JPWO2006046552A1 - Novel nitrogen-containing heterocyclic compounds and salts thereof - Google Patents

Abstract

[PROBLEMS] To provide a compound having strong antibacterial activity and useful as a preventive and therapeutic agent as an excellent antibacterial agent. R 2, R 3, R 4 and R 5 are the same or different and are a hydrogen atom or an optionally substituted alkyl or alkenyl group; Z 1 and Z 2 are a nitrogen atom or CH; X2 represents a carbonyl group, NH, or a bond; X3 represents a C1-4 alkylene group or a bond; R6 represents a group such as a substituted cyclic amine. The compound represented by “means” or a salt thereof is useful as an excellent antibacterial agent because it has strong antibacterial activity and high safety. [Selection figure] None

Description

  The present invention relates to a novel nitrogen-containing heterocyclic compound having a strong antibacterial activity against Gram-positive bacteria, Gram-negative bacteria and resistant bacteria, or a salt thereof, and an antibacterial agent containing them.

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 emergence of antibiotics effective against these resistant bacteria is strongly desired. For example, WO99 / 07682 (Patent Document 1) discloses a quinolone compound effective for MRSA. Further, compounds having an action mechanism different from that of existing drugs are described in WO04 / 002490 (Patent Document 2), WO04 / 002992 (Patent Document 3) and WO04 / 0899947 (Patent Document 4). Compounds are known.

WO99 / 07682 WO04 / 002490 Publication WO04 / 002992 Publication WO04 / 0899947 Publication

  Development of a drug having high antibacterial activity against Gram-positive bacteria, Gram-negative bacteria and resistant bacteria and having high safety is desired.

「式中、Ｒ^１は、ハロゲン原子、シアノ基、保護されていてもよいカルボキシル基または置換されていてもよいアルキル、アルコキシもしくはアシルオキシ基を；Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５は、同一または異なって水素原子、ハロゲン原子、シアノ基、保護されていてもよいカルボキシル基または置換されていてもよいアルキル、アルケニル、アルコキシ、シクロアルキル、アミノもしくはカルバモイル基を；Ｚ^１およびＺ^２は、窒素原子またはＣＲ^７「式中、Ｒ^７は、水素原子、ハロゲン原子、シアノ基、保護されていてもよいカルボキシル基または置換されていてもよいアルキル、アルケニル、アルコキシ、アミノもしくはカルバモイル基を意味する。」であり、かつ、Ｚ^１およびＺ^２の少なくとも一方が窒素原子を；Ｘ^１は、酸素原子、硫黄原子、スルフィニル基、スルホニル基、ＮＲ^８ａ「式中、Ｒ^８ａは、水素原子または置換されていてもよいアルキルもしくはアリール基を意味する。」またはＣＲ^９Ｒ^１０「式中、Ｒ^９およびＲ^１０は、同一または異なって水素原子または置換されていてもよいアルキル、ヒドロキシル、アミノもしくはメルカプト基を意味する。」を；Ｘ^２は、カルボニル基、ＮＲ^８ｂ「式中、Ｒ^８ｂは、水素原子または置換されていてもよいアルキルもしくはアリール基を意味する。」または結合手を；Ｘ^３は、Ｃ_１−４アルキレン基または結合手を；Ｒ^６は、一般式

「式中、Ｒ^１１は、１つ以上の水素原子、ハロゲン原子、保護されていてもよいヒドロキシルもしくはカルボキシル基または置換されていてもよいアミノ、低級アルキル、アルコキシもしくはカルバモイル基を；Ｒ^１１ａ、Ｒ^１１ｂおよびＲ^１１ｃは、同一または異なって水素原子、ハロゲン原子、保護されていてもよいヒドロキシルもしくはカルボキシル基または置換されていてもよいアミノ、低級アルキル、アルコキシもしくはカルバモイル基を；Ｒ^１２は、一般式

「式中、Ｒ^１４は、水素原子、保護されていてもよいカルボキシル基または置換されていてもよいシクロアルキル、シクロアルケニル、アルアルキル、アリールもしくは複素環式基を；Ｘ^４は、酸素原子、硫黄原子、カルボニル基または結合手を；Ｘ^５は、置換されていてもよいアルキレン基または結合手を；Ｘ^６は、置換されていてもよいアルキレン、アルケニレンもしくはアルキニレン基またはスルホニル基を；Ｘ^７は、置換されていてもよいアルキレン基または結合手を意味する。」で表される基を；Ｒ^１３は、水素原子、アミノ基の保護基または置換されていてもよいアルキルもしくはアリール基を意味する。」を意味する。」で表される含窒素複素環化合物またはその塩が、強い抗菌活性と高い安全性を有することを見出し、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 a halogen atom, a cyano group, an optionally protected carboxyl group or an optionally substituted alkyl, alkoxy or acyloxy group; R ² , R ³ , R ⁴ and R ⁵ are A hydrogen atom, a halogen atom, a cyano group, an optionally protected carboxyl group or an optionally substituted alkyl, alkenyl, alkoxy, cycloalkyl, amino or carbamoyl group; Z ¹ and Z ² are the same or different; Nitrogen atom or CR ⁷ wherein R ⁷ represents a hydrogen atom, a halogen atom, a cyano group, an optionally protected carboxyl group or an optionally substituted alkyl, alkenyl, alkoxy, amino or carbamoyl group. . it is "and, at least one of the nitrogen atoms of the ^{Z 1} and ^{Z 2; X 1} An oxygen atom, a sulfur atom, a sulfinyl group, ^{"wherein R 8a} denotes a hydrogen atom or an optionally substituted alkyl or aryl group." Sulfonyl group, ^{NR 8a} or ^CR 9 ^{R 10} "in the formula, R ⁹ and R ¹⁰ are the same or different and each represents a hydrogen atom or an optionally substituted alkyl, hydroxyl, amino or mercapto group. ”; X ² represents a carbonyl group, NR ^8b “ wherein R ^8b Represents a hydrogen atom or an optionally substituted alkyl or aryl group. ”Or a bond; X ³ represents a C _1-4 alkylene group or a bond; and R ⁶ represents a general formula.

"Wherein R ¹¹ represents one or more hydrogen atoms, halogen atoms, an optionally protected hydroxyl or carboxyl group or an optionally substituted amino, lower alkyl, alkoxy or carbamoyl group; R ^11a , R ^11b and R ^11c are the same or different and each represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl or carboxyl group or an optionally substituted amino, lower alkyl, alkoxy or carbamoyl group; R ¹² represents a general formula;

"Wherein R ¹⁴ represents a hydrogen atom, an optionally protected carboxyl group or an optionally substituted cycloalkyl, cycloalkenyl, aralkyl, aryl or heterocyclic group; X ⁴ represents an oxygen atom, A sulfur atom, a carbonyl group or a bond; X ⁵ represents an optionally substituted alkylene group or a bond; X ⁶ represents an optionally substituted alkylene, alkenylene or alkynylene group or a sulfonyl group; X ⁷ ., the mean an alkylene group or a bond may be substituted with group represented by "; R ¹³ is a hydrogen atom, means a protecting group or an optionally substituted alkyl or aryl group of an amino group To do. "Means. The nitrogen-containing heterocyclic compound represented by the above or a salt thereof has been found to have strong antibacterial activity and high safety, and has completed the present invention.

  The compound of the general formula [1] or a salt thereof is useful as an excellent antibacterial agent because it has strong antibacterial activity and high safety.

Hereinafter, the compound of 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, Linear or branched C _1-12 alkyl groups such as isobutyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl and octyl; lower alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, Linear or branched C _1-6 alkyl groups such as butyl, sec-butyl, isobutyl, tert-butyl, pentyl and isopentyl; an alkenyl group is, for example, vinyl, allyl, propenyl, isopropenyl, Butenyl, isobutenyl, 1,3-butadienyl, pentenyl 1,3-pentadienyl, hexenyl, straight-chain or branched C _2-12 alkenyl group such as heptenyl and octenyl; Alkynyl groups, for example, ethynyl, linear and 2-propynyl and 2-butynyl A branched or branched C _2-12 alkynyl group;

The cycloalkyl group, for example, cyclopropyl, cyclobutyl, C _3-8 cycloalkyl groups such as cyclopentyl and cyclohexyl; and cycloalkenyl groups, for example, cyclopropenyl, cyclobutenyl, C, such as cyclopentenyl and cyclohexenyl _{3- An 8-} cycloalkenyl group and a bicyclic cycloalkenyl group such as octahydronaphthyl; an alkylene group is, for example, a C _1-6 alkylene group such as methylene, ethylene, propylene, butylene and hexylene; an alkenylene group is For example, a C _2-12 alkenylene group such as vinylene, propenylene, butenylene, hexenylene, heptenylene and octenylene; an alkynylene group is, for example, ethynylene, propynylene, butynylene, hexylene A C _2-12 alkynylene group such as nylene, heptynylene and octynylene; an aryl group such as phenyl, naphthyl, 3,4-dihydronaphthyl, fluorenyl and phenanthrenyl; an aralkyl group such as benzyl , diphenylmethyl, trityl, Al _{C 1-6} alkyl groups such as phenethyl and naphthylmethyl; alkoxy groups, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy, tert- butoxy, pentyl a linear or branched C _1-6 alkyl group such as oxy, and isopentyloxy; the aralkyl group, for example, benzyloxy, diphenylmethyloxy, trityloxy, phenethyloxy Oyo Al C _1-6 alkyl group such as naphthyl methyloxy; Alkoxyalkyl groups, for example, a C _1-6 alkyloxy C _1-6 alkyl group such as methoxymethyl and 1-ethoxyethyl; an aralkyloxyalkyl Groups include, for example, ar C _1-6 alkyloxy C _1-6 alkyl groups such as benzyloxymethyl and phenethyloxymethyl;

Examples of the acyl group include linear or branched C _2-12 alkanoyl groups such as formyl group, acetyl, propionyl and isovaleryl, al C _1-6 alkylcarbonyl groups such as benzylcarbonyl, benzoyl and naphthoyl. Cyclic hydrocarbon carbonyl groups, nicotinoyl, thenoyl, heterocyclic carbonyl groups such as pyrrolidinocarbonyl and furoyl, succinyl group, glutaryl group, maleoyl group, phthaloyl group and amino acids (amino acids include, for example, glycine, alanine, valine) , Leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine, tyrosine, A linear or branched α-aminoalkanoyl group which may be protected at the N-terminus derived from ptophan, proline, hydroxyproline, etc .; an alkyloxycarbonyl group is, for example, Linear or branched C _1-12 alkyl such as methoxycarbonyl, ethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 2-ethylhexyloxycarbonyl, tert-butoxycarbonyl and tert-pentyloxycarbonyl the oxycarbonyl group; the aralkyl oxycarbonyl group, for example, Al C _1-6 alkyloxycarbonyl group such as benzyloxycarbonyl and phenethyloxycarbonyl group; and aryloxycarbonyl group, if , Groups such as phenyloxycarbonyl;

Acyloxy groups include, for example, linear or branched C _2-6 alkanoyloxy groups such as acetyloxy and propionyloxy, and aroyloxy groups such as benzoyloxy; acylalkyl groups include, for example, acetylmethyl, Groups such as benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methoxybenzoylmethyl and 1-benzoylethyl; acyloxyalkyl groups include, for example, acetoxymethyl, propionyloxymethyl and pivaloyloxymethyl groups such as; the alkylthioalkyl group, for example, a C _1-6 alkylthio C _1-6 alkyl group such as methylthiomethyl, ethylthiomethyl and propyl methylthiomethyl; and arylthio groups, e.g., phenyl Groups such as o; The alkanesulfonyl group, for example, methanesulfonyl, trichloromethane sulfonyl, trifluoromethanesulfonyl, ethanesulfonyl and propanesulfonyl optionally substituted C _1-6 alkanesulfonyl group with a halogen atom such as; An arylsulfonyl group is a group such as benzenesulfonyl, toluenesulfonyl and naphthalenesulfonyl; an alkanesulfonyloxy group is a halogen such as methanesulfonyloxy, trichloromethanesulfonyloxy, trifluoromethanesulfonyloxy and ethanesulfonyloxy. An optionally substituted C _1-6 alkanesulfonyloxy group; an arylsulfonyloxy group means, for example, benzenesulfonyloxy and A group such as ruenesulfonyloxy; an arylthioalkyl group such as phenylsulfanylmethyl and 2- (p-nitrophenylsulfanyl) ethyl; an arylsulfonylalkyl group such as p-toluenesulfonylethyl An arylsulfinyl group, for example, a group such as benzenesulfinyl; an alkylamino group, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, diisopropylamino and dibutyl Mono- or di-C _1-6 alkylamino groups such as amino;

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- A group such as dimethylaminomethylene and N, N-diethylaminomethylene; a dialalkylphosphoryl group such as dibenzylphosphoryl; a diarylphosphoryl group such as diphenylphosphoryl; an oxygen-containing heterocycle Examples of the formula group include groups such as 2-tetrahydropyranyl and 2-tetrahydrofuranyl; and examples of the oxygen-containing heterocyclic alkyl group include 5-methyl-2-oxo-2H-1,3-dioxole- Groups such as 4-ylmethyl; sulfur-containing heterocyclic groups Is a group such as tetrahydrothiopyranyl; a heterocyclic oxycarbonyl group is a group such as 2-furfuryloxycarbonyl, 8-quinolyloxycarbonyl; and a nitrogen-containing heterocyclic alkyl group Is a group such as phthalimidomethyl and succinimidomethyl; a nitrogen-containing heterocyclic alkylidene group is a group such as 3-hydroxy-4-pyridylmethylene; and a substituted silyl group is, for example, trimethylsilyl, triethyl A group such as silyl and tributylsilyl; an alkylsilylalkyl group is a group such as 2- (trimethylsilyl) ethyl;

Monocyclic heterocyclic groups include, for example, furyl, furfuryl, thienyl, 2-tenyl, pyrrolyl, 1-pyrrolyl, 2-pyrrolyl, imidazolyl, pyrazolyl, 3-pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, Groups such as thiadiazolyl, furazanyl, pyrrolidinyl, imidazolidinyl, pyridyl, pyrimidinyl, pyridazinyl, 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, 2-morpholinyl and 2-thiomorpholinyl;

Bicyclic heterocyclic groups include, for example, benzofuranyl, isobenzofuranyl, benzothienyl, benzo [b] thiophen-2-yl, indolyl, indol-2-yl, isoindolyl, indolinyl, benzimidazolyl, 1H- 1,2,3-benzotriazol-5-yl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, 1,2,3-benzooxadiazol-5-yl, 1,2,3-benzothiadiazole- 5-yl, 1H-indazolyl, purinyl, chromenyl, quinolyl, quinolin-2-yl, quinolin-3-yl, quinolin-6-yl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chroman-6-yl, Chromanil, isochromanyl, quinuclidinyl, 1, -Benzodioxanyl, 1,4-benzodioxanyl, benzomorpholinyl, benzomorpholonyl, quinoxalin-6-yl, 2,3-dihydro [1,4] dioxino [2,3-c] pyridine -7-yl, 3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl, 3,4-dihydro-2H-pyrido [3,2-b] [1 , 4] thiazin-6-yl, 3,4-dihydro-2H-benzothiazin-6-yl, 2,3-dihydrobenzo [b] [1,4] dioxin-6-yl, 3,4-dihydro-2H -Benzo [1,4] oxazin-7-yl, 3,4-dihydro-2H-benzo [b] [1,5] dioxepin-7-yl, 2,3-dihydrobenzo [b] furan-5-yl 3,4-dihydroisoquinoline-2 (1H) -i 1,2-dihydroquinolin-3-yl, 4H-benzo [1,4] oxazin-6-yl, 4H-benzo [1,4] thiazin-6-yl, 4H-pyrido [3,2-b] [1,4] thiazin-6-yl, imidazo [1,2-a] pyridin-2-yl, thieno [3,2-b] thiophen-2-yl, thieno [2,3-b] thiophen-2 Groups such as -yl, 2H-thiochromen-3-yl and benzo [1,3] dioxol-5-yl;

The heterocyclic group includes, for example, a monocyclic heterocyclic group; a bicyclic heterocyclic group; and thianthenyl, xanthenyl, phenoxathinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl , Means a tricyclic heterocyclic group such as phenanthrolinyl, phenazinyl, phenothiazinyl and phenoxazinyl.

  The amino-protecting group includes all groups that can be used as ordinary amino-protecting groups. W. Green 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.

  The hydroxyl protecting group includes all groups which can be used as usual hydroxyl protecting groups. W. Green 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 ordinary carboxyl-protecting groups. W. Green 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.

Optionally substituted alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, acyl, acyloxy, alkylene, alkenylene, alkynylene, aryl, aralkyl, heterocyclic, monocyclic heterocyclic and bicyclic Examples of the substituent of the substituent of the cyclic heterocyclic group include a halogen atom; a cyano group; a nitro group; an optionally protected hydroxyl group; an optionally protected carboxyl group; and an optionally protected amino group. An alkylamino group; a carbamoyl group; an alkanesulfonyl group; an alkanesulfonyl group substituted with a halogen atom; an arylsulfonyl group; an alkyl group; an alkenyl group; an alkynyl group; an alkoxy group; An alkyl group; an acyl group; Reel group; aralkyl group; mercapto group; alkylthio group; heterocyclic group; oxo group; and halogen atom, optionally protected hydroxyl group, optionally protected carboxyl group, lower alkyl group, aryl group and One or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, acyl, aryl, heterocyclic, amino and carbamoyl groups substituted with one or more groups selected from arylsulfinyl groups.
As specific substituents, fluorine atom, chlorine atom, bromine atom, iodine atom, cyano group, nitro group, hydroxyl group, carboxyl group, amino group, methylamino group, ethylamino group, dimethylamino group, diethylamino group, Carbamoyl group, methanesulfonyl group, chloromethanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, benzenesulfonyl group, toluenesulfonyl group, methyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, chloromethyl group, dichloromethyl Group, trichloromethyl group, hydroxymethyl group, carboxymethyl group, ethyl group, fluoroethyl group, difluoroethyl group, trifluoroethyl group, chloroethyl group, dichloroethyl group, trichloroethyl group, hydroxyethyl group, carboxy group Group, propyl group, fluoropropyl group, difluoropropyl group, trifluoropropyl group, chloropropyl group, dichloropropyl group, trichloropropyl group, hydroxypropyl group, carboxypropyl group, vinyl group, allyl group, ethynyl group, phenylethynyl Group, propynyl group, methoxy group, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, chloromethoxy group, dichloromethoxy group, trichloromethoxy group, ethoxy group, chloroethoxy group, dichloroethoxy group, trichloroethoxy group, benzyloxy Group, carboxymethoxy group, methoxycarbonyl group, ethoxycarbonyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, formyl group, acetyl group, chloroacetyl group, dialkyl Loacetyl group, propionyl group, benzoyl group, fluorobenzoyl group, difluorobenzoyl group, chlorobenzoyl group, dichlorobenzoyl group, phenyl group, fluorophenyl group, difluorophenyl group, trifluorophenyl group, chlorophenyl group, dichlorophenyl group, trichlorophenyl group , Chlorofluorophenyl group, hydroxyphenyl group, (fluoro) hydroxyphenyl group, (chloro) hydroxyphenyl group, carboxyphenyl group, (carboxy) fluorophenyl group, (carboxy) chlorophenyl group, benzyl group, phenethyl group, mercapto group, Methylthio, ethylthio, furyl, thienyl, pyrrolyl, azetidinyl, pyrrolidinyl, piperidyl, hydroxypyrrolidinyl, carboxypyrrolidinyl Group, hydroxypiperidyl group, carboxypiperidyl group, piperazinyl group, imidazolyl group, pyrazolyl group, pyridyl group, tetrahydropyridyl group, pyrimidinyl group, morpholinyl group, thiomorpholinyl group, quinolyl group, quinolidinyl group, tetrahydroquinolinyl group, tetrahydroiso Examples include quinolinyl group, quinuclidinyl group, thiazolyl group, tetrazolyl group, thiadiazolyl group, pyrrolinyl group, imidazolinyl group, imidazolidinyl group, pyrazolinyl group, pyrazolidinyl group, purinyl group, indazolyl group, benzenesulfinylmethyl group and oxo group.

The optionally substituted carbamoyl and amino group substituents include: an optionally protected hydroxyl group; an optionally protected amino group; an alkylamino group; an alkanesulfonyl group; an alkane substituted with a halogen atom. Sulfonyl group; arylsulfonyl group; alkyl group; alkenyl group; alkynyl group; alkoxy group; alkoxycarbonyl group; acyl group; acyl group substituted with a halogen atom; aryl group; And an aryl group substituted with one or more groups selected from an optionally protected carboxyl group; an aralkyl group; an aralkyl group substituted with a halogen atom; and one or more selected from a heterocyclic group The group of is mentioned.
Specific examples of the substituent include hydroxyl group, amino group, methylamino group, ethylamino group, dimethylamino group, diethylamino group, methanesulfonyl group, chloromethanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, benzenesulfonyl group, Toluenesulfonyl group, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, allyl group, propynyl group, methoxy group, ethoxy group, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, tert-butoxycarbonyl Group, formyl group, acetyl group, propionyl group, butyryl group, benzoyl group, fluorobenzoyl group, difluorobenzoyl group, chlorobenzoyl group, dichlorobenzoyl group, phenyl group, fluorophenyl group, difluoropheny group Group, trifluorophenyl group, chlorophenyl group, dichlorophenyl group, trichlorophenyl group, chlorofluorophenyl group, hydroxyphenyl group, (fluoro) hydroxyphenyl group, (chloro) hydroxyphenyl group, carboxyphenyl group, (carboxy) fluorophenyl group , (Carboxy) chlorophenyl group, benzyl group, fluorobenzyl group, difluorobenzyl group, chlorobenzyl group, dichlorobenzyl group, chlorofluorobenzyl group, phenethyl group, furyl group, thienyl group, pyrrolyl group, azetidinyl group, pyrrolidinyl group, piperidyl group Group, piperazinyl group, imidazolyl group, pyrazolyl group, pyridyl group, tetrahydropyridyl group, pyrimidinyl group, morpholinyl group, thiomorpholinyl group, quinolyl group, quinolidinyl group, Tiger tetrahydroquinolinyl group, tetrahydroisoquinolinyl group, quinuclidinyl group, a thiazolyl group, tetrazolyl group, thiadiazolyl group, pyrrolinyl group, imidazolinyl group, imidazolidinyl group, pyrazolinyl group, pyrazolidinyl group, include purinyl and indazolyl groups.

The substituents of the optionally substituted hydroxyl and mercapto groups include alkyl groups; alkenyl groups; alkynyl groups; cycloalkyl groups; acyl groups; aryl groups; aralkyl groups; and halogen atoms, optionally protected hydroxyls. And one or more groups selected from alkyl, alkenyl, alkynyl and aryl groups substituted by one or more groups selected from a group and an optionally protected carboxyl group.
Specific examples of the substituent include methyl group, carboxymethyl group, ethyl group, fluoroethyl group, difluoroethyl group, trifluoroethyl group, chloroethyl group, dichloroethyl group, trichloroethyl group, hydroxyethyl group, carboxyethyl group, Propyl group, fluoropropyl group, difluoropropyl group, trifluoropropyl group, chloropropyl group, dichloropropyl group, trichloropropyl group, hydroxypropyl group, carboxypropyl group, allyl group, propynyl group, cyclopropyl group, cyclobutyl group, cyclopentyl Group, cyclohexyl group, acetyl group, propionyl group, benzoyl group, phenyl group, fluorophenyl group, difluorophenyl group, trifluorophenyl group, chlorophenyl group, dichlorophenyl group, trichlorophenyl Nyl group, chlorofluorophenyl group, hydroxyphenyl group, (fluoro) hydroxyphenyl group, (chloro) hydroxyphenyl group, carboxyphenyl group, (carboxy) fluorophenyl group, (carboxy) chlorophenyl group, benzyl group and phenethyl group It is done.

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, hydrogen bromide and sulfuric acid; salts with organic carboxylic acids such as tartaric acid, formic acid, acetic acid, citric acid, trichloroacetic acid and trifluoroacetic acid; and Examples thereof include 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.

Among the compounds of the present invention, preferred compounds include the following compounds.
R ¹ is preferably a halogen atom, a cyano group or an optionally substituted alkyl, alkoxy or acyloxy group, more preferably a cyano group or an optionally substituted alkyl or alkoxy group. The compound which may be an alkoxy group is further preferable, and the compound which is an alkoxy group is further more preferable.

「式中、Ｒ^１１、Ｒ^１２およびＲ^１３は、前記と同様な意味を有する。」の場合、Ｒ^３またはＲ^４の少なくとも一方が、ハロゲン原子、保護されていてもよいカルボキシル基または置換されていてもよいカルバモイル、アルキル、アルケニルもしくはシクロアルキル基である化合物が好ましく、Ｒ^３が、水素原子、Ｒ^４が、保護されていてもよいカルボキシル基、保護されていてもよいカルボキシル基で置換されているアルキル、アルケニルもしくはシクロアルキル基または置換されていてもよいカルバモイル基で置換されているアルキルもしくはアルケニル基である化合物がより好ましく、Ｒ^３が、水素原子、Ｒ^４が、保護されていてもよいカルボキシル基で置換されているアルケニル基である化合物がさらに好ましく、Ｒ^２、Ｒ^３およびＲ^５が、水素原子、Ｒ^４が、保護されていてもよいカルボキシル基で置換されているアルケニル基である化合物がよりさらに好ましい。R ² , R ³ , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, an optionally protected carboxyl group or an optionally substituted alkyl, alkenyl, alkoxy, amino or carbamoyl. A compound which is a group is preferred, and a compound which is the same or different and is a hydrogen atom, a halogen atom, an optionally protected carboxyl group or an optionally substituted alkyl or alkenyl group, more preferably a same or different hydrogen atom, More preferred is a compound which is an optionally protected carboxyl group or an optionally substituted alkyl or alkenyl group, wherein one of R ² , R ³ , R ⁴ and R ⁵ is optionally substituted alkyl or alkenyl. Even more preferred are compounds in which the other group is a hydrogen atom. Properly, one of R ^{2, R 3,} R ⁴ and R ^5, alkyl or alkenyl group substituted with a carboxyl group, the other is a compound which is a hydrogen atom is particularly preferred.
However, Z ¹ is a nitrogen atom, Z ² is CR ⁷ "wherein R ⁷ has the same meaning as described above", R ⁶ is

In the case of “wherein R ¹¹ , R ¹² and R ¹³ have the same meaning as described above,” at least one of R ^{3 and} R ⁴ is a halogen atom, an optionally protected carboxyl group or a substituted group. Preferred is a compound which is an optionally substituted carbamoyl, alkyl, alkenyl or cycloalkyl group, wherein R ³ is a hydrogen atom, R ⁴ is substituted with an optionally protected carboxyl group or an optionally protected carboxyl group. More preferably, the compound is an alkyl, alkenyl or cycloalkyl group, or an alkyl or alkenyl group substituted with an optionally substituted carbamoyl group, wherein R ³ is a hydrogen atom, and R ⁴ is protected. More preferred are compounds which are alkenyl groups substituted by good carboxyl groups, R ² , R More preferred is a compound in which ³ and R ⁵ are a hydrogen atom and R ⁴ is an alkenyl group substituted with an optionally protected carboxyl group.

A compound in which ^one of Z ¹ and Z ² is a nitrogen atom and the other is CR ⁷ "wherein R ⁷ has the same meaning as described above" is preferable, and Z ¹ is a nitrogen atom, Z ² Is more preferably a compound of CR ⁷ “wherein R ⁷ has the same meaning as described above.”, More preferably a compound in which Z ¹ is a nitrogen atom and Z ² is CH.

X ¹ represents an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, NR ^8a wherein R ^8a has the same meaning as described above, or CR ^9a R ^{10a where} R ^9a and R ^10a are A hydrogen atom or an optionally substituted hydroxyl, amino or mercapto group ”is preferred, and NR ^8a wherein R ^8a has the same meaning as described above. Or the compound which is CR ^9a R ^10a “wherein R ^9a and R ^10a have the same meaning as described above” is more preferable, and the compound which is CH ₂ , NH or CHOH is more preferable.
A compound in which X ² is a carbonyl group or a bond is preferred.
A compound in which X ³ is CH ₂ or a bond is preferred.
Furthermore, in the combination of X ¹ , X ² and X ³ , a compound in which X ¹ -X ² -X ³ is NHCO, CH ₂ CH ₂ or CHOHCH ₂ is preferable.

「式中、Ｒ^１２ａは、一般式

「式中、Ｒ^１４ａは、置換されていてもよいアルアルキル、単環の複素環式または二環式の複素環式基を；Ｘ^６ａは、アルキレン基を；Ｘ^４およびＸ^５は、前記と同様な意味を有する。」で表される基を；Ｒ^１１、Ｒ^１１ａ、Ｒ^１１ｂ、Ｒ^１１ｃおよびＲ^１３は、前記と同様な意味を有する。」である化合物が好ましく、

「式中、Ｒ^１２ｂは、一般式

「式中、Ｒ^１４ｂは、置換されていてもよい単環の複素環式または二環式の複素環式基を；Ｘ^４ａは、酸素原子、硫黄原子または結合手を；ｍは、１−４の整数を意味する。」で表される基を；Ｒ^１３ａは、水素原子または置換されていてもよいアルキルもしくはアリール基を；Ｒ^１１、Ｒ^１１ａ、Ｒ^１１ｂおよびＲ^１１ｃは、前記と同様な意味を有する。」である化合物がより好ましく、

「式中、Ｒ^１２ｂは、前記と同様な意味を有する。」である化合物がさらに好ましく、

「式中、Ｒ^１２ｂは、前記と同様な意味を有する。」である化合物がよりさらに好ましく、

「式中、Ｒ^１２ｂは、前記と同様な意味を有する。」である化合物が特に好ましい。
ただし、Ｚ^２が、ＣＲ^７「式中、Ｒ^７は、前記と同様な意味を有する。」の場合、Ｒ^６が、

「式中、Ｒ^１１、Ｒ^１１ａ、Ｒ^１１ｂ、Ｒ^１１ｃ、Ｒ^１２ａおよびＲ^１３は、前記と同様な意味を有する。」である化合物が好ましく、

「式中、Ｒ^１１、Ｒ^１１ａ、Ｒ^１１ｂ、Ｒ^１１ｃ、Ｒ^１２ｂおよびＲ^１３ａは、前記と同様な意味を有する。」である化合物がより好ましく、

「式中、Ｒ^１２ｂは、前記と同様な意味を有する。」である化合物がさらに好ましく、

「式中、Ｒ^１２ｂは、前記と同様な意味を有する。」である化合物がよりさらに好ましい。R ⁶ is

Wherein R ^12a is a general formula

“Wherein R ^14a represents an optionally substituted aralkyl, monocyclic heterocyclic or bicyclic heterocyclic group; X ^6a represents an alkylene group; X ⁴ and X ⁵ represent the above-mentioned And R ¹¹ , R ^11a , R ^11b , R ^11c and R ¹³ have the same meaning as described above. Is preferred,

Wherein R ^12b is a general formula

“Wherein R ^14b represents a monocyclic heterocyclic or bicyclic heterocyclic group which may be substituted; X ^4a represents an oxygen atom, a sulfur atom or a bond; R ^13a represents a hydrogen atom or an optionally substituted alkyl or aryl group; R ¹¹ , R ^11a , R ^11b and R ^11c are as defined above. It has a meaning. Is more preferred,

More preferred is a compound wherein “wherein R ^12b has the same meaning as described above.”

More preferred is a compound wherein “wherein R ^12b has the same meaning as described above.”

A compound in which “wherein R ^12b has the same meaning as described above” is particularly preferable.
However, when Z ² is CR ⁷ "wherein R ⁷ has the same meaning as described above", R ⁶ is

A compound in which R ¹¹ , R ^11a , R ^11b , R ^11c , R ^12a and R ¹³ have the same meaning as described above is preferable,

More preferred are compounds wherein “wherein R ¹¹ , R ^11a , R ^11b , R ^11c , R ^12b and R ^13a have the same meaning as described above.”

More preferred is a compound wherein “wherein R ^12b has the same meaning as described above.”

A compound in which “wherein R ^12b has the same meaning as described above” is even more preferable.

