液およびクロロホルムを加え、有機層を分取し、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール＝３０：１］で精製した。得られた残留物の酢酸エチル2mL溶液に4mol/L塩化水素/酢酸エチル溶液2mLを加え、室温で30分間攪拌した。固形物を濾取し、黄色固体の７−メトキシ−１−（２−（４−（（（６−（３−チエニル）ピリジン−２−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩97mgを得た。
¹H-NMR(D₂O)δ値：2.07-2.23(2H,m),2.54-2.66(2H,m),3.20-3.36(2H,m),3.59-3.67(2H,m),3.73-3.83(1H,m),3.98-4.10(2H,m),4.07(3H,s),4.54-4.61(2H,m),4.70-4.90(2H,m),6.92(1H,d,J=9.8Hz),7.41-7.65(3H,m),7.70-7.80(1H,m),7.87-7.92(1H,m),7.97-8.10(1H,m),8.05(1H,d,J=9.8Hz),8.14(1H,s),8.44(1H,s) Example 134

1- (2- (4-aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride 0.14 g in a 5 mL methanol suspension at room temperature 28% Sodium methoxide / methanol solution 0.14 g, 6- (3-thienyl) pyridine-2-carbaldehyde 46 mg, molecular sieves 3A 0.10 g, acetic acid 28 μL and sodium cyanoborohydride 15 mg were added and stirred at the same temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction mixture, and the organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography [eluent: chloroform: methanol = 30: 1]. 2 mL of a 4 mol / L hydrogen chloride / ethyl acetate solution was added to a 2 mL solution of the obtained residue in ethyl acetate, and the mixture was stirred at room temperature for 30 minutes. The solid was collected by filtration and 7-methoxy-1- (2- (4-(((6- (3-thienyl) pyridin-2-yl) methyl) amino) piperidin-1-yl) ethyl) as a yellow solid 97 mg of -1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 2.07-2.23 (2H, m), 2.54-2.66 (2H, m), 3.20-3.36 (2H, m), 3.59-3.67 (2H, m), 3.73- 3.83 (1H, m), 3.98-4.10 (2H, m), 4.07 (3H, s), 4.54-4.61 (2H, m), 4.70-4.90 (2H, m), 6.92 (1H, d, J = 9.8 Hz), 7.41-7.65 (3H, m), 7.70-7.80 (1H, m), 7.87-7.92 (1H, m), 7.97-8.10 (1H, m), 8.05 (1H, d, J = 9.8Hz) , 8.14 (1H, s), 8.44 (1H, s)

１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.20gのメタノール2mL懸濁液に28％ナトリウムメトキシド/メタノール溶液0.28gおよび酢酸28μLを加えた。５−フルオロ−６−メトキシニコチンアルデヒド75mgを加え、次いで水素化シアノホウ素ナトリウム61mgを加え、室温で1時間20分間攪拌した。さらに、水素化シアノホウ素ナトリウム62mgを追加し、室温で1時間30分間攪拌した後、30〜35℃で1時間攪拌した。反応混合物にクロロホルムおよび飽和炭酸水素ナトリウム水溶液を加えた。有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせて、水および飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、得られた残留物を塩基性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＝１９：１−９：１］で精製し、得られた淡黄色油状物にジエチルエーテルを加え、固形物を濾取し、微黄色固体の１−（２−（４−（（（５−フルオロ−６−メトキシピリジン−３−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン97mgを得た。
¹H-NMR(CDCl₃)δ値：1.35-1.46(2H,m),1.86-1.95(2H,m),2.15-2.23(2H,m),2.47-2.58(1H,m),2.62-2.68(2H,m),2.92-3.02(2H,m),3.75(2H,m),3.98(3H,s),4.01(3H,s),4.33-4.40(2H,m),6.74(1H,d,J=9.8Hz),7.23(1H,d,J=2.3Hz),7.38(1H,dd,J=11.0,2.0Hz),7.82-7.86(2H,m),8.28(1H,d,J=2.3Hz) Example 135

1- (2- (4-Aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride 28% sodium methoxide in 2 mL of methanol suspension 0.28 g of methanol / methanol solution and 28 μL of acetic acid were added. 75 mg of 5-fluoro-6-methoxynicotinaldehyde was added, and then 61 mg of sodium cyanoborohydride was added, followed by stirring at room temperature for 1 hour and 20 minutes. Further, 62 mg of sodium cyanoborohydride was added and stirred at room temperature for 1 hour and 30 minutes, and then stirred at 30 to 35 ° C. for 1 hour. Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined and washed with water and saturated aqueous sodium chloride solution. It was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography [gradient elution of chloroform: methanol = 19: 1-9: 1] to obtain Diethyl ether was added to the pale yellow oil, and the solid was collected by filtration to give 1- (2- (4-(((5-fluoro-6-methoxypyridin-3-yl) methyl) amino) as a pale yellow solid. 97 mg of piperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.35-1.46 (2H, m), 1.86-1.95 (2H, m), 2.15-2.23 (2H, m), 2.47-2.58 (1H, m), 2.62-2.68 (2H, m), 2.92-3.02 (2H, m), 3.75 (2H, m), 3.98 (3H, s), 4.01 (3H, s), 4.33-4.40 (2H, m), 6.74 (1H, d , J = 9.8Hz), 7.23 (1H, d, J = 2.3Hz), 7.38 (1H, dd, J = 11.0,2.0Hz), 7.82-7.86 (2H, m), 8.28 (1H, d, J = 2.3Hz)

１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.14gのメタノール2mL懸濁液に28％ナトリウムメトキシド/メタノール溶液0.20g、６−エチル−５−フルオロニコチンアルデヒド53mgおよび酢酸20μLを加えた。次いで水素化シアノホウ素ナトリウム43mgを加え、室温で1時間20分間攪拌した。さらに、水素化シアノホウ素ナトリウム43mgを加え、室温で1時間攪拌した後、30〜40℃で1時間攪拌した。反応混合物にクロロホルム、飽和炭酸水素ナトリウム水溶液を加えた。有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせて、水および飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、得られた残留物を塩基性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＝９３：７−９：１］で精製し、淡黄色油状物の１−（２−（４−（（（６−エチル−５−フルオロピリジン−３−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン53mgを得た。
¹H-NMR(CDCl₃)δ値：1.29(3H,t,J=7.6Hz),1.36-1.47(2H,m),1.87-1.96(2H,m),2.15-2.24(2H,m),2.47-2.57(1H,m),2.62-2.68(2H,m),2.86(2H,dd,J=7.6,2.0Hz),2.95-3.02(2H,m),3.82(2H,s),3.98(3H,s),4.33-4.40(2H,m),6.75(1H,d,J=9.6Hz),7.20-7.24(1H,m),7.34-7.39(1H,m),7.85(1H,d,J=9.6Hz),8.25-8.27(1H,m),8.28(1H,d,J=2.4Hz) Example 136

1- (2- (4-Aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride 0.14 g in methanol 2 mL suspension in 28% sodium methoxide 0.20 g of methanol / methanol solution, 53 mg of 6-ethyl-5-fluoronicotinaldehyde and 20 μL of acetic acid were added. Next, 43 mg of sodium cyanoborohydride was added, and the mixture was stirred at room temperature for 1 hour and 20 minutes. Furthermore, after adding 43 mg of sodium cyanoborohydride and stirring at room temperature for 1 hour, it stirred at 30-40 degreeC for 1 hour. Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography [gradient elution of chloroform: methanol = 93: 7-9: 1] to give pale yellow 1- (2- (4-(((6-Ethyl-5-fluoropyridin-3-yl) methyl) amino) piperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridine- 53 mg of 2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.29 (3H, t, J = 7.6 Hz), 1.36-1.47 (2H, m), 1.87-1.96 (2H, m), 2.15-2.24 (2H, m), 2.47-2.57 (1H, m), 2.62-2.68 (2H, m), 2.86 (2H, dd, J = 7.6,2.0Hz), 2.95-3.02 (2H, m), 3.82 (2H, s), 3.98 ( 3H, s), 4.33-4.40 (2H, m), 6.75 (1H, d, J = 9.6Hz), 7.20-7.24 (1H, m), 7.34-7.39 (1H, m), 7.85 (1H, d, J = 9.6Hz), 8.25-8.27 (1H, m), 8.28 (1H, d, J = 2.4Hz)

実施例８と同様の手法により、１−（２−（４−（（（６−エチル−５−フルオロピリジン−３−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オンから１−（２−（４−（（（６−エチル−５−フルオロピリジン−３−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：1.30(3H,t,J=7.7Hz),2.00-2.14(2H,m),2.53-2.61(2H,m),2.99(2H,q,J=7.7Hz),3.23-3.35(2H,m),3.61-3.77(3H,m),3.96-4.05(2H,m),4.05(3H,s),4.47(2H,s),4.64-4.90(2H,m),6.90(1H,d,J=10.0Hz),7.51(1H,s),8.02(1H,d,J=9.2Hz),8.07(1H,d,J=10.0Hz),8.41-8.43(1H,m),8.51(1H,s) Example 137

In the same manner as in Example 8, 1- (2- (4-(((6-ethyl-5-fluoropyridin-3-yl) methyl) amino) piperidin-1-yl) ethyl) -7-methoxy- 1,5-Naphthyridin-2 (1H) -one to 1- (2- (4-(((6-ethyl-5-fluoropyridin-3-yl) methyl) amino) piperidin-1-yl) ethyl)- 7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.30 (3H, t, J = 7.7 Hz), 2.00-2.14 (2H, m), 2.53-2.61 (2H, m), 2.99 (2H, q, J = 7.7 Hz), 3.23-3.35 (2H, m), 3.61-3.77 (3H, m), 3.96-4.05 (2H, m), 4.05 (3H, s), 4.47 (2H, s), 4.64-4.90 (2H) , m), 6.90 (1H, d, J = 10.0Hz), 7.51 (1H, s), 8.02 (1H, d, J = 9.2Hz), 8.07 (1H, d, J = 10.0Hz), 8.41-8.43 (1H, m), 8.51 (1H, s)

実施例７９と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩および５−メチル−４−オキソ−４Ｈ−ピラン−２−カルバルデヒドから７−メトキシ−１−（２−（４−（（（５−メチル−４−オキソ−４Ｈ−ピラン−２−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−１,５−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.30-1.50(2H,m),1.80-1.95(5H,m),2.10-2.25(2H,m),2.45-2.55(1H,m),2.60-2.70(2H,m),2.90-3.05(2H,m),3.66(2H,s),3.98(3H,s),4.30-4.45(2H,m),6.33(1H,s),6.74(1H,d,J=9.6Hz),7.21-7.25(1H,m),7.66(1H,s),7.85(1H,d,J=9.6Hz),8.28(1H,d,J=2.4Hz) Example 138

In a similar manner to Example 79, 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride and 5-methyl- 4-oxo-4H-pyran-2-carbaldehyde to 7-methoxy-1- (2- (4-(((5-methyl-4-oxo-4H-pyran-2-yl) methyl) amino) piperidine- 1-yl) ethyl) -1,5-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.30-1.50 (2H, m), 1.80-1.95 (5H, m), 2.10-2.25 (2H, m), 2.45-2.55 (1H, m), 2.60-2.70 (2H, m), 2.90-3.05 (2H, m), 3.66 (2H, s), 3.98 (3H, s), 4.30-4.45 (2H, m), 6.33 (1H, s), 6.74 (1H, d , J = 9.6Hz), 7.21-7.25 (1H, m), 7.66 (1H, s), 7.85 (1H, d, J = 9.6Hz), 8.28 (1H, d, J = 2.4Hz)