「式中、Ｒ^１１、Ｒ^１２およびＲ^１３は、前記と同様な意味を有する。」である化合物が好ましく、Ｒ^３が、水素原子；Ｒ^４が、保護されていてもよいカルボキシル基で置換されているアルケニル基の場合、Ｒ^６が、

「式中、Ｒ^１２ｃは、一般式

「式中、Ｒ^１４ｃは、置換されていてもよいアリール、単環の複素環式または二環式の複素環式基を；Ｘ^６ｂは、置換されていてもよいアルキレン、アルケニレンまたはアルキニレン基を；Ｘ^４ａは、前記と同様な意味を有する。」で表される基を；Ｒ^１１およびＲ^１３ａは、前記と同様な意味を有する。」である化合物がより好ましい。さらに、Ｒ^１が、アルコキシ基；Ｒ^２およびＲ^５が、水素原子の場合、Ｒ^６が、

「式中、Ｘ^６ｃは、置換されていてもよいアルキレン基を；Ｒ^１１およびＲ^１４ｃは、前記と同様な意味を有する。」である化合物が好ましい。Note that at least one of R ^{3 and} R ⁴ is a halogen atom, an optionally protected carboxyl group, or an optionally substituted carbamoyl, alkyl, alkenyl, or cycloalkyl group; Z ¹ is a nitrogen atom; Z ² is , CR ⁷ "wherein R ⁷ has the same meaning as described above", R ⁶ is

A compound in which “wherein R ¹¹ , R ¹² and R ¹³ have the same meaning as described above” is preferable, R ³ is a hydrogen atom; R ⁴ is substituted with an optionally protected carboxyl group If an alkenyl group is, R ⁶ is,

Wherein R ^12c is a general formula

“Wherein R ^14c represents an optionally substituted aryl, monocyclic heterocyclic or bicyclic heterocyclic group; X ^6b represents an optionally substituted alkylene, alkenylene or alkynylene group. And X ^4a has the same meaning as described above.]; R ¹¹ and R ^13a have the same meaning as described above; Is more preferable. Furthermore, when R ¹ is an alkoxy group; and R ² and R ⁵ are hydrogen atoms, R ⁶ is

A compound in which “in the formula, X ^6c represents an ^optionally substituted alkylene group; R ¹¹ and R ^14c have the same meaning as described above.” Is preferable.

「式中、Ｒ^１４ｂおよびｍは、前記と同様な意味を有する。」である化合物が好ましく、−（ＣＨ_２）_ｍ−Ｒ^１４ｂ「式中、Ｒ^１４ｂおよびｍは、前記と同様の意味を有する。」である化合物がより好ましい。
上記、Ｒ^１２ａ、Ｒ^１２ｂおよびＲ^１２ｃにおいて、ｍが、１、２または３である化合物が好ましく、１または２である化合物がより好ましい。
上記、Ｒ^１２ａ、Ｒ^１２ｂおよびＲ^１２ｃにおいて、Ｒ^１４ｂが、置換されていてもよいアリール、単環の複素環式または二環式の複素環式基である化合物が好ましく、置換されていてもよい２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−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、３−フルオロ−４−メチルフェニル、４−（トリフルオロメチル）フェニル、ベンゾフラン−５−イル、１，２，３−ベンゾチアジアゾール−５−イルまたは５−（チオフェン−２−イル）−イソオキサゾール−３−イルである化合物がより好ましく、２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルである化合物がさらに好ましい。In the above R ⁶ , R ^12a , R ^12b and R ^12c are

A compound in which “wherein R ^14b and m have the same meaning as described above” is preferable, and — (CH ₂ ) _m —R ^14b “wherein R ^14b and m have the same meaning as described above. More preferably, the compound is
In the above R ^12a , R ^12b and R ^12c , a compound in which m is 1, 2 or 3 is preferable, and a compound in which 1 or 2 is more preferable.
In the above R ^12a , R ^12b, and R ^12c , a compound in which R ^14b is an optionally substituted aryl, monocyclic heterocyclic or bicyclic heterocyclic group is preferable. 2,3-dihydrobenzo [b] [1,4] dioxin-6-yl, 2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-yl, 3-fluoro-4 -Methylphenyl, 4- (trifluoromethyl) phenyl, benzofuran-5-yl, 1,2,3-benzothiadiazol-5-yl or 5- (thiophen-2-yl) -isoxazol-3-yl More preferred are compounds, and more preferred is a compound that is 2,3-dihydrobenzo [b] [1,4] dioxin-6-yl.

  Among the compounds of the present invention, representative compounds include, for example, compounds described in Tables 1, 2 and 3 below.

Next, the manufacturing method of this invention compound is demonstrated.
The compound 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^２ａ、Ｒ^３ａ、Ｒ^４ａおよびＲ^５ａは、同一または異なって水素原子、ハロゲン原子、シアノ基、保護されているカルボキシル基、置換されていてもよい保護されているアミノ基または置換されていてもよいアルキル、アルケニル、アルコキシ、シクロアルキルもしくはカルバモイル基を；Ｘ^１ａは、酸素原子、硫黄原子またはＮＲ^８ａ「式中、Ｒ^８ａは、前記と同様の意味を有する。」を；Ｚ^１ａおよびＺ^２ａは、窒素原子またはＣＲ^７ａ「式中、Ｒ^７ａは、水素原子、ハロゲン原子、シアノ基、保護されているカルボキシル基、置換されていてもよい保護されているアミノ基または置換されていてもよいアルキル、アルケニル、アルコキシもしくはカルバモイル基を意味する。」であり、かつ、Ｚ^１ａおよびＺ^２ａの少なくとも一方が窒素原子を；Ｒ¹、Ｒ^６およびＸ^３は、前記と同様の意味を有する。」[Production Method 1]

“Wherein R ^2a , R ^3a , R ^4a and R ^5a are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a protected carboxyl group, an optionally substituted protected amino group or An optionally substituted alkyl, alkenyl, alkoxy, cycloalkyl or carbamoyl group; X ^1a represents an oxygen atom, a sulfur atom or NR ^8a wherein R ^8a has the same meaning as described above; Z ^1a and Z ^2a are a nitrogen atom or CR ^7a wherein R ^7a is a hydrogen atom, a halogen atom, a cyano group, a protected carboxyl group, an optionally substituted protected amino group or a substituent which may be alkyl, alkenyl means an alkoxy or carbamoyl group. a ", and, Z ^1a and Z ² At least one of the nitrogen atoms; R ^1, R ⁶ and X ³ are each as defined above. "

The compound of the general formula [1a] can be produced by reacting the compound of the general formula [2] with a reactive derivative of the compound of the general formula [3] in the presence or absence of a base.
This reaction can be carried out by the method described in WO03 / 010138, WO03 / 087098 and Izumiya et al., Peptide synthesis basics and experiments, pp. 89-142, 1985, Maruzen, etc. or a method analogous thereto. Good.
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; ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether; dimethyl sulfoxide Sulfoxides such as; ketones such as acetone and 2-butanone; esters such as ethyl acetate; and the like.
Examples of the base optionally 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. It is done.
Examples of reactive derivatives used in this reaction include acid halides such as acid chloride and acid bromide; active esters such as p-nitrophenyl ester, N-hydroxysuccinimide ester and N-hydroxyphthalimide ester; ethyl chlorocarbonate And mixed acid anhydrides with monoalkyl carbonates such as isobutyl chlorocarbonate and mixed acid anhydrides with organic acids such as pivalic acid. These reactive derivatives may be used without isolation.
A reactive reagent may be generated in the system using a coupling reagent. Examples of the coupling reagent include carbodiimides such as N, N′-dicyclohexylcarbodiimide and N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide; carbonyls such as carbonyldiimidazole; acids such as diphenylphosphoryl azide Azides; acid cyanides such as diethyl phosphoryl cyanide; 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline; O-benzotriazol-1-yl-1,1,3,3-tetramethyluronium = Hexafluorophosphate and O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium = hexafluorophosphate.
In this reaction, the use amount of the base, the reactive derivative of the compound of the general formula [3], and the coupling reagent used in the reaction is 1 to 50 times mol, preferably 1 with respect to the compound of the general formula [2]. It may be ˜5 times mole.
This reaction may be carried out at −30 to 150 ° C., preferably at 0 to 100 ° C. for 30 minutes to 48 hours.

「式中、Ｒ^６ａは、

「式中、Ｙ^ａは、アミノ基の保護基を；Ｒ^１１、Ｒ^１１ａ、Ｒ^１１ｂ、Ｒ^１１ｃ、Ｒ^１２、Ｒ^１３は、前記と同様の意味を有する。」を；Ｒ^１、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｘ^１ａ、Ｚ^１ａおよびＺ^２ａは、前記と同様の意味を有する。」[Production Method 2]

“Wherein R ^6a is

“Wherein Y ^a represents an amino-protecting group; R ¹¹ , R ^11a , R ^11b , R ^11c , R ¹² , and R ¹³ have the same meanings as described above.”; R ¹ , R ^2a , R ^3a , R ^4a , R ^5a , X ^1a , Z ^1a and Z ^2a have the same meaning as described above. "

The compound of the general formula [1b] can be produced by reacting the compound of the general formula [2] with a carbonyl compound in the presence or absence of a base and then reacting with the compound of the general formula [4]. it can. The compound of the general formula [1b] is produced by reacting the compound of the general formula [4] with a carbonyl compound in the presence or absence of a base and then reacting with the compound of the general formula [2]. be able to. This reaction may be carried out by the method described in WO02 / 50061, WO02 / 56882, or the like or a method analogous thereto.
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; ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether; dimethyl sulfoxide Sulfoxides such as; ketones such as acetone and 2-butanone; esters such as ethyl acetate; and the like.
Examples of the carbonyl compound used in this reaction include 1,1′-carbonyldiimidazole, carbonyl chloride [phosgene], bis (trichloromethyl) carbonate [triphosgene], and the like.
Examples of the base optionally 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. It is done.
In this reaction, the amount of the base, compound of general formula [4] and carbonyl compound used as desired is 1 to 50 times mol, preferably 1 to 5 times mol of the compound of general formula [2]. I just need it.
This reaction may be carried out at −30 to 150 ° C., preferably at 0 to 100 ° C. for 30 minutes to 48 hours.

「式中、Ｑ^１は、

「式中、Ｒ^１１、Ｒ^１１ａ、Ｒ^１１ｂ、Ｒ^１１ｃ、Ｒ^１３は、前記と同様の意味を有する。」を；Ｌ^１は、脱離基を；Ｒ^１、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｒ^１４、Ｘ^１、Ｘ^２、Ｘ^３、Ｘ^４、Ｚ^１ａ、Ｚ^２ａおよびｍは、前記と同様の意味を有する。」[Production Method 3]

“Where Q ¹ is

“Wherein R ¹¹ , R ^11a , R ^11b , R ^11c and R ¹³ have the same meanings as described above”; L ¹ represents a leaving group; R ¹ , R ^2a , R ^3a , R ^{4a, R 5a, R 14,} X 1, X 2, X 3, X 4, Z 1a, Z 2a and m have the same meanings as defined above. "

(3-1)
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 is described in WO 02/50061, WO 02/56882 and Jerry March, Advanced Organic Chemistry 4th edition, pages 898-900, 1992, John Willy. -The method described in And Sons (John Wiley & Sons, INC.) Etc. may be performed 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. 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 and water, and the like. These may be used as a mixture.
Examples of the reducing agent used in this reaction include lithium complex hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, 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 general formula [6] and the reducing agent used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of general formula [5].
This reaction may be carried out at −30 to 150 ° C., preferably at 0 to 100 ° C. for 30 minutes to 120 hours.

(3-2)
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 [7] in the presence or absence of a base.
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 and water, and the like. These may be used as a mixture.
Examples of the base optionally 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. It is done.
In this reaction, the use amount of the base and the compound of the general formula [7] used as desired may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [5]. .
This reaction may be carried out at −30 to 150 ° C., preferably at 0 to 100 ° C. for 30 minutes to 48 hours.

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

“Wherein R ¹ , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , Z ^1a and Z ^2a have the same meaning as described above.

The compound of the general formula [1d] can be produced by reacting the compound of the general formula [8] with the compound of the general formula [4] in the presence of a reducing agent.
This reaction may be performed according to the production method 3-1.

「式中、Ｒ^１４ｄは、置換されていてもよいシクロアルキル、シクロアルケニル、アルアルキル、アリールまたは複素環式基を；Ｒ^１５は、Ｃ_１−４低級アルキル基を；Ｒ^１、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｑ^１、Ｘ^１、Ｘ^２、Ｘ^３、Ｚ^１ａおよびＺ^２ａは、前記と同様の意味を有する。」[Production Method 5]

“Wherein R ^14d represents an optionally substituted cycloalkyl, cycloalkenyl, aralkyl, aryl or heterocyclic group; R ¹⁵ represents a C _1-4 lower alkyl group; R ¹ , R ^2a , R ^3a , R ^4a , R ^5a , Q ¹ , X ¹ , X ² , X ³ , Z ^1a and Z ^2a have the same meaning as described above.

The compound of the general formula [1e] can be produced by reacting the compound of the general formula [5] with the compound of the general formula [9]. This reaction is carried out by the method described in Bioorganic and Medicinal Chemistry Letter (Bioorganic. Med. Chem. Lett.), Vol. 13, pp. 241-245, 2003, or the like. Just do it.
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 and water Mixed and may also be used.
In this reaction, the amount of the compound of general formula [9] used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of general formula [5].
This reaction may be carried out at −30 to 150 ° C., preferably 0 to 150 ° C. for 30 minutes to 48 hours.

「式中、Ｒ^１、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｒ^１４ｄ、Ｑ^１、Ｘ^１、Ｘ^２、Ｘ^３、Ｚ^１ａおよびＺ^２ａは、前記と同様の意味を有する。」[Production Method 6]

“Wherein R ¹ , R ^2a , R ^3a , R ^4a , R ^5a , R ^14d , Q ¹ , X ¹ , X ² , X ³ , Z ^1a and Z ^2a have the same meaning as described above.

The compound of the general formula [1f] can be produced by reacting the compound of the general formula [5] with the compound of the general formula [10] in the presence or absence of a solvent. This reaction may be carried out by the method described in the Chemical Society of Japan, New Experimental Science Course 14, Synthesis and Reaction of Organic Compounds III, pp. 162-1644, 1978, Maruzen et al.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene. An ether such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether; a sulfoxide such as dimethyl sulfoxide; a ketone such as acetone and 2-butanone; and an ester such as ethyl acetate; These may be used as a mixture.
In this reaction, the amount of the compound of general formula [10] used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of general formula [5].
This reaction may be carried out at −30 to 200 ° C., preferably at 0 to 100 ° C., for 30 minutes to 48 hours.

「式中、Ｔ^１は、酸素原子、硫黄原子またはＮＲ^８ａ「式中、Ｒ^８ａは、前記と同様の意味を有する。」を；Ｒ^１、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｒ^６ａ、Ｚ^１ａおよびＺ^２ａは、前記と同様の意味を有する。」[Production Method 7]

“In the formula, T ¹ is an oxygen atom, a sulfur atom or NR ^8a ”, wherein R ^8a has the same meaning as described above; R ¹ , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , Z ^1a and Z ^2a have the same meaning as described above. "

The compound of the general formula [1g] or [1h] can be produced by reacting the compound of the general formula [11] with the compound of the general formula [4]. This reaction may be performed by the method described in Journal of Organic Chemistry (J. Org. Chem.), Vol. 56, pages 5939 to 5942, 1991 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; and esters and water, such as ethyl acetate and the like, may be used which are mixed.
In this reaction, the amount of the compound of general formula [4] used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of general formula [11].
This reaction may be carried out at −30 to 150 ° C., preferably at 0 to 100 ° C. for 30 minutes to 48 hours.

「式中、Ｒ^１、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｒ^６ａ、Ｚ^１ａおよびＺ^２ａは、前記と同様の意味を有する。」[Production Method 8]

“Wherein R ¹ , R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , Z ^1a and Z ^2a have the same meaning as described above.

The compound of the general formula [1i] can be produced by reacting the compound of the general formula [28] with the compound of the general formula [4] in the presence or absence of a solvent. This reaction may be carried out by a method described in WO 2004/058144 or a method according 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; and esters and water, such as ethyl acetate and the like, may be used which are mixed.
In this reaction, the amount of the compound of general formula [4] used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of general formula [28].
This reaction may be carried out at −30 to 150 ° C., preferably 0 to 150 ° C. for 30 minutes to 48 hours.

「式中、Ｒ^１、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｒ^１４、Ｑ^１、Ｘ^１、Ｘ^２、Ｘ^３、Ｚ^１ａおよびＺ^２ａは、前記と同様の意味を有する。」[Production Method 9]

“Wherein R ¹ , R ^2a , R ^3a , R ^4a , R ^5a , R ¹⁴ , Q ¹ , X ¹ , X ² , X ³ , Z ^1a and Z ^2a have the same meaning as described above.

The compound of the general formula [1j] can be produced by reacting the compound of the general formula [5] with the compound of the general formula [29] in the presence or absence of a solvent. This reaction may be carried out by the method described in WO03 / 010138 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, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene. An ether such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether; a sulfoxide such as dimethyl sulfoxide; a ketone such as acetone and 2-butanone; and an ester such as ethyl acetate; These may be used as a mixture.
In this reaction, the amount of the compound of general formula [29] used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of general formula [5].
This reaction may be carried out at -30 to 200 ° C, preferably 0 to 150 ° C for 30 minutes to 48 hours.

「式中、Ｕ^１は、ハロゲン原子、アルカンスルホニルオキシ基またはアリールスルホニルオキシ基を；Ｒ^１、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｒ^６、Ｘ^３、Ｚ^１ａおよびＺ^２ａは、前記と同様の意味を有する。」[Production method 10]

“In the formula, U ¹ represents a halogen atom, an alkanesulfonyloxy group or an arylsulfonyloxy group; R ¹ , R ^2a , R ^3a , R ^4a , R ^5a , R ⁶ , X ³ , Z ^1a and Z ^2a are It has the same meaning as above. "

The compound of the general formula [1k] can be produced by reacting the compound of the general formula [15] with the compound of the general formula [30] in the presence or absence of a phosphine in the presence of a base and a catalyst. .
This reaction may be carried out by the method described in Organic Letters, Vol. 1, pp. 35-38, 1999, or the like.
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; ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether; dimethyl sulfoxide Sulfoxides such as; ketones such as acetone and 2-butanone; esters such as ethyl acetate; and the like.
Examples of the base used in this reaction include organic bases such as sodium = tert-butoxide, pyridine, dimethylaminopyridine and triethylamine; sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium carbonate, sodium carbonate and cesium carbonate. And inorganic bases such as
Examples of the catalyst used in this reaction include tetrakis (triphenylphosphine) palladium, palladium (II) acetate, palladium (II) chloride and tris (dibenzylideneacetone) dipalladium (0).
Examples of the phosphine optionally used in this reaction include triphenylphosphine, tri-tert-butylphosphine, diphenyl (orthotolyl) phosphine, tri (tolyl) phosphine, and 2,2′-bis (diphenylphosphino) -1. , 1'-binaphthyl and the like.
In this reaction, the used amount of the base and the compound of general formula [30] may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of general formula [15].
In this reaction, the amount of catalyst used may be 0.001 to 10 times mol, preferably 0.01 to 2 times mol for the compound of general formula [15].
In this reaction, the amount of phosphine used as desired may be 0.001 to 40 times mol, preferably 0.01 to 8 times mol for the compound of general formula [15].
This reaction may be carried out at −30 to 150 ° C., preferably at 0 to 100 ° C. for 30 minutes to 48 hours.

「式中、Ｕ^２は、ハロゲン原子、アルカンスルホニルオキシ基またはアリールスルホニルオキシ基を；Ｒ^１６は、カルボキシル基の保護基を；Ｒ^１、Ｒ^２ａ、Ｒ^３ａ、Ｒ^５ａ、Ｒ^６、Ｘ^１、Ｘ^２、Ｘ^３、Ｚ^１ａおよびＺ^２ａは、前記と同様の意味を有する。」
一般式［１ｍ］の化合物は、触媒の存在下、塩基の存在下または不存在下、ホスフィンの存在下または不存在下、一般式［１ｌ］の化合物を一般式［１４］の化合物と反応させることにより製造することができる。この反応は、たとえば、辻ら、遷移金属が拓く有機合成、第19〜22頁、1997年、丸善などに記載された方法またはそれに準じた方法で行えばよい。
一般式［１４］の化合物としては、メチル＝アクリラート、エチル＝アクリラートおよびｔｅｒｔ−ブチル＝アクリラートなどが挙げられる。
この反応に使用される溶媒としては、反応に悪影響を及ぼさないものであればよく、たとえば、たとえば、メタノール、エタノール、２−プロパノールおよび２−メチル−２−プロパノールなどのアルコール類；Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミドおよび１−メチル−２−ピロリドンなどのアミド類；塩化メチレン、クロロホルムおよびジクロロエタンなどのハロゲン化炭化水素類；ベンゼン、トルエンおよびキシレンなどの芳香族炭化水素類；ジオキサン、テトラヒドロフラン、アニソール、エチレングリコールジメチルエーテル、ジエチレングリコールジメチルエーテル、ジエチレングリコールジエチルエーテルおよびエチレングリコールモノメチルエーテルなどのエーテル類；ジメチルスルホキシドなどのスルホキシド類；アセトンおよび２−ブタノンなどのケトン類；酢酸エチルなどのエステル類；アセトニトリルなどのニトリル類ならびに水などが挙げられ、これらは混合して使用してもよい。
この反応に使用される触媒としては、たとえば、ビス（トリフェニルホスフィン）パラジウムジクロリド（II）、テトラキス（トリフェニルホスフィン）パラジウム、酢酸パラジウム（II）、塩化パラジウム（II）、ビス（トリ−tｅｒｔ−ブチルホスフィン）パラジウム（０）およびトリス（ジベンジリデンアセトン）二パラジウム（０）などが挙げられる。
この反応において所望により使用されるホスフィンとしては、たとえば、トリフェニルホスフィン、トリ−tｅｒｔ−ブチルホスフィン、ジフェニル（オルトトリル）ホスフィン、トリ（トリル）ホスフィンおよび２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチルなどが挙げられる。
この反応において所望により使用される塩基としては、たとえば、ピリジン、ジメチルアミノピリジン、トリエチルアミン、Ｎ，Ｎ−ジメチルベンジルアミン、酢酸ナトリウムおよび酢酸カリウムなどの有機塩基；水酸化ナトリウム、水酸化カリウム、炭酸水素ナトリウム、炭酸カリウムおよび炭酸ナトリウムなどの無機塩基などが挙げられる。
この反応において、一般式［１４］の化合物の使用量は、一般式［１ｌ］の化合物に対して1〜10倍モル、好ましくは1〜5倍モルであればよい。
この反応において、触媒の使用量は、一般式［１ｌ］の化合物に対して0.001〜10倍モル、好ましくは0.01〜2倍モルであればよい。
この反応において、所望により使用されるホスフィンの使用量は、一般式［１ｌ］の化合物に対して0.001〜40倍モル、好ましくは0.01〜８倍モルであればよい。
この反応において、塩基の使用量は、一般式［１ｌ］の化合物に対して1〜10倍モル、好ましくは1〜5倍モルであればよい。
この反応は、−30〜200℃、好ましくは0〜100℃で30分間〜48時間実施すればよい。[Production Method 11]

“In the formula, U ² represents a halogen atom, an alkanesulfonyloxy group or an arylsulfonyloxy group; R ¹⁶ represents a protecting group for a carboxyl group; R ¹ , R ^2a , R ^3a , R ^5a , R ⁶ , X ¹ , X ² , X ³ , Z ^1a and Z ^2a have the same meaning as above.
The compound of the general formula [1m] is reacted with the compound of the general formula [1l] in the presence of a catalyst, in the presence or absence of a base, and in the presence or absence of a phosphine. Can be manufactured. This reaction may be performed, for example, by the method described in, for example, Organic Synthesis Opened by Transition Metals, pp. 19-22, 1997, Maruzen et al.
Examples of the compound of the general formula [14] include methyl acrylate, ethyl acrylate, tert-butyl acrylate and the like.
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— Amides such as 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; Dioxane , Tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, ethers such as diethylene glycol diethyl ether and ethylene glycol monomethyl ether; dimethyl sulfoxide, etc. Sulfoxide such; 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.
Examples of the catalyst used in this reaction include bis (triphenylphosphine) palladium dichloride (II), tetrakis (triphenylphosphine) palladium, palladium (II) acetate, palladium (II) chloride, bis (tri-tert- Butylphosphine) palladium (0) and tris (dibenzylideneacetone) dipalladium (0).
Examples of the phosphine optionally used in this reaction include triphenylphosphine, tri-tert-butylphosphine, diphenyl (orthotolyl) phosphine, tri (tolyl) phosphine, and 2,2′-bis (diphenylphosphino) -1. , 1'-binaphthyl and the like.
Examples of the base optionally used in this reaction include organic bases such as pyridine, dimethylaminopyridine, triethylamine, N, N-dimethylbenzylamine, sodium acetate and potassium acetate; sodium hydroxide, potassium hydroxide and hydrogen carbonate. Examples thereof include inorganic bases such as sodium, potassium carbonate and sodium carbonate.
In this reaction, the amount of the compound of the general formula [14] used may be 1 to 10 times mol, preferably 1 to 5 times mol, of the compound of the general formula [1l].
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 [1l].
In this reaction, the amount of phosphine used as desired may be 0.001 to 40 times mol, preferably 0.01 to 8 times mol, of the compound of general formula [1l].
In this reaction, the amount of the base used may be 1 to 10 times mol, preferably 1 to 5 times mol, of the compound of the general formula [1l].
This reaction may be carried out at −30 to 200 ° C., preferably at 0 to 100 ° C., for 30 minutes to 48 hours.

The general formulas [1a], [1b], [1c], [1d], [1e], [1f], [1g], [1h], [1i], [1j], [1j], 1k], [1l] and [1m] or a salt thereof is subjected to a reaction known per se such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis, for example. Alternatively, the compounds can be derived into other compounds of the general formula [1] or salts thereof by appropriately combining these reactions.
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.

  Next, general formulas [2], [3], [4], [5], [8], [9], [11], [28], [29] and A method for producing the compound [30] will be described.

  Examples of the compound of the general formula [2] include 8-amino-2-methylquinoline and 8-amino-2-methoxyquinoline [Journal of American Chemical Society (J. Am. Chem. Soc.), No. 68, 1553-1556, 1946, and Australian Journal of Chemistry (Aus. J. Org. Chem.), 56, 39-44, 2003] are known. . Further, the compound of the general formula [2] is produced by combining methods known per se, and can be produced, for example, by the production method shown below.

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

“Wherein R ¹ , R ^2a , R ^3a , R ^4a , R ^5a , Z ^1a and Z ^2a have the same meaning as described above.

  As the compound of the general formula [12], for example, 7-methoxyisoquinoline [Organic Reaction (Org. React.), Vol. VI, pp. 191 to 206] and 2-cyanoquinoline are known.

(A-1)
The compound of the general formula [2a] can be produced by reacting the compound of the general formula [12] with sodium amide. This reaction may be performed by, for example, the method described in Journal of Organic Chemistry (J. Org. Chem.), Vol. 11, pp. 239 to 246, 1946, or the like.
The solvent used in this reaction may be any solvent that does not adversely affect the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; aromatic amines such as dimethylaniline and diethylaniline As well as liquid ammonia, these may be used in combination.
In this reaction, the amount of sodium amide used may be 1 to 10 times mol, preferably 1 to 5 times mol, of the compound of the general formula [12].
This reaction may be carried out at −100 to 150 ° C. for 30 minutes to 48 hours.

(A-2)
The compound of the general formula [13] can be produced by nitrating the compound of the general formula [12].
Nitration of the compound of general formula [12] is described, for example, by Jerry March, Advanced Organic Chemistry 4th edition, pages 522-525, 1992, John Willy and -The method described in Sands (John Wiley & Sons, INC.) Or the like may be performed.

(A-3)
The compound of the general formula [2a] can be produced by reducing the compound of the general formula [13].
Reduction of the compound of general formula [13] can be performed, for example, by Jerry March, Advanced Organic Chemistry 4th edition, pp. 1026-1217, 1992, John Willie and What is necessary is just to carry out by the method described in Sands (John Wiley & Sons, INC.) Etc. or a method according to it.

「式中、Ｒ^４ｂは、ハロゲン原子を；Ｒ^１、Ｒ^２ａ、Ｒ^３ａ、Ｒ^１６、Ｚ^１ａおよびＺ^２ａは、前記と同様の意味を有する。」[Production method B]

“Wherein R ^4b represents a halogen atom; R ¹ , R ^2a , R ^3a , R ¹⁶ , Z ^1a and Z ^2a have the same meaning as described above.

  Examples of the compound of the general formula [2b] include 8-amino-2-methylquinoline and 8-amino-2-methoxyquinoline [Journal of American Chemical Society (J. Am. Chem. Soc.), No. 68, 1553-1556, 1946 and Australian Journal of Chemistry (Aus. J. Chem.), 56, 39-44, 2003].

(B-1)
The compound of the general formula [2c] can be produced by halogenating the compound of the general formula [2b]. This reaction is described, for example, by Jerry March, Advanced Organic Chemistry 4th edition, pages 531-534, 1992, John Wiley & Sons. , INC.) Or the like, or a method similar thereto.

(B-2)
The compound of the general formula [2d] is reacted with the compound of the general formula [2c] in the presence of a catalyst, in the presence or absence of a base, and in the presence or absence of a phosphine. Can be manufactured. This reaction may be performed according to the production method 11.

(B-3)
The compound of the general formula [2e] can be produced by reducing the compound of the general formula [2d]. This reaction is described, for example, by Jerry March, Advanced Organic Chemistry 4th edition, pp. 771-780, 1992, John Wiley & Sons. , INC.)
The method described in the above or the like may be performed.
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; benzene, toluene, xylene and the like Aromatic hydrocarbons; ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and ethylene glycol monomethyl ether; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and 2-butanone; Examples thereof include esters such as ethyl acetate and water, and these may be used as a mixture.
Examples of the reducing agent used in this reaction include hydrogenated complex compounds such as sodium cyanoborohydride and sodium borohydride, and borane.
In this reaction, the reducing agent may be used in an amount of 0.5 to 10 times the amount of the compound of the general formula [2d].
Further, reduction using a metal such as zinc under acidic conditions; electrolytic reduction using copper or platinum as a cathode; catalytic reduction using Raney nickel, platinum oxide, palladium carbon, or palladium black as a catalyst can also be used.
In this reaction, the amount of the catalyst used may be 0.001 to 5 moles compared to the compound of the general formula [2d].
This reaction may be carried out at −30 to 200 ° C., preferably at 0 to 100 ° C., for 30 minutes to 48 hours.

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

“Wherein R ¹ , R ^2a , R ^3a , R ^4a , R ^5a , U ¹ , Z ^1a and Z ^2a have the same meaning as described above.

(C-1)
The compound of the general formula [2f] can be produced by diazotizing the compound of the general formula [2b], reacting with the sulfur compound A, and then hydrolyzing.
As a solvent used in this reaction, water is usually used.
Examples of the sulfur compound A used in this reaction include thiourea and potassium xanthate.
In this reaction, the amount of the sulfur compound A used may be 1 to 20 times the mol of the compound of the general formula [2b].
This reaction may be carried out at -30 to 200 ° C, preferably 0 to 150 ° C for 30 minutes to 48 hours.

(C-2)
The compound of the general formula [2f] can be produced by reacting the compound of the general formula [15] with the sulfur compound B and then deprotecting as necessary.
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 and water Mixed and may also be used.
Examples of the sulfur compound B used in this reaction include inorganic sulfur compounds such as sodium sulfide and organic sulfur compounds such as phenylmethanethiol and 1,1-dimethylethanethiol.
In this reaction, the sulfur compound B may be used in an amount of 1 to 20 times the mol of the compound of the general formula [15].
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^１７は、低級アルキル基を；Ｒ^１、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｕ^１、Ｚ^１ａおよびＺ^２ａは、前記と同様の意味を有する。」[Production Method D]

“Wherein R ¹⁷ represents a lower alkyl group; R ¹ , R ^2a , R ^3a , R ^4a , R ^5a , U ¹ , Z ^1a and Z ^2a have the same meaning as described above.