１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.20gのメタノール2mL懸濁液に28％ナトリウムメトキシド/メタノール溶液0.28g、５−フルオロ−６−（ピロリジン−１−イル）ニコチンアルデヒド94mgおよび酢酸28μLを加えた。次いで水素化シアノホウ素ナトリウム61mgを加え、室温で2時間20分間攪拌した。反応混合物にクロロホルム、飽和炭酸水素ナトリウム水溶液および水を加えた。有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせて、水および飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、得られた残留物を塩基性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＝９５：５−９：１］で精製し、ジエチルエーテルを加え、固形物を濾取し、微黄色固体の１−（２−（４−（（（５−フルオロ−６−（ピロリジン−１−イル）ピリジン−３−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン91mgを得た。
¹H-NMR(CDCl₃)δ値：1.34-1.47(2H,m),1.85-1.99(6H,m),2.12-2.23(2H,m),2.47-2.55(1H,m),2.61-2.67(2H,m),2.92-3.01(2H,m),3.58-3.65(4H,m),3.67(2H,s),3.98(3H,s),4.33-4.40(2H,m),6.74(1H,d,J=9.6Hz),7.18(1H,d,J=15.6Hz),7.22-7.25(1H,m),7.81(1H,s),7.84(1H,d,J=9.6Hz),8.28(1H,d,J=2.2Hz) Example 139

1- (2- (4-Aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride 28% sodium methoxide in 2 mL of methanol suspension 0.28 g of methanol / methanol solution, 94 mg of 5-fluoro-6- (pyrrolidin-1-yl) nicotinaldehyde and 28 μL of acetic acid were added. Next, 61 mg of sodium cyanoborohydride was added, and the mixture was stirred at room temperature for 2 hours and 20 minutes. Chloroform, saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined and washed with water and saturated aqueous sodium chloride solution. It was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography [gradient elution of chloroform: methanol = 95: 5-9: 1] and diethyl ether. The solid was collected by filtration and 1- (2- (4-(((5-fluoro-6- (pyrrolidin-1-yl) pyridin-3-yl) methyl) amino) piperidine- 91 mg of 1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.34-1.47 (2H, m), 1.85-1.99 (6H, m), 2.12-2.23 (2H, m), 2.47-2.55 (1H, m), 2.61-2.67 (2H, m), 2.92-3.01 (2H, m), 3.58-3.65 (4H, m), 3.67 (2H, s), 3.98 (3H, s), 4.33-4.40 (2H, m), 6.74 (1H , d, J = 9.6Hz), 7.18 (1H, d, J = 15.6Hz), 7.22-7.25 (1H, m), 7.81 (1H, s), 7.84 (1H, d, J = 9.6Hz), 8.28 (1H, d, J = 2.2Hz)

実施例３０と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩および５−（２−フリル）イソオキサゾール−３−カルバルデヒドから１−（２−（４−（（（５−（２−フリル）イソオキサゾール−３−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.36-1.49(2H,m),1.87-1.97(2H,m),2.15-2.25(2H,m),2.52-2.62(1H,m),2.65(2H,t,J=7.1Hz),2.94-3.02(2H,m),3.93(2H,s),3.97(3H,s),4.36(2H,t,J=7.1Hz),6.44(1H,s),6.53(1H,dd,J=3.4,1.7Hz),6.74(1H,d,J=9.6Hz),6.89(1H,d,J=3.4Hz),7.21-7.24(1H,m),7.54(1H,d,J=1.7Hz),7.84(1H,d,J=9.6Hz),8.28(1H,d,J=2.0Hz) Example 140

In a manner similar to that in Example 30, 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride and 5- (2 1- (2- (4-(((5- (2-furyl) isoxazol-3-yl) methyl) amino) piperidin-1-yl) ethyl) -7 from -furyl) isoxazole-3-carbaldehyde -Methoxy-1,5-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.36-1.49 (2H, m), 1.87-1.97 (2H, m), 2.15-2.25 (2H, m), 2.52-2.62 (1H, m), 2.65 (2H , t, J = 7.1Hz), 2.94-3.02 (2H, m), 3.93 (2H, s), 3.97 (3H, s), 4.36 (2H, t, J = 7.1Hz), 6.44 (1H, s) , 6.53 (1H, dd, J = 3.4,1.7Hz), 6.74 (1H, d, J = 9.6Hz), 6.89 (1H, d, J = 3.4Hz), 7.21-7.24 (1H, m), 7.54 ( 1H, d, J = 1.7Hz), 7.84 (1H, d, J = 9.6Hz), 8.28 (1H, d, J = 2.0Hz)

実施例１３４と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩および５−（２−チエニル）ニコチンアルデヒドから７−メトキシ−１−（２−（４−（（（５−（２−チエニル）ピリジン−３−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：2.04-2.19(2H,m),2.57-2.67(2H,m),3.24-3.38(2H,m),3.60-3.70(2H,m),3.75-3.86(1H,m),4.01-4.09(2H,m),4.06(3H,s),4.58-4.64(2H,m),4.71-4.87(2H,m),6.90(1H,d,J=9.6Hz),7.29(1H,dd,J=5.0,3.8Hz),7.48-7.59(1H,m),7.71-7.79(2H,m),8.07(1H,d,J=9.6Hz),8.43(1H,d,J=2.2Hz),8.74-8.94(2H,m),9.10-9.20(1H,m) Example 141

In a manner similar to that in Example 134, 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride and 5- (2 -Thienyl) nicotinaldehyde to 7-methoxy-1- (2- (4-(((5- (2-thienyl) pyridin-3-yl) methyl) amino) piperidin-1-yl) ethyl) -1,5 -Naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 2.04-2.19 (2H, m), 2.57-2.67 (2H, m), 3.24-3.38 (2H, m), 3.60-3.70 (2H, m), 3.75- 3.86 (1H, m), 4.01-4.09 (2H, m), 4.06 (3H, s), 4.58-4.64 (2H, m), 4.71-4.87 (2H, m), 6.90 (1H, d, J = 9.6 Hz), 7.29 (1H, dd, J = 5.0, 3.8Hz), 7.48-7.59 (1H, m), 7.71-7.79 (2H, m), 8.07 (1H, d, J = 9.6Hz), 8.43 (1H , d, J = 2.2Hz), 8.74-8.94 (2H, m), 9.10-9.20 (1H, m)

実施例３０と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩および６−（２−チエニル）ニコチンアルデヒドから７−メトキシ−１−（２−（４−（（（６−（２−チエニル）ピリジン−３−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.38-1.50(2H,m),1.87-1.97(2H,m),2.14-2.25(2H,m),2.49-2.70(3H,m),2.95-3.03(2H,m),3.84(2H,s),3.98(3H,s),4.35-4.39(2H,m),6.74(1H,d,J=9.6Hz),7.09-7.14(1H,m),7.20-7.25(1H,m),7.38(1H,d,J=5.1Hz),7.57(1H,d,J=3.6Hz),7.61-7.72(2H,m),7.84(1H,d,J=9.6Hz),8.28(1H,d,J=1.9Hz),8.48-8.52(1H,m) Example 142

In a manner similar to that in Example 30, 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride and 6- (2 -Thienyl) nicotinaldehyde to 7-methoxy-1- (2- (4-(((6- (2-thienyl) pyridin-3-yl) methyl) amino) piperidin-1-yl) ethyl) -1,5 -Naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.38-1.50 (2H, m), 1.87-1.97 (2H, m), 2.14-2.25 (2H, m), 2.49-2.70 (3H, m), 2.95-3.03 (2H, m), 3.84 (2H, s), 3.98 (3H, s), 4.35-4.39 (2H, m), 6.74 (1H, d, J = 9.6Hz), 7.09-7.14 (1H, m), 7.20-7.25 (1H, m), 7.38 (1H, d, J = 5.1Hz), 7.57 (1H, d, J = 3.6Hz), 7.61-7.72 (2H, m), 7.84 (1H, d, J = 9.6Hz), 8.28 (1H, d, J = 1.9Hz), 8.48-8.52 (1H, m)

実施例３０と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩および５−（２−フリル）イソオキサゾール−３−カルバルデヒドから７−フルオロ−１−（２−（４−（（（５−（２−フリル）イソオキサゾール−３−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.35-1.47(2H,m),1.87-1.96(2H,m),2.14-2.24(2H,m),2.53-2.60(1H,m),2.65(2H,t,J=7.0Hz),2.92-2.99(2H,m),3.93(2H,s),4.32(2H,t,J=7.0Hz),6.44(1H,s),6.53(1H,dd,J=3.2,2.0Hz),6.86(1H,d,J=9.6Hz),6.89(1H,d,J=3.2Hz),7.50-7.58(2H,m),7.88(1H,d,J=9.6Hz),8.42(1H,d,J=2.0Hz) Example 143

In a manner similar to that in Example 30, 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one hydrochloride and 5- (2 -Furyl) isoxazole-3-carbaldehyde to 7-fluoro-1- (2- (4-(((5- (2-furyl) isoxazol-3-yl) methyl) amino) piperidin-1-yl) Ethyl) -1,5-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.35-1.47 (2H, m), 1.87-1.96 (2H, m), 2.14-2.24 (2H, m), 2.53-2.60 (1H, m), 2.65 (2H , t, J = 7.0Hz), 2.92-2.99 (2H, m), 3.93 (2H, s), 4.32 (2H, t, J = 7.0Hz), 6.44 (1H, s), 6.53 (1H, dd, J = 3.2,2.0Hz), 6.86 (1H, d, J = 9.6Hz), 6.89 (1H, d, J = 3.2Hz), 7.50-7.58 (2H, m), 7.88 (1H, d, J = 9.6 Hz), 8.42 (1H, d, J = 2.0Hz)

１−（２−（４−（（３，４−ジヒドロ−２Ｈ−ピラノ（２，３−ｃ）ピリジン−６−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩60mgのメタノール2mL懸濁液に、28％ナトリウムメトキシド／メタノール溶液60mgを加え、加熱還流下4時間攪拌した。水および酢酸エチルを加え、有機層を分取し、水層を塩化ナトリウムで飽和後酢酸エチルで2回抽出した。有機層および抽出液を合わせ、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物に酢酸エチル1mLを加え、室温で4.0mol/L塩化水素／酢酸エチル溶液1mLを加えた。減圧下で溶媒を留去し、得られた残留物に酢酸エチルを加え、固形物を濾取し、黄色固体の１−（２−（４−（（３，４−ジヒドロ−２Ｈ−ピラノ（２，３−ｃ）ピリジン−６−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩31mgを得た。
¹H-NMR(D₂O)δ値：2.00-2.12(4H,m),2.50-2.60(2H,m),2.92(2H,t,J=6.2Hz),3.20-3.34(2H,m),3.60-3.74(3H,m),3.98-4.07(2H,m),4.05(3H,s),4.34(2H,t,J=5.2Hz),4.43(2H,s),4.70-4.90(2H,m),6.89(1H,d,J=9.9Hz),7.48-7.52(2H,m),8.07(1H,d,J=9.9Hz),8.18(1H,s),8.42(1H,d,J=1.7Hz) Example 144

1- (2- (4-((3,4-dihydro-2H-pyrano (2,3-c) pyridin-6-ylmethyl) amino) piperidin-1-yl) ethyl) -7-fluoro-1,5 -To a suspension of naphthyridine-2 (1H) -one hydrochloride 60 mg in 2 mL of methanol was added 60 mg of 28% sodium methoxide / methanol solution, and the mixture was stirred for 4 hours while heating under reflux. Water and ethyl acetate were added, the organic layer was separated, and the aqueous layer was saturated with sodium chloride and extracted twice with ethyl acetate. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 1 mL of ethyl acetate was added to the obtained residue, and 1 mL of a 4.0 mol / L hydrogen chloride / ethyl acetate solution was added at room temperature. The solvent was distilled off under reduced pressure, ethyl acetate was added to the obtained residue, the solid was collected by filtration, and 1- (2- (4-((3,4-dihydro-2H-pyrano ( 2,3-c) pyridin-6-ylmethyl) amino) piperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride 31 mg was obtained.
¹ H-NMR (D ₂ O) δ value: 2.00-2.12 (4H, m), 2.50-2.60 (2H, m), 2.92 (2H, t, J = 6.2Hz), 3.20-3.34 (2H, m) 3.60-3.74 (3H, m), 3.98-4.07 (2H, m), 4.05 (3H, s), 4.34 (2H, t, J = 5.2Hz), 4.43 (2H, s), 4.70-4.90 (2H , m), 6.89 (1H, d, J = 9.9Hz), 7.48-7.52 (2H, m), 8.07 (1H, d, J = 9.9Hz), 8.18 (1H, s), 8.42 (1H, d, (J = 1.7Hz)

実施例１と同様の手法により、（７−フルオロ−４−メチル−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒドおよびｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（ピペリジン−４−イル）カルバマートからｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−フルオロ−４−メチル−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.30-1.70(13H,m),2.07-2.25(2H,m),2.53(3H,d,J=1.0Hz),2.59(2H,t,J=7.1Hz),2.94-3.02(2H,m),4.04-4.18(1H,m),4.20-4.48(8H,m),6.70-6.76(2H,m),7.41-7.48(1H,m),8.05(1H,s),8.41(1H,d,J=2.2Hz) Example 145

In the same manner as in Example 1, (7-fluoro-4-methyl-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde and tert-butyl = (2,3-dihydro (1, 4) Dioxino (2,3-c) pyridin-7-ylmethyl) (piperidin-4-yl) carbamate to tert-butyl = (2,3-dihydro (1,4) dioxino (2,3-c) pyridine- 7-ylmethyl) (1- (2- (7-fluoro-4-methyl-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.30-1.70 (13H, m), 2.07-2.25 (2H, m), 2.53 (3H, d, J = 1.0 Hz), 2.59 (2H, t, J = 7.1 Hz), 2.94-3.02 (2H, m), 4.04-4.18 (1H, m), 4.20-4.48 (8H, m), 6.70-6.76 (2H, m), 7.41-7.48 (1H, m), 8.05 ( 1H, s), 8.41 (1H, d, J = 2.2Hz)

実施例４と同様の手法により、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−フルオロ−４−メチル−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートから１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−フルオロ−４−メチル−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：2.01-2.16(2H,m),2.53-2.62(2H,m),2.56(3H,s),3.22-3.36(2H,m),3.60-3.67(2H,m),3.72-3.82(1H,m),3.97-4.08(2H,m),4.48-4.53(2H,m),4.57(2H,s),4.61-4.66(2H,m),4.70-4.78(2H,m),6.89(1H,s),7.53(1H,s),7.93(1H,dd,J=10.4,2.2Hz),8.41(1H,s),8.55(1H,d,J=2.2Hz) Example 146

In the same manner as in Example 4, tert-butyl = (2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) (1- (2- (7-fluoro-4 -Methyl-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate to 1- (2- (4-((2,3-dihydro (1,4)) Dioxino (2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -7-fluoro-4-methyl-1,5-naphthyridin-2 (1H) -one hydrochloride was obtained. .
¹ H-NMR (D ₂ O) δ value: 2.01-2.16 (2H, m), 2.53-2.62 (2H, m), 2.56 (3H, s), 3.22-3.36 (2H, m), 3.60-3.67 ( 2H, m), 3.72-3.82 (1H, m), 3.97-4.08 (2H, m), 4.48-4.53 (2H, m), 4.57 (2H, s), 4.61-4.66 (2H, m), 4.70- 4.78 (2H, m), 6.89 (1H, s), 7.53 (1H, s), 7.93 (1H, dd, J = 10.4,2.2Hz), 8.41 (1H, s), 8.55 (1H, d, J = 2.2Hz)

実施例３０と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩および５−（２−フリル）ニコチンアルデヒドから１−（２−（４−（（（５−（２−フリル）ピリジン−３−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：1.38-1.54(2H,m),1.89-2.00(2H,m),2.14-2.28(2H,m),2.52-2.62(1H,m),2.66(2H,t,J=7.3Hz),2.97-3.05(2H,m),3.87(2H,s),3.98(3H,s),4.38(2H,t,J=7.3Hz),6.52(1H,dd,J=3.3,1.8Hz),6.73-6.77(2H,m),7.23-7.27(1H,m),7.53(1H,d,J=1.4Hz),7.85(1H,d,J=9.8Hz),7.92-7.96(1H,s),8.28(1H,d,J=2.2Hz),8.44(1H,d,J=2.0Hz),8.82(1H,d,J=2.0Hz) Example 147

In a manner similar to that in Example 30, 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride and 5- (2 -Furyl) nicotinaldehyde to 1- (2- (4-(((5- (2-furyl) pyridin-3-yl) methyl) amino) piperidin-1-yl) ethyl) -7-methoxy-1,5 -Naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.38-1.54 (2H, m), 1.89-2.00 (2H, m), 2.14-2.28 (2H, m), 2.52-2.62 (1H, m), 2.66 (2H , t, J = 7.3Hz), 2.97-3.05 (2H, m), 3.87 (2H, s), 3.98 (3H, s), 4.38 (2H, t, J = 7.3Hz), 6.52 (1H, dd, J = 3.3,1.8Hz), 6.73-6.77 (2H, m), 7.23-7.27 (1H, m), 7.53 (1H, d, J = 1.4Hz), 7.85 (1H, d, J = 9.8Hz), 7.92-7.96 (1H, s), 8.28 (1H, d, J = 2.2Hz), 8.44 (1H, d, J = 2.0Hz), 8.82 (1H, d, J = 2.0Hz)

ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−フルオロ−４−メチル−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート72mgのメタノール2.5mL溶液に28％ナトリウムメトキシド／メタノール溶液77mgを室温で加え、加熱還流下、2時間攪拌した。室温まで冷却した後、反応混合物に水およびクロロホルムを加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、飽和塩化ナトリウム水溶液で洗浄し無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー［溶離液；クロロホルム］で精製し、淡褐色油状物のｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−メトキシ−４−メチル−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート82mgを得た。
¹H-NMR(CDCl₃)δ値：1.32-1.72(13H,m),2.07-2.25(2H,m),2.51(3H,d,J=1.0Hz),2.56-2.62(2H,m),2.96-3.05(2H,m),3.95(3H,s),4.05-4.17(1H,m),4.25-4.45(8H,m),6.62(1H,d,J=1.0Hz),6.71-6.76(1H,m),7.16(1H,d,J=2.4Hz),8.05(1H,s),8.28(1H,d,J=2.4Hz) Example 148

tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (1- (2- (7-fluoro-4-methyl-2-oxo-1, To a solution of 5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate in 72 mL of methanol was added 77% of 28% sodium methoxide / methanol solution at room temperature, and the mixture was stirred for 2 hours with heating under reflux. After cooling to room temperature, water and chloroform were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography [eluent: chloroform], and tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) as a light brown oily substance. 82 mg of pyridin-7-ylmethyl) (1- (2- (7-methoxy-4-methyl-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate are obtained. It was.
¹ H-NMR (CDCl ₃ ) δ value: 1.32-1.72 (13H, m), 2.07-2.25 (2H, m), 2.51 (3H, d, J = 1.0 Hz), 2.56-2.62 (2H, m), 2.96-3.05 (2H, m), 3.95 (3H, s), 4.05-4.17 (1H, m), 4.25-4.45 (8H, m), 6.62 (1H, d, J = 1.0Hz), 6.71-6.76 ( 1H, m), 7.16 (1H, d, J = 2.4Hz), 8.05 (1H, s), 8.28 (1H, d, J = 2.4Hz)

実施例４と同様の手法により、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−メトキシ−４−メチル−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートから１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−４−メチル−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：1.98-2.14(2H,m),2.50-2.61(2H,m),2.54(3H,s),3.20-3.35(2H,m),3.58-3.66(2H,m),3.68-3.79(1H,m),3.95-4.09(2H,m),4.05(3H,s),4.45-4.50(2H,m),4.51(2H,s),4.56-4.62(2H,m),4.71-4.89(2H,m),6.77-6.80(1H,m),7.43(1H,s),7.46(1H,d,J=2.3Hz),8.35(1H,s),8.38(1H,d,J=2.3Hz) Example 149

In the same manner as in Example 4, tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) (1- (2- (7-methoxy-4 -Methyl-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate to 1- (2- (4-((2,3-dihydro (1,4)) Dioxino (2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -7-methoxy-4-methyl-1,5-naphthyridin-2 (1H) -one hydrochloride was obtained. .
¹ H-NMR (D ₂ O) δ value: 1.98-2.14 (2H, m), 2.50-2.61 (2H, m), 2.54 (3H, s), 3.20-3.35 (2H, m), 3.58-3.66 ( 2H, m), 3.68-3.79 (1H, m), 3.95-4.09 (2H, m), 4.05 (3H, s), 4.45-4.50 (2H, m), 4.51 (2H, s), 4.56-4.62 ( 2H, m), 4.71-4.89 (2H, m), 6.77-6.80 (1H, m), 7.43 (1H, s), 7.46 (1H, d, J = 2.3Hz), 8.35 (1H, s), 8.38 (1H, d, J = 2.3Hz)

実施例１と同様の手法により、（７−（ジフルオロメトキシ）−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒドおよびｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（ピペリジン−４−イル）カルバマートからｔｅｒｔ−ブチル＝（１−（２−（７−（ジフルオロメトキシ）−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.30-1.70(13H,m),2.08-2.26(2H,m),2.58-2.65(2H,m),2.92-3.01(2H,m),4.00-4.18(1H,m),4.22-4.48(8H,m),6.70(1H,t,J=72.1Hz),6.73(1H,s),6.86(1H,d,J=9.9Hz),7.58(1H,d,J=2.1Hz),7.88(1H,d,J=9.8Hz),8.05(1H,s),8.41(1H,d,J=2.1Hz) Example 150

In a similar manner as in Example 1, (7- (difluoromethoxy) -2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde and tert-butyl = (2,3-dihydro (1,4 ) Dioxino (2,3-c) pyridin-7-ylmethyl) (piperidin-4-yl) carbamate to tert-butyl = (1- (2- (7- (difluoromethoxy) -2-oxo-1,5- Naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.30-1.70 (13H, m), 2.08-2.26 (2H, m), 2.58-2.65 (2H, m), 2.92-3.01 (2H, m), 4.00-4.18 (1H, m), 4.22-4.48 (8H, m), 6.70 (1H, t, J = 72.1Hz), 6.73 (1H, s), 6.86 (1H, d, J = 9.9Hz), 7.58 (1H, d, J = 2.1Hz), 7.88 (1H, d, J = 9.8Hz), 8.05 (1H, s), 8.41 (1H, d, J = 2.1Hz)

実施例４と同様の手法により、ｔｅｒｔ−ブチル＝（１−（２−（７−（ジフルオロメトキシ）−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）カルバマートから７−（ジフルオロメトキシ）−１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：1.99-2.14(2H,m),2.50-2.60(2H,m),3.22-3.34(2H,m),3.59-3.78(3H,m),3.96-4.06(2H,m),4.44-4.50(2H,m),4.48(2H,s),4.54-4.60(2H,m),4.70-4.88(2H,m),7.01(1H,d,J=9.8Hz),7.06(1H,t,J=72.2Hz),7.39(1H,s),7.87(1H,d,J=2.1Hz),8.10(1H,d,J=9.8Hz),8.33(1H,s),8.57(1H,d,J=2.1Hz) Example 151