(D-1)
The compound of the general formula [2g] can be produced by diazotizing the compound of the general formula [2b] and then treating with an acid.
As a solvent used in this reaction, water is usually used.
Examples of the acid used in this reaction include hydrochloric acid, sulfuric acid and nitric acid.
In this reaction, the amount of acid used may be 1 to 100 moles compared to the compound of the general formula [2b].
This reaction may be carried out at -30 to 200 ° C, preferably 0 to 150 ° C for 30 minutes to 48 hours.

(D-2)
The compound of the general formula [2g] can be produced by reacting the compound of the general formula [15] with the compound of the general formula [16] and then deprotecting the compound.
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 and water Mixed and may also be used.
Examples of the compound of the general formula [16] used in this reaction include metal alkoxides such as sodium methoxide and sodium ethoxide.
In this reaction, the amount of the compound represented by the general formula [16] may be 1 to 20 times the mol of the compound represented by the general formula [15].
This reaction may be carried out at 0 to 200 ° C., preferably 0 to 150 ° C., for 30 minutes to 48 hours.
Removal of the group represented by R ¹⁷ is for example described in W.W. W. Green et al., Protective Groups in Organic Synthesis, 3rd edition, pages 246-292, 1999, John Wiley & Sons (John Wiley & Sons, INC.).

「式中、Ｒ^１４、Ｌ^１、Ｑ^１、Ｘ^３、Ｘ^４およびｍは、前記と同様の意味を有する。」The compound of the general formula [3] is produced by combining methods known per se, and can be produced, for example, by the production method shown below.
[Production Method E]

“Wherein R ¹⁴ , L ¹ , Q ¹ , X ³ , X ⁴ and m have the same meaning as described above.”

  As a compound of the general formula [17], for example, 4-piperidinecarboxylic acid is known.

(E-1)
Examples of the compound of the general formula [6] include 2,3- (methylenedioxy) benzaldehyde, 1,4-benzodioxan-6-carbaldehyde and (2,3-dihydro [1,4] dioxin-6-yl. ) Acetaldehyde [WO02 / 50061] is known.
The compound of the general formula [3a] can be produced by reacting the compound of the general formula [17] with the compound of the general formula [6] in the presence of a reducing agent.
This reaction may be performed according to the production method 3-1.

(E-2)
Examples of the compound of the general formula [7] include 2- (3-oxo-3,4-dihydro-2H-benzothiazin-6-yl) ethyl methanesulfonate and 2- (benzo [1,3] dioxol-5. -Yl) ethyl methanesulfonate and the like are known.
The compound of the general formula [3a] can be produced by reacting the compound of the general formula [17] with the compound of the general formula [7].
This reaction may be performed according to production method 3-2.

「式中、Ｑ^２は、

「式中、Ｒ^１１、Ｒ^１１ａ、Ｒ^１１ｂ、Ｒ^１１ｃおよびＲ^１３は、前記と同様の意味を有する。」
を；Ｙ^ｃは、アミノ基の保護基を；Ｒ^１４、Ｌ^１、Ｘ^４およびｍは、前記と同様の意味を有する。」Although the compound of General formula [4] is manufactured by combining a method known per se, it can be manufactured by the manufacturing method shown next, for example.
[Production Method F]

“Where Q ² is

“Wherein R ¹¹ , R ^11a , R ^11b , R ^11c and R ¹³ have the same meaning as described above.
Y ^c represents an amino-protecting group; R ¹⁴ , L ¹ , X ⁴ and m have the same meaning as described above. "

  As a compound of the general formula [18], for example, tert-butyl = piperazinecarboxylate is known.

(F-1)
Examples of the compound of the general formula [6] include 2,3- (methylenedioxy) benzaldehyde, 1,4-benzodioxan-6-carbaldehyde and (2,3-dihydro [1,4] dioxin-6-yl. ) Acetaldehyde [WO02 / 50061] is known.
The compound of the general formula [4a] can be produced by reacting the compound of the general formula [18] with the compound of the general formula [6] and then deprotecting the compound.
The reaction of the compound of the general formula [18] and the compound of the general formula [6] may be performed according to the production method 3-1.
Removal of the protecting group for the amino group represented by Y ^c is described in, for example, W.C. W. Green et al., Protective Groups in Organic Synthesis, 3rd edition, pages 494-653, 1999, John Wiley & Sons (John Wiley & Sons, INC.).

(F-2)
Examples of the compound of the general formula [7] include 2- (3-oxo-3,4-dihydro-2H-benzothiazin-6-yl) ethyl methanesulfonate and 2- (benzo [1,3] dioxol-5. -Yl) ethyl methanesulfonate and the like are known.
The compound of the general formula [4a] can be produced by reacting the compound of the general formula [18] with the compound of the general formula [7] and then deprotecting the compound.
The reaction of the compound of general formula [18] and the compound of general formula [7] may be carried out according to production method 3-2.
Removal of the protecting group for the amino group represented by Y ^c is described in, for example, W.C. W. Green et al., Protective Groups in Organic Synthesis, 3rd edition, pages 494-653, 1999, John Wiley & Sons (John Wiley & Sons, INC.).

「式中、Ｙ^ｄは、アミノ基の保護基を；Ｒ^１、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｑ^１、Ｘ^１ａ、Ｘ^３、Ｚ^１ａおよびＺ^２ａは、前記と同様の意味を有する。The compound of the general formula [5] is produced by combining methods known per se, and can be produced, for example, by the production method shown below.
[Production method G]

“In the formula, Y ^d represents an amino-protecting group; R ¹ , R ^2a , R ^3a , R ^4a , R ^5a , Q ¹ , X ^1a , X ³ , Z ^1a and Z ^2a are the same as above. Has meaning.

As the compound of the general formula [19], for example, 4- (tert-butoxycarbonyl) piperidinecarboxylic acid and the like are known.
The compound of general formula [5a] can be produced by reacting the compound of general formula [2] with a reactive derivative of the compound of general formula [19] and then deprotecting.
The reaction of the compound of the general formula [2] and the reactive derivative of the compound of the general formula [19] may be performed according to the production method 1.
Removal of the protecting group for the amino group represented by Y ^d is described in, for example, W. Green et al., Protective Groups in Organic Synthesis, 3rd edition, pages 494-653, 1999, John Wiley & Sons (John Wiley & Sons, INC.).

「式中、Ｙ^ｅは、アミノ基の保護基を；Ｒ^１、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｑ^２、Ｘ^１ａ、Ｚ^１ａおよびＺ^２ａは、前記と同様の意味を有する。[Production Method H]

“In the formula, Y ^e represents an amino-protecting group; R ¹ , R ^2a , R ^3a , R ^4a , R ^5a , Q ² , X ^1a , Z ^1a and Z ^2a have the same meaning as described above. .

As compounds of the general formula [20], for example, 1-tert-butoxycarbonylpiperazine and 4-((tert-butoxycarbonyl) amino) piperidine are known.
The compound of the general formula [5b] is obtained by reacting the compound of the general formula [2] with a carbonyl compound in the presence or absence of a base, reacting with the compound of the general formula [20], and then deprotecting. Can be manufactured. In addition, the compound of the general formula [5b] is reacted with the compound of the general formula [2] after reacting the compound of the general formula [20] with a carbonyl compound in the presence or absence of a base, and then deprotected. Can be manufactured.
The reaction of the compound of the general formula [2] and the compound of the general formula [20] may be performed according to the production method 2.
Removal of the protecting group for the amino group represented by Y ^e is described in, for example, W. Green et al., Protective groups in Organic synthesis, 3rd edition, pages 494-653, 1999, John Wiley & Sons (John Wiley) & Sons, INC.).

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

“Wherein L ² represents a leaving group; R ¹ , R ^2a , R ^3a , R ^4a , R ^5a , Q ² , X ^1a , Y ^e , Z ^1a and Z ^2a have the same meaning as described above. Have. "

As a compound of the general formula [21], for example, (1- (tert-butoxycarbonyl) piperidin-4-yl) methyl = methanesulfonate is known.
The compound of the general formula [5c] can be produced by reacting the compound of the general formula [2] with the compound of the general formula [21] in the presence or absence of a base and then deprotecting the compound.
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 and water Mixed and may also be used.
Examples of the base optionally 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. It is done.
In this reaction, the compound and the base used in the general formula [21] may be used in an amount of 1 to 20 moles compared to the compound of the general formula [2].
This reaction may be carried out at 0 to 200 ° C., preferably 0 to 150 ° C., for 30 minutes to 48 hours.
Removal of the protecting group for the amino group represented by Y ^e is described in, for example, W. Green et al., Protective groups in Organic synthesis, 3rd edition, pages 494-653, 1999, John Wiley & Sons (John Wiley) & Sons, INC.).

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

“Wherein R ¹ , R ^2a , R ^3a , R ^4a , R ^5a , Q ² , T ¹ , Y ^e , Z ^1a and Z ^2a have the same meaning as described above.

The compound of the general formula [5d] can be produced by reacting the compound of the general formula [11] with the compound of the general formula [20] and then deprotecting the compound.
The reaction of the compound of the general formula [11] and the compound of the general formula [20] may be performed according to the production method 7.
Removal of the protecting group for the amino group represented by Y ^e is described in, for example, W. Green et al., Protective groups in Organic synthesis, 3rd edition, pages 494-653, 1999, John Wiley & Sons (John Wiley) & Sons, INC.).

「式中、Ｒ^１８およびＲ^１９は、ハロゲン原子を；ｎは、２−５の整数を；Ｒ^１、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｑ^１、Ｙ^ｄ、Ｚ^１ａおよびＺ^２ａは、前記と同様の意味を有する。」[Production method K]

“Wherein R ¹⁸ and R ¹⁹ are halogen atoms; n is an integer of 2-5; R ¹ , R ^2a , R ^3a , R ^4a , R ^5a , Q ¹ , Y ^d , Z ^1a and Z ^2a has the same meaning as above. "

(K-1)
As the compound of the general formula [22], for example, 4-bromomethyl-1- (tert-butoxycarbonyl) piperidine, 4-bromomethyl-1- (benzyloxycarbonyl) piperidine and the like are known.
The compound of the general formula [5e] can be produced by reacting the compound of the general formula [8] with a Wittig reagent produced from the compound of the general formula [22], followed by reduction and deprotection. it can.
The Wittig reaction is described, for example, by Jerry March, Advanced Organic Chemistry 4th edition, pages 956-963, 1992, John Wiley & Sons. , INC.), Etc., or a method according to it. The Wittig reagent produced from the compound of general formula [22] can be produced, for example, by reacting the compound of general formula [22] with triphenylphosphine.
For the reduction, for example, catalytic reduction using a catalyst may be used. Examples of the catalyst used in this reaction include Raney nickel, platinum oxide, palladium carbon, or palladium black. This reaction is described, for example, by Jerry March, Advanced Organic Chemistry 4th edition, pp. 771-780, 1992, John Wiley & Sons. , INC.)
The method described in the above or the like may be performed.
Removal of the protecting group for the amino group represented by Y ^d is described in, for example, W. Green et al., Protective groups in Organic synthesis, 3rd edition, pages 494-653, 1999, John Wiley & Sons (John Wiley) & Sons, INC.).

(K-2)
The compound of general formula [5e] can be produced by reacting the compound of general formula [24] with a Wittig reagent produced from the compound of general formula [23], followed by reduction and deprotection. it can.
The compound of the general formula [23] can be produced from the compound of the general formula [8] by using, for example, a carbon chain extension reaction.
Examples of the compound of the general formula [24] include 1-benzylpiperidine-4-carbaldehyde, 1- (tert-butoxycarbonyl) piperidine-4-carbaldehyde, 1-acetylpiperidine-4-carbaldehyde and 1-trifluoro Acetyl piperidine-4-carbaldehyde and the like are known.
This reaction may be performed according to production method K-1.

  As a compound of the general formula [8], for example, 7-methoxyisoquinoline-1-carbaldehyde [J. Med. Chem., Vol. 13, pp. 1177-1124, 1970] Etc. are known. Further, the compound of the general formula [8] is produced by combining methods known per se, and can be produced, for example, by the production method shown below.

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

“Wherein R ¹ , R ^2a , R ^3a , R ^4a , R ^5a , Z ^1a and Z ^2a have the same meaning as described above.

As a compound of the general formula [25], for example, 2-chloro-8-methylquinoline [(Journal of Organic Chemistry (J. Org. Chem.), 37, 4410-4415, 1972) ], 7-methoxy-1-methylisoquinoline, 7,8-dimethoxy-1-methylisoquinoline and the like are known.
The compound of the general formula [8] can be produced by oxidizing the compound of the general formula [25].
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene. A sulfoxide such as dimethyl sulfoxide, an acid such as acetic acid, water and the like, and these may be used as a mixture.
Examples of the oxidizing agent used in this reaction include chromium trioxide, manganese dioxide, chromyl chloride, and selenium dioxide.
In this reaction, the amount of the oxidizing agent used may be 0.5 to 10 moles compared to the compound of the general formula [25].
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^１４ｄおよびＲ^１５は、前記と同様の意味を有する。」The compound of the general formula [9] is produced by combining methods known per se, and can be produced, for example, by the production method shown below.
[Production method M]

“Wherein R ^14d and R ¹⁵ have the same meaning as described above.”

  As a compound of the general formula [26], for example, 2,3-dihydro-1,4-benzodioxin-6-yl isothiocyanate is known.

(M-1)
The compound of the general formula [27] can be produced by reacting the compound of the general formula [26] with ammonia.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene. Ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and diethylene glycol diethyl ether; ketones such as acetone and 2-butanone, and esters such as ethyl acetate, and the like. May be. Moreover, you may use aqueous ammonia as a solvent.
In this reaction, the amount of ammonia used may be equimolar or more with respect to the compound of the general formula [26].
This reaction may be carried out at −30 to 200 ° C., preferably at 0 to 100 ° C., for 30 minutes to 48 hours.

(M-2)
The compound of general formula [9] can be produced by reacting the compound of general formula [27] with an alkyl agent. This reaction may be carried out, for example, by the method described in DE 10/061541 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 and water Mixed and may also be used.
Examples of the alkylating agent used in this reaction include alkyl halides such as methyl iodide and ethyl iodide.
In this reaction, the amount of the alkylating agent to be used may be 1 to 10 times mol, preferably 1 to 5 times mol, of the compound of general formula [27].
This reaction may be carried out at −30 to 200 ° C., preferably at 0 to 100 ° C., for 30 minutes to 48 hours.

  As the compound of the general formula [11], for example, 7-methoxy-1- (oxiran-2-yl) isoquinoline [J. Med. Chem., Vol. 13, 1117 to 1124] Page, 1970]. In addition, the compound of the general formula [11] is produced by combining methods known per se, and can be produced, for example, by the production method shown below.

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

“Wherein R ¹ , R ^2a , R ^3a , R ^4a , R ^5a , Z ^1a and Z ^2a have the same meaning as described above.

(N-1)
The compound of the general formula [11a] can be produced by reacting the compound of the general formula [8] with sulfur ylide.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene. Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and ethylene glycol monomethyl ether; sulfoxides such as dimethyl sulfoxide, water and the like, and these may be used in combination.
Examples of sulfur ylides used in this reaction include sulfur ylides used in usual oxirane synthesis, such as dimethylsulfonium methylide, dimethyloxosulfonium methylide, dimethylamino (methyl) oxosulfonium methylide and dimethylamino. (Phenyl) oxosulfonium methylide and the like.
In this reaction, the amount of sulfur ylide used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [8].
This reaction may be carried out at −30 to 150 ° C., preferably at 0 to 100 ° C. for 30 minutes to 48 hours.

(N-2)
The compound of the general formula [11b] can be produced by reacting the compound of the general formula [11a] with potassium isocyanate.
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. These sulfoxides and water may be mentioned, and these may be used as a mixture.
In this reaction, the amount of potassium isocyanate used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [11a].
This reaction may be carried out at −30 to 150 ° C., preferably at 0 to 100 ° C. for 30 minutes to 48 hours.

「式中、Ｒ^１、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ、Ｒ^５ａ、Ｕ^１、Ｚ^１ａおよびＺ^２ａは、前記と同様の意味を有する。」[Production method O]

“Wherein R ¹ , R ^2a , R ^3a , R ^4a , R ^5a , U ¹ , Z ^1a and Z ^2a have the same meaning as described above.

The compound of the general formula [28] can be produced by reacting the compound of the general formula [15] with a vinyl metal compound in the presence of a catalyst, in the presence or absence of a base.
Examples of the vinyl metal compound used in this reaction include organotin compounds such as (tributyl) (vinyl) tin and organoboron compounds such as vinylboranoic acid pinacol ester.
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— Amides such as 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; Dioxane , Tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, ethers such as diethylene glycol diethyl ether and ethylene glycol monomethyl ether; dimethyl sulfoxide, etc. Sulfoxide such; 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.

Examples of the catalyst used in this reaction include bis (triphenylphosphine) palladium dichloride (II), tetrakis (triphenylphosphine) palladium, palladium (II) acetate, palladium (II) chloride, bis (tri-tert- Butylphosphine) palladium (0) and tris (dibenzylideneacetone) dipalladium (0).
Bases optionally used in this reaction include, for example, organic bases such as pyridine, dimethylaminopyridine, triethylamine, N, N-dimethylbenzylamine, sodium acetate and potassium acetate; sodium hydroxide, potassium hydroxide, hydrogen carbonate Examples thereof include inorganic bases such as sodium, potassium carbonate and sodium carbonate.
In this reaction, the amount of the vinyl metal compound used may be 1 to 10 times mol, preferably 1 to 5 times mol, of the compound of the general formula [15].
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 [15].
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 [15].
This reaction may be carried out at −30 to 200 ° C., preferably at 0 to 100 ° C., for 30 minutes to 48 hours.

「式中、Ｕ^３は、ハロゲン原子、アルカンスルホニルオキシ基およびアリールスルホニルオキシ基を；Ｒ^１4ｄは、前記と同様の意味を有する。」[Production method P]

“Wherein U ³ represents a halogen atom, an alkanesulfonyloxy group and an arylsulfonyloxy group; R ^14d has the same meaning as described above.

  The compound of the general formula [29] can be produced by reacting the compound of the general formula [31] with a vinyl metal compound in the presence of a catalyst, in the presence or absence of a base. This reaction may be carried out according to production method O.

「式中、Ｒ^６およびＸ^３は、前記と同様の意味を有する。」[Production method Q]

“Wherein R ⁶ and X ³ have the same meaning as described above.”

  The compound of the general formula [30] can be produced by reacting the reactive derivative of the compound of the general formula [3] with ammonia in the presence or absence of a base. This reaction may be carried out according to production method 1.

「式中、Ｒ^１、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ｂ、Ｒ^５ａ、Ｒ^１６、Ｑ^２、Ｔ^１、Ｙ^ｅ、Ｚ^１ａおよびＺ^２ａは、前記と同様の意味を有する。」[Production method R]

“Wherein R ¹ , R ^2a , R ^3a , R ^4b , R ^5a , R ¹⁶ , Q ² , T ¹ , Y ^e , Z ^1a and Z ^2a have the same meaning as described above.

(R-1)
The compound of the general formula [5f] can be produced by reacting the compound of the general formula [11c] with the compound of the general formula [20]. This reaction may be performed according to the production method 7.

(R-2)
The compound of the general formula [5g] is deprotected after reacting the compound of the general formula [5f] with the compound of the general formula [14] in the presence of a catalyst and a base, in the presence or absence of phosphine. Can be manufactured. This reaction may be performed according to the production method 11.

  The general formulas [2a], [2b], [2c], [2d], [2e], [2f], [2g], [3a], [4a], [5a], [5a], [5a], [ 5b], [5c], [5d], [5e], [5f], [5g], [8], [9], [11a], [11b], [13], [27], [28] , [29] and [30] are subjected to a reaction known per se such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis, or the reaction is appropriately performed. In combination, it can be derived into other compounds.

In the present ^{specification, R 1, R 2, R} 2a, R 3, R 3a, R 4, R 4a, R 5, R 5a, R 7, R 7a, R 8a, R 8b, R 9, R 9a, Each group of R ¹⁰ , R ^10a , R ¹¹ , R ^11a , R ^11b and R ^11c is a halogen atom, an optionally protected hydroxyl and carboxyl group, an optionally substituted alkanesulfonyl group, and a protected group. The alkyl group may be substituted with one or more groups selected from an alkyl group substituted with an optionally carboxyl group and an optionally substituted alkyl, alkenyl, alkynyl, alkoxy and aryl group. Preferred substituents include: a halogen atom; an optionally protected hydroxyl and carboxyl group; an alkanesulfonyl group optionally substituted with a halogen atom; an alkyl group substituted with an optionally protected carboxyl group; and Examples include a halogen atom, an optionally protected hydroxyl group or an optionally protected carboxyl group, an alkyl, alkenyl, alkynyl, alkoxy and aryl group. More preferable substituents include a halogen atom; a hydroxyl group; a carboxyl group; a methanesulfonyl group optionally substituted with a halogen atom; and one or more groups selected from a halogen atom, a hydroxyl group, and a carboxyl group. Mention may be made of methyl, ethyl, propyl, vinyl, allyl, ethynyl, methoxy, ethoxy and phenyl groups.

R ¹³ and R ^13a may be substituted with one or more groups selected from an optionally substituted alkyl, alkenyl, alkynyl, alkoxy and aryl group. Preferred substituents include halogen atoms, optionally protected hydroxyl groups or optionally protected alkyl groups, alkenyl, alkynyl, alkoxy and aryl groups that may be substituted. More preferred substituents include methyl, ethyl, propyl, vinyl, allyl, ethynyl, methoxy and phenyl groups which may be substituted with one or more groups selected from a halogen atom, a hydroxyl group and a carboxyl group.

R ¹⁴ , R ^14a , R ^14b , R ^14c and R ^14d are a halogen atom, a nitro group, a cyano group, an oxo group, an optionally protected hydroxy, amino and carboxyl group, and an optionally substituted alkyl, alkenyl , Alkynyl, alkoxy, alkylthio, acyl, aryl, heterocyclic, amino and carbamoyl groups may be substituted with one or more groups. Preferred substituents include a halogen atom; a nitro group; a cyano group; an oxo group; an optionally protected hydroxy, amino and carboxyl group; and a halogen atom, an optionally protected hydroxyl group, and an optionally protected group. Examples include alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, aryl, heterocyclic, amino and carbamoyl groups which may be substituted with a carboxyl group, a lower alkyl group, an aryl group or an arylsulfinyl group. More preferred substituents are halogen atom; nitro group; cyano group; oxo group; hydroxyl group; amino group; carboxyl group; and halogen atom, hydroxyl group, carboxyl group, methyl group, ethyl group, phenyl group, phenylsulfinylmethyl. Methyl, ethyl, propyl, vinyl, allyl, ethynyl, methoxy, ethoxy, methylthio, ethylthio, acetyl, propionyl, phenyl, furyl, thienyl, thiazolyl, oxazolyl, optionally substituted with one or more groups selected from the group Examples include pyridyl, pyrimidinyl, amino and carbamoyl groups.

X ⁵ , X ⁶ , X ^6a , X ^6b and X ⁷ are each a halogen atom, an optionally protected hydroxy, amino or carboxyl group and an optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, amino and It may be substituted with one or more groups selected from a carbamoyl group and the like. Preferred substituents include a halogen atom; an optionally protected hydroxyl, amino and carboxyl group; and a halogen atom, an optionally protected hydroxyl group or an optionally protected carboxyl group. Alkyl, alkenyl, alkynyl, alkoxy and aryl groups are mentioned. More preferred substituents are a halogen atom; a hydroxyl group; an amino group; a carboxyl group; and methyl, ethyl, propyl, vinyl optionally substituted with one or more groups selected from a halogen atom, a hydroxyl group, and a carboxyl group , Allyl, ethynyl, methoxy, ethoxy and phenyl groups.

  When the compound of the present invention is used as a pharmaceutical, formulation adjuvants such as excipients, carriers, and diluents that are 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.

  Next, the usefulness of the compound of the present invention will be described in the following test examples.

Test example 1 Sensitivity test 1
Antibacterial activity (MIC) was measured by the micro liquid dilution method recommended by the Japanese Society of Chemotherapy.
Staphylococcus aureus (S. aureus FDA209) was used as the cells. The cells cultured overnight at 35 ° C. on a Mueller-Hinton agar (MHA) 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 solution was inoculated into a cation-adjusted Mueller-Hinton broth (CAMHB) containing a test substance and cultured at 35 ° C. overnight. The lowest drug concentration at which no bacterial growth was observed macroscopically was defined as MIC. The results are shown in Table 4.

Test example 2 Sensitivity test 2
Antibacterial activity (MIC) was measured in the same manner as in Test Example 1 using methicillin-resistant Staphylococcus aureus (S. aureus F3095) as the cells. The results are shown in Table 5.

Test Example 3 Cytotoxicity test 1
The compounds of Examples 8, 9 and 15 were selected as test substances.
The test substance is dissolved in dimethyl sulfoxide, diluted with Eagle's Minimum Essential Medium (E'MEM) supplemented with 10% Fetal Bovine Serum (FBS), and the test substance solution (51.2 μg / mL ) Was prepared. Vero cells 3 × 10 ³ cells / 100 μL / well suspended in E'MEM containing 100 μL / well of test substance solution and 10% FBS were combined and cultured at 37 ° C. for 3 days in a 5% CO ₂ incubator. . After incubation, E ′ containing 1 mg / mL 2,3-bis- [2-methoxy-4-nitro-5-sulfonyl] -2H-tetrazolium-5-carboxyanilide (XTT) and 25 μmol / L phenazine methosulfate (PMS) 50 μL of MEM was added to each well. After culturing at 37 ° C. for 2 hours, the absorbance at 450 nm was measured using a microplate reader, and the ratio (T / C) between the value of the test substance-treated well and the value of the test substance-free well was calculated. The results are shown in Table 6.

Test Example 4 Cytotoxicity test 2
The test substance was dissolved in dimethyl sulfoxide and diluted with Eagles Minimum Essential Medium (E'MEM) supplemented with 10% Fetal Bovine Serum (FBS) to prepare a test substance solution. Vero cells 3 × 10 ³ cells / 100 μL / well suspended in E'MEM containing 100 μL / well of test substance solution and 10% FBS were combined and cultured at 37 ° C. for 3 days in a 5% CO ₂ incubator. . After culture, 1 mg / mL 2,3-bis- [2-methoxy-4-nitro-5-sulfophenyl] -2H-tetrazolium-5-carboxyanilide (2,3-bis [2-Methoxy-4-nitro-5 -sulfophenyl] -2H-tetrazolium-5-carboxanilid (XTT) and 50 μL of E′MEM containing 25 mmol / L phenazine methosulfate (PMS) were added to each well. After culturing at 37 ° C. for 2 hours, the absorbance at 450 nm was measured using a microplate reader, and the test substance concentration (CC ₅₀ , Μg / mL). The results are shown in Table 7.

Test Example 5 Infection Experiment 1
The compound of Example 8 was selected as the test substance.
S. aureus Smith cultured overnight at 37 ° C. on a Mueller-Hinton agar (MHA) plate was suspended to a final concentration of 10 ⁹ CFU / mL. This suspension was diluted 10-fold with a 1/15 mol / L phosphate buffer solution (pH 7) containing 5.6% mucin to obtain an inoculum solution. To induce infection in mice (ICR system, 4 weeks old, male, 5 mice / group), 0.4 mL of the inoculum was inoculated intraperitoneally (4 × 10 ⁷ CFU / animal).
The test substance was dissolved in 22.5% 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) to a final concentration of 10 mg / mL. The test substance solution was subcutaneously administered once (100 mg / kg) 1 hour after infection. The control group received 22.5% HP-β-CD. Mice were observed daily and the number of surviving animals 3 days after infection was recorded. The results are shown in Table 8.

Test Example 6 Infection Experiment 2
The compounds of Examples 50 and 126 were selected as test substances.
S. aureus Smith cultured overnight at 37 ° C. on a Mueller-Hinton agar (MHA) plate was suspended to a final concentration of 10 ⁹ CFU / mL. This suspension was diluted 10-fold with a 1/15 mol / L phosphate buffer solution (pH 7) containing 5.6% mucin to obtain an inoculum solution. To induce infection in mice (ICR system, 4 weeks old, male, 5 mice / group), 0.4 mL of the inoculum was inoculated intraperitoneally (4 × 10 ⁷ CFU / animal).
The test substance was dissolved in 0.1 mol / L sodium hydroxide aqueous solution to adjust the concentration to 1 mg / mL. The test substance solution was administered subcutaneously once 1 hour after infection. The control group received 22.5% HP-β-CD. Mice were observed daily and the number of surviving animals 3 days after infection was recorded. The results are shown in Table 9.

Test Example 7 Reverse Mutation Test Using Bacteria The compound of Example 1 was selected as a test substance.
Using Salmonella typhimurium TA98 and Salmonella typhimurium TA100), the presence or absence of gene mutagenesis was examined by a preincubation method. A test substance was dissolved or suspended in water, and a dilution series was prepared using a glass test tube so as to obtain a predetermined test substance concentration. In the case of the direct method, a phosphate buffer was added, and in the case of the metabolic activation method, rat liver-derived S9mix was added. After adding two pre-cultured Salmonella typhimurium strains, a glass test tube was preincubated in a warm bath at 37 ° C. for 20 minutes. Thereafter, soft agar was added to each glass test tube, and this whole amount was seeded on a 10 cm radius petri dish (Tesmedia flat plate) and cultured at 37 ° C. for 48 hours. After completion of the culture, the number of revertant colonies in each plate was measured using a colony counter. A case where the number of revertant colonies more than twice that of the negative control group was observed was regarded as positive.
The compound of Example 1 was negative.

Test Example 8 Bone marrow micronucleus test using mice The compound of Example 1 was selected as a test substance.
Mice (ICR system, 8 weeks old, male, 5 / group) were repeatedly subcutaneously administered with 100 mg / kg of the test substance for 2 days. To the negative control group, physiological saline was administered subcutaneously. Twenty-four hours after the last dose, mice were euthanized by cervical dislocation and bilateral femurs were collected. The bone marrow of the femur was washed with calf serum, a bone marrow smear was prepared, and stained with May-Grünwald to obtain a micronucleus sample. This micronucleus sample is observed under a microscope (600 times magnification), and the appearance frequency (micronucleus appearance frequency) of the number of micronucleated red blood cells (number of polychromatic red blood cells with micronuclei) per 1000 polychromatic red blood cells is calculated. did. Subsequently, a statistically significant difference test of the occurrence frequency of micronuclei between the negative control group and the test substance administration group was performed by a conditional binomial test using a Kastenbaum and Bowman number table. A case where a significant increase in the appearance frequency of micronuclei was observed as compared with the negative control group was regarded as positive.
The compound of Example 1 was negative.