In the same manner as in Example 4, tert-butyl = (1- (2- (7- (difluoromethoxy) -2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidine-4- Yl) (2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) carbamate to 7- (difluoromethoxy) -1- (2- (4-((2,3- Dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.99-2.14 (2H, m), 2.50-2.60 (2H, m), 3.22-3.34 (2H, m), 3.59-3.78 (3H, m), 3.96 4.06 (2H, m), 4.44-4.50 (2H, m), 4.48 (2H, s), 4.54-4.60 (2H, m), 4.70-4.88 (2H, m), 7.01 (1H, d, J = 9.8 Hz), 7.06 (1H, t, J = 72.2Hz), 7.39 (1H, s), 7.87 (1H, d, J = 2.1Hz), 8.10 (1H, d, J = 9.8Hz), 8.33 (1H, s), 8.57 (1H, d, J = 2.1Hz)

１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩86mgのメタノール4mL懸濁液に１，５−ナフチリジン−３−カルバルデヒド33mg、28％ナトリウムメトキシド/メタノール溶液0.12gおよび酢酸12μLを加えた。次いで水素化シアノホウ素ナトリウム26mgを加え、室温で4時間攪拌した。反応混合物にクロロホルム、飽和炭酸水素ナトリウム水溶液および水を加えた。有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせて、水および飽和塩化ナトリウム水溶液で洗浄した。無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、得られた残留物を塩基性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＝８７：１３−８５：１５］で精製し、淡黄色油状物の７−メトキシ−１−（２−（４−（（１，５−ナフチリジン−３−イルメチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オン11mgを得た。
¹H-NMR(CDCl₃)δ値：1.42-1.53(2H,m),1.93-2.00(2H,m),2.14-2.26(2H,m),2.56-2.69(3H,m),2.96-3.40(2H,m),3.98(3H,s),4.10(2H,s),4.35-4.39(2H,m),6.74(1H,d,J=9.8Hz),7.21-7.25(1H,m),7.62(1H,dd,J=8.5,4.3Hz),7.84(1H,d,J=9.8Hz),8.28(1H,d,J=2.4Hz),8.31-8.34(1H,m),8.38-8.42(1H,m),8.97(1H,dd,J=4.3,1.6Hz),8.99(1H,d,J=2.0Hz) Example 152

1- (2- (4-Aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride 86 mg of methanol in a 4 mL suspension of 1,5-naphthyridine- 33 mg of 3-carbaldehyde, 0.12 g of 28% sodium methoxide / methanol solution and 12 μL of acetic acid were added. Next, 26 mg of sodium cyanoborohydride was added, and the mixture was stirred at room temperature for 4 hours. Chloroform, saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography [gradient elution of chloroform: methanol = 87: 13-85: 15] to give pale yellow 7-Methoxy-1- (2- (4-((1,5-naphthyridin-3-ylmethyl) amino) piperidin-1-yl) ethyl) -1,5-naphthyridin-2 (1H) -one as an oil 11 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.42-1.53 (2H, m), 1.93-2.00 (2H, m), 2.14-2.26 (2H, m), 2.56-2.69 (3H, m), 2.96-3.40 (2H, m), 3.98 (3H, s), 4.10 (2H, s), 4.35-4.39 (2H, m), 6.74 (1H, d, J = 9.8Hz), 7.21-7.25 (1H, m), 7.62 (1H, dd, J = 8.5,4.3Hz), 7.84 (1H, d, J = 9.8Hz), 8.28 (1H, d, J = 2.4Hz), 8.31-8.34 (1H, m), 8.38-8.42 (1H, m), 8.97 (1H, dd, J = 4.3,1.6Hz), 8.99 (1H, d, J = 2.0Hz)

実施例１０３と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩および６−（２−フリル）ピラジン−２−カルバルデヒドから、１−（２−（４−（（（６−（２−フリル）ピラジン−２−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オンの塩酸塩を得た。
¹H-NMR(CD₃OD)δ値：2.06-2.20(2H,m),2.46-2.59(2H,m),3.04-3.70(5H,m),3.85-4.01(2H,m),4.08(3H,s),4.59(2H,s),4.70-5.08(2H,m),6.70(1H,dd,J=3.6,1.8Hz),6.80(1H,d,J=9.6Hz),7.40(1H,d,J=3.6Hz),7.53-7.59(1H,m),7.79-7.82(1H,m),7.99(1H,d,J=9.6Hz),8.34(1H,d,J=2.2Hz),8.58(1H,s),9.02(1H,s) Example 153

In a manner similar to that described in Example 103, 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride and 6- (2 -Furyl) pyrazine-2-carbaldehyde to 1- (2- (4-(((6- (2-furyl) pyrazin-2-yl) methyl) amino) piperidin-1-yl) ethyl) -7- The hydrochloride salt of methoxy-1,5-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (CD ₃ OD) δ value: 2.06-2.20 (2H, m), 2.46-2.59 (2H, m), 3.04-3.70 (5H, m), 3.85-4.01 (2H, m), 4.08 ( 3H, s), 4.59 (2H, s), 4.70-5.08 (2H, m), 6.70 (1H, dd, J = 3.6, 1.8Hz), 6.80 (1H, d, J = 9.6Hz), 7.40 (1H , d, J = 3.6Hz), 7.53-7.59 (1H, m), 7.79-7.82 (1H, m), 7.99 (1H, d, J = 9.6Hz), 8.34 (1H, d, J = 2.2Hz) , 8.58 (1H, s), 9.02 (1H, s)

ｔｅｒｔ−ブチル＝（１−（２−（７−ブロモ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）カルバマート0.10gのジオキサン2mL溶液に窒素雰囲気下、２−トリブチルスタニルオキサゾール90mgおよびビス（トリ−ｔｅｒｔ−ブチルホスフィン）パラジウム（０）17mgを加え、加熱還流下6時間30分間攪拌した。フラッシュ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＝９８：２−９５：５］で精製し、黄色油状物のｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−（１，３−オキサゾール−２−イル）−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート87mgを得た。
¹H-NMR(CDCl₃)δ値：1.30-1.86(13H,m),2.12-2.25(2H,m),2.67(2H,t,J=6.7Hz),2.97-3.06(2H,m),4.00-4.42(9H,m),6.71(1H,s),6.95(1H,d,J=9.8Hz),7.34(1H,s),7.86(1H,s),7.93(1H,d,J=9.8Hz),8.05(1H,s),8.44(1H,s),9.18(1H,d,J=1.5Hz) Example 154

tert-butyl = (1- (2- (7-bromo-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) (2,3-dihydro (1,4 ) Dioxyno (2,3-c) pyridin-7-ylmethyl) carbamate 0.10 g of dioxane in 2 mL was charged with 90 mg of 2-tributylstannyl oxazole and 17 mg of bis (tri-tert-butylphosphine) palladium (0) in a nitrogen atmosphere. In addition, the mixture was stirred for 6 hours and 30 minutes with heating under reflux. Purification by flash silica gel column chromatography [gradient elution of chloroform: methanol = 98: 2-95: 5] and tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3- c) Pyridin-7-ylmethyl) (1- (2- (7- (1,3-oxazol-2-yl) -2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidine- 87 mg of 4-yl) carbamate were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.30-1.86 (13H, m), 2.12-2.25 (2H, m), 2.67 (2H, t, J = 6.7 Hz), 2.97-3.06 (2H, m), 4.00-4.42 (9H, m), 6.71 (1H, s), 6.95 (1H, d, J = 9.8Hz), 7.34 (1H, s), 7.86 (1H, s), 7.93 (1H, d, J = 9.8Hz), 8.05 (1H, s), 8.44 (1H, s), 9.18 (1H, d, J = 1.5Hz)

実施例２と同様の手法により、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−（１，３−オキサゾール−２−イル）−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートから１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−（１，３−オキサゾール−２−イル）−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：2.00-2.15(2H,m),2.50-2.60(2H,m),3.24-3.36(2H,m),3.63-3.76(3H,m),3.95-4.15(2H,m),4.42-4.58(6H,m),4.70-4.95(2H,m),7.10(1H,d,J=9.8Hz),7.35(1H,s),7.45(1H,s),8.10(1H,s),8.14(1H,d,J=9.8Hz),8.31(1H,s),8.56(1H,s),9.19(1H,d,J=1.5Hz) Example 155

In the same manner as in Example 2, tert-butyl = (2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) (1- (2- (7- (1, 3-oxazol-2-yl) -2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate to 1- (2- (4-((2,3- Dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -7- (1,3-oxazol-2-yl) -1,5-naphthyridine -2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 2.00-2.15 (2H, m), 2.50-2.60 (2H, m), 3.24-3.36 (2H, m), 3.63-3.76 (3H, m), 3.95- 4.15 (2H, m), 4.42-4.58 (6H, m), 4.70-4.95 (2H, m), 7.10 (1H, d, J = 9.8Hz), 7.35 (1H, s), 7.45 (1H, s) , 8.10 (1H, s), 8.14 (1H, d, J = 9.8Hz), 8.31 (1H, s), 8.56 (1H, s), 9.19 (1H, d, J = 1.5Hz)

実施例１５４と同様の手法により、ｔｅｒｔ−ブチル＝（１−（２−（７−ブロモ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）カルバマートからｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（２−オキソ−７−（１，３−チアゾール−２−イル）−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.12-1.90(13H,m),2.10-2.23(2H,m),2.62-2.75(2H,m),2.98-3.08(2H,m),4.20-4.48(9H,m),6.70(1H,s),6.94(1H,d,J=9.8Hz),7.46-7.52(1H,m),7.92(1H,d,J=9.8Hz),7.95-7.99(1H,m),8.04(1H,s),8.42(1H,s),9.05(1H,s) Example 156

In the same manner as in Example 154, tert-butyl = (1- (2- (7-bromo-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) ( 2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) carbamate to tert-butyl = (2,3-dihydro (1,4) dioxino (2,3-c) pyridine -7-ylmethyl) (1- (2- (2-oxo-7- (1,3-thiazol-2-yl) -1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl ) Carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.12-1.90 (13H, m), 2.10-2.23 (2H, m), 2.62-2.75 (2H, m), 2.98-3.08 (2H, m), 4.20-4.48 (9H, m), 6.70 (1H, s), 6.94 (1H, d, J = 9.8Hz), 7.46-7.52 (1H, m), 7.92 (1H, d, J = 9.8Hz), 7.95-7.99 ( 1H, m), 8.04 (1H, s), 8.42 (1H, s), 9.05 (1H, s)

実施例２と同様の手法により、ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（２−オキソ−７−（１，３−チアゾール−２−イル）−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートから１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−（１，３−チアゾール−２−イル）−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：2.03-2.18(2H,m),2.53-2.64(2H,m),3.24-3.39(2H,m),3.62-3.84(3H,m),3.99-4.10(2H,m),4.48-4.64(6H,m),4.70-4.90(2H,m),7.09(1H,d,J=9.9Hz),7.54(1H,s),7.84(1H,d,J=3.2Hz),8.05(1H,d,J=3.2Hz),8.12(1H,d,J=9.9Hz),8.41(1H,s),8.48(1H,s),9.08(1H,d,J=1.5Hz) Example 157