Next, the present invention will be described with reference to Examples and Examples, but the present invention is not limited to these.
The mixing ratio in the eluent is a volume ratio. 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 reverse phase silica gel column chromatography is YMC Co., Ltd., ODS-AM120-S50.
In each example, each abbreviation has the following meaning.
Ac: acetyl, Boc: tert-butoxycarbonyl, Bu: ^butyl, t Bu: tert-butyl, Et: ethyl, Me: methyl, Ms: methanesulfonyl, Ph: phenyl, Tf: trifluoromethylsulfonyl
DMSO-d ₆ : Heavy dimethyl sulfoxide

１−（ｔｅｒｔ−ブトキシカルボニル）ピペラジン2.1g、（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）アセトアルデヒド2.4gおよび酢酸0.64mLの塩化メチレン55mL溶液に、水冷下、トリアセトキシ水素化ホウ素ナトリウム2.9gを加え、25時間攪拌した。反応混合物に水50mLおよび酢酸エチル100mLを加えた。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、淡黄色油状物のｔｅｒｔ−ブチル＝４−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペラジン−１−カルボキシラート4.5gを得た。
¹H-NMR(CDCl₃)δ値：1.46(9H,s),2.40-2.50(4H,m),2.50-2.60(2H,m),2.65-2.75(2H,m),3.40-3.50(4H,m),4.24(4H,s),6.66(1H,dd,J=8.2,2.0Hz),6.71(1H,d,J=2.0Hz),6.78(1H,d,J=8.2Hz)Reference example 1

To a solution of 2.1 g of 1- (tert-butoxycarbonyl) piperazine, 2.4 g of (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) acetaldehyde and 0.64 mL of acetic acid in 55 mL of methylene chloride under water cooling, 2.9 g of sodium triacetoxyborohydride was added and stirred for 25 hours. 50 mL of water and 100 mL of ethyl acetate were added to the reaction mixture. 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 silica gel column chromatography [eluent: hexane: ethyl acetate = 1: 1], and tert-butyl 4- (2- (2,3-dihydrobenzo [b [1,4] dioxin-6-yl) ethyl) piperazine-1-carboxylate (4.5 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.46 (9H, s), 2.40-2.50 (4H, m), 2.50-2.60 (2H, m), 2.65-2.75 (2H, m), 3.40-3.50 (4H , m), 4.24 (4H, s), 6.66 (1H, dd, J = 8.2, 2.0Hz), 6.71 (1H, d, J = 2.0Hz), 6.78 (1H, d, J = 8.2Hz)

ｔｅｒｔ−ブチル＝４−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペラジン−１−カルボキシラート4.5gの塩化メチレン溶液13mLに、トリフルオロ酢酸13mLを加え、2時間攪拌した。減圧下で溶媒を留去し、1.6mol/L塩化水素/酢酸エチル30mLを加え、減圧下で溶媒を留去し、淡橙色固体の１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペラジンの塩酸塩3.2gを得た。
¹H-NMR(DMSO-d₆)δ値：2.90-3.00(2H,m),3.20-3.60(10H,m),4.21(4H,s),6.70-6.75(1H,m),6.75-6.85(2H,m),9.79(2H,broad)Reference example 2

tert-Butyl = 4- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperazine-1-carboxylate (4.5 g) in methylene chloride solution (13 mL) was mixed with trifluoroacetic acid. 13 mL was added and stirred for 2 hours. The solvent was distilled off under reduced pressure, 30 ml of 1.6 mol / L hydrogen chloride / ethyl acetate was added, the solvent was distilled off under reduced pressure, and 1- (2- (2,3-dihydrobenzo [b] 3.2 g of [1,4] dioxin-6-yl) ethyl) piperazine hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.90-3.00 (2H, m), 3.20-3.60 (10H, m), 4.21 (4H, s), 6.70-6.75 (1H, m), 6.75-6.85 (2H, m), 9.79 (2H, broad)

イソニペコチン酸0.30gのＮ，Ｎ−ジメチルホルムアミド13mL溶液に、25℃で（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）アセトアルデヒド0.21gおよび酢酸0.13mLを加え、攪拌後、トリアセトキシ水素化ホウ素ナトリウム0.37gを加え、2時間10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；クロロホルム：メタノール：トリフルオロ酢酸＝４０：１０：１］で精製した。得られた物質に水2mLおよび水酸化ナトリウム96mgを加え、炭酸ガスを吹き込んだ。ついで、6.0mol/L塩酸でpH3.0に調整し、炭酸ガスを吹き込んだ。析出物をろ取し、白色固体の１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸0.17gを得た。ろ液を水酸化ナトリウム水溶液でpH7.5に調整し、逆相シリカゲルカラムクロマトグラフィー［溶離液；アセトニトリル：水＝１：４］で精製し、ジエチルエーテルを加え、析出物をろ取し、白色固体の１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸61mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.45-1.55(2H,m),1.70-1.80(2H,m),1.90-2.00(2H,m),2.10-2.20(1H,m),2.35-2.45(2H,m),2.55-2.60(2H,m),2.75-2.85(2H,m),4.19(4H,s),6.60-6.75(3H,m)Reference example 3

To a solution of 0.30 g of isonipecotic acid in 13 mL of N, N-dimethylformamide was added 0.21 g of (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) acetaldehyde and 0.13 mL of acetic acid at 25 ° C. and stirred. Thereafter, 0.37 g of sodium triacetoxyborohydride was added and stirred for 2 hours and 10 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol: trifluoroacetic acid = 40: 10: 1]. 2 mL of water and 96 mg of sodium hydroxide were added to the obtained material, and carbon dioxide gas was blown into the material. Next, the pH was adjusted to 3.0 with 6.0 mol / L hydrochloric acid, and carbon dioxide gas was blown into the system. The precipitate was collected by filtration to obtain 0.17 g of 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxylic acid as a white solid. The filtrate was adjusted to pH 7.5 with an aqueous sodium hydroxide solution and purified by reverse phase silica gel column chromatography [eluent: acetonitrile: water = 1: 4], diethyl ether was added, and the precipitate was collected by filtration and white. 61 mg of solid 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxylic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.45-1.55 (2H, m), 1.70-1.80 (2H, m), 1.90-2.00 (2H, m), 2.10-2.20 (1H, m), 2.35 -2.45 (2H, m), 2.55-2.60 (2H, m), 2.75-2.85 (2H, m), 4.19 (4H, s), 6.60-6.75 (3H, m)

（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）アセトアルデヒド3.5gのジクロロエタン17.5mL溶液に、室温でイソニペコチン酸エチルエステル3.0mLを加え、20分間攪拌した。ついで、酢酸1.1mLを加え、30分間攪拌した後、同温度でトリアセトキシ水素化ホウ素ナトリウム6.2gを加え、1時間攪拌した。反応混合物に水20mL、クロロホルム20mLおよび6.0mol/L塩酸を加え、pH1.0に調整した。有機層を分取し、水および飽和炭酸水素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＝１：１］で精製した。得られた油状物を酢酸エチルに溶解させ、水および6.0mol/L塩酸を加え、pH1.0に調整した。水層を分取し、有機層を1.0mol/L塩酸で抽出した。水層および抽出液を合わせ、酢酸エチルで洗浄した。水層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、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、黄色油状物のエチル＝１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボキシラート2.1gを得た。
¹H-NMR(CDCl₃)δ値：1.25(3H,t,J=7.1Hz),1.74-1.83(2H,m),1.85-1.95(2H,m),2.00-2.15(2H,m),2.25-2.35(1H,m),2.50-2.60(2H,m),2.65-2.75(2H,m),2.90-3.00(2H,m),4.13(2H,q,J=7.1Hz),4.23(4H,s),6.66(1H,dd,J=8.2,2.1Hz),6.71(1H,d,J=2.1Hz),6.77(1H,d,J=8.2Hz)Reference example 4

To a solution of 3.5 g of (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) acetaldehyde in 17.5 mL of dichloroethane was added 3.0 mL of isonipecotic acid ethyl ester at room temperature and stirred for 20 minutes. Next, 1.1 mL of acetic acid was added and stirred for 30 minutes, and then 6.2 g of sodium triacetoxyborohydride was added at the same temperature and stirred for 1 hour. 20 mL of water, 20 mL of chloroform and 6.0 mol / L hydrochloric acid were added to the reaction mixture to adjust to pH 1.0. The organic layer was separated, washed successively with water and saturated aqueous sodium hydrogen carbonate 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 = 1: 1]. The obtained oil was dissolved in ethyl acetate, and water and 6.0 mol / L hydrochloric acid were added to adjust to pH 1.0. The aqueous layer was separated, and the organic layer was extracted with 1.0 mol / L hydrochloric acid. The aqueous layer and the extract were combined and washed with ethyl acetate. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the aqueous layer to adjust to pH 7.8. 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 yellow oily substance ethyl = 1- (2- (2,3-dihydrobenzo [B] 2.1 g of [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.25 (3H, t, J = 7.1 Hz), 1.74-1.83 (2H, m), 1.85-1.95 (2H, m), 2.00-2.15 (2H, m), 2.25-2.35 (1H, m), 2.50-2.60 (2H, m), 2.65-2.75 (2H, m), 2.90-3.00 (2H, m), 4.13 (2H, q, J = 7.1Hz), 4.23 ( 4H, s), 6.66 (1H, dd, J = 8.2, 2.1Hz), 6.71 (1H, d, J = 2.1Hz), 6.77 (1H, d, J = 8.2Hz)

エチル＝１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボキシラート2.0gのエタノール10mL溶液に、室温で1.0mol/L水酸化ナトリウム水溶液12.5mLを加え、1時間攪拌した。減圧下で溶媒を留去し、水および酢酸エチルを加えた。水層を分取し、有機層を水で抽出した。水層と抽出液を合わせ、酢酸エチルで洗浄した。水層に6.0mol/L塩酸を加え、pH7.0に調整した後、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；アセトニトリル：水＝１：９］で精製し、白色固体の１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸1.4gを得た。
¹H-NMRは、参考例３のデータと一致した。Reference Example 5

Ethyl = 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxylate 2.0 g in ethanol 10 mL solution at room temperature 1.0 mol / L Sodium hydroxide aqueous solution 12.5mL was added and it stirred for 1 hour. The solvent was distilled off under reduced pressure, and water and ethyl acetate were added. The aqueous layer was separated and the organic layer was extracted with water. The aqueous layer and the extract were combined and washed with ethyl acetate. 6.0 mol / L hydrochloric acid was added to the aqueous layer to adjust to pH 7.0, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by reverse phase silica gel column chromatography [eluent: acetonitrile: water = 1: 9] to give 1- (2- (2,3-dihydrobenzo [b] [1,4] Dioxin-6-yl) ethyl) piperidine-4-carboxylic acid 1.4 g was obtained.
¹ H-NMR agreed with the data of Reference Example 3.

８−アミノ−２−メトキシキノリン1.0gの酢酸21mL溶液に、氷冷下、臭素0.39mLの酢酸15mL溶液を分割して添加した。反応混合物に飽和チオ硫酸ナトリウム水溶液10mLおよび酢酸エチル50mLを加え、20％水酸化ナトリウム水溶液でpH5.6に調整した。有機層を分取し、水層を酢酸エチル50mL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、ヘキサンを加え、析出物をろ取し、白色固体の５−ブロモ−２−メトキシキノリン−８−アミン0.56gを得た。
¹H-NMR(CDCl₃)δ値：4.07(3H,s),4.76(2H,s),6.79(1H,d,J=8.2Hz),6.98(1H,d,J=9.0Hz),7.41(1H,d,J=8.2Hz),8.29(1H,d,J=9.0Hz)Reference Example 6

To a 21 mL acetic acid solution of 1.0 g of 8-amino-2-methoxyquinoline, a 15 mL acetic acid solution of 0.39 mL bromine was added in portions under ice cooling. To the reaction mixture, 10 mL of saturated aqueous sodium thiosulfate solution and 50 mL of ethyl acetate were added, and the pH was adjusted to 5.6 with 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted twice with 50 mL of 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 = 10: 1], hexane was added, the precipitate was collected by filtration, and white solid 5-bromo-2-methoxyquinoline- 0.56 g of 8-amine was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 4.07 (3H, s), 4.76 (2H, s), 6.79 (1H, d, J = 8.2 Hz), 6.98 (1H, d, J = 9.0 Hz), 7.41 (1H, d, J = 8.2Hz), 8.29 (1H, d, J = 9.0Hz)

８−アミノ−２−メトキシキノリン0.20gのピリジン2.2mL溶液に、氷冷下、1.0mol/L一塩化ヨウ素/塩化メチレン1.1mLを加え、30分間攪拌した。反応混合物に酢酸エチル20mLおよび飽和チオ硫酸ナトリウム水溶液10mLを加え、20％水酸化ナトリウム水溶液でpH11.0に調整した。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、ヘキサンを加え、析出物をろ取し、白色固体の５−ヨード−２−メトキシキノリン−８−アミン0.21gを得た。
¹H-NMR(CDCl₃)δ値：4.07(3H,s),4.80(2H,s),6.69(1H,d,J=8.1Hz),6.94(1H,d,J=9.0Hz),7.67(1H,dd,J=8.1,0.74Hz),8.15(1H,dd,J=9.0,0.74Hz)Reference Example 7

To a 2.2 mL pyridine solution of 0.20 g of 8-amino-2-methoxyquinoline, 1.0 mL / L iodine monochloride / methylene chloride (1.1 mL) was added under ice cooling, and the mixture was stirred for 30 minutes. To the reaction mixture, 20 mL of ethyl acetate and 10 mL of a saturated aqueous sodium thiosulfate solution were added, and the pH was adjusted to 11.0 with a 20% aqueous sodium hydroxide solution. 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 [eluent: hexane: ethyl acetate = 10: 1], hexane was added, the precipitate was collected by filtration, and white solid 5-iodo-2-methoxyquinoline- 0.21 g of 8-amine was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 4.07 (3H, s), 4.80 (2H, s), 6.69 (1H, d, J = 8.1 Hz), 6.94 (1H, d, J = 9.0 Hz), 7.67 (1H, dd, J = 8.1,0.74Hz), 8.15 (1H, dd, J = 9.0,0.74Hz)

５−ヨード−２−メトキシキノリン−８−アミン0.21gのＮ，Ｎ−ジメチルアセトアミド2.0mL溶液に、トリエチルアミン0.29mL、ｔｅｒｔ−ブチル＝アクリラート0.15mLおよび酢酸パラジウム（II）16mgを加え、窒素気流下、100〜110℃で6時間加熱した。反応混合物に水10mLおよび酢酸エチル10mLを加えた。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＝５：１］で精製し、黄色油状物のｔｅｒｔ−ブチル＝（Ｅ）−３−（８−アミノ−２−メトキシキノリン−５−イル）アクリラート0.16gを得た。
¹H-NMR(CDCl₃)δ値：1.55(9H,s),4.06(3H,s),5.04(2H,s),6.32(1H,d,J=15.6Hz),6.89(1H,d,J=8.4Hz),6.98(1H,d,J=9.0Hz),7.58(1H,d,J=8.4Hz),8.20(1H,d,J=15.6Hz),8.39(1H,d,J=9.0Hz)Reference Example 8

To a solution of 0.21 g of 5-iodo-2-methoxyquinolin-8-amine in 2.0 mL of N, N-dimethylacetamide was added 0.29 mL of triethylamine, 0.15 mL of tert-butyl acrylate and 16 mg of palladium (II) acetate, and a nitrogen stream was added. And heated at 100-110 ° C. for 6 hours. 10 mL of water and 10 mL of ethyl acetate were added to the reaction mixture. 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 silica gel column chromatography [eluent: hexane: ethyl acetate = 5: 1], and tert-butyl = (E) -3- (8-amino-2-methoxyquinoline as a yellow oily substance. 0.16 g of -5-yl) acrylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.55 (9H, s), 4.06 (3H, s), 5.04 (2H, s), 6.32 (1H, d, J = 15.6 Hz), 6.89 (1H, d, J = 8.4Hz), 6.98 (1H, d, J = 9.0Hz), 7.58 (1H, d, J = 8.4Hz), 8.20 (1H, d, J = 15.6Hz), 8.39 (1H, d, J = 9.0Hz)

ｔｅｒｔ−ブチル＝（Ｅ）−３−（８−アミノ−２−メトキシキノリン−５−イル）アクリラート0.16gのエタノール2.7mL溶液に、10％パラジウム−炭素32mgを加え、水素雰囲気下、1時間攪拌した。不溶物をろ去し、減圧下で溶媒を留去し、黄色固体のｔｅｒｔ−ブチル＝３−（８−アミノ−２−メトキシキノリン−５−イル）プロピオナート0.13gを得た。
¹H-NMR(CDCl₃)δ値：1.43(9H,s),2.56(2H,t,J=7.9Hz),3.19(2H,t,J=7.9Hz),4.07(3H,s),6.94(1H,d,J=9.2Hz),6.99(1H,d,J=7.6Hz),7.07(1H,d,J=7.6Hz),8.17(1H,d,J=9.2Hz)Reference Example 9

tert-Butyl (E) -3- (8-amino-2-methoxyquinolin-5-yl) acrylate 0.16 g of ethanol 2.7 mL solution was added with 10% palladium-carbon 32 mg and stirred under hydrogen atmosphere for 1 hour. did. Insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 0.13 g of tert-butyl 3- (8-amino-2-methoxyquinolin-5-yl) propionate as a yellow solid.
¹ H-NMR (CDCl ₃ ) δ values: 1.43 (9H, s), 2.56 (2H, t, J = 7.9 Hz), 3.19 (2H, t, J = 7.9 Hz), 4.07 (3H, s), 6.94 (1H, d, J = 9.2Hz), 6.99 (1H, d, J = 7.6Hz), 7.07 (1H, d, J = 7.6Hz), 8.17 (1H, d, J = 9.2Hz)

（１）１−（ｔｅｒｔ−ブトキシカルボニル）ピペリジン−４−カルボン酸0.79gおよび８−アミノ−２−メトキシキノリン0.50gのＮ，Ｎ−ジメチルホルムアミド6mL溶液に、室温でトリエチルアミン1.2mLおよびＯ−（７−アザベンゾトリアゾール−１−イル）−１，１，３，３−テトラメチルウロニウム＝ヘキサフルオロホスフェート1.7gを加え、2時間10分間攪拌した。Ｏ−（７−アザベンゾトリアゾール−１−イル）−１，１，３，３−テトラメチルウロニウム＝ヘキサフルオロホスフェート0.55gを加え、30分間攪拌した。反応混合物を酢酸エチル20mLおよび水20mL混液に加えた。有機層を分取し、水層を酢酸エチル20mLで抽出した。有機層および抽出液を合わせ、飽和塩化アンモニウム水溶液、飽和炭酸水素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、褐色油状物のｔｅｒｔ−ブチル＝４−（２−メトキシキノリン−８−イルカルバモイル）ピペリジン−1−カルボキシラートを得た。
（２）得られたｔｅｒｔ−ブチル＝４−（２−メトキシキノリン−８−イルカルバモイル）ピペリジン−１−カルボキシラートのエタノール10mL溶液に、10mol/L塩化水素/メタノール10mLを加え、１時間30分間攪拌した後、減圧下で溶媒を留去した。得られた残留物をクロロホルム、酢酸エチル、ジエチルエーテルおよびメタノールの混液に溶解し、炭酸カリウムを加え、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［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Ｎ−（２−メトキシキノリン−８−イル）ピペリジン−４−カルボキサミド1.0gを得た。
¹H-NMR(DMSO-d₆)δ値：1.85-1.95(2H,m),2.10-2.15(2H,m),2.90-3.05(3H,m),3.30-3.70(2H,m),4.11(3H,s),7.11(1H,d,J=9.0Hz),7.41(1H,t,J=7.6Hz),7.62(1H,d,J=7.6Hz),8.29(1H,d,J=9.0Hz),8.46(1H,d,J=7.6Hz),9.69(1H,s)Reference Example 10

(1) To a solution of 0.79 g of 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid and 0.50 g of 8-amino-2-methoxyquinoline in 6 mL of N, N-dimethylformamide at room temperature, 1.2 mL of triethylamine and O- ( 7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium = hexafluorophosphate (1.7 g) was added, and the mixture was stirred for 2 hours and 10 minutes. 0.55 g of O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium = hexafluorophosphate was added and stirred for 30 minutes. The reaction mixture was added to a mixture of 20 mL ethyl acetate and 20 mL water. The organic layer was separated, and the aqueous layer was extracted with 20 mL of ethyl acetate. The organic layer and the extract were combined, washed successively with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, evaporated under reduced pressure to give a brown oily tert- Butyl = 4- (2-methoxyquinolin-8-ylcarbamoyl) piperidine-1-carboxylate was obtained.
(2) 10 mL of 10 mol / L hydrogen chloride / methanol was added to 10 mL of ethanol solution of the obtained tert-butyl 4- (2-methoxyquinolin-8-ylcarbamoyl) piperidine-1-carboxylate for 1 hour 30 minutes. After stirring, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in a mixed solution of chloroform, ethyl acetate, diethyl ether and methanol, potassium carbonate was added, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 10: 1] to obtain 1.0 g of white solid N- (2-methoxyquinolin-8-yl) piperidine-4-carboxamide. It was.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.85-1.95 (2H, m), 2.10-2.15 (2H, m), 2.90-3.05 (3H, m), 3.30-3.70 (2H, m), 4.11 (3H, s), 7.11 (1H, d, J = 9.0Hz), 7.41 (1H, t, J = 7.6Hz), 7.62 (1H, d, J = 7.6Hz), 8.29 (1H, d, J = 9.0Hz), 8.46 (1H, d, J = 7.6Hz), 9.69 (1H, s)

２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルアミン3.0gのクロロホルム80mL溶液に、Ｎ，Ｎ’−カルボニルジイミダゾール4.2gを加え、45分間加熱還流した。反応混合物を室温まで冷却し、エチル＝イソニペコタート3.1gのクロロホルム20mL溶液を加え、室温で30分間攪拌し、トリエチルアミン2.8mLを加え、1時間25分間攪拌した。析出物をろ去し、塩化アンモニウム水溶液50mLを加えた。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：アセトン＝５０：１］で精製し、褐色泡状物のエチル＝１−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）カルバモイル）ピペリジン−４−カルボキシラート3.0gを得た。
¹H-NMR(CDCl₃)δ値：1.27(3H,t,J=7.2Hz),1.65-1.80(2H,m),1.90-2.00(2H,m),2.48-2.54(1H,m),2.95-3.05(2H,m),3.90-4.00(2H,m),4.16(2H,q,J=7.2Hz),4.20-4.25(4H,m),6.19(1H,s),6.70-6.80(2H,m),6.92(1H,d,J=2.4Hz)Reference Example 11

To a solution of 3.0 g of 2,3-dihydrobenzo [b] [1,4] dioxin-6-ylamine in 80 mL of chloroform was added 4.2 g of N, N′-carbonyldiimidazole, and the mixture was heated to reflux for 45 minutes. The reaction mixture was cooled to room temperature, ethyl = isonipecotate 3.1 g in chloroform (20 mL) was added, and the mixture was stirred at room temperature for 30 min, triethylamine (2.8 mL) was added, and the mixture was stirred for 1 hr 25 min. The precipitate was removed by filtration, and 50 mL of an aqueous ammonium chloride solution was 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 silica gel column chromatography [eluent: chloroform: acetone = 50: 1] to give brown foam ethyl = 1-((2,3-dihydrobenzo [b] [1,4 Dioxin-6-yl) carbamoyl) piperidine-4-carboxylate (3.0 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.27 (3H, t, J = 7.2 Hz), 1.65-1.80 (2H, m), 1.90-2.00 (2H, m), 2.48-2.54 (1H, m), 2.95-3.05 (2H, m), 3.90-4.00 (2H, m), 4.16 (2H, q, J = 7.2Hz), 4.20-4.25 (4H, m), 6.19 (1H, s), 6.70-6.80 ( 2H, m), 6.92 (1H, d, J = 2.4Hz)

エチル＝１−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）カルバモイル）ピペリジン−４−カルボキシラート2.0gのテトラヒドロフラン−水（1：1）40mL混液に、氷冷下、水酸化ナトリウム0.26gを加え、室温で3時間攪拌した。反応混合物にトルエン20mLおよび水30mLを加え、不溶物をろ去した。水層を分取し、トルエン20mLで洗浄し、酢酸エチル50mLを加え、6.0mol/L塩酸でpH1.5に調整した。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、淡黄色固体の１−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）カルバモイル）ピペリジン−４−カルボン酸1.3gを得た。
¹H-NMR(DMSO-d₆)δ値：1.40-1.50(2H,m),1.75-1.85(2H,m),2.40-2.55(1H,m),2.80-2.90(2H,m),3.95-4.00(2H,m),4.15-4.20(4H,m),6.69(1H,d,J=8.8Hz),6.85(1H,dd,J=8.8,2.4Hz),7.03(1H,d,J=2.4Hz),8.28(1H,s)Reference Example 12

Ethyl = 1-((2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) carbamoyl) piperidine-4-carboxylate (2.0 g) in tetrahydrofuran-water (1: 1) 40 mL mixture with ice Under cooling, 0.26 g of sodium hydroxide was added, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture, 20 mL of toluene and 30 mL of water were added, and insoluble materials were removed by filtration. The aqueous layer was separated, washed with 20 mL of toluene, added with 50 mL of ethyl acetate, and adjusted to pH 1.5 with 6.0 mol / L hydrochloric acid. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 1-((2,3-dihydrobenzo [b] [1,4] dioxin-6-yl as a pale yellow solid. ) 1.3 g of carbamoyl) piperidine-4-carboxylic acid were obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.40-1.50 (2H, m), 1.75-1.85 (2H, m), 2.40-2.55 (1H, m), 2.80-2.90 (2H, m), 3.95 -4.00 (2H, m), 4.15-4.20 (4H, m), 6.69 (1H, d, J = 8.8Hz), 6.85 (1H, dd, J = 8.8,2.4Hz), 7.03 (1H, d, J = 2.4Hz), 8.28 (1H, s)

２，３−ジヒドロ−１，４−ベンゾジオキシン−６−イル＝イソチオシアナート1.0gのアンモニア水1.6mLおよびジオキサン1.6mL混液を30分間攪拌した。反応混合物にジエチルエーテルを加えた後、析出物をろ取し、白色固体の１−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）チオウレア1.0gを得た。
¹H-NMR(DMSO-d₆)δ値：3.30(2H,s),4.22(4H,s),6.70-6.75(1H,m),6.75-6.80(1H,m),6.85-6.95(1H,m),9.46(1H,s)Reference Example 13

A mixture of 1.6 mL of aqueous ammonia of 1.0 g of 2,3-dihydro-1,4-benzodioxin-6-yl isothiocyanate and 1.6 mL of dioxane was stirred for 30 minutes. Diethyl ether was added to the reaction mixture, and then the precipitate was collected by filtration to obtain 1.0 g of 1- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) thiourea as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.30 (2H, s), 4.22 (4H, s), 6.70-6.75 (1H, m), 6.75-6.80 (1H, m), 6.85-6.95 (1H , m), 9.46 (1H, s)

１−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）チオウレア1.0gのアセトン5.0mLおよびメタノール10mL混液に、ヨウ化メチル0.30mLを加え、1時間50分間加熱還流した。反応混合物を室温まで冷却し、減圧下で溶媒を留去し、淡橙色泡状物の１−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）−２−メチルイソチオウレアのヨウ化水素酸塩1.8gを得た。
¹H-NMR(DMSO-d₆)δ値：2.65(3H,s),4.27(4H,s),6.78(1H,dd,J=8.5,2.4Hz),6.88(1H,d,J=2.4Hz),6.97(1H,d,J=8.5Hz)Reference Example 14

1- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) thiourea (1.0 g) in acetone (5.0 mL) and methanol (10 mL) was added with 0.30 mL of methyl iodide and heated to reflux for 1 hour and 50 minutes. did. The reaction mixture was cooled to room temperature, evaporated under reduced pressure, and pale orange foam 1- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -2-methyl. 1.8 g of isothiourea hydroiodide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.65 (3H, s), 4.27 (4H, s), 6.78 (1H, dd, J = 8.5, 2.4 Hz), 6.88 (1H, d, J = 2.4 Hz), 6.97 (1H, d, J = 8.5Hz)

１−（ｔｅｒｔ−ブトキシカルボニル）ピペリジン−４−カルボン酸0.14gのＮ，Ｎ−ジメチルホルムアミド2mL溶液に、氷冷下、Ｎ，Ｎ’−カルボニルジイミダゾール0.10gを加え、室温で1時間攪拌した後、７−メトキシイソキノリン−１−アミン0.10gを加え、同温度で1時間、40℃で1時間、50℃で1時間攪拌した。反応混合物に酢酸エチル20mLおよび水20mLを加えた後、1.0mol/L塩酸を加え、pH3.0に調整した。有機層を分取し、水層を酢酸エチル10mLで抽出した。有機層および抽出液を合わせ、飽和炭酸水素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、淡褐色固体のｔｅｒｔ−ブチル＝４−（（７−メトキシイソキノリン−１−イル）カルバモイル）ピペリジン−１−カルボキシラート0.17gを得た。
¹H-NMR(DMSO-d₆)δ値：1.41(9H,s),1.51-1.61(2H,m),1.89-1.92(2H,m),2.70-2.90(3H,m),3.86(3H,s),4.00-4.04(2H,m),7.15-7.20(1H,m),7.44(1H,dd,J=9.0,2.4Hz),7.67(1H,d,J=5.6Hz),7.92(1H,d,J=9.0Hz),8.19(1H,d,J=5.6Hz),10.41(1H,s)Reference Example 15

To a solution of 0.14 g of 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid in 2 mL of N, N-dimethylformamide was added 0.10 g of N, N′-carbonyldiimidazole under ice cooling, and the mixture was stirred at room temperature for 1 hour. Thereafter, 0.10 g of 7-methoxyisoquinolin-1-amine was added, and the mixture was stirred at the same temperature for 1 hour, at 40 ° C for 1 hour, and at 50 ° C for 1 hour. After adding 20 mL of ethyl acetate and 20 mL of water to the reaction mixture, 1.0 mol / L hydrochloric acid was added to adjust the pH to 3.0. The organic layer was separated and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and tert-butyl = 4- ( 0.17 g of (7-methoxyisoquinolin-1-yl) carbamoyl) piperidine-1-carboxylate was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.41 (9H, s), 1.51-1.61 (2H, m), 1.89-1.92 (2H, m), 2.70-2.90 (3H, m), 3.86 (3H , s), 4.00-4.04 (2H, m), 7.15-7.20 (1H, m), 7.44 (1H, dd, J = 9.0,2.4Hz), 7.67 (1H, d, J = 5.6Hz), 7.92 ( 1H, d, J = 9.0Hz), 8.19 (1H, d, J = 5.6Hz), 10.41 (1H, s)

ｔｅｒｔ−ブチル＝４−（（７−メトキシイソキノリン−１−イル）カルバモイル）ピペリジン−１−カルボキシラート150mgの塩化メチレン3mL溶液に、室温でトリフルオロ酢酸1.5mLを加え、同温度で1時間攪拌した後、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30mLおよび飽和炭酸水素ナトリウム水溶液30mLを加え、水層を分取した。水層にクロロホルム30mLを加えた後、20％水酸化ナトリウム水溶液を加え、pH10.0に調整した。有機層を分取し、水層をクロロホルム10mL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、淡褐色固体のＮ−（７−メトキシイソキノリン−１−イル）ピペリジン−４−カルボキサミド70mgを得た。
¹H-NMR(CDCl₃)δ値：1.77-1.86(2H,m),2.03-2.06(2H,m),2.69-2.75(3H,m),3.18-3.21(2H,m),3.93(3H,s),7.00-8.50(5H,m)Reference Example 16

tert-Butyl = 4-((7-methoxyisoquinolin-1-yl) carbamoyl) piperidine-1-carboxylate (150 mg) in methylene chloride (3 mL) was added 1.5 mL of trifluoroacetic acid at room temperature and stirred at the same temperature for 1 hour. Thereafter, the solvent was distilled off under reduced pressure. To the obtained residue, 30 mL of chloroform and 30 mL of saturated aqueous sodium hydrogen carbonate solution were added, and the aqueous layer was separated. After adding 30 mL of chloroform to the aqueous layer, 20% aqueous sodium hydroxide solution was added to adjust the pH to 10.0. The organic layer was separated, and the aqueous layer was extracted with 10 mL of 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 N- (7-methoxyisoquinolin-1-yl) piperidine- 4-Carboxamide 70 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.77-1.86 (2H, m), 2.03-2.06 (2H, m), 2.69-2.75 (3H, m), 3.18-3.21 (2H, m), 3.93 (3H , s), 7.00-8.50 (5H, m)

２，４−ジクロロキノリン1.0gの濃硫酸5.0mL溶液に、氷冷下、発煙硝酸224μLを滴下し、30分間攪拌した。室温で2時間攪拌した後、反応混合物を氷水に注ぎ、トルエン10mLを加えた後、20％水酸化ナトリウム水溶液を加え、pH12.0に調整した。不溶物をろ去し、ろ滓をトルエン10mLで洗浄した。有機層を分取し、水層をトルエン10mLで抽出した。有機層および抽出液を合わせ、水10mLおよび飽和塩化ナトリウム水溶液10mL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＝５：１］で精製し、淡黄色固体の２，４−ジクロロ−８−ニトロキノリン0.32gを得た。
¹H-NMR(CDCl₃)δ値：7.66(1H,s),7.72-7.76(1H,m),8.11(1H,dd,J=7.6,1.2Hz),8.44(1H,dd,J=8.5,1.2Hz)Reference Example 17