In the same manner as in Example 2, tert-butyl = (2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) (1- (2- (2-oxo-7 -(1,3-thiazol-2-yl) -1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate to 1- (2- (4-((2,3- Dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -7- (1,3-thiazol-2-yl) -1,5-naphthyridine -2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 2.03-2.18 (2H, m), 2.53-2.64 (2H, m), 3.24-3.39 (2H, m), 3.62-3.84 (3H, m), 3.99- 4.10 (2H, m), 4.48-4.64 (6H, m), 4.70-4.90 (2H, m), 7.09 (1H, d, J = 9.9Hz), 7.54 (1H, s), 7.84 (1H, d, J = 3.2Hz), 8.05 (1H, d, J = 3.2Hz), 8.12 (1H, d, J = 9.9Hz), 8.41 (1H, s), 8.48 (1H, s), 9.08 (1H, d, (J = 1.5Hz)

実施例１０３と同様の手法により１−（２−（４−アミノピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩および５，６，７，８−テトラヒドロキノキサリン−２−カルバルデヒドから７−フルオロ−１−（２−（４−（（５，６，７，８−テトラヒドロキノキサリン−２−イルメチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：1.89-1.97(4H,m),2.04-2.15(2H,m),2.52-2.62(2H,m),2.94-3.01(4H,m),3.20-3.36(2H,m), 3.63(2H,t,J=6.0Hz),3.68-3.78(1H,m),3.97-4.07(2H,m),4.49(2H,s),4.75-5.00(2H,m),7.00(1H,d,J=9.8Hz),7.96(1H,d,J=10.5Hz),8.10(1H,d,J=9.8Hz),8.40(1H,s),8.57(1H,s) Example 158

In a manner similar to Example 103, 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one hydrochloride and 5,6,7 , 8-tetrahydroquinoxaline-2-carbaldehyde to 7-fluoro-1- (2- (4-((5,6,7,8-tetrahydroquinoxalin-2-ylmethyl) amino) piperidin-1-yl) ethyl) -1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.89-1.97 (4H, m), 2.04-2.15 (2H, m), 2.52-2.62 (2H, m), 2.94-3.01 (4H, m), 3.20- 3.36 (2H, m), 3.63 (2H, t, J = 6.0Hz), 3.68-3.78 (1H, m), 3.97-4.07 (2H, m), 4.49 (2H, s), 4.75-5.00 (2H, m), 7.00 (1H, d, J = 9.8Hz), 7.96 (1H, d, J = 10.5Hz), 8.10 (1H, d, J = 9.8Hz), 8.40 (1H, s), 8.57 (1H, s)

実施例１３４と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩および５−（２−フリル）−１，３−オキサゾール−２−カルバルデヒドから７−フルオロ−１−（２−（４−（（（５−（２−フリル）−１，３−オキサゾール−２−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：2.00-2.14(2H,m),2.50-2.60(2H,m),3.20-3.34(2H,m),3.63(2H,t,J=6.1Hz),3.68-3.80(1H,m),3.98-4.06(2H,m),4.62(2H,s),4.70-4.88(2H,m),6.60-6.70(1H,m),6.85(1H,d,J=3.4Hz),6.99(1H,d,J=9.8Hz),7.40(1H,s),7.65(1H,s),7.95(1H,d,J=9.8Hz),8.10(1H,d,J=9.8Hz),8.56(1H,s) Example 159

In a manner similar to that in Example 134, 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one hydrochloride and 5- (2 -Furyl) -1,3-oxazole-2-carbaldehyde to 7-fluoro-1- (2- (4-(((5- (2-furyl) -1,3-oxazol-2-yl) methyl) Amino) piperidin-1-yl) ethyl) -1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 2.00-2.14 (2H, m), 2.50-2.60 (2H, m), 3.20-3.34 (2H, m), 3.63 (2H, t, J = 6.1Hz) , 3.68-3.80 (1H, m), 3.98-4.06 (2H, m), 4.62 (2H, s), 4.70-4.88 (2H, m), 6.60-6.70 (1H, m), 6.85 (1H, d, J = 3.4Hz), 6.99 (1H, d, J = 9.8Hz), 7.40 (1H, s), 7.65 (1H, s), 7.95 (1H, d, J = 9.8Hz), 8.10 (1H, d, J = 9.8Hz), 8.56 (1H, s)

実施例１１７と同様の手法により、１−（２−（３−（（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）メチル）ピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩から１−（２−（３−（（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）メチル）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オンを得た。
¹H-NMR(CDCl₃)δ値：0.90-1.04(1H,m),1.48-2.18(6H,m),2.47-2.54(2H,m),2.60-2.68(2H,m),2.89-2.98(1H.m),3.01-3.09(1H,m),3.74(2H,s),3.97(3H,s),4.24-4.43(6H,m),6.74(1H,d,J=9.8Hz),6.81(1H,s),7.27-7.28(1H,m),7.84(1H,d,J=9.8Hz),8.10(1H,s),8.27(1H,d,J=2.4Hz) Example 160

In the same manner as in Example 117, 1- (2- (3-(((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) methyl) piperidine- 1- (2- (3-(((2,3-dihydro (1,4) dioxino (2)) from 1-yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one hydrochloride , 3-c) pyridin-7-ylmethyl) amino) methyl) piperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one.
¹ H-NMR (CDCl ₃ ) δ value: 0.90-1.04 (1H, m), 1.48-2.18 (6H, m), 2.47-2.54 (2H, m), 2.60-2.68 (2H, m), 2.89-2.98 (1H.m), 3.01-3.09 (1H, m), 3.74 (2H, s), 3.97 (3H, s), 4.24-4.43 (6H, m), 6.74 (1H, d, J = 9.8Hz), 6.81 (1H, s), 7.27-7.28 (1H, m), 7.84 (1H, d, J = 9.8Hz), 8.10 (1H, s), 8.27 (1H, d, J = 2.4Hz)

実施例８と同様の手法により、１−（２−（３−（（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）メチル）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オンから１−（２−（３−（（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）メチル）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：1.33-1.50(1H,m),1.76-1.94(1H,m),1.99-2.17(2H,m),2.32-2.47(1H,m),2.88-3.13(2H,m).3.16-3.31(2H,m),3.54-3.68(2H,m),3.75-3.85(1H,m),3.95-4.04(1H,m),4.06(3H,s),4.44-4.65(6H,m),4.70-4.90(2H,m),6.91(1H,d,J=9.8Hz),7.51(1H,s),7.55(1H,d,J=2.3Hz),8.07(1H,d,J=9.8Hz),8.38(1H,s),8.43(1H,d,J=2.3Hz) Example 161

In the same manner as in Example 8, 1- (2- (3-(((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) methyl) piperidine- 1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one to 1- (2- (3-(((2,3-dihydro (1,4) dioxino (2,3 -C) Pyridin-7-ylmethyl) amino) methyl) piperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.33-1.50 (1H, m), 1.76-1.94 (1H, m), 1.99-2.17 (2H, m), 2.32-2.47 (1H, m), 2.88- 3.13 (2H, m) .3.16-3.31 (2H, m), 3.54-3.68 (2H, m), 3.75-3.85 (1H, m), 3.95-4.04 (1H, m), 4.06 (3H, s), 4.44-4.65 (6H, m), 4.70-4.90 (2H, m), 6.91 (1H, d, J = 9.8Hz), 7.51 (1H, s), 7.55 (1H, d, J = 2.3Hz), 8.07 (1H, d, J = 9.8Hz), 8.38 (1H, s), 8.43 (1H, d, J = 2.3Hz)

実施例１０３と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩および３，４−ジヒドロ−２Ｈ−ピラノ（３，２−ｃ）ピリジン−７−カルバルデヒドから１−（２−（４−（（３，４−ジヒドロ−２Ｈ−ピラノ（３，２−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：2.00-2.15(4H,m),2.50-2.64(2H,m),2.92(2H,t,J=6.4Hz),3.24-3.36(2H,m),3.64(2H,t,J=5.9Hz),3.68-3.80(1H,m),3.96-4.07(2H,m),4.51-4.59(4H,m),4.70-4.90(2H,m),7.00(1H,d,J=9.8Hz),7.38(1H,s),7.96(1H,dd,J=10.4,2.2Hz),8.11(1H,d,J=9.8Hz),8.44(1H,s),8.57(1H,d,J=2.2Hz) Example 162

In a similar manner to Example 103, 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one hydrochloride and 3,4- Dihydro-2H-pyrano (3,2-c) pyridine-7-carbaldehyde to 1- (2- (4-((3,4-dihydro-2H-pyrano (3,2-c) pyridin-7-ylmethyl) Amino) piperidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 2.00-2.15 (4H, m), 2.50-2.64 (2H, m), 2.92 (2H, t, J = 6.4Hz), 3.24-3.36 (2H, m) , 3.64 (2H, t, J = 5.9Hz), 3.68-3.80 (1H, m), 3.96-4.07 (2H, m), 4.51-4.59 (4H, m), 4.70-4.90 (2H, m), 7.00 (1H, d, J = 9.8Hz), 7.38 (1H, s), 7.96 (1H, dd, J = 10.4,2.2Hz), 8.11 (1H, d, J = 9.8Hz), 8.44 (1H, s) , 8.57 (1H, d, J = 2.2Hz)

実施例１４４と同様の手法により、１−（２−（４−（（３，４−ジヒドロ−２Ｈ−ピラノ（３，２−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オンから１−（２−（４−（（３，４−ジヒドロ−２Ｈ−ピラノ（３，２−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩を得た。
¹H-NMR(D₂O)δ値：2.00-2.15(4H,m),2.50-2.61(2H,m),2.92(2H,t,J=6.2Hz),3.21-3.36(2H,m),3.64(2H,t,J=5.9Hz),3.68-3.79(1H,m),3.98-4.08(2H,m),4.05(3H,s),4.51-4.58(2H,m),4.56(2H,s),4.77-4.90(2H,m),6.88(1H,d,J=9.6Hz),7.37(1H,s),7.48(1H,s),8.06(1H,d,J=9.6Hz),8.41(1H,s),8.44(1H,s) Example 163

In a manner similar to Example 144, 1- (2- (4-((3,4-dihydro-2H-pyrano (3,2-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl ) -7-fluoro-1,5-naphthyridin-2 (1H) -one to 1- (2- (4-((3,4-dihydro-2H-pyrano (3,2-c) pyridin-7-ylmethyl) Amino) piperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 2.00-2.15 (4H, m), 2.50-2.61 (2H, m), 2.92 (2H, t, J = 6.2Hz), 3.21-3.36 (2H, m) , 3.64 (2H, t, J = 5.9Hz), 3.68-3.79 (1H, m), 3.98-4.08 (2H, m), 4.05 (3H, s), 4.51-4.58 (2H, m), 4.56 (2H , s), 4.77-4.90 (2H, m), 6.88 (1H, d, J = 9.6Hz), 7.37 (1H, s), 7.48 (1H, s), 8.06 (1H, d, J = 9.6Hz) , 8.41 (1H, s), 8.44 (1H, s)

実施例１と同様の手法により、（２−オキソ−７−（トリフルオロメチル）−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒドおよびｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（ピペリジン−４−イル）カルバマートからｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（２−オキソ−７−（トリフルオロメチル）−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.33-1.71(13H,m),2.10-2.26(2H,m),2.63(2H,t,J=6.6Hz),2.93-3.01(2H,m),4.07-4.18(1H,m),4.25-4.37(8H,m),6.71(1H,s),7.02(1H,d,J=9.8Hz),7.95(1H,d,J=9.8Hz),8.02(1H,s),8.05(1H,s),8.75(1H,s) Example 164