To a solution of 1.0 g of 2,4-dichloroquinoline in 5.0 mL of concentrated sulfuric acid was added dropwise 224 μL of fuming nitric acid under ice cooling, followed by stirring for 30 minutes. After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water, 10 mL of toluene was added, and then 20% aqueous sodium hydroxide solution was added to adjust to pH 12.0. The insoluble material was removed by filtration, and the filter cake was washed with 10 mL of toluene. The organic layer was separated, and the aqueous layer was extracted with 10 mL of toluene. The organic layer and the extract were combined, washed sequentially with 10 mL of water and 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 5: 1] to obtain 0.32 g of 2,4-dichloro-8-nitroquinoline as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ value: 7.66 (1H, s), 7.72-7.76 (1H, m), 8.11 (1H, dd, J = 7.6, 1.2 Hz), 8.44 (1H, dd, J = 8.5 , 1.2Hz)

28％ナトリウムメトキシド/メタノール0.30gにメタノール10mLを加えた後、２，４−ジクロロ−８−ニトロキノリン0.15gを加え、1時間30分間加熱還流した。さらに、28％ナトリウムメトキシド/メタノール0.15gを加え、2時間加熱還流した。さらに、28％ナトリウムメトキシド/メタノール0.15gを加え、１時間加熱還流した後、室温まで冷却した。反応混合物に酢酸エチル30mLおよび水30mLを加えた。有機層を分取し、水層を酢酸エチル10mLで抽出した。有機層および抽出液を合わせ、水10mLおよび飽和塩化ナトリウム水溶液10mL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。得られた残留物にヘキサンを加え、析出物をろ取し、淡褐色固体の２，４−ジメトキシ−８−ニトロキノリン0.14gを得た。
¹H-NMR(CDCl₃)δ値：4.03(3H,s),4.04(3H,s),6.31(1H,s),7.36(1H,dd,J=8.2,7.6Hz),7.93(1H,dd,J=7.6,1.5Hz),8.24(1H,dd,J=8.2,1.5Hz)Reference Example 18

10 mL of methanol was added to 0.30 g of 28% sodium methoxide / methanol, 0.15 g of 2,4-dichloro-8-nitroquinoline was added, and the mixture was heated to reflux for 1 hour 30 minutes. Furthermore, 0.15 g of 28% sodium methoxide / methanol was added, and the mixture was heated to reflux for 2 hours. Further, 0.15 g of 28% sodium methoxide / methanol was added, and the mixture was heated to reflux for 1 hour and then cooled to room temperature. To the reaction mixture were added 30 mL of ethyl acetate and 30 mL of water. The organic layer was separated and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed sequentially with 10 mL of water and 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Hexane was added to the obtained residue, and the precipitate was collected by filtration to obtain 0.14 g of 2,4-dimethoxy-8-nitroquinoline as a light brown solid.
¹ H-NMR (CDCl ₃ ) δ value: 4.03 (3H, s), 4.04 (3H, s), 6.31 (1H, s), 7.36 (1H, dd, J = 8.2, 7.6 Hz), 7.93 (1H, dd, J = 7.6,1.5Hz), 8.24 (1H, dd, J = 8.2,1.5Hz)

２，４−ジメトキシ−８−ニトロキノリン0.14gの酢酸10mL懸濁液に、室温で10％パラジウム−炭素28mgを加え、水素雰囲気下で2時間攪拌した。不溶物をろ去し、減圧下で溶媒を留去した。得られた残留物に酢酸エチル30mLおよび飽和炭酸水素ナトリウム水溶液30mLを加えた。有機層を分取し、水層を酢酸エチル20mL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＝３：１］で精製し、白色固体の２，４−ジメトキシキノリン−８−アミン52mgを得た。
¹H-NMR(CDCl₃)δ値：3.97(3H,s),4.03(3H,s),4.69(2H,s),6.21(1H,s),6.90(1H,dd,J=7.6,1.2Hz),7.13(1H,dd,J=8.3,7.6Hz),7.40(1H,dd,J=8.3,1.2Hz)Reference Example 19

To a suspension of 0.14 g of 2,4-dimethoxy-8-nitroquinoline in 10 mL of acetic acid was added 28 mg of 10% palladium-carbon at room temperature, and the mixture was stirred under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. To the obtained residue, 30 mL of ethyl acetate and 30 mL of saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated, and the aqueous layer was extracted with 20 mL of 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 = 3: 1] to obtain 52 mg of 2,4-dimethoxyquinolin-8-amine as a white solid.
¹ H-NMR (CDCl ₃ ) δ value: 3.97 (3H, s), 4.03 (3H, s), 4.69 (2H, s), 6.21 (1H, s), 6.90 (1H, dd, J = 7.6, 1.2 Hz), 7.13 (1H, dd, J = 8.3,7.6Hz), 7.40 (1H, dd, J = 8.3,1.2Hz)

２−クロロ−３−メチルキノリン2.0gの濃硫酸10mL溶液に、氷冷下、発煙硝酸0.5mLを滴下し、室温で5時間攪拌した。反応混合物を氷水に注ぎ、析出物をろ取し、水50mLで洗浄し、橙色固体を得た。得られた固体にクロロホルム30mLおよび水20mLを加え、20％水酸化ナトリウム水溶液を加え、pH12.0に調整した。有機層を分取し、水層をクロロホルム20mL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＝３：１］で精製し、橙色固体の２−クロロ−３−メチル−８−ニトロキノリン0.62gを得た。
¹H-NMR(CDCl₃)δ値：2.58(3H,s),7.58-7.62(1H,m),7.97(1H,d,J=8.3Hz),8.03(1H,d,J=7.6Hz),8.07(1H,s)Reference Example 20

To a 10 mL concentrated sulfuric acid solution of 2.0 g of 2-chloro-3-methylquinoline, 0.5 mL of fuming nitric acid was added dropwise under ice cooling, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into ice water, and the precipitate was collected by filtration and washed with 50 mL of water to obtain an orange solid. To the obtained solid, 30 mL of chloroform and 20 mL of water were added, and 20% aqueous sodium hydroxide solution was added to adjust to pH 12.0. The organic layer was separated, and the aqueous layer was extracted with 20 mL of 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 silica gel column chromatography [eluent: hexane: ethyl acetate = 3: 1] to obtain 0.62 g of 2-chloro-3-methyl-8-nitroquinoline as an orange solid.
¹ H-NMR (CDCl ₃ ) δ value: 2.58 (3H, s), 7.58-7.62 (1H, m), 7.97 (1H, d, J = 8.3 Hz), 8.03 (1H, d, J = 7.6 Hz) , 8.07 (1H, s)

２−クロロ−３−メチル−８−ニトロキノリン0.30gのメタノール10mL懸濁液に、28％ナトリウムメトキシド/メタノール0.39gを加え、2時間加熱還流した。反応混合物を室温まで冷却し、酢酸エチル30mLおよび水20mLを加えた。有機層を分取し、水層を酢酸エチル10mL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。得られた残留物にヘキサンを加え、不溶物をろ取し、淡桃色固体の２−メトキシ−３−メチル−８−ニトロキノリン0.25gを得た。
¹H-NMR(CDCl₃)δ値：2.36(3H,s),4.09(3H,s),7.36-7.40(1H,m),7.83-7.85(2H,m),7.91(1H,dd,J=7.6,1.2Hz)Reference Example 21

To a 10 mL suspension of 2-chloro-3-methyl-8-nitroquinoline 0.30 g in methanol was added 28% sodium methoxide / methanol 0.39 g and heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and 30 mL of ethyl acetate and 20 mL of water were added. The organic layer was separated and the aqueous layer was extracted with 10 mL of 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. Hexane was added to the obtained residue, and insoluble matter was collected by filtration to obtain 0.25 g of 2-methoxy-3-methyl-8-nitroquinoline as a pale pink solid.
¹ H-NMR (CDCl ₃ ) δ value: 2.36 (3H, s), 4.09 (3H, s), 7.36-7.40 (1H, m), 7.83-7.85 (2H, m), 7.91 (1H, dd, J = 7.6,1.2Hz)

２−メトキシ−３−メチル−８−ニトロキノリン0.22gの酢酸10mL懸濁液に、室温で10％パラジウム−炭素44mgを加え、水素雰囲気下で2時間攪拌した。不溶物をろ去し、ろ滓をクロロホルム20mLで2回洗浄し、減圧下で溶媒を留去した。得られた残留物に酢酸エチル30mLおよび飽和炭酸水素ナトリウム水溶液20mLを加え、有機層を分取し、水層を酢酸エチル20mL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＝３：１］で精製し、淡黄緑色固体の２−メトキシ−３−メチルキノリン−８−アミン0.18gを得た。
¹H-NMR(CDCl₃)δ値：2.32(3H,d,J=0.98Hz),4.08(3H,s),4.50-4.90(2H,broad),6.86(1H,dd,J=7.6,1.2Hz),7.04(1H,dd,J=8.0,1.2Hz),7.13-7.17(1H,m),7.70(1H,d,J=0.98Hz)Reference Example 22

To a suspension of 0.22 g of 2-methoxy-3-methyl-8-nitroquinoline in 10 mL of acetic acid was added 44 mg of 10% palladium-carbon at room temperature, and the mixture was stirred under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, the filter cake was washed twice with 20 mL of chloroform, and the solvent was distilled off under reduced pressure. To the obtained residue, 30 mL of ethyl acetate and 20 mL of a saturated aqueous sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with 20 mL of 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 = 3: 1] to obtain 0.18 g of 2-methoxy-3-methylquinolin-8-amine as a pale yellow green solid.
¹ H-NMR (CDCl ₃ ) δ value: 2.32 (3H, d, J = 0.98 Hz), 4.08 (3H, s), 4.50-4.90 (2H, broad), 6.86 (1H, dd, J = 7.6,1.2 Hz), 7.04 (1H, dd, J = 8.0,1.2Hz), 7.13-7.17 (1H, m), 7.70 (1H, d, J = 0.98Hz)

７−メトキシイソキノリン−１−カルバルデヒド0.50gのジメチルスルホキシド5mL溶液に、室温でトリメチルスルホニムヨージド0.71gおよび水酸化カリウム0.19gを加え、60℃で1時間攪拌した。反応混合物を室温まで冷却し、水10mLおよび酢酸エチル10mLを加えた。有機層を分取し、水層を酢酸エチル5mL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、淡黄色油状物の７−メトキシ−１−（オキシラン−２−イル）イソキノリン0.44gを得た。
¹H-NMR(CDCl₃)δ値：3.30(1H,dd,J=5.9,4.1Hz),3.37(1H,dd,J=5.9,2.6Hz),3.97(3H,s),4.56(1H,dd,J=4.1,2.6Hz),7.36(1H,dd,J=8.9,2.5Hz),7.53(1H,d,J=5.6Hz),7.61(1H,d,J=2.5Hz),7.74(1H,d,J=8.9Hz),8.39(1H,d,J=5.6Hz)Reference Example 23

To a 5 mL dimethyl sulfoxide solution of 0.50 g of 7-methoxyisoquinoline-1-carbaldehyde, 0.71 g of trimethylsulfonium iodide and 0.19 g of potassium hydroxide were added at room temperature, and the mixture was stirred at 60 ° C. for 1 hour. The reaction mixture was cooled to room temperature and 10 mL water and 10 mL ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with 5 mL of 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 obtain 0.44 g of 7-methoxy-1- (oxiran-2-yl) isoquinoline as a pale yellow oil. It was.
¹ H-NMR (CDCl ₃ ) δ value: 3.30 (1H, dd, J = 5.9, 4.1 Hz), 3.37 (1H, dd, J = 5.9, 2.6 Hz), 3.97 (3H, s), 4.56 (1H, dd, J = 4.1,2.6Hz), 7.36 (1H, dd, J = 8.9,2.5Hz), 7.53 (1H, d, J = 5.6Hz), 7.61 (1H, d, J = 2.5Hz), 7.74 ( 1H, d, J = 8.9Hz), 8.39 (1H, d, J = 5.6Hz)

７−メトキシ−１−（オキシラン−２−イル）イソキノリン0.30gのＮ，Ｎ−ジメチルホルムアミド6mL溶液に、室温で４−（（ｔｅｒｔ−ブトキシカルボニル）アミノ）ピペリジン0.36gおよび過塩素酸リチウム0.16gを加え、80℃で1時間攪拌した。反応混合物を室温まで冷却し、水10mLおよび酢酸エチル20mLを加え、有機層を分取し、水層を酢酸エチル10mL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＝9：1］で精製し、白色固体のｔｅｒｔ−ブチル＝1−（２−ヒドロキシ−２−（７−メトキシイソキノリン−１−イル）エチル）ピペリジン−４−イルカルバマート0.46gを得た。
¹H-NMR(CDCl₃)δ値：1.46-1.61(2H,m),1.46(9H,m),1.93-2.01(2H,m),2.30-2.40(2H,m),2.76-2.80(2H,m),3.01-3.13(2H,m),3.40-3.70(1H,m),3.95(3H,s),4.45-4.70(1H,m),5.50(1H,dd,J=8.4,3.2Hz),7.36(1H,dd,J=8.8,2.2Hz),7.43(1H,d,J=2.2Hz),7.53(1H,d,J=5.4Hz),7.76(1H,d,J=8.8Hz),8.35(1H,d,J=5.4Hz)Reference Example 24

To a solution of 0.30 g of 7-methoxy-1- (oxiran-2-yl) isoquinoline in 6 mL of N, N-dimethylformamide at room temperature is added 0.36 g of 4-((tert-butoxycarbonyl) amino) piperidine and 0.16 g of lithium perchlorate. And stirred at 80 ° C. for 1 hour. The reaction mixture was cooled to room temperature, 10 mL of water and 20 mL of ethyl acetate were added, the organic layer was separated, and the aqueous layer was extracted with 10 mL of 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: chloroform: methanol = 9: 1], and white solid tert-butyl = 1- (2-hydroxy-2- (7-methoxyisoquinoline-1- 0.46 g of yl) ethyl) piperidin-4-ylcarbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.46-1.61 (2H, m), 1.46 (9H, m), 1.93-2.01 (2H, m), 2.30-2.40 (2H, m), 2.76-2.80 (2H , m), 3.01-3.13 (2H, m), 3.40-3.70 (1H, m), 3.95 (3H, s), 4.45-4.70 (1H, m), 5.50 (1H, dd, J = 8.4,3.2Hz ), 7.36 (1H, dd, J = 8.8, 2.2Hz), 7.43 (1H, d, J = 2.2Hz), 7.53 (1H, d, J = 5.4Hz), 7.76 (1H, d, J = 8.8Hz) ), 8.35 (1H, d, J = 5.4Hz)

７−メトキシ−１−（オキシラン−２−イル）イソキノリン0.22gのＮ，Ｎ−ジメチルホルムアミド3mL溶液に、室温で１−（ｔｅｒｔ−ブトキシカルボニル）ピペラジン0.22gおよび過塩素酸リチウム0.11gを加え、60℃で1時間、90℃で1時間攪拌した。反応混合物を室温まで冷却し、水10mLおよび酢酸エチル10mLを加えた。有機層を分取し、水層を酢酸エチル10mL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、褐色油状物のｔｅｒｔ−ブチル＝４−（２−ヒドロキシ−２−（７−メトキシイソキノリン−１−イル）エチル）ピペラジンカルボキシラート0.33gを得た。
¹H-NMR(CDCl₃)δ値：1.47(9H,s),2.55-2.70(4H,m),2.74-2.88(2H,m),3.44-3.60(4H,m),3.96(3H,s),5.12(1H,s),5.53(1H,dd,J=8.4,2.8Hz),7.37(1H,dd,J=9.2,2.4Hz),7.41(1H,d,J=2.4Hz),7.54(1H,d,J=5.6Hz),7.77(1H,d,J=9.2Hz),8.36(1H,d,J=5.6Hz)Reference Example 25

To a solution of 0.22 g of 7-methoxy-1- (oxiran-2-yl) isoquinoline in 3 mL of N, N-dimethylformamide was added 0.22 g of 1- (tert-butoxycarbonyl) piperazine and 0.11 g of lithium perchlorate at room temperature, The mixture was stirred at 60 ° C for 1 hour and at 90 ° C for 1 hour. The reaction mixture was cooled to room temperature and 10 mL water and 10 mL ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted twice with 10 mL of 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: chloroform], and tert-butyl = 4- (2-hydroxy-2- (7-methoxyisoquinolin-1-yl) ethyl) piperazine as a brown oily substance. 0.33 g of carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.47 (9H, s), 2.55-2.70 (4H, m), 2.74-2.88 (2H, m), 3.44-3.60 (4H, m), 3.96 (3H, s ), 5.12 (1H, s), 5.53 (1H, dd, J = 8.4, 2.8Hz), 7.37 (1H, dd, J = 9.2, 2.4Hz), 7.41 (1H, d, J = 2.4Hz), 7.54 (1H, d, J = 5.6Hz), 7.77 (1H, d, J = 9.2Hz), 8.36 (1H, d, J = 5.6Hz)

ｔｅｒｔ−ブチル＝４−（２−ヒドロキシ−２−（７−メトキシイソキノリン−１−イル）エチル）ピペラジンカルボキシラート0.33gの塩化メチレン6mL溶液に、氷冷下、トリフルオロ酢酸2mLを加え、室温で1時間攪拌した後、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20mLおよび水10mLを加え、20％水酸化ナトリウム水溶液をでpH12.5に調整した。有機層を分取し、水層をクロロホルム10mL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、炭酸カリウムで乾燥させ、減圧下で溶媒を留去し、褐色油状物の１−（７−メトキシイソキノリン−１−イル）−２−（ピペラジン−１−イル）エタノール0.21gを得た。
¹H-NMR(CDCl₃)δ値：2.66-2.87(6H,m),2.94-3.03(4H,m),3.97(3H,s),5.54(1H,dd,J=8.6,3.0Hz),7.37(1H,dd,J=8.9,2.5Hz),7.48(1H,d,J=2.5Hz),7.54(1H,d,J=5.6Hz),7.77(1H,d,J=8.9Hz),8.36(1H,d,J=5.6Hz)Reference Example 26

To a solution of 0.33 g of tert-butyl = 4- (2-hydroxy-2- (7-methoxyisoquinolin-1-yl) ethyl) piperazinecarboxylate in 6 mL of methylene chloride was added 2 mL of trifluoroacetic acid under ice cooling, and at room temperature. After stirring for 1 hour, the solvent was distilled off under reduced pressure. To the obtained residue, 20 mL of chloroform and 10 mL of water were added, and the pH was adjusted to 12.5 with a 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted twice with 10 mL of chloroform. The organic layer and the extract were combined, washed with saturated aqueous sodium chloride, dried over potassium carbonate, evaporated under reduced pressure to give 1- (7-methoxyisoquinolin-1-yl) -2- 0.21 g of (piperazin-1-yl) ethanol was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.66-2.87 (6H, m), 2.94-3.03 (4H, m), 3.97 (3H, s), 5.54 (1H, dd, J = 8.6,3.0 Hz), 7.37 (1H, dd, J = 8.9,2.5Hz), 7.48 (1H, d, J = 2.5Hz), 7.54 (1H, d, J = 5.6Hz), 7.77 (1H, d, J = 8.9Hz), 8.36 (1H, d, J = 5.6Hz)

エチル＝１，２−ジヒドロ−２−オキソキノリン−３−カルボキシラート1.0gに、オキシ塩化リン5.0mL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、減圧下で溶媒を留去した。得られた残留物に水20mLおよび酢酸エチル20mLを加えた。有機層を分取し、水層を酢酸エチル10mL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。得られた残留物にヘキサンおよびジエチルエーテルを加え、不溶物をろ取し、褐色固体のエチル＝２−クロロキノリン−３−カルボキシラート0.86gを得た。
¹H-NMR(CDCl₃)δ値：1.47(3H,t,J=7.2Hz),4.49(2H,q,J=7.2Hz),7.65-7.69(1H,m),7.85-7.91(1H,m),7.93-7.95(1H,m),8.12-8.14(1H,m),8.75(1H,s)Reference Example 27

To 1.0 g of ethyl = 1,2-dihydro-2-oxoquinoline-3-carboxylate, 5.0 mL of phosphorus oxychloride was added, and the mixture was stirred for 1 hour with heating under reflux. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. 20 mL of water and 20 mL of ethyl acetate were added to the obtained residue. The organic layer was separated, and the aqueous layer was extracted twice with 10 mL of 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. Hexane and diethyl ether were added to the obtained residue, and insoluble matter was collected by filtration to obtain 0.86 g of brown solid ethyl = 2-chloroquinoline-3-carboxylate.
¹ H-NMR (CDCl ₃ ) δ value: 1.47 (3H, t, J = 7.2 Hz), 4.49 (2H, q, J = 7.2 Hz), 7.65-7.69 (1H, m), 7.85-7.91 (1H, m), 7.93-7.95 (1H, m), 8.12-8.14 (1H, m), 8.75 (1H, s)

エチル＝２−クロロキノリン−３−カルボキシラート0.80gの濃硫酸4mL溶液に、5℃で発煙硝酸0.2mLを加え、室温で3時間攪拌した。反応混合物を氷水に注ぎ、酢酸エチル20mLを加えた。有機層を分取し、水層を酢酸エチル10mLで抽出した。有機層および抽出液を合わせ、水、飽和炭酸水素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。得られた残留物にジエチルエーテルを加え、不溶物をろ取し、褐色固体のエチル＝２−クロロ−８−ニトロキノリン−３−カルボキシラート0.49gを得た。
¹H-NMR(CDCl₃)δ値：1.47(3H,t,J=7.2Hz),4.50(2H,q,J=7.2Hz),7.69-7.74(1H,m),8.13(1H,dd,J=8.4,1.2Hz),8.19(1H,dd,J=7.4,1.2Hz),8.72(1H,s)Reference Example 28

To a solution of 0.82 g of ethyl 2-chloroquinoline-3-carboxylate in 4 mL of concentrated sulfuric acid was added 0.2 mL of fuming nitric acid at 5 ° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water and 20 mL of ethyl acetate was added. The organic layer was separated and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed successively with water, saturated aqueous sodium hydrogen carbonate solution 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 insoluble matter was collected by filtration to obtain 0.49 g of brown solid ethyl 2-chloro-8-nitroquinoline-3-carboxylate.
¹ H-NMR (CDCl ₃ ) δ value: 1.47 (3H, t, J = 7.2 Hz), 4.50 (2H, q, J = 7.2 Hz), 7.69-7.74 (1H, m), 8.13 (1H, dd, J = 8.4,1.2Hz), 8.19 (1H, dd, J = 7.4,1.2Hz), 8.72 (1H, s)

エチル＝２−クロロ−８−ニトロキノリン−３−カルボキシラート0.49gのメタノール5mL懸濁液に、28％ナトリウムメトキシド/メタノール0.40gを加え、加熱還流下、1時間攪拌した。反応混合物に6mol/L塩酸0.5mL、酢酸エチル20mL、水20mLおよび飽和炭酸水素ナトリウム水溶液5mLを加えた。有機層を分取し、水層を酢酸エチル10mL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。残留物にジエチルエーテルを加え、不溶物をろ取した。得られた固体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、褐色固体のメチル＝２−メトキシ−８−ニトロキノリン−３−カルボキシラート0.23gを得た。
¹H-NMR(CDCl₃)δ値：3.98(3H,s),4.16(3H,s),7.49(1H,t,J=8.0Hz),8.00(1H,dd,J=8.0,1.4Hz),8.09(1H,dd,J=8.0,1.4Hz),8.67(1H,s)Reference Example 29

To a suspension of ethyl 2-chloro-8-nitroquinoline-3-carboxylate (0.49 g) in methanol (5 mL) was added 28% sodium methoxide / methanol (0.40 g), and the mixture was stirred with heating under reflux for 1 hour. To the reaction mixture were added 0.5 mL of 6 mol / L hydrochloric acid, 20 mL of ethyl acetate, 20 mL of water, and 5 mL of a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated and the aqueous layer was extracted with 10 mL of 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 residue, and the insoluble material was collected by filtration. The obtained solid was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 3: 1] to obtain 0.23 g of methyl 2-methoxy-8-nitroquinoline-3-carboxylate as a brown solid.
¹ H-NMR (CDCl ₃ ) δ value: 3.98 (3H, s), 4.16 (3H, s), 7.49 (1H, t, J = 8.0 Hz), 8.00 (1H, dd, J = 8.0, 1.4 Hz) , 8.09 (1H, dd, J = 8.0,1.4Hz), 8.67 (1H, s)

メチル＝２−メトキシ−８−ニトロキノリン−３−カルボキシラート0.22gの酢酸4mL懸濁液に、室温で10％パラジウム−炭素50mgを加え、水素雰囲気下、1時間攪拌した。不溶物をろ去し、減圧下で溶媒を留去した。酢酸エチル、水および飽和炭酸水素ナトリウム水溶液を加え、pH8.0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＝３：１］で精製し、黄色固体のメチル＝８−アミノ−２−メトキシキノリン−３−カルボキシラート0.18gを得た。
¹H-NMR(CDCl₃)δ値：3.96(3H,s),4.15(3H,s),4.74(2H,s),6.99(1H,dd,J=7.3,1.5Hz),7.17(1H,dd,J=8.0,1.5Hz),7.21-7.25(１H,m),8.58(1H,s)Reference Example 30

To a suspension of 0.22 g of methyl-2-methoxy-8-nitroquinoline-3-carboxylate in 4 mL of acetic acid was added 50 mg of 10% palladium-carbon at room temperature, and the mixture was stirred for 1 hour in a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. Ethyl acetate, water and saturated aqueous sodium hydrogen carbonate solution were added to adjust to pH 8.0. 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 = 3: 1] to obtain 0.18 g of methyl = 8-amino-2-methoxyquinoline-3-carboxylate as a yellow solid. .
¹ H-NMR (CDCl ₃ ) δ value: 3.96 (3H, s), 4.15 (3H, s), 4.74 (2H, s), 6.99 (1H, dd, J = 7.3, 1.5 Hz), 7.17 (1H, dd, J = 8.0,1.5Hz), 7.21-7.25 (1H, m), 8.58 (1H, s)

１，４−ベンゾジオキサン−６−カルバルデヒド0.20gのジクロロエタン5mL溶液に、室温で４−（（ｔｅｒｔ−ブトキシカルボニル）アミノ）ピペリジン0.27gおよび酢酸77μLを加え、同温度で20分間攪拌した。ついで、同温度でトリアセトキシ水素化ホウ素ナトリウム0.39gを加え、2時間10分間攪拌した。さらに、４−（（ｔｅｒｔ−ブトキシカルボニル）アミノ）ピペリジン49mgを加え、55分間攪拌した後、トリアセトキシ水素化ホウ素ナトリウム0.13gを加え、50分間攪拌した。反応混合物に水10mLおよびクロロホルム10mL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＝２０：１］で精製し、無色泡状物のｔｅｒｔ−ブチル＝１−（（２，３−ジヒドロベンゾ［ｂ］［１，４］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0.42gを得た。
¹H-NMR(CDCl₃)δ値：1.43(9H,s),1.70-2.10(4H,m),2.25-2.50(2H,m),2.95-3.20(2H,m),3.45-3.80(3H,m),4.26(4H,s),4.50-4.60(1H,broad),6.85(1H,d,J=7.8Hz),6.90-7.00(2H,m)Reference Example 31

To a solution of 0.20 g of 1,4-benzodioxan-6-carbaldehyde in 5 mL of dichloroethane was added 0.27 g of 4-((tert-butoxycarbonyl) amino) piperidine and 77 μL of acetic acid at room temperature, and the mixture was stirred at the same temperature for 20 minutes. Next, 0.39 g of sodium triacetoxyborohydride was added at the same temperature and stirred for 2 hours and 10 minutes. Further, 49 mg of 4-((tert-butoxycarbonyl) amino) piperidine was added and stirred for 55 minutes, and then 0.13 g of sodium triacetoxyborohydride was added and stirred for 50 minutes. 10 mL of water and 10 mL of 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 colorless foam tert-butyl = 1-((2,3-dihydrobenzo [b] [1 , 4] dioxin-6-yl) methyl) piperidin-4-ylcarbamate 0.42 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.43 (9H, s), 1.70-2.10 (4H, m), 2.25-2.50 (2H, m), 2.95-3.20 (2H, m), 3.45-3.80 (3H , m), 4.26 (4H, s), 4.50-4.60 (1H, broad), 6.85 (1H, d, J = 7.8Hz), 6.90-7.00 (2H, m)

ｔｅｒｔ−ブチル＝１−（（２，３−ジヒドロベンゾ［ｂ］［１，４］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0.40gの塩化メチレン4mL溶液に、氷冷下、トリフルオロ酢酸1mLを加え、室温で1時間攪拌し、減圧下で溶媒を留去した。得られた残留物に酢酸エチル4mLおよび4.0mol/L塩化水素/酢酸エチル0.86mLを加え、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、減圧下で溶媒を留去した。再び酢酸エチルを加え、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、析出物をろ取し、白色固体の１−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）メチル）ピペリジン−４−アミンの塩酸塩0.28gを得た。
¹H-NMR(DMSO-d₆)δ値：1.85-2.00(2H,m),2.00-2.15(2H,m),2.85-3.00(2H,m),3.15-3.30(1H,m),3.30-3.40(2H,m),4.05-4.12(2H,m),4.26(4H,s),6.91(1H,d,J=8.7Hz),7.01(1H,d,J=8.7Hz),7.16(1H,s),8.25-8.50(3H,m),10.75-10.95(1H,broad)Reference Example 32

To a solution of 0.40 g of tert-butyl = 1-((2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) methyl) piperidin-4-ylcarbamate in 4 mL of methylene chloride under ice cooling, 1 mL of trifluoroacetic acid was added, stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. To the obtained residue, 4 mL of ethyl acetate and 0.86 mL of 4.0 mol / L hydrogen chloride / ethyl acetate were added and stirred, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the solvent was distilled off under reduced pressure. Ethyl acetate was added again, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the precipitate was collected by filtration to give 1-((2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) methyl) piperidine-4 as a white solid. -0.28 g of amine hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.85 to 2.00 (2H, m), 2.00 to 2.15 (2H, m), 2.85 to 3.00 (2H, m), 3.15 to 3.30 (1H, m), 3.30 -3.40 (2H, m), 4.05-4.12 (2H, m), 4.26 (4H, s), 6.91 (1H, d, J = 8.7Hz), 7.01 (1H, d, J = 8.7Hz), 7.16 ( 1H, s), 8.25-8.50 (3H, m), 10.75-10.95 (1H, broad)

Ｎ−メチル−１，３−プロパンジアミン1.0gのテトラヒドロフラン10mL溶液に、室温で２−（（ｔｅｒｔ−ブトキシカルボニル）オキシイミノ）−２−フェニルアセトニトリル2.8gを加え、20分間攪拌した。ついで、トリエチルアミン1.7mLを加え、室温で14時間攪拌し、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［シリカゲル；富士シリシア化学株式会社、ＮＨ−ＤＭ１０２０、溶離液；クロロホルム：メタノール＝４０：１］および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＝３：１］で精製し、黄色油状物のｔｅｒｔ−ブチル＝３−（メチルアミノ）プロピルカルバマート0.36gを得た。
¹H-NMR(CDCl₃)δ値：1.44(9H,s),1.45-1.55(1H,broad),1.65(2H,quintet,J=6.6Hz),2.42(3H,s),2.63(2H,t,J=6.6Hz),3.10-3.25(2H,m),4.90-5.10(1H,broad)Reference Example 33

To a solution of 1.0 g of N-methyl-1,3-propanediamine in 10 mL of tetrahydrofuran was added 2.8 g of 2-((tert-butoxycarbonyl) oxyimino) -2-phenylacetonitrile at room temperature and stirred for 20 minutes. Then, 1.7 mL of triethylamine was added and stirred at room temperature for 14 hours, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [silica gel; Fuji Silysia Chemical Ltd., NH-DM1020, eluent: chloroform: methanol = 40: 1] and silica gel column chromatography [eluent: chloroform: methanol = 3: 1]. To obtain 0.36 g of tert-butyl = 3- (methylamino) propylcarbamate as a yellow oily substance.
¹ H-NMR (CDCl ₃ ) δ value: 1.44 (9H, s), 1.45-1.55 (1H, broad), 1.65 (2H, quintet, J = 6.6 Hz), 2.42 (3H, s), 2.63 (2H, t, J = 6.6Hz), 3.10-3.25 (2H, m), 4.90-5.10 (1H, broad)

ｔｅｒｔ−ブチル＝３−（メチルアミノ）プロピルカルバマート0.14gのＮ，Ｎ−ジメチルホルムアミド2mL溶液に、７−メトキシ−１−（オキシラン−２−イル）イソキノリン0.10gのＮ，Ｎ−ジメチルホルムアミド1mL溶液および過塩素酸リチウム53mgを加え、80℃で1時間50分間攪拌した。反応混合物を室温まで冷却し、水5mLおよび酢酸エチル5mLを加え、6.0mol/L塩酸を加え、pH4.0に調整した。有機層を分取し、水層に20％水酸化ナトリウム水溶液を加え、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；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＝３−（（２−ヒドロキシ−２−（７−メトキシイソキノリン−１−イル）エチル）（メチル）アミノ）プロピルカルバマート0.13gを得た。
¹H-NMR(CDCl₃)δ値：1.45(9H,s),1.65-1.75(2H,m),2.50(3H,s),2.55-2.75(2H,m),2.75-2.90(2H,m),3.10-3.30(2H,m),3.97(3H,s),5.25-5.35(1H,broad),5.54(1H,dd,J=8.2,2.6Hz),7.37(1H,dd,J=8.8,2.4Hz),7.42(1H,d,J=2.4Hz),7.55(1H,d,J=5.6Hz),7.77(1H,d,J=8.8Hz),8.36(1H,d,J=5.6Hz)Reference Example 34

tert-Butyl = 3- (methylamino) propylcarbamate 0.14 g of N, N-dimethylformamide in 2 mL solution, 7-methoxy-1- (oxiran-2-yl) isoquinoline 0.10 g of N, N-dimethylformamide 1 mL The solution and 53 mg of lithium perchlorate were added, and the mixture was stirred at 80 ° C. for 1 hour and 50 minutes. The reaction mixture was cooled to room temperature, 5 mL of water and 5 mL of ethyl acetate were added, and 6.0 mol / L hydrochloric acid was added to adjust to pH 4.0. The organic layer was separated, 20% aqueous sodium hydroxide solution was added to the aqueous layer, and the mixture 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: chloroform: methanol = 10: 1], and tert-butyl = 3-((2-hydroxy-2- (7-methoxyisoquinoline-) as a yellow oily substance. 0.13 g of 1-yl) ethyl) (methyl) amino) propylcarbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.45 (9H, s), 1.65-1.75 (2H, m), 2.50 (3H, s), 2.55-2.75 (2H, m), 2.75-2.90 (2H, m ), 3.10-3.30 (2H, m), 3.97 (3H, s), 5.25-5.35 (1H, broad), 5.54 (1H, dd, J = 8.2, 2.6Hz), 7.37 (1H, dd, J = 8.8 , 2.4Hz), 7.42 (1H, d, J = 2.4Hz), 7.55 (1H, d, J = 5.6Hz), 7.77 (1H, d, J = 8.8Hz), 8.36 (1H, d, J = 5.6 Hz)

ｔｅｒｔ−ブチル＝３−（（２−ヒドロキシ−２−（７−メトキシイソキノリン−１−イル）エチル）（メチル）アミノ）プロピルカルバマート0.13gの塩化メチレン2mL溶液に、氷冷下、トリフルオロ酢酸1mLを加え、室温で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10mL、水10mLおよび20％水酸化ナトリウム水溶液を加え、pH11.5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、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−（（３−アミノプロピル）（メチル）アミノ）−１−（７−メトキシイソキノリン−１−イル）エタノール0.10gを得た。
¹H-NMR(CDCl₃)δ値：1.65-1.72(2H,m),2.46(3H,s),2.50-2.90(6H,m),3.96(3H,s),5.50(1H,dd,J=7.8,3.7Hz),7.34-7.37(1H,m),7.48-7.49(1H,m),7.53(1H,d,J=5.6Hz),7.76(1H,d,J=9.0Hz),8.35(1H,d,J=5.6Hz)Reference Example 35

tert-Butyl = 3-((2-Hydroxy-2- (7-methoxyisoquinolin-1-yl) ethyl) (methyl) amino) propylcarbamate 0.13 g in methylene chloride (2 mL) was added with trifluoroacetic acid under ice-cooling. 1 mL was added and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and 10 mL of chloroform, 10 mL of water and a 20% aqueous sodium hydroxide solution were added to the resulting residue to adjust to pH 11.5. 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 2-((3-aminopropyl) (methyl) amino) as a brown oil. 0.10 g of -1- (7-methoxyisoquinolin-1-yl) ethanol was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.65-1.72 (2H, m), 2.46 (3H, s), 2.50-2.90 (6H, m), 3.96 (3H, s), 5.50 (1H, dd, J = 7.8,3.7Hz), 7.34-7.37 (1H, m), 7.48-7.49 (1H, m), 7.53 (1H, d, J = 5.6Hz), 7.76 (1H, d, J = 9.0Hz), 8.35 (1H, d, J = 5.6Hz)

２−（２−ブロモエチルチオ）チオフェン0.10gのＮ，Ｎ−ジメチルホルムアミド3mL溶液に、４−（（ｔｅｒｔ−ブトキシカルボニル）アミノ）ピペリジン99mgおよび炭酸カリウム68mgを加え、60℃で3時間30分間攪拌した。反応混合物を室温まで冷却し、水10mLおよび酢酸エチル10mL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、白色固体のｔｅｒｔ−ブチル＝１−（２−（チオフェン−２−イルチオ）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：1.35-1.50(2H,m),1.44(9H,s),1.85-1.95(2H,m),2.05-2.15(2H,m),2.58-2.62(2H,m), 2.75-2.85(2H,m),2.88-2.92(2H,m),3.35-3.50(1H,m),4.30-4.50(1H,m),6.96(1H,dd,J=5.3,3.5Hz),7.11(1H,dd,J=3.5,1.2Hz),7.33(1H,dd,J=5.3,1.2Hz)Reference Example 36

To a solution of 0.10 g of 2- (2-bromoethylthio) thiophene in 3 mL of N, N-dimethylformamide was added 99 mg of 4-((tert-butoxycarbonyl) amino) piperidine and 68 mg of potassium carbonate, and at 60 ° C. for 3 hours and 30 minutes. Stir. The reaction mixture was cooled to room temperature and 10 mL water and 10 mL 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: chloroform: methanol = 50: 1] and tert-butyl = 1- (2- (thiophen-2-ylthio) ethyl) piperidine-4 as a white solid. -0.12 g of ylcarbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.35-1.50 (2H, m), 1.44 (9H, s), 1.85-1.95 (2H, m), 2.05-2.15 (2H, m), 2.58-2.62 (2H , m), 2.75-2.85 (2H, m), 2.88-2.92 (2H, m), 3.35-3.50 (1H, m), 4.30-4.50 (1H, m), 6.96 (1H, dd, J = 5.3, 3.5Hz), 7.11 (1H, dd, J = 3.5,1.2Hz), 7.33 (1H, dd, J = 5.3,1.2Hz)

ｔｅｒｔ−ブチル＝１−（２−（チオフェン−２−イルチオ）エチル）ピペリジン−４−イルカルバマート110mgの塩化メチレン2mL溶液に、氷冷下、トリフルオロ酢酸1mLを加え、室温で40分間攪拌し、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10mL、水10mLおよび20％水酸化ナトリウム水溶液を加え、pH11.0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、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−（２−（チオフェン−２−イルチオ）エチル）ピペリジン−４−アミン70mgを得た。
¹H-NMR(CDCl₃)δ値：1.20-1.55(2H,m),1.46(2H,s),1.75-1.85(2H,m),2.05(2H,td,J=11.5,2.1Hz),2.55-2.70(3H,m),2.75-2.95(4H,m),6.96(1H,dd,J=5.4,3.5Hz),7.12(1H,dd,J=3.5,1.2Hz),7.33(1H,dd,J=5.4,1.2Hz)Reference Example 37

tert-Butyl = 1- (2- (thiophen-2-ylthio) ethyl) piperidin-4-ylcarbamate 110 mg of methylene chloride in 2 mL was added with 1 mL of trifluoroacetic acid under ice cooling and stirred at room temperature for 40 minutes. The solvent was distilled off under reduced pressure. To the obtained residue, 10 mL of chloroform, 10 mL of water and 20% aqueous sodium hydroxide solution were added to adjust to pH 11.0. 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- (thiophen-2-ylthio) ethyl) as a colorless oil. 70 mg of piperidine-4-amine was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.20-1.55 (2H, m), 1.46 (2H, s), 1.75-1.85 (2H, m), 2.05 (2H, td, J = 11.5, 2.1 Hz), 2.55-2.70 (3H, m), 2.75-2.95 (4H, m), 6.96 (1H, dd, J = 5.4,3.5Hz), 7.12 (1H, dd, J = 3.5,1.2Hz), 7.33 (1H, (dd, J = 5.4,1.2Hz)

１−（ｔｅｒｔ−ブトキシカルボニル）ピペリジン−４−カルボン酸0.15gのＮ，Ｎ−ジメチルホルムアミド2mL溶液に、氷冷下、Ｎ，Ｎ’−カルボニルジイミダゾール0.11gを加え、室温で80分間攪拌した。ついで、（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）メチル）アミン0.10gのＮ，Ｎ−ジメチルホルムアミド1mL溶液を加え、室温で1時間、50℃で1時間攪拌した。反応混合物を室温まで冷却し、水10mLおよび酢酸エチル10mLを加え、6.0mol/L塩酸を加え、pH3.5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、水で洗浄し、20％水酸化ナトリウム水溶液を加え、pH10.0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＝４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）メチルカルバモイル）ピペリジン−１−カルボキシラート0.17gを得た。
¹H-NMR(CDCl₃)δ値：1.45(9H,s),1.55-1.75(2H,m),1.80-1.90(2H,m),2.20-2.30(1H,m),2.65-2.85(2H,m),4.05-4.20(2H,m),4.25(4H,s),4.32(2H,d,J=5.6Hz),5.60-5.70(1H,broad),6.73(1H,dd,J=8.2,1.7Hz),6.77(1H,d,J=1.7Hz),6.82(1H,d,J=8.2Hz)Reference Example 38

To a solution of 0.15 g of 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid in 2 mL of N, N-dimethylformamide was added 0.11 g of N, N′-carbonyldiimidazole under ice cooling, and the mixture was stirred at room temperature for 80 minutes. . Then, ((2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) methyl) amine (0.10 g) in N, N-dimethylformamide (1 mL) was added, and the mixture was added at room temperature for 1 hour and at 50 ° C. for 1 hour. Stir for hours. The reaction mixture was cooled to room temperature, 10 mL of water and 10 mL of ethyl acetate were added, and 6.0 mol / L hydrochloric acid was added to adjust to pH 3.5. 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 20% aqueous sodium hydroxide solution was added to adjust to pH 10.0. 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 silica gel column chromatography [eluent: chloroform: methanol = 50: 1], and tert-butyl = 4-((2,3-dihydrobenzo [b] [ 1,4] dioxin-6-yl) methylcarbamoyl) piperidine-1-carboxylate 0.17 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.45 (9H, s), 1.55-1.75 (2H, m), 1.80-1.90 (2H, m), 2.20-2.30 (1H, m), 2.65-2.85 (2H , m), 4.05-4.20 (2H, m), 4.25 (4H, s), 4.32 (2H, d, J = 5.6Hz), 5.60-5.70 (1H, broad), 6.73 (1H, dd, J = 8.2 , 1.7Hz), 6.77 (1H, d, J = 1.7Hz), 6.82 (1H, d, J = 8.2Hz)

ｔｅｒｔ−ブチル＝４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）メチルカルバモイル）ピペリジン−１−カルボキシラート0.17gの塩化メチレン2mL溶液に、氷冷下、トリフルオロ酢酸1mLを加え、室温で30分間攪拌し、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10mL、水10mLおよび20％水酸化ナトリウム水溶液を加え、pH11.0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、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、淡黄色泡状物のＮ−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）メチル）ピペリジン−４−カルボキサミド0.12gを得た。
¹H-NMR(CDCl₃)δ値：1.60-1.70(2H,m),1.80-1.90(2H,m),2.25(1H,tt,J=11.7,3.8Hz),2.40(1H,s),2.63(2H,td,J=12.3,2.6Hz),3.10-3.20(2H,m),4.24(4H,s),4.31(2H,d,J=5.6Hz),5.87(1H,s),6.72(1H,dd,J=8.2,2.0Hz),6.76(1H,d,J=2.0Hz),6.81(1H,d,J=8.2Hz)Reference Example 39

tert-Butyl = 4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) methylcarbamoyl) piperidine-1-carboxylate 0.17 g in methylene chloride 2 mL solution under ice-cooling 1 mL of trifluoroacetic acid was added and stirred at room temperature for 30 minutes, and the solvent was distilled off under reduced pressure. To the obtained residue, 10 mL of chloroform, 10 mL of water and 20% aqueous sodium hydroxide solution were added to adjust to pH 11.0. 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 solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give N-((2,3-dihydrobenzo [b ] [1,4] dioxin-6-yl) methyl) piperidine-4-carboxamide 0.12 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.60-1.70 (2H, m), 1.80-1.90 (2H, m), 2.25 (1H, tt, J = 11.7,3.8 Hz), 2.40 (1H, s), 2.63 (2H, td, J = 12.3,2.6Hz), 3.10-3.20 (2H, m), 4.24 (4H, s), 4.31 (2H, d, J = 5.6Hz), 5.87 (1H, s), 6.72 (1H, dd, J = 8.2,2.0Hz), 6.76 (1H, d, J = 2.0Hz), 6.81 (1H, d, J = 8.2Hz)

２−クロロ−７−フルオロキノリン0.12gの濃硫酸2.0mL溶液に、氷冷下、発煙硝酸28μLを滴下し、室温で１時間、40℃で30分間、50℃で30分間攪拌した。次いで、発煙硝酸14μLを滴下し、50℃で30分間攪拌した。反応混合物を氷水に注ぎ、析出物をろ取し、淡褐色固体を得た。この固体にクロロホルム30mLおよび水10mLを加え、20％水酸化ナトリウム水溶液を加えてpH12.0に調整した。有機層を分取し、水層をクロロホルム10mLで抽出した。有機層および抽出液を合わせ、水10mLおよび飽和塩化ナトリウム水溶液10mL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およびヘキサンを加え、析出物をろ取し、淡褐色固体の２−クロロ−７−フルオロ−８−ニトロキノリン66mgを得た。
¹H-NMR(CDCl₃)δ値：7.48-7.53(2H,m),7.99(1H,dd,J=9.3,5.4Hz),8.18(1H,d,J=8.5Hz)Reference Example 40

To a 2.0 mL concentrated sulfuric acid solution of 0.12 g of 2-chloro-7-fluoroquinoline, 28 μL of fuming nitric acid was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour, at 40 ° C. for 30 minutes, and at 50 ° C. for 30 minutes. Next, 14 μL of fuming nitric acid was added dropwise and stirred at 50 ° C. for 30 minutes. The reaction mixture was poured into ice water, and the precipitate was collected by filtration to obtain a light brown solid. To this solid, 30 mL of chloroform and 10 mL of water were added, and 20% aqueous sodium hydroxide solution was added to adjust to pH 12.0. The organic layer was separated, and the aqueous layer was extracted with 10 mL of chloroform. The organic layer and the extract were combined, washed sequentially with 10 mL of water and 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Diethyl ether and hexane were added to the obtained residue, and the precipitate was collected by filtration to obtain 66 mg of 2-chloro-7-fluoro-8-nitroquinoline as a light brown solid.
¹ H-NMR (CDCl ₃ ) δ value: 7.48-7.53 (2H, m), 7.99 (1H, dd, J = 9.3, 5.4Hz), 8.18 (1H, d, J = 8.5Hz)

28％ナトリウムメトキシド/メタノール72mgにメタノール3mLを加えた後、２−クロロ−７−フルオロ−８−ニトロキノリン56mgを加え、1時間加熱還流した。反応混合物に酢酸エチル20mLおよび水20mLを加え、有機層を分取し、水層を酢酸エチル10mLで抽出した。有機層および抽出液を合わせ、水10mLおよび飽和塩化ナトリウム水溶液10mL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＝１：１］で精製し、淡褐色固体の２，７−ジメトキシ−８−ニトロキノリン25mgを得た。
¹H-NMR(CDCl₃)δ値：4.01(3H,s),4.03(3H,s),6.84(1H,d,J=9.0Hz),7.17(1H,d,J=9.0Hz),7.78(1H,d,J=9.0Hz),7.93(1H,d,J=9.0Hz)Reference Example 41

3 mL of methanol was added to 72 mg of 28% sodium methoxide / methanol, 56 mg of 2-chloro-7-fluoro-8-nitroquinoline was added, and the mixture was heated to reflux for 1 hour. To the reaction mixture, 20 mL of ethyl acetate and 20 mL of water were added, the organic layer was separated, and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed sequentially with 10 mL of water and 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 1: 1] to obtain 25 mg of 2,7-dimethoxy-8-nitroquinoline as a light brown solid.
¹ H-NMR (CDCl ₃ ) δ value: 4.01 (3H, s), 4.03 (3H, s), 6.84 (1H, d, J = 9.0 Hz), 7.17 (1H, d, J = 9.0 Hz), 7.78 (1H, d, J = 9.0Hz), 7.93 (1H, d, J = 9.0Hz)

２，７−ジメトキシ−８−ニトロキノリン25mgの酢酸3mL懸濁液に、室温で10％パラジウム−炭素5mgを加え、水素雰囲気下で１時間攪拌した。不溶物をろ去し、減圧下で溶媒を留去した。得られた残留物に酢酸エチル30mLおよび飽和炭酸水素ナトリウム水溶液20mLを加えた。有機層を分取し、水層を酢酸エチル10mL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、褐色油状物の２，７−ジメトキシキノリン−８−アミン22mgを得た。
¹H-NMR(CDCl₃)δ値：3.97(3H,s),4.06(3H,s),4.67(2H,s),6.75(1H,d,J=9.0Hz),7.06-7.11(2H,m),7.87(1H,d,J=8.8Hz)Reference Example 42

To a suspension of 25 mg of 2,7-dimethoxy-8-nitroquinoline in 3 mL of acetic acid was added 5 mg of 10% palladium-carbon at room temperature, and the mixture was stirred for 1 hour under a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. To the obtained residue, 30 mL of ethyl acetate and 20 mL of a saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated and the aqueous layer was extracted with 10 mL of 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, evaporated under reduced pressure to give a brown oily 2,7-dimethoxyquinolin-8-amine 22 mg Got.
¹ H-NMR (CDCl ₃ ) δ value: 3.97 (3H, s), 4.06 (3H, s), 4.67 (2H, s), 6.75 (1H, d, J = 9.0 Hz), 7.06-7.11 (2H, m), 7.87 (1H, d, J = 8.8Hz)

（１）４−（ｔｅｒｔ−ブトキシカルボニル）アミノシクロヘキサン−１−カルボン酸0.15gのＮ，Ｎ−ジメチルホルムアミド2mL溶液に、氷冷下、Ｎ，Ｎ’−カルボニルジイミダゾール0.11gを加え、室温で1時間攪拌した後、７−メトキシイソキノリン−１−アミン0.10gを加え、50℃で3時間攪拌した。反応混合物に酢酸エチル20mLおよび水20mLを加えた後、6.0mol/L塩酸を加え、pH3.0に調整した。有機層を分取し、水層を酢酸エチル10mLで抽出した。有機層および抽出液を合わせ、飽和炭酸水素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［溶離液；ヘキサン：酢酸エチル＝１：１］で精製し、淡黄色泡状物のｔｅｒｔ−ブチル＝４−（（７−メトキシイソキノリン−１−イル）カルバモイル）シクロヘキシルカルバマート0.21gを得た。
（２）得られたｔｅｒｔ−ブチル＝４−（（７−メトキシイソキノリン−１−イル）カルバモイル）シクロヘキシルカルバマート0.20gの塩化メチレン1mL溶液に、室温でトリフルオロ酢酸1mLを加え、同温度で1時間30分間攪拌した後、減圧下で溶媒を留去した。得られた残留物に水10mLおよびクロロホルム10mLを加え、20％水酸化ナトリウム水溶液を加え、pH12.0に調整した。有機層を分取し、水層をクロロホルム10mL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、淡黄色の４−アミノ−Ｎ−（７−メトキシイソキノリン−１−イル）シクロヘキサンカルボキサミド0.16gを得た。
¹H-NMR(CDCl₃)δ値：1.10-2.30(8H,m),2.50-3.10(2H,m),3.90(3H,s),6.95-8.20(5H,m)Reference Example 43

(1) To a solution of 0.15 g of 4- (tert-butoxycarbonyl) aminocyclohexane-1-carboxylic acid in 2 mL of N, N-dimethylformamide was added 0.11 g of N, N′-carbonyldiimidazole under ice cooling, and at room temperature. After stirring for 1 hour, 0.10 g of 7-methoxyisoquinolin-1-amine was added and stirred at 50 ° C. for 3 hours. After adding 20 mL of ethyl acetate and 20 mL of water to the reaction mixture, 6.0 mol / L hydrochloric acid was added to adjust the pH to 3.0. The organic layer was separated and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed successively with a saturated aqueous sodium bicarbonate solution 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: hexane: ethyl acetate = 1: 1], and tert-butyl 4-((7-methoxyisoquinolin-1-yl) as a pale yellow foam. 0.21 g of carbamoyl) cyclohexyl carbamate was obtained.
(2) To 1 ml of methylene chloride in 0.20 g of the obtained tert-butyl 4-((7-methoxyisoquinolin-1-yl) carbamoyl) cyclohexyl carbamate was added 1 ml of trifluoroacetic acid at room temperature. After stirring for 30 minutes, the solvent was distilled off under reduced pressure. To the obtained residue, 10 mL of water and 10 mL of chloroform were added, and 20% aqueous sodium hydroxide solution was added to adjust to pH 12.0. The organic layer was separated, and the aqueous layer was extracted twice with 10 mL of 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 pale yellow 4-amino-N- (7-methoxyisoquinolin-1-yl). ) 0.16 g of cyclohexanecarboxamide was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.10-2.30 (8H, m), 2.50-3.10 (2H, m), 3.90 (3H, s), 6.95-8.20 (5H, m)

５−ヨード−２−メトキシキノリン−８−アミン4.0gのＮ，Ｎ−ジメチルホルムアミド26mL溶液に、シアン化銅（I）2.4gおよびテトラキス（トリフェニルホスフィン）パラジウム1.6gを加え、窒素気流下、100〜110℃で4時間20分間加熱した。反応混合物に水50mL、25％アンモニア水20mLおよび酢酸エチル50mLを加え、ろ過し、不溶物とろ液を分離した。
ろ液の有機層を分取し、水層を酢酸エチル20mLで2回抽出した。有機層および抽出液を合わせ、25％アンモニア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た。
不溶物に25％アンモニア水20mLおよび酢酸エチル50mLを加え、不溶物をろ去した。有機層を分取し、水層を酢酸エチル20mLで2回抽出した。有機層および抽出液を合わせ、25％アンモニア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た。
乾燥されたすべての溶液を合わせ、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、ヘキサンを加え、析出物をろ取し、褐色固体の８−アミノ−２−メトキシキノリン−５−カルボニトリル1.6gを得た。
¹H-NMR(CDCl₃)δ値：4.07(3H,s),5.29(2H,s),6.82(1H,d,J=8.0Hz),7.08(1H,d,J=8.9Hz),7.58(1H,d,J=8.0Hz),8.27(1H,d,J=8.9Hz)Reference Example 44

To a solution of 4.0 g of 5-iodo-2-methoxyquinolin-8-amine in 26 mL of N, N-dimethylformamide, 2.4 g of copper (I) cyanide and 1.6 g of tetrakis (triphenylphosphine) palladium were added. Heated at 100-110 ° C. for 4 hours and 20 minutes. Water (50 mL), 25% aqueous ammonia (20 mL) and ethyl acetate (50 mL) were added to the reaction mixture, followed by filtration to separate the insoluble material and the filtrate.
The organic layer of the filtrate was separated, and the aqueous layer was extracted twice with 20 mL of ethyl acetate. The organic layer and the extract were combined, washed successively with 25% aqueous ammonia and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.
To the insoluble material, 20% 25% aqueous ammonia and 50 mL of ethyl acetate were added, and the insoluble material was removed by filtration. The organic layer was separated, and the aqueous layer was extracted twice with 20 mL of ethyl acetate. The organic layer and the extract were combined, washed successively with 25% aqueous ammonia and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.
All the dried solutions were combined 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], hexane was added, the precipitate was collected by filtration, and a brown solid of 8-amino-2-methoxyquinoline- 1.6 g of 5-carbonitrile was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 4.07 (3H, s), 5.29 (2H, s), 6.82 (1H, d, J = 8.0 Hz), 7.08 (1H, d, J = 8.9 Hz), 7.58 (1H, d, J = 8.0Hz), 8.27 (1H, d, J = 8.9Hz)

８−アミノ−２−メトキシキノリン−５−カルボニトリル0.10gの75％エタノール水0.50mL溶液に、水酸化ナトリウム80mgを加え、3時間10分間加熱還流した。エチレングリコール0.50mLを加え、8時間40分間加熱還流した。反応混合物に水20mLおよび酢酸エチル20mLを加えた。有機層を分取し、水層を酢酸エチル10mL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＝２５：１］で精製し、ジエチルエーテルを加え、析出物をろ取し、淡褐色固体の８−アミノ−２−メトキシキノリン−５−カルボキサミド14mgを得た。
¹H-NMR(CDCl₃)δ値：4.06(3H,s),5.10(2H,s),6.81(1H,d,J=8.0Hz),7.00(1H,d,J=9.3Hz),7.51(1H,d,J=8.0Hz),8.95(1H,d,J=9.3Hz)Reference Example 45

80 mg of sodium hydroxide was added to a 0.50 mL solution of 0.10 g of 8-amino-2-methoxyquinoline-5-carbonitrile in 75% aqueous ethanol, and the mixture was heated to reflux for 3 hours and 10 minutes. Ethylene glycol 0.50mL was added, and it heated and refluxed for 8 hours and 40 minutes. 20 mL of water and 20 mL of ethyl acetate were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with 10 mL of 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. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 25: 1], diethyl ether was added, the precipitate was collected by filtration, and a light brown solid of 8-amino-2-methoxyquinoline. 14 mg of -5-carboxamide was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 4.06 (3H, s), 5.10 (2H, s), 6.81 (1H, d, J = 8.0 Hz), 7.00 (1H, d, J = 9.3 Hz), 7.51 (1H, d, J = 8.0Hz), 8.95 (1H, d, J = 9.3Hz)

２−クロロキノリン−８−オール65mgのＮ，Ｎ−ジメチルホルムアミド3mL溶液に、氷冷下、60％水素化ナトリウム17mg加え、10分間攪拌した後、（１−（ｔｅｒｔ−ブトキシカルボニル）ピペリジン−４−イル）メチル＝メタンスルホナート0.11gを加え、室温で30分間、80℃で3時間攪拌した。60％水素化ナトリウム8.6mgを加え、80〜100℃で1時間攪拌した。反応混合物に酢酸エチル20mLおよび水10mLを加え、1mol/mL塩酸を加えてpH4.0に調整した。有機層を分取し、水層を酢酸エチル10mL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＝２：１］で精製し、黄色油状物のｔｅｒｔ−ブチル＝４−（（２−クロロキノリン−８−イルオキシ）メチル）ピペリジン−１−カルボキシラート82mgを得た。
¹H-NMR(CDCl₃)δ値：1.23-1.36(2H,m),1.47(9H,s),1.94-2.02(2H,m),2.20-2.32(1H,m),2.73-2.85(2H,m),4.02-4.08(2H,m),4.11-4.25(2H,m),7.09(1H,dd,J=7.9,1.0Hz),7.38(1H,dd,J=7.9,1.0Hz),7.39(1H,d,J=8.7Hz),7.46(1H,t,J=7.9Hz),8.06(1H,d,J=8.7Hz)Reference Example 46

To a solution of 65 mg of 2-chloroquinolin-8-ol in 3 mL of N, N-dimethylformamide was added 17 mg of 60% sodium hydride under ice cooling, and the mixture was stirred for 10 minutes, and then (1- (tert-butoxycarbonyl) piperidine-4 -Yl) Methyl methanesulfonate 0.11g was added, and it stirred at room temperature for 30 minutes and 80 degreeC for 3 hours. 8.6 mg of 60% sodium hydride was added, and the mixture was stirred at 80 to 100 ° C. for 1 hour. Ethyl acetate (20 mL) and water (10 mL) were added to the reaction mixture, and 1 mol / mL hydrochloric acid was added to adjust to pH 4.0. The organic layer was separated and the aqueous layer was extracted with 10 mL of 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 = 2: 1], and tert-butyl 4-((2-chloroquinolin-8-yloxy) methyl) as a yellow oily substance. 82 mg of piperidine-1-carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.23-1.36 (2H, m), 1.47 (9H, s), 1.94.2.02 (2H, m), 2.20-2.32 (1H, m), 2.73-2.85 (2H , m), 4.02-4.08 (2H, m), 4.11-4.25 (2H, m), 7.09 (1H, dd, J = 7.9,1.0Hz), 7.38 (1H, dd, J = 7.9,1.0Hz), 7.39 (1H, d, J = 8.7Hz), 7.46 (1H, t, J = 7.9Hz), 8.06 (1H, d, J = 8.7Hz)

ｔｅｒｔ−ブチル＝４−（（２−クロロキノリン−８−イルオキシ）メチル）ピペリジン−１−カルボキシラート80mgにトルエン3mLおよびメタノール3mLを加え、28％ナトリウムメトキシド/メタノール62mgを加えた後、1時間加熱還流した。さらに、28％ナトリウムメトキシド/メタノール124mgおよびトルエン2mLを加え、2時間加熱還流した。さらに、28％ナトリウムメトキシド/メタノール124mgおよびトルエン2mLを加え、3時間加熱還流した。反応混合物に酢酸エチル10mLおよび水10mLを加え、有機層を分取し、水層を酢酸エチル10mL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、淡褐油状物のｔｅｒｔ−ブチル＝４−（（２−メトキシキノリン−８−イルオキシ）メチル）ピペリジン−１−カルボキシラート62mgを得た。
¹H-NMR(CDCl₃)δ値：1.30-1.50(2H,m),1.47(9H,s),1.94-2.02(2H,m),2.10-2.25(1H,m),2.75-2.88(2H,m),4.03-4.09(2H,m),4.09(3H,s),4.12-4.25(2H,m),6.92(1H,d,J=8.9Hz),7.05(1H,dd,J=7.8,1.5Hz),7.27(1H,t,J=7.8Hz),7.33(1H,dd,J=7.8,1.5Hz),7.96(1H,d,J=8.9Hz)Reference Example 47

tert-Butyl = 4-((2-chloroquinolin-8-yloxy) methyl) piperidine-1-carboxylate was added to 3 mg of toluene and 3 mL of methanol, and 28% sodium methoxide / methanol 62 mg was added, and then 1 hour. Heated to reflux. Furthermore, 28% sodium methoxide / methanol 124 mg and toluene 2 mL were added, and the mixture was heated to reflux for 2 hours. Furthermore, 28% sodium methoxide / methanol 124 mg and toluene 2 mL were added, and the mixture was heated to reflux for 3 hours. To the reaction mixture, 10 mL of ethyl acetate and 10 mL of water were added, the organic layer was separated, and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, 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 to give tert-butyl = 4-((2- 62 mg of methoxyquinolin-8-yloxy) methyl) piperidine-1-carboxylate were obtained.
_{^{1 H-NMR (CDCl 3)}} δ value: 1.30-1.50 (2H, m), 1.47 (9H, s), 1.94-2.02 (2H, m), 2.10-2.25 (1H, m), 2.75-2.88 (2H , m), 4.03-4.09 (2H, m), 4.09 (3H, s), 4.12-4.25 (2H, m), 6.92 (1H, d, J = 8.9Hz), 7.05 (1H, dd, J = 7.8 1.5Hz), 7.27 (1H, t, J = 7.8Hz), 7.33 (1H, dd, J = 7.8, 1.5Hz), 7.96 (1H, d, J = 8.9Hz)