In the same manner as in Example 1, (2-oxo-7- (trifluoromethyl) -1,5-naphthyridin-1 (2H) -yl) acetaldehyde and tert-butyl = (2,3-dihydro (1, 4) Dioxino (2,3-c) pyridin-7-ylmethyl) (piperidin-4-yl) carbamate to tert-butyl = (2,3-dihydro (1,4) dioxino (2,3-c) pyridine- 7-ylmethyl) (1- (2- (2-oxo-7- (trifluoromethyl) -1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.33-1.71 (13H, m), 2.10-2.26 (2H, m), 2.63 (2H, t, J = 6.6 Hz), 2.93-3.01 (2H, m), 4.07-4.18 (1H, m), 4.25-4.37 (8H, m), 6.71 (1H, s), 7.02 (1H, d, J = 9.8Hz), 7.95 (1H, d, J = 9.8Hz), 8.02 (1H, s), 8.05 (1H, s), 8.75 (1H, s)

ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（２−オキソ−７−（トリフルオロメチル）−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート80mgのイソプロピルアルコール1.4mL溶液に濃塩酸57μLを加え、加熱還流下で1時間30分間攪拌した。反応混合物を室温まで冷却し、固形物を濾取し、淡褐色固体の１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−（トリフルオロメチル）−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩70mgを得た。
¹H-NMR(D₂O)δ値：1.94-2.07(2H,m),2.44-2.52(2H,m),3.10-3.20(2H,m),3.50-3.63(3H,m),3.87-3.94(2H,m),4.29(2H,s),4.36-4.46(4H,m),4.75-4.85(2H,m),7.09(1H,s),7.17(1H,d,J=10.0Hz),8.14-8.19(2H,m),8.39(1H,s),8.93(1H,s) Example 165

tert-butyl = (2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) (1- (2- (2-oxo-7- (trifluoromethyl) -1, Concentrated hydrochloric acid (57 μL) was added to a solution of 80 mg of 5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate in 1.4 mL of isopropyl alcohol, and the mixture was stirred for 1 hour and 30 minutes under heating and reflux. The reaction mixture was cooled to room temperature, the solid was collected by filtration, and a light brown solid 1- (2- (4-((2,3-dihydro (1,4) dioxino (2,3-c) pyridine-7) was obtained. 70 mg of -ylmethyl) amino) piperidin-1-yl) ethyl) -7- (trifluoromethyl) -1,5-naphthyridin-2 (1H) -one hydrochloride were obtained.
¹ H-NMR (D ₂ O) δ value: 1.94-2.07 (2H, m), 2.44-2.52 (2H, m), 3.10-3.20 (2H, m), 3.50-3.63 (3H, m), 3.87- 3.94 (2H, m), 4.29 (2H, s), 4.36-4.46 (4H, m), 4.75-4.85 (2H, m), 7.09 (1H, s), 7.17 (1H, d, J = 10.0Hz) , 8.14-8.19 (2H, m), 8.39 (1H, s), 8.93 (1H, s)

実施例３と同様の手法により、（７−フルオロ−６−メチル−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒドおよびｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（ピペリジン−４−イル）カルバマートからｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−フルオロ−６−メチル−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.25-1.70(13H,m),2.05-2.25(2H,m),2.50-2.61(2H,m),2.58(3H,d,J=2.9Hz),2.95-3.00(2H,m),4.01-4.20(1H,m),4.23-4.40(8H,m),6.72(1H,s),6.81(1H,d,J=9.8Hz),7.41(1H,d,J=10.7Hz),7.81(1H,d,J=9.8Hz),8.05(1H,s) Example 166

In a similar manner as in Example 3, (7-fluoro-6-methyl-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde and tert-butyl = (2,3-dihydro (1, 4) Dioxino (2,3-c) pyridin-7-ylmethyl) (piperidin-4-yl) carbamate to tert-butyl = (2,3-dihydro (1,4) dioxino (2,3-c) pyridine- 7-ylmethyl) (1- (2- (7-fluoro-6-methyl-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.25-1.70 (13H, m), 2.05-2.25 (2H, m), 2.50-2.61 (2H, m), 2.58 (3H, d, J = 2.9Hz), 2.95-3.00 (2H, m), 4.01-4.20 (1H, m), 4.23-4.40 (8H, m), 6.72 (1H, s), 6.81 (1H, d, J = 9.8Hz), 7.41 (1H, d, J = 10.7Hz), 7.81 (1H, d, J = 9.8Hz), 8.05 (1H, s)

ｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（１−（２−（７−フルオロ−６−メチル−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）カルバマート0.48gのイソプロピルアルコール4.7mL溶液に濃塩酸0.44mLを加え、60℃まで昇温し、3時間攪拌した。反応混合物を室温まで冷却し、固形物を濾取し、白色固体の１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−フルオロ−６−メチル−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.33gを得た。
¹H-NMR(D₂O)δ値：1.99-2.14(2H,m),2.49-2.61(2H,m),2.59(3H,d,J=2.4Hz),3.19-3.34(2H,m),3.56-3.74(3H,m),3.94-4.04(2H,m),4.39(2H,s),4.39-4.54(4H,m),4.73(2H,t,J=6.0Hz),6.96(1H,d,J=9.9Hz),7.23(1H,S),7.88(1H,d,J=10.5Hz),8.02(1H,d,J=9.9Hz),8.23(1H,s) Example 167

tert-butyl = (2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) (1- (2- (7-fluoro-6-methyl-2-oxo-1, To a solution of 0.48 g of 5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) carbamate was added 0.44 mL of concentrated hydrochloric acid, and the mixture was warmed to 60 ° C. and stirred for 3 hours. The reaction mixture was cooled to room temperature, and the solid was collected by filtration to give 1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-c) pyridine-7- 0.33 g of ylmethyl) amino) piperidin-1-yl) ethyl) -7-fluoro-6-methyl-1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.99-2.14 (2H, m), 2.49-2.61 (2H, m), 2.59 (3H, d, J = 2.4Hz), 3.19-3.34 (2H, m) , 3.56-3.74 (3H, m), 3.94-4.04 (2H, m), 4.39 (2H, s), 4.39-4.54 (4H, m), 4.73 (2H, t, J = 6.0Hz), 6.96 (1H , d, J = 9.9Hz), 7.23 (1H, S), 7.88 (1H, d, J = 10.5Hz), 8.02 (1H, d, J = 9.9Hz), 8.23 (1H, s)

１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−フルオロ−６−メチル−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.16gにクロロホルムおよび飽和炭酸水素ナトリウム水溶液を加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、無水硫酸ナトリウムで乾燥させ、溶媒を減圧留去した。残留物にメタノール2.6mL、28％ナトリウムメトキシド／メタノール溶液0.15mLを加え、加熱還流下、2時間攪拌した。室温に冷却し、クロロホルムおよび飽和炭酸水素ナトリウム水溶液を加え、有機層を分取し、水層をクロロホルムで抽出した。有機層および抽出液を合わせ、無水硫酸ナトリウムで乾燥させ、溶媒を減圧留去した。得られた残留物にイソプロピルアルコール1.4mLおよび濃塩酸93μL加え、室温で30分間攪拌した。反応混合物を氷冷し、固形物を濾取し、白色固体の１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−６−メチル−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.15gを得た。
¹H-NMR(D₂O)δ値：1.95-2.15(2H,m),2.50-2.60(2H,m),2.59(3H,s),3.30-3.35(2H,m),3.60-3.75(3H,m),3.95-4.10(2H,m),4.09(3H,s),4.38-4.55(6H,m),4.75-4.85(2H,m),6.91(1H,d,J=9.8Hz),7.27(1H,s),7.49(1H,s),8.04(1H,d,J=9.8Hz),8.26(1H,s) Example 168

1- (2- (4-((2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -7-fluoro-6 Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to 0.16 g of methyl-1,5-naphthyridin-2 (1H) -one hydrochloride, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To the residue, 2.6 mL of methanol and 0.15 mL of 28% sodium methoxide / methanol solution were added, and the mixture was stirred for 2 hours while heating under reflux. After cooling to room temperature, chloroform and saturated aqueous sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue, 1.4 mL of isopropyl alcohol and 93 μL of concentrated hydrochloric acid were added and stirred at room temperature for 30 minutes. The reaction mixture was ice-cooled, the solid was collected by filtration, and 1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) was obtained as a white solid. 0.15 g of amino) piperidin-1-yl) ethyl) -7-methoxy-6-methyl-1,5-naphthyridin-2 (1H) -one hydrochloride was obtained.
¹ H-NMR (D ₂ O) δ value: 1.95-2.15 (2H, m), 2.50-2.60 (2H, m), 2.59 (3H, s), 3.30-3.35 (2H, m), 3.60-3.75 ( 3H, m), 3.95-4.10 (2H, m), 4.09 (3H, s), 4.38-4.55 (6H, m), 4.75-4.85 (2H, m), 6.91 (1H, d, J = 9.8Hz) , 7.27 (1H, s), 7.49 (1H, s), 8.04 (1H, d, J = 9.8Hz), 8.26 (1H, s)

実施例７８と同様の手法により、１−（２−（４−アミノピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩およびｔｅｒｔ−ブチル＝（５−ホルミルピラジン−２−イル）カルバマートからｔｅｒｔ−ブチル＝（５−（（（１−（２−（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）アミノ）メチル）ピラジン−２−イル）カルバマートを得た。
¹H-NMR(CDCl₃)δ値：1.40-1.60(11H,m),1.87-1.97(2H,m),2.13-2.25(2H,m),2.49-2.58(1H,m),2.61-2.70(2H,m),2.95-3.05(2H,m),3.91(2H,s),3.98(3H,s),4.33-4.42(2H,m),6.74(1H,d,J=9.6Hz),7.15-7.19(1H,m),7.84(1H,d,J=9.6Hz),8.20(1H,s),8.28(1H,d,J=2.4Hz),9.19(1H,s) Example 169

In the same manner as in Example 78, 1- (2- (4-aminopiperidin-1-yl) ethyl) -7-methoxy-1,5-naphthyridin-2 (1H) -one hydrochloride and tert-butyl = (5-Formylpyrazin-2-yl) carbamate to tert-butyl = (5-(((1- (2- (7-methoxy-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl ) Piperidin-4-yl) amino) methyl) pyrazin-2-yl) carbamate.
¹ H-NMR (CDCl ₃ ) δ value: 1.40-1.60 (11H, m), 1.87-1.97 (2H, m), 2.13-2.25 (2H, m), 2.49-2.58 (1H, m), 2.61-2.70 (2H, m), 2.95-3.05 (2H, m), 3.91 (2H, s), 3.98 (3H, s), 4.33-4.42 (2H, m), 6.74 (1H, d, J = 9.6Hz), 7.15-7.19 (1H, m), 7.84 (1H, d, J = 9.6Hz), 8.20 (1H, s), 8.28 (1H, d, J = 2.4Hz), 9.19 (1H, s)

実施例１６７と同様の手法により、ｔｅｒｔ−ブチル＝（５−（（（１−（２−（７−メトキシ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）アミノ）メチル）ピラジン−２−イル）カルバマートから１−（２−（４−（（（５−アミノピラジン−２−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−７−メトキシ−１，５−ナフチリジン−２（１Ｈ）−オンの塩酸塩を得た。
¹H-NMR(D₂O)δ値：1.97-2.13(2H,m),2.49-2.60(2H,m),3.19-3.34(2H,m),3.57-3.74(3H,m),3.96-4.07(2H,m),4.04(3H,s),4.30-4.38(2H,m),4.78-4.80(2H,m),6.85-6.91(1H,m),7.43-7.52(1H,m),7.98-8.32(2H,m),8.06(1H,d,J=9.8Hz),8.40(1H,d,J=2.2Hz) Example 170