ｔｅｒｔ−ブチル＝４−（（２−メトキシキノリン−８−イルオキシ）メチル）ピペリジン−１−カルボキシラート60mgの塩化メチレン3mL溶液に、トリフルオロ酢酸1mLを加え、室温で1時間攪拌した。減圧下で溶媒を留去し、得られた残留物に酢酸エチル30mLおよび水10mLを加え、20％水酸化ナトリウム水溶液を加え、pH12.0に調整した。有機層を分取し、水層を酢酸エチル10mL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、淡黄色油状物の８−（（ピペリジン−４−イル）メトキシ）−２−メトキシキノリン42mgを得た。
¹H-NMR(CDCl₃)δ値：1.34-1.46(2H,m),1.80-2.06(2H,m),2.10-2.24(1H,m),2.26-2.35(1H,m),2.68-2.77(2H,m),3.16-3.24(2H,m),4.04(2H,d,J=6.6Hz),4.10(3H,s),6.91(1H,d,J=8.8Hz),7.06(1H,dd,J=7.9,1.6Hz),7.27(1H,t,J=7.8Hz),7.32(1H,dd,J=7.8,1.5Hz),7.95(1H,d,J=8.8Hz)Reference Example 48

To a solution of 60 mg of tert-butyl = 4-((2-methoxyquinolin-8-yloxy) methyl) piperidine-1-carboxylate in 3 mL of methylene chloride was added 1 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, 30 mL of ethyl acetate and 10 mL of water were added to the obtained residue, and 20% aqueous sodium hydroxide solution was added to adjust to pH 12.0. The organic layer was separated and the aqueous layer was extracted with 10 mL of 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 removed under reduced pressure to give 8-((piperidin-4-yl) methoxy)- 42 mg of 2-methoxyquinoline was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.34-1.46 (2H, m), 1.80-2.06 (2H, m), 2.10-2.24 (1H, m), 2.26-2.35 (1H, m), 2.68-2.77 (2H, m), 3.16-3.24 (2H, m), 4.04 (2H, d, J = 6.6Hz), 4.10 (3H, s), 6.91 (1H, d, J = 8.8Hz), 7.06 (1H, dd, J = 7.9,1.6Hz), 7.27 (1H, t, J = 7.8Hz), 7.32 (1H, dd, J = 7.8,1.5Hz), 7.95 (1H, d, J = 8.8Hz)

２−クロロキノリン−４−カルボン酸2.0gの塩化メチレン20mL懸濁液に、室温でオキサリルクロリド1.0mLおよびＮ，Ｎ−ジメチルホルムアミド２滴を加え、室温で2時間攪拌した。ついで、メタノール2mLを滴下し、室温で１時間攪拌した。反応混合物を氷水で冷却し、飽和炭酸水素ナトリウム水溶液30mLを加えた。有機層を分取し、水層をクロロホルム20mL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。得られた残留物にヘキサンを加え、不溶物をろ取し、淡黄色固体のメチル＝２−クロロキノリン−４−カルボキシラート1.4gを得た。
¹H-NMR(CDCl₃)δ値：4.05(3H,s),7.64-7.70(1H,m),7.77-7.82(1H,m),7.91(1H,s),8.06-8.10(1H,m),8.71-8.76(1H,m)Reference Example 49

To 20 mL of methylene chloride suspension of 2.0 g of 2-chloroquinoline-4-carboxylic acid, 1.0 mL of oxalyl chloride and 2 drops of N, N-dimethylformamide were added at room temperature, and the mixture was stirred at room temperature for 2 hours. Then, 2 mL of methanol was added dropwise and stirred at room temperature for 1 hour. The reaction mixture was cooled with ice water, and 30 mL of saturated aqueous sodium hydrogen carbonate solution was added. The organic layer was separated, and the aqueous layer was extracted with 20 mL of 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. Hexane was added to the obtained residue, and insoluble matter was collected by filtration to obtain 1.4 g of methyl 2-chloroquinoline-4-carboxylate as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ value: 4.05 (3H, s), 7.64-7.70 (1H, m), 7.77-7.82 (1H, m), 7.91 (1H, s), 8.06-8.10 (1H, m ), 8.71-8.76 (1H, m)

メチル＝２−クロロキノリン−４−カルボキシラート1.3gの濃硫酸6.0mL溶液に、氷冷下、発煙硝酸0.27mLを滴下し、室温で30分間、50℃で1時間攪拌した。反応混合物を氷水に注ぎ、酢酸エチル50mLを加えた。有機層を分取し、水層を酢酸エチル30mLで抽出した。有機層および抽出液を合わせ、水、飽和炭酸水素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。得られた残留物をジイソプロピルエーテルで抽出し、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＝２：１］で精製し、淡黄白色固体のメチル＝２−クロロ−８−ニトロキノリン−４−カルボキシラート0.25gを得た。
¹H-NMR(CDCl₃)δ値：4.08(3H,s),7.74(1H,dd,J=8.6,7.6Hz),8.06(1H,s),8.08(1H,dd,J=7.6,1.3Hz),9.03(1H,dd,J=8.6,1.3Hz)Reference Example 50

To a 6.0 mL concentrated sulfuric acid solution of 1.3 g of methyl-2-chloroquinoline-4-carboxylate, 0.27 mL of fuming nitric acid was added dropwise under ice cooling, and the mixture was stirred at room temperature for 30 minutes and at 50 ° C. for 1 hour. The reaction mixture was poured into ice water and 50 mL of ethyl acetate was added. The organic layer was separated and the aqueous layer was extracted with 30 mL of ethyl acetate. The organic layer and the extract were combined, washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was extracted with diisopropyl ether, 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 obtain 0.25 g of methyl 2-chloro-8-nitroquinoline-4-carboxylate as a pale yellowish white solid. Obtained.
¹ H-NMR (CDCl ₃ ) δ value: 4.08 (3H, s), 7.74 (1H, dd, J = 8.6, 7.6 Hz), 8.06 (1H, s), 8.08 (1H, dd, J = 7.6, 1.3) Hz), 9.03 (1H, dd, J = 8.6,1.3Hz)

メチル＝２−クロロ−８−ニトロキノリン−４−カルボキシラート0.20gのメタノール5mL懸濁液に28％ナトリウムメトキシド/メタノール0.22gを加え、1時間加熱還流した。反応混合物に酢酸エチル30mLおよび水20mLを加えた。有機層を分取し、水層を酢酸エチル20mL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、淡褐色固体のメチル＝２−メトキシ−８−ニトロキノリン−４−カルボキシラート0.11gを得た。
¹H-NMR(CDCl₃)δ値：4.04(3H,s),4.08(3H,s),7.51(1H,dd,J=8.5,7.9Hz),7.57(1H,s),7.97(1H,dd,J=7.9,1.4Hz),8.88(1H,dd,J=8.5,1.4Hz)Reference Example 51

To a suspension of methyl 2-chloro-8-nitroquinoline-4-carboxylate 0.20 g in methanol 5 mL was added 28% sodium methoxide / methanol 0.22 g, and the mixture was heated to reflux for 1 hour. To the reaction mixture, 30 mL of ethyl acetate and 20 mL of water were added. The organic layer was separated, and the aqueous layer was extracted with 20 mL of ethyl acetate. The organic layer and the extract were combined, washed sequentially with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give methyl-2-methoxy-8-nitroquinoline- as a light brown solid. 0.11 g of 4-carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 4.04 (3H, s), 4.08 (3H, s), 7.51 (1H, dd, J = 8.5, 7.9 Hz), 7.57 (1H, s), 7.97 (1H, dd, J = 7.9,1.4Hz), 8.88 (1H, dd, J = 8.5,1.4Hz)

メチル＝２−メトキシ−８−ニトロキノリン−４−カルボキシラート100mgの酢酸3mL溶液に、室温で10％パラジウム−炭素20mgを加え、水素雰囲気下で1時間攪拌した。不溶物をろ去し、減圧下で溶媒を留去した。得られた残留物に酢酸エチル20mLおよび水10mLを加え、氷冷下、飽和炭酸水素ナトリウム水溶液でpH9.0に調整した。有機層を分取し、水層を酢酸エチル10mL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、褐色油状物のメチル＝８−アミノ−２−メトキシキノリン−４−カルボキシラート79mgを得た。
¹H-NMR(CDCl₃)δ値：4.00(3H,s),4.08(3H,s),4.72-4.82(2H,broad),6.96(1H,dd,J=7.6,1.2Hz),7.27(1H,dd,J=8.5,7.6Hz),7.41(1H,s),7.89(1H,dd,J=8.5,1.2Hz)Reference Example 52

To a solution of methyl 2-methoxy-8-nitroquinoline-4-carboxylate (100 mg) in acetic acid (3 mL) was added 10% palladium-carbon (20 mg) at room temperature, and the mixture was stirred under a hydrogen atmosphere for 1 hour. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. To the obtained residue, ethyl acetate (20 mL) and water (10 mL) were added, and the mixture was adjusted to pH 9.0 with a saturated aqueous sodium hydrogencarbonate solution under ice cooling. The organic layer was separated and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, 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 methyl 8-amino-2-methoxyquinoline-4-carboxy as a brown oil. 79 mg of lath was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 4.00 (3H, s), 4.08 (3H, s), 4.72-4.82 (2H, broad), 6.96 (1H, dd, J = 7.6, 1.2 Hz), 7.27 ( 1H, dd, J = 8.5,7.6Hz), 7.41 (1H, s), 7.89 (1H, dd, J = 8.5,1.2Hz)

２−クロロ−８−メチルキノリン1.50gのメタノール12mL溶液に、室温でナトリウムメトキシド1.96gおよびテトラブチルアンモニウムブロミド1.36gを加え、6日間加熱還流した。放冷後、反応混合物に水50mLおよびクロロホルム50mLを加えた。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６０、溶離液；ヘキサン：酢酸エチル＝２０：１］で精製し、無色油状物の２−メトキシ−８−メチルキノリン1.25gを得た。
¹H-NMR(CDCl₃)δ値：2.72(3H,s),4.08(3H,s),6.90(1H,d,J=8.8Hz),7.24(1H,d,J=7.5Hz),7.28(1H,d,J=7.5Hz),7.44-7.60(1H,m),7.94(1H,d,J=8.8Hz)Reference Example 53

To a solution of 2-chloro-8-methylquinoline 1.50 g in methanol 12 mL, sodium methoxide 1.96 g and tetrabutylammonium bromide 1.36 g were added at room temperature, and the mixture was heated to reflux for 6 days. After allowing to cool, 50 mL of water and 50 mL of chloroform were added to the reaction mixture. The organic layer was separated and 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: hexane: ethyl acetate = 20: 1], and colorless oily 2-methoxy-8-methylquinoline 1.25 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.72 (3H, s), 4.08 (3H, s), 6.90 (1H, d, J = 8.8 Hz), 7.24 (1H, d, J = 7.5 Hz), 7.28 (1H, d, J = 7.5Hz), 7.44-7.60 (1H, m), 7.94 (1H, d, J = 8.8Hz)

２−メトキシ−８−メチルキノリン20.1gの四塩化炭素500mL溶液に、室温でＮ−ブロモコハク酸イミド20.6gおよびベンゾイル＝ペルオキシド（75％）3.64gを加え、1時間加熱還流した。反応混合物を放冷後、不溶物をろ去し、ろ液を減圧下で濃縮し、クロロホルム300mLおよび10％炭酸ナトリウム水溶液300mLを加えた。有機層を分取し、水300mLで洗浄後、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８−ブロモメチル−２−メトキシキノリン30.1gを得た。
¹H-NMR(CDCl₃)δ値：4.12(3H,s),5.12(2H,s),6.93(1H,d,J=8.9Hz),7.32(1H,dd,J=8.1,7.2Hz),7.68(1H,dd,J=8.1,1.6Hz),7.72(1H,dd,J=7.2,1.4Hz),7.96(1H,d,J=8.9Hz)Reference Example 54

To a solution of 20.1 g of 2-methoxy-8-methylquinoline in 500 mL of carbon tetrachloride, 20.6 g of N-bromosuccinimide and 3.64 g of benzoyl peroxide (75%) were added at room temperature, and the mixture was heated to reflux for 1 hour. The reaction mixture was allowed to cool, insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and 300 mL of chloroform and 300 mL of 10% aqueous sodium carbonate were added. The organic layer was separated, washed with 300 mL of water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 30.1 g of 8-bromomethyl-2-methoxyquinoline as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ value: 4.12 (3H, s), 5.12 (2H, s), 6.93 (1H, d, J = 8.9 Hz), 7.32 (1H, dd, J = 8.1, 7.2 Hz) , 7.68 (1H, dd, J = 8.1,1.6Hz), 7.72 (1H, dd, J = 7.2,1.4Hz), 7.96 (1H, d, J = 8.9Hz)

８−ブロモメチル−２−メトキシキノリン29.0gのアセトニトリル900mL溶液に、室温でＮ−メチルモルホリン−Ｎ−オキシド38.5gおよび４Ａモレキュラーシーブス1.50gを加え、室温で2時間30分間攪拌した。反応混合物を少量のシリカゲルを用いてろ過し、ろ液を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；ヘキサン：酢酸エチル＝７：１］で精製し、淡黄色固体の２−メトキシキノリン−８−カルバルデヒド11.4gを得た。
¹H-NMR(CDCl₃)δ値：4.12(3H,s),7.00(1H,d,J=8.8Hz),7.49(1H,t,J=7.9Hz),7.98(1H,dd,J=7.9,1.5Hz),8.05(1H,d,J=8.8Hz),8.24(1H,dd,J=7.5,1.5Hz),11.37(1H,d,J=0.7Hz)Reference Example 55

38.5 g of N-methylmorpholine-N-oxide and 1.50 g of 4A molecular sieves were added to a solution of 29.0 g of 8-bromomethyl-2-methoxyquinoline in 900 mL of acetonitrile at room temperature, and the mixture was stirred at room temperature for 2 hours and 30 minutes. The reaction mixture was filtered using a small amount of silica gel, and the solvent was distilled off from the filtrate under reduced pressure. The obtained residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent: hexane: ethyl acetate = 7: 1] to give 2-methoxyquinoline-8-carbaldehyde as a pale yellow solid. 11.4 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 4.12 (3H, s), 7.00 (1H, d, J = 8.8 Hz), 7.49 (1H, t, J = 7.9 Hz), 7.98 (1H, dd, J = 7.9, 1.5Hz), 8.05 (1H, d, J = 8.8Hz), 8.24 (1H, dd, J = 7.5,1.5Hz), 11.37 (1H, d, J = 0.7Hz)

２−メトキシキノリン−８−カルバルデヒド2.00gのアセトニトリル20mL溶液に、室温でトリメチルスルホニウムヨージド2.18g、水酸化カリウム1.20gおよび水48mgを加え、60℃で5時間攪拌した。反応混合物をろ過後、ろ液を減圧濃縮し、得られた残留物に酢酸エチル50mLおよび水20mLを加えた。有機層を分取し、飽和塩化ナトリウム水溶液20mLで2回洗浄し、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−８−（オキシラン−２−イル）キノリン2.35gを得た。
¹H-NMR(CDCl₃)δ値：2.82(1H,dd,J=5.8,2.7Hz),3.34(1H,dd,J=5.8,4.2Hz),4.10(3H,s),5.01(1H,dd,J=4.2,2.7Hz),6.94(1H,d,J=8.9Hz),7.36(1H,t,J=7.3Hz),7.49(1H,dd,J=7.3,1.6Hz),7.66(1H,dd,J=7.9,1.4Hz),8.00(1H,d,J=9.0Hz)Reference Example 56

To a 20 mL acetonitrile solution of 2.00 g of 2-methoxyquinoline-8-carbaldehyde, 2.18 g of trimethylsulfonium iodide, 1.20 g of potassium hydroxide and 48 mg of water were added at room temperature, and the mixture was stirred at 60 ° C. for 5 hours. After filtration of the reaction mixture, the filtrate was concentrated under reduced pressure, and 50 mL of ethyl acetate and 20 mL of water were added to the resulting residue. The organic layer was separated, washed twice with 20 mL of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2-methoxy-8- (oxiran-2-yl) as a yellow oil. ) 2.35 g of quinoline was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.82 (1H, dd, J = 5.8, 2.7 Hz), 3.34 (1H, dd, J = 5.8, 4.2 Hz), 4.10 (3H, s), 5.01 (1H, dd, J = 4.2,2.7Hz), 6.94 (1H, d, J = 8.9Hz), 7.36 (1H, t, J = 7.3Hz), 7.49 (1H, dd, J = 7.3,1.6Hz), 7.66 ( 1H, dd, J = 7.9,1.4Hz), 8.00 (1H, d, J = 9.0Hz)

２−メトキシ−８−（オキシラン−２−イル）キノリン0.70gのＮ，Ｎ−ジメチルホルムアミド10mL溶液に、室温で１−ｔｅｒｔ−ブトキシカルボニルピペラジン0.78gおよび過塩素酸リチウム0.44gを加え、80℃で1時間30分間攪拌した。放冷後、反応混合物に酢酸エチル40mLおよび水40mLを加えた。有機層を分取し、水層を酢酸エチル40mL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40mL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；ヘキサン：酢酸エチル＝２：３］で精製し、無色ガム状のｔｅｒｔ−ブチル＝４−（２−ヒドロキシ−２−（２−メトキシキノリン−８−イル）エチル）ピペラジンカルボキシラート0.51gを得た。
¹H-NMR(CDCl₃)δ値：1.48(9H,s),2.40-2.54(2H,m),2.60(1H,dd,J=12.5,9.9Hz),2.68-2.84(2H,m),2.98(1H,dd,J=12.5,3.3Hz),3.45-3.55(4H,m),4.04(3H,s),5.75(1H,dd,J=9.9,3.3Hz),6.90(1H,d,J=8.8Hz),7.34-7.44(1H,m),7.62(1H,dd,J=8.1,1.5Hz),7.78-7.86(1H,m),7.98(1H,d,J=8.8Hz)Reference Example 57

To a solution of 0.70 g of 2-methoxy-8- (oxiran-2-yl) quinoline in 10 mL of N, N-dimethylformamide was added 0.78 g of 1-tert-butoxycarbonylpiperazine and 0.44 g of lithium perchlorate at room temperature. For 1 hour 30 minutes. After allowing to cool, 40 mL of ethyl acetate and 40 mL of water were added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted with 40 mL of ethyl acetate. The organic layer and the extract were combined, washed with 40 mL of 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; hexane: ethyl acetate = 2: 3], and colorless gum-like tert-butyl = 4- (2- 0.51 g of hydroxy-2- (2-methoxyquinolin-8-yl) ethyl) piperazinecarboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.48 (9H, s), 2.40-2.54 (2H, m), 2.60 (1H, dd, J = 12.5, 9.9 Hz), 2.68-2.84 (2H, m), 2.98 (1H, dd, J = 12.5,3.3Hz), 3.45-3.55 (4H, m), 4.04 (3H, s), 5.75 (1H, dd, J = 9.9,3.3Hz), 6.90 (1H, d, J = 8.8Hz), 7.34-7.44 (1H, m), 7.62 (1H, dd, J = 8.1,1.5Hz), 7.78-7.86 (1H, m), 7.98 (1H, d, J = 8.8Hz)

ｔｅｒｔ−ブチル＝４−（２−ヒドロキシ−２−（２−メトキシキノリン−８−イル）エチル）ピペラジンカルボキシラート0.49gのクロロホルム9mL溶液に、氷冷下、トリフルオロ酢酸3mLを滴下し、室温で40分間攪拌した。反応混合物を減圧濃縮後、クロロホルム20mLおよび水10mLを加え、20％水酸化ナトリウム水溶液でpH11〜12に調整（pH試験紙）した。有機層を分取し、水層をクロロホルム20mL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30mL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−メトキシキノリン−８−イル）−２−（ピペラジン−１−イル）エタノール0.46gを得た。
¹H-NMR(CDCl₃)δ値：2.44-2.58(2H,m),2.70-2.88(2H,m),2.90-3.06(6H,m),4.04(3H,s),5.78(1H,dd,J=9.9,3.3Hz),6.90(1H,d,J=8.9Hz),7.40(1H,t,J=7.9Hz),7.62(1H,dd,J=7.9,1.4Hz),7.84(1H,dd,J=7.3,1.4Hz),7.98(1H,d,J=8.9Hz)Reference Example 58

tert-Butyl 4- (2-hydroxy-2- (2-methoxyquinolin-8-yl) ethyl) piperazinecarboxylate 0.49 g in chloroform 9 mL solution was added dropwise with ice-cooling 3 mL trifluoroacetic acid at room temperature. Stir for 40 minutes. The reaction mixture was concentrated under reduced pressure, chloroform (20 mL) and water (10 mL) were added, and the mixture was adjusted to pH 11-12 with 20% aqueous sodium hydroxide solution (pH test paper). The organic layer was separated, and the aqueous layer was extracted with 20 mL of chloroform. The organic layer and the extract were combined, washed with 30 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 1- (2-methoxyquinolin-8-yl)- 0.46 g of 2- (piperazin-1-yl) ethanol was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.44-2.58 (2H, m), 2.70-2.88 (2H, m), 2.90-3.06 (6H, m), 4.04 (3H, s), 5.78 (1H, dd , J = 9.9,3.3Hz), 6.90 (1H, d, J = 8.9Hz), 7.40 (1H, t, J = 7.9Hz), 7.62 (1H, dd, J = 7.9,1.4Hz), 7.84 (1H , dd, J = 7.3,1.4Hz), 7.98 (1H, d, J = 8.9Hz)

窒素雰囲気下、オキサリルクロリド0.93gのジクロロメタン28mL溶液を−78℃に冷却し、ジメチルスルホキシド2.3gのジクロロメタン20mL溶液、続けて１−ベンジル−４−ピペリジンメタノール1.2gのジクロロメタン20mL溶液をそれぞれ5分間かけて滴下した。−70〜−60℃で1時間攪拌後、トリエチルアミン2.7mLを5分間かけて滴下し、−65℃で20分、室温で10分間攪拌した。反応混合物に水60mLを加えて有機層を分取し、水層をクロロホルム50mL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、淡黄色油状物の１−ベンジル−４−ピペリジンカルバルデヒド1.3gを得た。
¹H-NMR(CDCl₃)δ値：1.60-1.76(2H,m),1.82-1.94(2H,m),2.04-2.16(2H,m),2.18-2.30(1H,m),2.78-2.86(2H,m),3.50(2H,s),7.21-7.37(5H,m),9.64(1H,d,J=1.1Hz)Reference Example 59

In a nitrogen atmosphere, a solution of 0.93 g of oxalyl chloride in 28 mL of dichloromethane was cooled to −78 ° C., and 2.3 g of dimethyl sulfoxide in 20 mL of dichloromethane, followed by 20 mL of dichloromethane in 1.2 g of 1-benzyl-4-piperidinemethanol for 5 minutes each. And dripped. After stirring at −70 to −60 ° C. for 1 hour, 2.7 mL of triethylamine was added dropwise over 5 minutes, followed by stirring at −65 ° C. for 20 minutes and at room temperature for 10 minutes. 60 mL of water was added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with 50 mL of 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 obtain 1.3 g of 1-benzyl-4-piperidinecarbaldehyde as a pale yellow oil. It was.
¹ H-NMR (CDCl ₃ ) δ value: 1.60-1.76 (2H, m), 1.82-1.94 (2H, m), 2.04-2.16 (2H, m), 2.18-2.30 (1H, m), 2.78-2.86 (2H, m), 3.50 (2H, s), 7.21-7.37 (5H, m), 9.64 (1H, d, J = 1.1Hz)

８−ブロモメチル−２−メトキシキノリン2.1gのトルエン25mL溶液に、室温でトリフェニルホスフィン2.2gのトルエン15mL溶液を10分間かけて滴下し、30分間攪拌後、80℃で1時間30分間攪拌した。反応混合物を放冷後、沈殿物をろ取し、白色粉末の（２−メトキシキノリン−８−イル）メチルトリフェニルホスホニウムブロミド2.19gを得た。
¹H-NMR(CDCl₃)δ値：3.63(3H,s),6.04(2H,d,J=14.5Hz),6.68(1H,d,J=8.9Hz),7.12-7.29(2H,m),7.48-7.74(15H,m),7.76-7.83(1H,m),7.86(1H,d,J=8.9Hz)Reference Example 60

To a toluene 25 mL solution of 8-bromomethyl-2-methoxyquinoline 2.1 g, a toluene 15 mL solution of triphenylphosphine 2.2 g was added dropwise at room temperature over 10 minutes, stirred for 30 minutes, and then stirred at 80 ° C. for 1 hour 30 minutes. After allowing the reaction mixture to cool, the precipitate was collected by filtration to obtain 2.19 g of (2-methoxyquinolin-8-yl) methyltriphenylphosphonium bromide as a white powder.
¹ H-NMR (CDCl ₃ ) δ value: 3.63 (3H, s), 6.04 (2H, d, J = 14.5Hz), 6.68 (1H, d, J = 8.9Hz), 7.12-7.29 (2H, m) , 7.48-7.74 (15H, m), 7.76-7.83 (1H, m), 7.86 (1H, d, J = 8.9Hz)

窒素雰囲気下、（２−メトキシキノリン−８−イル）メチルトリフェニルホスホニウムブロミド1.3gのテトラヒドロフラン15mL溶液を−78℃に冷却し、2.6mol/Lのブチルリチウム1.1mLを3分間かけて滴下し、50分間攪拌した。１−ベンジル−４−ピペリジンカルバルデヒド0.52gのテトラヒドロフラン6mL溶液を4分間かけて滴下した。反応混合物を室温で1時間40分間攪拌した後に減圧下で濃縮した。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］で精製し、淡黄色油状物の８−［２−（１−ベンジルピペリジン−４−イル）ビニル］−２−メトキシキノリン0.67gを得た。得られた生成物はＥ体、Ｚ体の混合物であり、このまま次工程に用いた。Reference Example 61

Under a nitrogen atmosphere, a solution of 1.3 g of (2-methoxyquinolin-8-yl) methyltriphenylphosphonium bromide in 15 mL of tetrahydrofuran was cooled to −78 ° C., and 1.1 mL of 2.6 mol / L butyllithium was added dropwise over 3 minutes. Stir for 50 minutes. A solution of 0.52 g of 1-benzyl-4-piperidinecarbaldehyde in 6 mL of tetrahydrofuran was added dropwise over 4 minutes. The reaction mixture was stirred at room temperature for 1 hour and 40 minutes and then concentrated 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] to give 8- [2- (1-benzylpiperidin-4-yl] as a pale yellow oil. ) Vinyl] -2-methoxyquinoline 0.67g was obtained. The obtained product was a mixture of E-form and Z-form and was used in the next step as it was.

８−［２−（１−ベンジルピペリジン−４−イル）ビニル］−２−メトキシキノリン0.65gのエタノール20mL溶液に、室温で10％パラジウム−炭素0.21gを加え、水素雰囲気下、2時間攪拌した。不溶物をろ去し、減圧下で溶媒を留去して黄色油状物の８−［２−（１−ベンジルピペリジン−４−イル）エチル］−２−メトキシキノリン0.63gを得た。
¹H-NMR(CDCl₃)δ値：1.32-1.92(7H,m),1.94-2.18(2H,m),2.92-3.08(2H,m),3.10-3.25(2H,m),3.61(2H,s),4.04(3H,s),6.88(1H,d,J=8.8Hz),7.22-7.48(7H,m),7.52-7.59(1H,m),7.95(1H,d,J=8.8Hz)Reference Example 62

To a solution of 0.65 g of 8- [2- (1-benzylpiperidin-4-yl) vinyl] -2-methoxyquinoline in 20 mL of ethanol was added 0.21 g of 10% palladium-carbon at room temperature, and the mixture was stirred under a hydrogen atmosphere for 2 hours. . The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 0.63 g of 8- [2- (1-benzylpiperidin-4-yl) ethyl] -2-methoxyquinoline as a yellow oily substance.
¹ H-NMR (CDCl ₃ ) δ value: 1.32-1.92 (7H, m), 1.94-2.18 (2H, m), 2.92-3.08 (2H, m), 3.10-3.25 (2H, m), 3.61 (2H , s), 4.04 (3H, s), 6.88 (1H, d, J = 8.8Hz), 7.22-7.48 (7H, m), 7.52-7.59 (1H, m), 7.95 (1H, d, J = 8.8 Hz)

８−［２−（１−ベンジルピペリジン−４−イル）エチル］−２−メトキシキノリン0.63gのエタノール50mL溶液に、室温で10％パラジウム−炭素0.22gを加え、水素添加（3.4kgf/cm²）した。12時間攪拌後、不溶物をろ去し、減圧下で溶媒を留去して、淡黄色油状物の２−メトキシ−８−（２−（ピペリジン−４−イル）エチル）キノリン0.44gを得た。
¹H-NMR(CDCl₃)δ値：1.36(2H,dt,J=12.4,3.7Hz),1.43-1.57(1H,m),1.68-1.78(2H,m),1.82-1.93(2H,m),2.67(2H,t,J=12.1Hz),3.12-3.24(4H,m),4.05(3H,s),6.89(1H,d,J=8.7Hz),7.29(1H,t,J=7.9Hz),7.46(1H,d,J=7.0Hz),7.57(1H,d,J=8.1Hz),7.96(1H,d,J=8.7Hz)Reference Example 63

To a solution of 0.63 g of 8- [2- (1-benzylpiperidin-4-yl) ethyl] -2-methoxyquinoline in 50 mL of ethanol was added 0.22 g of 10% palladium-carbon at room temperature, and hydrogenated (3.4 kgf / cm ² )did. After stirring for 12 hours, the insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 0.44 g of 2-methoxy-8- (2- (piperidin-4-yl) ethyl) quinoline as a pale yellow oil. It was.
¹ H-NMR (CDCl ₃ ) δ value: 1.36 (2H, dt, J = 12.4,3.7 Hz), 1.43-1.57 (1H, m), 1.68-1.78 (2H, m), 1.82-1.93 (2H, m ), 2.67 (2H, t, J = 12.1Hz), 3.12-3.24 (4H, m), 4.05 (3H, s), 6.89 (1H, d, J = 8.7Hz), 7.29 (1H, t, J = 7.9Hz), 7.46 (1H, d, J = 7.0Hz), 7.57 (1H, d, J = 8.1Hz), 7.96 (1H, d, J = 8.7Hz)

キノリン−８−オール5.0gの硫酸15mL溶液に、5℃で臭素1.85mLを滴下し、3時間攪拌した。反応混合物を氷100gに注ぎ、氷が溶解するまで放置した。不溶物をろ去し、ろ液を20％水酸化ナトリウム水溶液でpH6.0に調整し、析出物をろ取した。析出物をクロロホルムに溶解し、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、褐色固体6.9gを得た。得られた褐色固体2.0gのテトラヒドロフラン20mL溶液に、氷冷下、60％水素化ナトリウム0.36gを加え、10分間攪拌した。テトラヒドロフラン20mLおよびベンジルブロミド1.1mLを順次加え、室温で1時間、還流下2時間攪拌した。Ｎ，Ｎ−ジメチルホルムアミド20mLを加え、還流下1時間攪拌した。反応混合物に酢酸エチル20mLおよび水20mLを加えた。有機層を分取し、水層を酢酸エチル20mL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＝５：１］で精製し、白色固体の８−ベンジルオキシ−５−ブロモキノリン1.5gを得た。
¹H-NMR(CDCl₃)δ値：5.44(2H,s),6.91(1H,d,J=8.5Hz),7.28-7.65(7H,m),8.50(1H,dd,J=8.5,1.7Hz),9.00(1H,dd,J=4.2,1.7Hz)Reference Example 64