In the same manner as in Example 167, tert-butyl = (5-(((1- (2- (7-methoxy-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidine- 4-yl) amino) methyl) pyrazin-2-yl) carbamate to 1- (2- (4-(((5-aminopyrazin-2-yl) methyl) amino) piperidin-1-yl) ethyl) -7 The hydrochloride salt of -methoxy-1,5-naphthyridin-2 (1H) -one was obtained.
¹ H-NMR (D ₂ O) δ value: 1.97-2.13 (2H, m), 2.49-2.60 (2H, m), 3.19-3.34 (2H, m), 3.57-3.74 (3H, m), 3.96- 4.07 (2H, m), 4.04 (3H, s), 4.30-4.38 (2H, m), 4.78-4.80 (2H, m), 6.85-6.91 (1H, m), 7.43-7.52 (1H, m), 7.98-8.32 (2H, m), 8.06 (1H, d, J = 9.8Hz), 8.40 (1H, d, J = 2.2Hz)

１−（２−（４−アミノピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン211mgおよび２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｂ）ピリジン−７−カルバルデヒド120mgのクロロホルム22mL溶液に酢酸88mgを加え、室温で14時間攪拌した。反応混合物に水素化トリアセトキシホウ素ナトリウム232mgを加え、2時間攪拌した。飽和炭酸水素ナトリウム水溶液を加え、有機層を分取した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［シリカゲル；関東化学株式会社、シリカゲル６０Ｎ、溶離液；クロロホルム：メタノール＝１０：１］で精製し、淡黄色固体の１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｂ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン185mgを得た。
１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｂ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オン185mgの酢酸エチル4mL溶液に4mol/L塩化水素／酢酸エチル2mLを加え、室温で1時間攪拌した。固形物を濾取し、白色固体の１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｂ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−７−フルオロ−１，５−ナフチリジン−２（１Ｈ）−オンの塩酸塩244mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.01-2.12(2H,m),2.34-2.41(2H,m),3.17(2H,s),3.24-3.35(3H,m),3.75-3.82(2H,m),4.11-4.17(2H,m),4.25-4.30(2H,m),4.41-4.45(2H,m),4.59-4.65(2H,m),6.89(1H,d,J=9.6Hz),7.61-7.67(1H,m),7.90-7.95(1H,m),8.01(1H,d,J=9.6Hz),8.32-8.39(1H,m),8.60-8.65(1H,m),9.61-9.76(3H,m),10.79-11.02(1H,m) Example 171

1- (2- (4-Aminopiperidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one 211 mg and 2,3-dihydro (1,4) dioxino (2, 3-b) 88 mg of acetic acid was added to 22 mL of chloroform in 120 mg of pyridine-7-carbaldehyde, and the mixture was stirred at room temperature for 14 hours. To the reaction mixture, 232 mg of sodium triacetoxyborohydride was added and stirred for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60N, eluent: chloroform: methanol = 10: 1], and 1- (2- (4-(( 2,3-dihydro (1,4) dioxyno (2,3-b) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -7-fluoro-1,5-naphthyridine-2 (1H)- 185 mg was obtained.
1- (2- (4-((2,3-dihydro (1,4) dioxino (2,3-b) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -7-fluoro-1 , 5-naphthyridin-2 (1H) -one To a solution of 185 mg of ethyl acetate in 4 mL was added 4 mol / L hydrogen chloride / ethyl acetate (2 mL), and the mixture was stirred at room temperature for 1 hour. The solid was collected by filtration, and white solid 1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-b) pyridin-7-ylmethyl) amino) piperidine-1- Yl) ethyl) -7-fluoro-1,5-naphthyridin-2 (1H) -one hydrochloride 244 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.01-2.12 (2H, m), 2.34-2.41 (2H, m), 3.17 (2H, s), 3.24-3.35 (3H, m), 3.75-3.82 (2H, m), 4.11-4.17 (2H, m), 4.25-4.30 (2H, m), 4.41-4.45 (2H, m), 4.59-4.65 (2H, m), 6.89 (1H, d, J = 9.6Hz), 7.61-7.67 (1H, m), 7.90-7.95 (1H, m), 8.01 (1H, d, J = 9.6Hz), 8.32-8.39 (1H, m), 8.60-8.65 (1H, m ), 9.61-9.76 (3H, m), 10.79-11.02 (1H, m)

（７−ブロモ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）アセトアルデヒド7.00gにｔｅｒｔ−ブチル＝（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）（ピペリジン−４−イル）カルバマート10.07gのクロロホルム140mL溶液および酢酸1.57gを加え、室温で19時間攪拌した後、水素化トリアセトキシホウ素ナトリウム8.77gを加えて2時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液140mLを加え、有機層を分取した。次いで飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。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［シリカゲル；富士シリシア化学株式会社、Chromatorex-NH、溶離液；ヘキサン：酢酸エチルの勾配溶離＝５０：５０−５：９５］で精製した後に、エタノール24mLにて再結晶することにより白色固体のｔｅｒｔ−ブチル＝（１−（２−（７−ブロモ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）カルバマート11.26gを得た。
¹H-NMR(CDCl₃)δ値：1.32-1.55(9H,m),1.69(4H,m),2.20(2H,m),2.62(2H,t,J=6.6Hz),2.97(2H,d,J=11.5Hz),4.12(1H,s),4.27(4H,m),4.32(4H,m),6.72(1H,s),6.90(1H,d,J=9.6Hz),7.85(1H,d,J=9.6Hz),8.01(1H,s),8.06(1H,s),8.54(1H,d,J=1.4Hz) Example 172

(7-Bromo-2-oxo-1,5-naphthyridin-1 (2H) -yl) acetaldehyde 7.00 g and tert-butyl = (2,3-dihydro (1,4) dioxyno (2,3-c) pyridine A solution of 10.7 g of -7-ylmethyl) (piperidin-4-yl) carbamate in 140 mL of chloroform and 1.57 g of acetic acid were added, and the mixture was stirred at room temperature for 19 hours. 140 mL of saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the organic layer was separated. Subsequently, it wash | cleaned by saturated sodium chloride aqueous solution, it was made to dry with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Fuji Silysia Chemical Co., Ltd., Chromatorex-NH, eluent; hexane: ethyl acetate gradient elution = 50: 50-5: 95], and then purified into 24 mL of ethanol. Tert-butyl = (1- (2- (7-bromo-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) ( There was obtained 11.26 g of 2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) carbamate.
¹ H-NMR (CDCl ₃ ) δ value: 1.32-1.55 (9H, m), 1.69 (4H, m), 2.20 (2H, m), 2.62 (2H, t, J = 6.6 Hz), 2.97 (2H, d, J = 11.5Hz), 4.12 (1H, s), 4.27 (4H, m), 4.32 (4H, m), 6.72 (1H, s), 6.90 (1H, d, J = 9.6Hz), 7.85 ( 1H, d, J = 9.6Hz), 8.01 (1H, s), 8.06 (1H, s), 8.54 (1H, d, J = 1.4Hz)

ｔｅｒｔ−ブチル＝（１−（２−（７−ブロモ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）カルバマート0.51gに室温で2mol/L塩化水素／エタノール溶液18mLを加え、室温にて59時間、50℃にて9時間攪拌した後、生じた固形物を濾取した。次いでクロロホルム3mLに懸濁させ、トリフルオロ酢酸5mLを加えて室温にて100分間攪拌した後、減圧下で溶媒を留去した。残留物にクロロホルム10mL、水3mLを加え、2mol/L水酸化ナトリウム水溶液にてpH10に調整した後、有機層を分取した。水層をクロロホルムにて2回抽出して有機層を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。残留物を酢酸エチル2mL、エタノール3mLに溶解させ、2mol/L塩酸／エタノール溶液10mLを加えて15分間攪拌後、減圧下で溶媒を留去した。残留物に酢酸エチル4mLを加えて懸濁させ、濾取することにより微黄色固体の７−ブロモ−１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.41gを得た。
¹H-NMR(D₂O)δ値：2.03-2.15(2H,m),2.59(2H,d,J=13.3Hz),3.30(2H,s),3.64(2H,t,J=5.7Hz),3.79(1H,tt,J=11.9,4.1Hz),4.04(2H,s),4.51(2H,dd),4.59(2H,s),4.65(2H,m),4.75(2H,t,J=6.2Hz),7.04(1H,d,J=9.6Hz),7.56(1H,s),8.05(1H,d,J=9.6Hz),8.37(1H,d,J=0.9Hz),8.42(1H,s),8.70(1H,d,J=1.8Hz) Example 173

tert-butyl = (1- (2- (7-bromo-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) (2,3-dihydro (1,4 ) Dioxino (2,3-c) pyridin-7-ylmethyl) carbamate 0.51g was added with 18mL of 2mol / L hydrogen chloride / ethanol solution at room temperature and stirred for 59 hours at room temperature and 9 hours at 50 ° C. The solid was collected by filtration. Next, the suspension was suspended in 3 mL of chloroform, 5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 100 minutes, and then the solvent was distilled off under reduced pressure. Chloroform 10 mL and water 3 mL were added to the residue, and the pH was adjusted to 10 with a 2 mol / L aqueous sodium hydroxide solution, and then the organic layer was separated. The aqueous layer was extracted twice with chloroform, and the organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 2 mL of ethyl acetate and 3 mL of ethanol, 10 mL of 2 mol / L hydrochloric acid / ethanol solution was added and stirred for 15 minutes, and then the solvent was distilled off under reduced pressure. The residue was suspended by adding 4 mL of ethyl acetate, and collected by filtration to give 7-bromo-1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,4 3-c) Pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -1,5-naphthyridin-2 (1H) -one hydrochloride 0.41 g was obtained.
¹ H-NMR (D ₂ O) δ value: 2.03-2.15 (2H, m), 2.59 (2H, d, J = 13.3Hz), 3.30 (2H, s), 3.64 (2H, t, J = 5.7Hz ), 3.79 (1H, tt, J = 11.9, 4.1Hz), 4.04 (2H, s), 4.51 (2H, dd), 4.59 (2H, s), 4.65 (2H, m), 4.75 (2H, t, J = 6.2Hz), 7.04 (1H, d, J = 9.6Hz), 7.56 (1H, s), 8.05 (1H, d, J = 9.6Hz), 8.37 (1H, d, J = 0.9Hz), 8.42 (1H, s), 8.70 (1H, d, J = 1.8Hz)

ｔｅｒｔ−ブチル＝（１−（２−（７−ブロモ−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）カルバマート0.85gの１，４−ジオキサン5mL溶液にｔｅｒｔ−ブチルカルバマート0.20g、炭酸セシウム0.69g、トリス（ベンジリデンアセトン）ジパラジウム13mgおよび４，５−ビス（ジフェニルホスフィノ）−９，９−ジメチルキサンテン24mgを加え、窒素雰囲気下、90℃にて38時間攪拌した。室温まで冷却後、不溶物を濾別し、減圧下で濾液を濃縮した。残留物をシリカゲルカラムクロマトグラフィー［シリカゲル；関東化学株式会社、シリカゲル６０、溶離液；ヘキサン：酢酸エチルの勾配溶離＝３３：６７−５：９５］で精製し、白色固体のｔｅｒｔ−ブチル＝（１−（２−（７−（（ｔｅｒｔ−ブトキシカルボニル）アミノ）−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）カルバマート0.68gを得た。
¹H-NMR(CDCl₃)δ値：1.33-1.51(9H,m),1.53(9H,s),1.55-1.65(2H,m),1.78(2H,s),2.11-2.26(2H,m),2.66(2H,t,J=7.1Hz),3.01(2H,d,J=10.5Hz),4.06-4.15(1H,m),4.24-4.29(2H,m),4.29-4.37(5H,m),4.37-4.44(1H,m),6.72(1H,s),6.76(1H,d,J=9.6Hz),7.09-7.24(1H,m),7.80(1H,d,J=9.6Hz),8.04(1H,s),8.25(1H,d,J=1.4Hz),8.32(1H,s) Example 174

tert-butyl = (1- (2- (7-bromo-2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) (2,3-dihydro (1,4 ) Dioxyno (2,3-c) pyridin-7-ylmethyl) carbamate 0.85 g in 1,4-dioxane 5 mL solution, tert-butyl carbamate 0.20 g, cesium carbonate 0.69 g, tris (benzylideneacetone) dipalladium 13 mg and 4 , 5-bis (diphenylphosphino) -9,9-dimethylxanthene (24 mg) was added, and the mixture was stirred at 90 ° C. for 38 hours under a nitrogen atmosphere. After cooling to room temperature, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent; hexane: ethyl acetate gradient elution = 33: 67-5: 95], and white solid tert-butyl = (1 -(2- (7-((tert-butoxycarbonyl) amino) -2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) (2,3-dihydro (1 , 4) Dioxino (2,3-c) pyridin-7-ylmethyl) carbamate 0.68 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.33-1.51 (9H, m), 1.53 (9H, s), 1.55-1.65 (2H, m), 1.78 (2H, s), 2.11-2.26 (2H, m ), 2.66 (2H, t, J = 7.1Hz), 3.01 (2H, d, J = 10.5Hz), 4.06-4.15 (1H, m), 4.24-4.29 (2H, m), 4.29-4.37 (5H, m), 4.37-4.44 (1H, m), 6.72 (1H, s), 6.76 (1H, d, J = 9.6Hz), 7.09-7.24 (1H, m), 7.80 (1H, d, J = 9.6Hz) ), 8.04 (1H, s), 8.25 (1H, d, J = 1.4Hz), 8.32 (1H, s)

ｔｅｒｔ−ブチル＝（１−（２−（７−（（ｔｅｒｔ−ブトキシカルボニル）アミノ）−２−オキソ−１，５−ナフチリジン−１（２Ｈ）−イル）エチル）ピペリジン−４−イル）（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）カルバマート0.66gのメタノール8mL溶液に室温にて4mol/L塩化水素／酢酸エチル溶液8mLを加えて18時間攪拌後、固形物を濾取した。次いで、クロロホルム3mLに懸濁させ、室温にてトリフルオロ酢酸6mLを加えて2時間攪拌後、減圧下で溶媒を留去した。残留物にクロロホルムおよび水を加え、2mol/L水酸化ナトリウム水溶液にてpH9に調整した後、有機層を分取した。水層をクロロホルムにて3回抽出して有機層を合わせ、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、白色泡状物の７−アミノ−１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オン0.31gを得た。
¹H-NMR(CDCl₃)δ値：1.44-1.52(2H,m),1.94(2H,d,J=12.4Hz),2.20(2H,t,J=11.0Hz),2.51-2.57(1H,m),2.60-2.65(2H,m),2.98-3.03(2H,m),3.80(2H,s),4.20(2H,s),4.26-4.30(2H,m),4.30-4.35(4H,m),6.63(1H,d,J=9.6Hz),6.82(1H,s),7.00(1H,d,J=1.8Hz),7.76(1H,d,J=9.6Hz),8.03(1H,d,J=1.8Hz),8.11(1H,s) Example 175

tert-butyl = (1- (2- (7-((tert-butoxycarbonyl) amino) -2-oxo-1,5-naphthyridin-1 (2H) -yl) ethyl) piperidin-4-yl) (2 , 3-Dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) carbamate 0.66 g in 8 mL of methanol was added at room temperature with 8 mL of 4 mol / L hydrogen chloride / ethyl acetate solution and stirred for 18 hours. Thereafter, the solid was collected by filtration. Subsequently, the resultant was suspended in 3 mL of chloroform, 6 mL of trifluoroacetic acid was added at room temperature, and the mixture was stirred for 2 hours, and then the solvent was distilled off under reduced pressure. Chloroform and water were added to the residue, and the pH was adjusted to 9 with a 2 mol / L aqueous sodium hydroxide solution, and then the organic layer was separated. The aqueous layer was extracted three times with chloroform, and the organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and white foam 7-amino-1 was obtained. -(2- (4-((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -1,5-naphthyridine- 0.31 g of 2 (1H) -one was obtained.
¹ H-NMR (CDCl ₃ ) δ values: 1.44-1.52 (2H, m), 1.94 (2H, d, J = 12.4 Hz), 2.20 (2H, t, J = 11.0 Hz), 2.51-2.57 (1H, m), 2.60-2.65 (2H, m), 2.98-3.03 (2H, m), 3.80 (2H, s), 4.20 (2H, s), 4.26-4.30 (2H, m), 4.30-4.35 (4H, m), 6.63 (1H, d, J = 9.6Hz), 6.82 (1H, s), 7.00 (1H, d, J = 1.8Hz), 7.76 (1H, d, J = 9.6Hz), 8.03 (1H, d, J = 1.8Hz), 8.11 (1H, s)

７−アミノ−１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オン0.095gのエタノール3mLおよび酢酸エチル2mL溶液に室温で2mol/L塩化水素／エタノール溶液4mLを加え、室温にて20分間攪拌した後、減圧下で溶媒を留去した。残留物にジエチルエーテル8mLを加えて懸濁させ、固形物を濾取し、黄色固体の７−アミノ−１−（２−（４−（（２，３−ジヒドロ（１，４）ジオキシノ（２，３−ｃ）ピリジン−７−イルメチル）アミノ）ピペリジン−１−イル）エチル）−１，５−ナフチリジン−２（１Ｈ）−オン塩酸塩0.41gを得た。
¹H-NMR(CDCl₃)δ値：2.02-2.12(2H,m),2.56(2H,d,J=13.3Hz),3.28(2H,t,J=10.5Hz),3.62(2H,t,J=6.0Hz),3.69-3.76(1H,m),3.98-4.05(2H,m),4.44-4.49(4H,m),4.54-4.58(2H,m),4.71(2H,t,J=6.0Hz),6.83(1H,d,J=9.6Hz),7.37(1H,s),7.48(1H,d,J=2.3Hz),7.99(1H,d,J=9.6Hz),8.18(1H,d,J=2.3Hz),8.31(1H,s) Example 176

7-amino-1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -1 , 5-naphthyridin-2 (1H) -one 0.095 g of ethanol and 2 mL of ethyl acetate were added with 2 mL of a 2 mol / L hydrogen chloride / ethanol solution at room temperature and stirred at room temperature for 20 minutes, and then the solvent was removed under reduced pressure. Distilled off. To the residue was added 8 mL of diethyl ether to suspend, and the solid was collected by filtration to give a yellow solid of 7-amino-1- (2- (4-((2,3-dihydro (1,4) dioxyno (2 , 3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -1,5-naphthyridin-2 (1H) -one hydrochloride 0.41 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.02-2.12 (2H, m), 2.56 (2H, d, J = 13.3 Hz), 3.28 (2H, t, J = 10.5 Hz), 3.62 (2H, t, J = 6.0Hz), 3.69-3.76 (1H, m), 3.98-4.05 (2H, m), 4.44-4.49 (4H, m), 4.54-4.58 (2H, m), 4.71 (2H, t, J = 6.0Hz), 6.83 (1H, d, J = 9.6Hz), 7.37 (1H, s), 7.48 (1H, d, J = 2.3Hz), 7.99 (1H, d, J = 9.6Hz), 8.18 (1H , d, J = 2.3Hz), 8.31 (1H, s)

Formulation Example 1 Tablet The compound of Example 4 was pulverized in a mortar and sieved using a sieve having an opening of 500 μm. To 1.25 g of the pulverized powder, 1.39 g of mannitol (Merck, Partec M100) and 0.30 g of low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., L-HPC LH-11) were added and mixed for 30 minutes. To this mixed powder, 0.06 g of magnesium stearate (Merck) was added and mixed for 2 minutes to obtain a tableting powder of 3.0 g. The obtained tableting powder was tableted using a tableting machine (Okada Seiko, compression moldability measuring device Tabflex TB10), with a punch of 8.5 mm in diameter, 1 tablet mass 300 mg, tableting pressure 8 kN, 1 tablet A tablet containing 100 mg of the free base of the compound of Example 4 in it was obtained.

Formulation Example 2 Tablet The compound of Example 2 was pulverized in a mortar and sieved using a sieve having an opening of 500 μm. 1.29 g of lactose (Megure, Tablets 80) and 0.44 g of crystalline cellulose (Asahi Kasei Chemicals, Theolas PH302) were added to 1.24 g of this pulverized powder and mixed for 30 minutes. To this mixed powder, 0.03 g of magnesium stearate (Merck) was added and mixed for 2 minutes to obtain a tableted powder of 3.0 g. The obtained tableting powder was tableted using a tableting machine (Okada Seiko, compression moldability measuring device Tabflex TB10), with a punch of 8.5 mm in diameter, 1 tablet mass 300 mg, tableting pressure 8 kN, 1 tablet A tablet having 100 mg of the free base of the compound of Example 2 in it was obtained.

Formulation Example 3 Injection The compound 312.3 mg of Example 4 was dissolved by adding about 35 mL of water for injection (Otsuka Pharmaceutical) and adjusted to pH 5.5 with 0.1 mol / L aqueous sodium hydroxide (Wako Pure Chemical Industries). To this solution, 346.1 mg of sodium chloride for injection (Tonda Pharmaceutical) was added and dissolved, and then water for injection (Otsuka Pharmaceutical) was added to make the total volume 50 mL. The resulting solution was sterilized by filtration through a filter having a pore size of 0.22 μm (Millipore, Milex GV, diameter 33 mm). 30 mL of the resulting solution was filled into a glass vial (Fuji Glass, 50PSC), closed with a rubber stopper (SRI hybrid) and a flip-off cap, containing 5 mg / mL of the free base of the compound of Example 4. An injection with a pH of 5.7 and an osmotic pressure ratio of 1 was obtained.

Formulation Example 4 Injection The compound 310.8 mg of Example 2 was dissolved by adding about 35 mL of water for injection (Otsuka Pharmaceutical) and adjusted to pH 5.5 with a 0.1 mol / L sodium hydroxide aqueous solution (Wako Pure Chemical Industries). To this solution, 353.5 mg of sodium chloride for injection (Tonda Pharmaceutical) was added and dissolved, and then water for injection (Otsuka Pharmaceutical) was added to make the total volume 50 mL. The resulting solution was sterilized by filtration through a filter having a pore size of 0.22 μm (Millipore, Milex GV, diameter 33 mm). 30 mL of the resulting solution was filled into a glass vial (Fuji Glass, 50PSC), closed with a rubber stopper (SRI hybrid) and a flip-off cap, containing 5 mg / mL of the free base of the compound of Example 2. An injection with a pH of 5.7 and an osmotic pressure ratio of 1 was obtained.

Claims (2)

1- (2- (4-((2,3-dihydro (1,4) dioxino (2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -7-fluoro-1 , 5-naphthyridin-2 (1H) -one or a salt thereof, penicillin-resistant pneumococci, vancomycin-resistant enterococcus faecalis, vancomycin-resistant enterococcus faecium, gonorrhea, acne, welsh, fragilis, gingivalis, prevotella Antibacterial agent against bacterial species selected from Intermedia and Fusobacterium nucleatum. 1- (2- (4-((2,3-dihydro (1,4) dioxyno (2,3-c) pyridin-7-ylmethyl) amino) piperidin-1-yl) ethyl) -7-methoxy-1 , 5-Naphthyridin-2 (1H) -one or a salt thereof
Penicillin-resistant pneumococci, vancomycin-resistant Enterococcus faecalis, vancomycin-resistant Enterococcus faecium, Neisseria gonorrhoeae, acne, Clostridium perfringens, Fraziris, gingivalis, Prevotella intermedia and Fusobacterium nucleatum
Antibacterial agent against bacterial species selected from