To a 15 mL sulfuric acid solution of 5.0 g of quinolin-8-ol, 1.85 mL of bromine was added dropwise at 5 ° C. and stirred for 3 hours. The reaction mixture was poured into 100 g of ice and allowed to stand until the ice melted. The insoluble material was removed by filtration, the filtrate was adjusted to pH 6.0 with 20% aqueous sodium hydroxide solution, and the precipitate was collected by filtration. The precipitate was dissolved in chloroform, the organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 6.9 g of a brown solid. To a 20 mL tetrahydrofuran solution of 2.0 g of the obtained brown solid, 0.36 g of 60% sodium hydride was added under ice cooling, and the mixture was stirred for 10 minutes. Tetrahydrofuran (20 mL) and benzyl bromide (1.1 mL) were sequentially added, and the mixture was stirred at room temperature for 1 hour and under reflux for 2 hours. 20 mL of N, N-dimethylformamide was added and stirred for 1 hour under reflux. To the reaction mixture, 20 mL of ethyl acetate and 20 mL of water were added. The organic layer was separated, and the aqueous layer was extracted with 20 mL of 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 = 5: 1] to obtain 1.5 g of 8-benzyloxy-5-bromoquinoline as a white solid.
¹ H-NMR (CDCl ₃ ) δ value: 5.44 (2H, s), 6.91 (1H, d, J = 8.5 Hz), 7.28-7.65 (7H, m), 8.50 (1H, dd, J = 8.5, 1.7 Hz), 9.00 (1H, dd, J = 4.2,1.7Hz)

８−ベンジルオキシ−５−ブロモキノリン0.50gのクロロホルム4mL溶液に、5℃でメタクロロ過安息香酸0.44gを加え、室温で6時間攪拌した。メタクロロ過安息香酸0.44gを加え、1時間攪拌した。反応混合物にクロロホルム10mLおよび水10mLを加え、飽和炭酸水素ナトリウム水溶液でpH8.4に調整した。有機層を分取し、水層をクロロホルム10mL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］で精製し、褐色固体の８−ベンジルオキシ−５−ブロモキノリン＝１−オキシド0.41gを得た。
¹H-NMR(CDCl₃)δ値：5.28(2H,s),6.99(1H,d,J=8.6Hz),7.28-7.41(4H,m),7.57-7.63(2H,m),7.71(1H,d,J=8.6Hz),8.04(1H,dd,J=8.8,0.7Hz),8.51(1H,dd,J=6.1,1.0Hz)Reference Example 65

To a solution of 0.50 g of 8-benzyloxy-5-bromoquinoline in 4 mL of chloroform was added 0.44 g of metachloroperbenzoic acid at 5 ° C., and the mixture was stirred at room temperature for 6 hours. 0.44 g of metachloroperbenzoic acid was added and stirred for 1 hour. Chloroform 10 mL and water 10 mL were added to the reaction mixture, and the pH was adjusted to 8.4 with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted with 10 mL of 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] to obtain 0.41 g of 8-benzyloxy-5-bromoquinoline = 1-oxide as a brown solid.
¹ H-NMR (CDCl ₃ ) δ value: 5.28 (2H, s), 6.99 (1H, d, J = 8.6 Hz), 7.28-7.41 (4H, m), 7.57-7.63 (2H, m), 7.71 ( 1H, d, J = 8.6Hz), 8.04 (1H, dd, J = 8.8,0.7Hz), 8.51 (1H, dd, J = 6.1,1.0Hz)

８−ベンジルオキシ−５−ブロモキノリン＝１−オキシド1.9gのクロロホルム15mL溶液に、オキシ塩化リン0.65mLを加え、室温で1時間攪拌した。オキシ塩化リン0.65mLを加え、30分間攪拌した。減圧下で溶媒を留去し、酢酸エチル15mLおよび飽和炭酸水素ナトリウム水溶液15mLを加え、20％水酸化ナトリウム水溶液でpH7.5に調整した。有機層を分取し、水層を酢酸エチル10mL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８−ベンジルオキシ−５−ブロモ−２−クロロキノリン1.9gを得た。
¹H-NMR(CDCl₃)δ値：5.43(2H,s),6.93(1H,d,J=8.6Hz),7.26-7.52(6H,m),7.62(1H,d,J=8.3Hz),8.43(1H,dd,J=8.8,1.7Hz)Reference Example 66

0.65 mL of phosphorus oxychloride was added to a 15 mL chloroform solution of 1.9 g of 8-benzyloxy-5-bromoquinoline = 1-oxide, and the mixture was stirred at room temperature for 1 hour. 0.65 mL of phosphorus oxychloride was added and stirred for 30 minutes. The solvent was distilled off under reduced pressure, 15 mL of ethyl acetate and 15 mL of saturated aqueous sodium hydrogen carbonate solution were added, and the pH was adjusted to 7.5 with 20% aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with 10 mL of 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 8-benzyloxy-5-bromo-2-chloroquinoline 1.9. g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 5.43 (2H, s), 6.93 (1H, d, J = 8.6Hz), 7.26-7.52 (6H, m), 7.62 (1H, d, J = 8.3Hz) , 8.43 (1H, dd, J = 8.8,1.7Hz)

８−ベンジルオキシ−５−ブロモ−２−クロロキノリン1.9gから参考例１８と同様にして、白色固体の８−ベンジルオキシ−５−ブロモ−２−メトキシキノリン1.6gを得た。
¹H-NMR(CDCl₃)δ値：4.13(3H,s),5.34(2H,s),6.96-7.03(2H,m),7.28-7.58(6H,m),8.33(1H,d,J=9.0Hz)Reference Example 67

In the same manner as in Reference Example 18 from 1.9 g of 8-benzyloxy-5-bromo-2-chloroquinoline, 1.6 g of 8-benzyloxy-5-bromo-2-methoxyquinoline as a white solid was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 4.13 (3H, s), 5.34 (2H, s), 6.96-7.03 (2H, m), 7.28-7.58 (6H, m), 8.33 (1H, d, J = 9.0Hz)

８−ベンジルオキシ−５−ブロモ−２−メトキシキノリン0.50gのブタノ−ル4mLおよびトリエチルアミン4mL混合溶液に、ビス（トリフェニルホスフィン）パラジウムジクロリド0.10gを加え、一酸化炭素雰囲気下で4時間加熱還流した。反応混合物をろ過し、残渣をクロロホルムで洗浄した。ろ液および洗液を合わせ、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、白色固体のブチル＝８−ベンジルオキシ−２−メトキシキノリン−５−カルボキシラート0.38gを得た。
¹H-NMR(CDCl₃)δ値：1.00(3H,t,J=7.3Hz),1.45-1.56(2H,m),1.74-1.84(2H,m),4.13(3H,s),4.35(2H,J=7.1Hz),5.40(2H,s),7.04-7.08(2H,m),7.30-7.42(3H,m),7.54-7.60(2H,m),8.09(1H,d,J=8.3Hz),9.29(1H,d,J=9.3Hz)Reference Example 68

To a mixed solution of 0.5 mL of 8-benzyloxy-5-bromo-2-methoxyquinoline in 4 mL of butanol and 4 mL of triethylamine, 0.10 g of bis (triphenylphosphine) palladium dichloride is added, and heated under reflux for 4 hours in a carbon monoxide atmosphere. did. The reaction mixture was filtered and the residue was washed with chloroform. The filtrate and washings were combined 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] to obtain 0.38 g of white solid butyl = 8-benzyloxy-2-methoxyquinoline-5-carboxylate. It was.
¹ H-NMR (CDCl ₃ ) δ value: 1.00 (3H, t, J = 7.3 Hz), 1.45-1.56 (2H, m), 1.74-1.84 (2H, m), 4.13 (3H, s), 4.35 ( 2H, J = 7.1Hz), 5.40 (2H, s), 7.04-7.08 (2H, m), 7.30-7.42 (3H, m), 7.54-7.60 (2H, m), 8.09 (1H, d, J = 8.3Hz), 9.29 (1H, d, J = 9.3Hz)

ブチル＝８−ベンジルオキシ−２−メトキシキノリン−５−カルボキシラート0.41gのテトラヒドロフラン7mL溶液に、5％パラジウム−炭素80mgのテトラヒドロフラン2mL懸濁液を加え、水素雰囲気下で4時間攪拌した。不溶物をろ去し、減圧下で溶媒を留去し、白色固体のブチル＝８−ヒドロキシ−２−メトキシキノリン−５−カルボキシラート0.33gを得た。
¹H-NMR(CDCl₃)δ値：1.00(3H,t,J=7.4Hz),1.46-1.56(2H,m),1.75-1.83(2H,m),4.08(3H,s),4.36(2H,t,J=6.6Hz),7.05(1H,d,J=9.3Hz),7.12(1H,d,J=8.3Hz),8.15(1H,d,J=8.3Hz),8.22(1H,s),9.33(1H,d,J=9.3Hz)Reference Example 69

To a solution of 0.41 g of butyl 8-benzyloxy-2-methoxyquinoline-5-carboxylate in 7 mL of tetrahydrofuran was added a suspension of 5% palladium-carbon 80 mg of tetrahydrofuran 2 mL, and the mixture was stirred under a hydrogen atmosphere for 4 hours. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 0.33 g of butyl 8-hydroxy-2-methoxyquinoline-5-carboxylate as a white solid.
¹ H-NMR (CDCl ₃ ) δ value: 1.00 (3H, t, J = 7.4 Hz), 1.46-1.56 (2H, m), 1.75-1.83 (2H, m), 4.08 (3H, s), 4.36 ( 2H, t, J = 6.6Hz), 7.05 (1H, d, J = 9.3Hz), 7.12 (1H, d, J = 8.3Hz), 8.15 (1H, d, J = 8.3Hz), 8.22 (1H, s), 9.33 (1H, d, J = 9.3Hz)

ブチル＝８−ヒドロキシ−２−メトキシキノリン−５−カルボキシラート0.16gの塩化メチレン5mL溶液に、２，６−ルチジン0.10mLおよび４−ジメチルアミノピリジン7mgを加え、2℃に冷却した後、無水トリフルオロメタンスルホン酸0.11mLを滴下し、1時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液10mLを加えた。有機層を分取し、水層を塩化メチレン5mL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＝３０：１］で精製し、白色油状物のブチル＝２−メトキシ−８−（（トリフルオロメタンスルホニル）オキシ）キノリン−５−カルボキシラート0.17gを得た。
¹H-NMR(CDCl₃)δ値：1.01(3H,t,J=7.4Hz),1.45-1.56(2H,m),1.77-1.84(2H,m),4.14(3H,s),4.41(2H,t,J=6.6Hz),7.11(1H,d,J=9.5Hz),7.52(1H,d,J=8.3Hz),8.10(1H,d,J=8.3Hz),9.20(1H,d,J=9.5Hz)Reference Example 70

To a solution of 0.16 g of butyl 8-hydroxy-2-methoxyquinoline-5-carboxylate in 5 mL of methylene chloride, 0.10 mL of 2,6-lutidine and 7 mg of 4-dimethylaminopyridine were added, cooled to 2 ° C., and then anhydrous trifluoro 0.11 mL of romethanesulfonic acid was added dropwise and stirred for 1 hour. To the reaction mixture, 10 mL of saturated aqueous ammonium chloride solution was added. The organic layer was separated and the aqueous layer was extracted with 5 mL of methylene chloride. 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 = 30: 1], and white oily butyl-2-methoxy-8-((trifluoromethanesulfonyl) oxy) quinoline-5. -0.17 g of carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.01 (3H, t, J = 7.4 Hz), 1.45-1.56 (2H, m), 1.77-1.84 (2H, m), 4.14 (3H, s), 4.41 ( 2H, t, J = 6.6Hz), 7.11 (1H, d, J = 9.5Hz), 7.52 (1H, d, J = 8.3Hz), 8.10 (1H, d, J = 8.3Hz), 9.20 (1H, d, J = 9.5Hz)

５−ブロモ−２−メトキシ−８−メチルキノリン1.5gのベンゼン7.5mL溶液に、室温でＮ−ブロモスクシンイミド1.1gおよび２，２’−アゾビス（イソブチロニトリル）58mgを加え、1時間50分間加熱還流した。反応混合物を室温まで冷却後、酢酸エチルおよび水を加えた。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５−ブロモ−８−ブロモメチル−２−メトキシキノリン1.9gを得た。
¹H-NMR(CDCl₃)δ値：4.14(3H,s),5.08(2H,s),7.02(1H,d,J=9.0Hz),7.57(1H,d,J=7.8Hz),7.61(1H,d,J=7.8Hz),8.37(1H,d,J=9.0Hz)Reference Example 71

To a 7.5 mL solution of benzene in 1.5 g of 5-bromo-2-methoxy-8-methylquinoline, 1.1 g of N-bromosuccinimide and 58 mg of 2,2′-azobis (isobutyronitrile) were added at room temperature for 1 hour and 50 minutes. Heated to reflux. After cooling the reaction mixture to room temperature, ethyl acetate and water 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 to obtain 1.9 g of yellow solid 5-bromo-8-bromomethyl-2-methoxyquinoline. It was.
¹ H-NMR (CDCl ₃ ) δ value: 4.14 (3H, s), 5.08 (2H, s), 7.02 (1H, d, J = 9.0 Hz), 7.57 (1H, d, J = 7.8 Hz), 7.61 (1H, d, J = 7.8Hz), 8.37 (1H, d, J = 9.0Hz)

５−ブロモ−８−ブロモメチル−２−メトキシキノリン1.9gの酢酸5mL溶液に、室温でヘキサメチレンテトラミン3.2gの水5mL溶液を加え、1時間30分間加熱還流した。反応混合物を氷冷下まで冷却後、クロロホルムを加え、20％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、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、淡黄色固体の５−ブロモ−２−メトキシキノリン−８−カルバルデヒド0.48gを得た。
¹H-NMR(CDCl₃)δ値：4.13(3H,s),7.08(1H,d,J=9.3Hz),7.77(1H,d,J=8.0Hz),8.07(1H,d,J=8.0Hz),8.44(1H,d,J=9.3Hz),11.31(1H,s)Reference Example 72

To a 5 mL acetic acid solution of 1.9 g of 5-bromo-8-bromomethyl-2-methoxyquinoline was added a 5 mL solution of 3.2 g of hexamethylenetetramine in water at room temperature, and the mixture was heated to reflux for 1 hour 30 minutes. The reaction mixture was cooled to ice-cooling, chloroform was added, and the pH was adjusted to 7.0 with 20% 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. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 10: 1] to obtain 0.48 g of 5-bromo-2-methoxyquinoline-8-carbaldehyde as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ value: 4.13 (3H, s), 7.08 (1H, d, J = 9.3 Hz), 7.77 (1H, d, J = 8.0 Hz), 8.07 (1H, d, J = 8.0Hz), 8.44 (1H, d, J = 9.3Hz), 11.31 (1H, s)

５−ブロモ−２−メトキシキノリン−８−カルバルデヒド0.20gのジメチルスルホキシド5mL溶液に、室温でトリメチルスルホニウムヨージド0.24g、氷冷下で水酸化カリウム65mgを加え、30℃で1時間30分間攪拌した。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、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、橙色固体の５−ブロモ−２−メトキシ−８−（オキシラン−２−イル）キノリン0.20gを得た。
¹H-NMR(CDCl₃)δ値：2.77(1H,dd,J=5.6,2.6Hz),3.30(1H,dd,J=5.6,4.1Hz),4.09(3H,s),4.90-4.96(1H,m),7.02(1H,d,J=9.0Hz),7.33(1H,d,J=7.9Hz),7.61(1H,d,J=7.9Hz),8.38(1H,d,J=9.0Hz)Reference Example 73

To a solution of 0.20 g of 5-bromo-2-methoxyquinoline-8-carbaldehyde in 5 mL of dimethyl sulfoxide, add 0.24 g of trimethylsulfonium iodide at room temperature and 65 mg of potassium hydroxide under ice cooling, and stir at 30 ° C. for 1 hour and 30 minutes. did. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, 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 5-bromo-2-methoxy-8- (oxiran-2-yl) as an orange solid. ) 0.20 g of quinoline was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.77 (1H, dd, J = 5.6, 2.6 Hz), 3.30 (1H, dd, J = 5.6, 4.1 Hz), 4.09 (3H, s), 4.90-4.96 ( 1H, m), 7.02 (1H, d, J = 9.0Hz), 7.33 (1H, d, J = 7.9Hz), 7.61 (1H, d, J = 7.9Hz), 8.38 (1H, d, J = 9.0 Hz)

５−ブロモ−２−メトキシ−８−（オキシラン−２−イル）キノリン90mgのジエチルエーテル3mL溶液に、−20℃で5％（トリフルオロボラン−ジエチルエーテル錯体）ジエチルエーテル溶液92μLを加え、室温で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および酢酸エチルを加えた。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、淡黄色固体の（５−ブロモ−２−メトキシキノリン−８−イル）アセトアルデヒド35mgを得た。
¹H-NMR(CDCl₃)δ値：4.00(3H,s),4.02-4.05(2H,m),7.01(1H,d,J=9.0Hz),7.39(1H,d,J=7.8Hz),7.63(1H,d,J=7.8Hz),8.38(1H,d,J=9.0Hz),9.81-9.84(1H,m)Reference Example 74

To a solution of 90 mg of 5-bromo-2-methoxy-8- (oxiran-2-yl) quinoline in 3 mL of diethyl ether was added 92 μL of a 5% (trifluoroborane-diethyl ether complex) diethyl ether solution at −20 ° C., and at room temperature. Stir for 5 hours. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. 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 silica gel column chromatography [eluent: hexane: ethyl acetate = 10: 1] to obtain 35 mg of (5-bromo-2-methoxyquinolin-8-yl) acetaldehyde as a pale yellow solid. .
¹ H-NMR (CDCl ₃ ) δ value: 4.00 (3H, s), 4.02-4.05 (2H, m), 7.01 (1H, d, J = 9.0 Hz), 7.39 (1H, d, J = 7.8 Hz) , 7.63 (1H, d, J = 7.8Hz), 8.38 (1H, d, J = 9.0Hz), 9.81-9.84 (1H, m)

メチル＝３−アミノ−４−メチルベンゾアート1.0gを氷冷下、ピリジン5.0mLに溶解させ、（２Ｅ）−３−エトキシアクリロイルクロリド0.90gを滴下した。同温度で10分間攪拌後、室温まで昇温し、4時間攪拌した。反応混合物を氷水に注ぎ、固形物をろ取し、水で洗浄し、橙色固体のメチル＝３−（（（２Ｅ）−３−エトキシアクリロイル）アミノ）−４−メチルベンゾアート1.7gを得た。
¹H-NMR(CDCl₃)δ値：1.35(3H,t,J=7.1Hz),2.31(3H,s),3.89(3H,s),3.95(2H,q,J=7.1Hz),5.34(1H,d,J=12.2Hz),6.79(1H,s),7.26(1H,d,J=7.9Hz),7.66(1H,d,J=12.2Hz),7.76(1H,dd,J=7.9,1.6Hz),8.40(1H,s)Reference Example 75

1.0 g of methyl = 3-amino-4-methylbenzoate was dissolved in 5.0 mL of pyridine under ice cooling, and 0.90 g of (2E) -3-ethoxyacryloyl chloride was added dropwise. After stirring at the same temperature for 10 minutes, the mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was poured into ice water and the solid was collected by filtration and washed with water to obtain 1.7 g of orange solid methyl = 3-(((2E) -3-ethoxyacryloyl) amino) -4-methylbenzoate. .
¹ H-NMR (CDCl ₃ ) δ value: 1.35 (3H, t, J = 7.1 Hz), 2.31 (3H, s), 3.89 (3H, s), 3.95 (2H, q, J = 7.1 Hz), 5.34 (1H, d, J = 12.2Hz), 6.79 (1H, s), 7.26 (1H, d, J = 7.9Hz), 7.66 (1H, d, J = 12.2Hz), 7.76 (1H, dd, J = 7.9, 1.6Hz), 8.40 (1H, s)

濃硫酸70mLに氷冷下、メチル＝３−（（（２Ｅ）−エトキシアクリロイル）アミノ）−４−メチルベンゾアート10gを分割で添加した。同温度で30分間攪拌後、室温まで昇温し、6時間攪拌した。反応混合物を氷水80mLに注ぎ、酢酸エチルを加えた。水層を分取し、メタノール50mLを加えて、60〜70℃で7時間攪拌した。減圧下で溶媒を留去し、得られた残留物に、水を加えて不溶物をろ取した。得られた不溶物を酢酸エチルに懸濁し、2分間加熱還流した。放冷後、固形物をろ取し、黄白色固体のメチル＝８−メチル−２−オキソ−１，２−ジヒドロキノリン−５−カルボキシラート3.0gを得た。
¹H-NMR(DMSO-d₆)δ値：2.50(3H,s),3.89(3H,s),6.66(1H,d,J=10.0Hz),7.46(1H,d,J=7.8Hz),7.65(1H,d,J=7.8Hz),8.69(1H,d,J=10.0Hz),11.02(1H,s)Reference Example 76

To 70 mL of concentrated sulfuric acid, 10 g of methyl = 3-(((2E) -ethoxyacryloyl) amino) -4-methylbenzoate was added in portions under ice cooling. After stirring at the same temperature for 30 minutes, the temperature was raised to room temperature and stirred for 6 hours. The reaction mixture was poured into 80 mL of ice water and ethyl acetate was added. The aqueous layer was separated, 50 mL of methanol was added, and the mixture was stirred at 60 to 70 ° C. for 7 hours. The solvent was distilled off under reduced pressure, water was added to the resulting residue, and the insoluble material was collected by filtration. The obtained insoluble material was suspended in ethyl acetate and heated to reflux for 2 minutes. After allowing to cool, the solid was collected by filtration to obtain 3.0 g of methyl = 8-methyl-2-oxo-1,2-dihydroquinoline-5-carboxylate as a pale yellow solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.50 (3H, s), 3.89 (3H, s), 6.66 (1H, d, J = 10.0Hz), 7.46 (1H, d, J = 7.8Hz) , 7.65 (1H, d, J = 7.8Hz), 8.69 (1H, d, J = 10.0Hz), 11.02 (1H, s)

メチル＝８−メチル−２−オキソ−１，２−ジヒドロキノリン−５−カルボキシラート2.9gをオキシ塩化リン18mLに懸濁し、3時間加熱還流した。放冷後、反応混合物を氷水に注ぎ、固形物をろ取し、水で洗浄し、黄色固体のメチル＝２−クロロ−８−メチルキノリン−５−カルボキシラート3.7gを得た。
¹H-NMR(CDCl₃)δ値：2.82(3H,s),3.99(3H,s),7.49(1H,d,J=9.0Hz),7.61(1H,d,J=7.6Hz),8.20(1H,d,J=7.6Hz),9.37(1H,d,J=9.0Hz)Reference Example 77

Methyl = 8-methyl-2-oxo-1,2-dihydroquinoline-5-carboxylate (2.9 g) was suspended in 18 mL of phosphorus oxychloride and heated to reflux for 3 hours. After allowing to cool, the reaction mixture was poured into ice water, and the solid matter was collected by filtration and washed with water to obtain 3.7 g of methyl 2-chloro-8-methylquinoline-5-carboxylate as a yellow solid.
¹ H-NMR (CDCl ₃ ) δ value: 2.82 (3H, s), 3.99 (3H, s), 7.49 (1H, d, J = 9.0 Hz), 7.61 (1H, d, J = 7.6 Hz), 8.20 (1H, d, J = 7.6Hz), 9.37 (1H, d, J = 9.0Hz)

参考例１８と同様な方法で、メチル＝２−クロロ−８−メチルキノリン−５−カルボキシラート3.5gからメチル＝２−メトキシ−８−メチルキノリン−５−カルボキシラート1.5gを得た。
¹H-NMR(CDCl₃)δ値：2.75(3H,s),3.96(3H,s),4.08(3H,s),7.01(1H,d,J=9.3Hz),7.50(1H,d,J=7.6Hz),8.01(1H,d,J=7.6Hz),9.20(1H,d,J=9.3Hz)Reference Example 78

In the same manner as in Reference Example 18, 1.5 g of methyl 2-methoxy-8-methylquinoline-5-carboxylate was obtained from 3.5 g of methyl 2-chloro-8-methylquinoline-5-carboxylate.
¹ H-NMR (CDCl ₃ ) δ value: 2.75 (3H, s), 3.96 (3H, s), 4.08 (3H, s), 7.01 (1H, d, J = 9.3 Hz), 7.50 (1H, d, J = 7.6Hz), 8.01 (1H, d, J = 7.6Hz), 9.20 (1H, d, J = 9.3Hz)

メチル＝２−メトキシ−８−メチルキノリン−５−カルボキシラート1.5gのベンゼン12mL溶液に、室温でＮ−ブロモスクシンイミド1.1gおよび２，２’−アゾビス（イソブチロニトリル）70mgを加え、2時間加熱還流した。反応混合物を放冷後、水および酢酸エチルを加えた。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、黄色固体のメチル＝８−ブロモメチル−２−メトキシキノリン−５−カルボキシラート2.1gを得た。
¹H-NMR(CDCl₃)δ値：3.98(3H,s),4.11(3H,s),5.11(2H,s),7.04(1H,d,J=9.4Hz),7.74(1H,d,J=7.7Hz),8.02(1H,d,J=7.7Hz),9.15(1H,d,J=9.4Hz)Reference Example 79

To a solution of 1.5 g of methyl-2-methoxy-8-methylquinoline-5-carboxylate in 12 mL of benzene was added 1.1 g of N-bromosuccinimide and 70 mg of 2,2′-azobis (isobutyronitrile) at room temperature for 2 hours. Heated to reflux. The reaction mixture was allowed to cool, and water and ethyl acetate were added. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.1 g of yellow solid methyl = 8-bromomethyl-2-methoxyquinoline-5-carboxylate.
¹ H-NMR (CDCl ₃ ) δ value: 3.98 (3H, s), 4.11 (3H, s), 5.11 (2H, s), 7.04 (1H, d, J = 9.4 Hz), 7.74 (1H, d, J = 7.7Hz), 8.02 (1H, d, J = 7.7Hz), 9.15 (1H, d, J = 9.4Hz)

メチル＝８−ブロモメチル−２−メトキシキノリン−５−カルボキシラート2.0gの塩化メチレン10mL溶液に、氷冷下、ジメチルスルホキシド20mLおよびトリメチルアミン＝Ｎ−オキシド＝二水和物4.3gを加え、5〜10℃で2時間20分間攪拌した、トリメチルアミン＝Ｎ−オキシド＝二水和物4.3gを加え、1時間30分間攪拌した。トリメチルアミン＝Ｎ−オキシド＝二水和物4.3gを加え、45分間攪拌した。反応混合物に飽和塩化ナトリウム水溶液、水および酢酸エチルを加えた。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［溶離液；ヘキサン：酢酸エチル＝５：１］で精製し、黄色固体のメチル＝８−ホルミル−２―メトキシキノリン−５−カルボキシラート0.61gを得た。
¹H-NMR(CDCl₃)δ値：4.02(3H,s),4.12(3H,s),7.08(1H,d,J=9.4Hz),8.11(1H,d,J=7.8Hz),8.20(1H,d,J=7.8Hz),9.13(1H,d,J=9.4Hz),11.38(1H,s)Reference Example 80

To a solution of 2.0 g of methyl = 8-bromomethyl-2-methoxyquinoline-5-carboxylate in 10 mL of methylene chloride was added 20 mL of dimethyl sulfoxide and 4.3 g of trimethylamine = N-oxide = dihydrate under ice cooling, and 5-10 The mixture was stirred at 2 ° C. for 2 hours and 20 minutes, 4.3 g of trimethylamine = N-oxide = dihydrate was added, and the mixture was stirred for 1 hour and 30 minutes. 4.3 g of trimethylamine = N-oxide = dihydrate was added and stirred for 45 minutes. To the reaction mixture was added saturated aqueous sodium chloride solution, water and ethyl acetate. The organic layer was separated and 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 = 5: 1] to obtain 0.61 g of methyl = 8-formyl-2-methoxyquinoline-5-carboxylate as a yellow solid. .
¹ H-NMR (CDCl ₃ ) δ value: 4.02 (3H, s), 4.12 (3H, s), 7.08 (1H, d, J = 9.4 Hz), 8.11 (1H, d, J = 7.8 Hz), 8.20 (1H, d, J = 7.8Hz), 9.13 (1H, d, J = 9.4Hz), 11.38 (1H, s)

メチル＝８−ホルミル−２−メトキシキノリン−５−カルボキシラート20mgのＮ，Ｎ−ジメチルホルムアミド1mL溶液に、室温でトリメチルスルホニウムヨージド19mg、氷冷下で60％水素化ナトリウム4mgを加え、同温度で30分間攪拌した。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、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、黄色油状物のメチル＝２−メトキシ−８−（オキシラン−２−イル）キノリン−５−カルボキシラート20mgを得た。
¹H-NMR(CDCl₃)δ値：2.77(1H,dd,J=5.9,2.6Hz),3.34(1H,dd,J=5.9,4.4Hz),3.98(3H,s),4.09(3H,s),5.02(1H,dd,J=4.4,2.6Hz),7.05(1H,d,J=9.3Hz),7.51(1H,d,J=7.7Hz),8.08(1H,d,J=7.7Hz),9.20(1H,d,J=9.3Hz)Reference Example 81

To a solution of 20 mg of methyl 8-formyl-2-methoxyquinoline-5-carboxylate in 1 mL of N, N-dimethylformamide was added 19 mg of trimethylsulfonium iodide at room temperature and 4 mg of 60% sodium hydride under ice cooling. For 30 minutes. Ethyl acetate and water were added to the reaction mixture. 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 a yellow oily methyl 2-methoxy-8- (oxiran-2-yl). 20 mg of quinoline-5-carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.77 (1H, dd, J = 5.9, 2.6 Hz), 3.34 (1H, dd, J = 5.9, 4.4 Hz), 3.98 (3H, s), 4.09 (3H, s), 5.02 (1H, dd, J = 4.4, 2.6Hz), 7.05 (1H, d, J = 9.3Hz), 7.51 (1H, d, J = 7.7Hz), 8.08 (1H, d, J = 7.7) Hz), 9.20 (1H, d, J = 9.3Hz)

２−クロロ−６−メトキシ−８−ニトロキノリン0.10gのメタノール2mL懸濁液に、室温で28％ナトリウムメトキシド/メタノール0.24gのメタノール0.5mL溶液を加え、5時間加熱還流した。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、淡黄色固体の２，６−ジメトキシ−８−ニトロキノリン50mgを得た。
¹H-NMR(CDCl₃)δ値：3.94(3H,s),4.03(3H,s),6.99(1H,d,J=9.0Hz),7.26(1H,s),7.63(1H,d,J=2.7Hz),7.94(1H,d,J=9.0Hz)Reference Example 82

To a 2 mL methanol suspension of 0.10 g 2-chloro-6-methoxy-8-nitroquinoline, a 0.5 mL methanol solution of 28% sodium methoxide / methanol 0.24 g was added at room temperature and heated to reflux for 5 hours. The reaction mixture was cooled to room temperature 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 with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 50 mg of 2,6-dimethoxy-8-nitroquinoline as a pale yellow solid. .
¹ H-NMR (CDCl ₃ ) δ value: 3.94 (3H, s), 4.03 (3H, s), 6.99 (1H, d, J = 9.0 Hz), 7.26 (1H, s), 7.63 (1H, d, J = 2.7Hz), 7.94 (1H, d, J = 9.0Hz)

２，６−ジメトキシ−８−ニトロキノリン45mgの酢酸5mL溶液に、室温で10％パラジウム−炭素9mgを加え、水素雰囲気下で2時間攪拌した。不溶物をろ去し、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［溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、白色固体の２，６−ジメトキシキノリン−８−アミン14mgを得た。
¹H-NMR(CDCl₃)δ値：3.85(3H,s),4.03(3H,s),4.66-4.90(2H,m),6.47(1H,d,J=2.6Hz),6.58(1H,d,J=2.6Hz),6.86(1H,d,J=8.8Hz),7.83(1H,d,J=8.8Hz)Reference Example 83

To a 5 mL acetic acid solution of 45 mg of 2,6-dimethoxy-8-nitroquinoline, 9 mg of 10% palladium-carbon was added at room temperature, and the mixture was stirred for 2 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, 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, 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 = 10: 1] to obtain 14 mg of 2,6-dimethoxyquinolin-8-amine as a white solid.
¹ H-NMR (CDCl ₃ ) δ value: 3.85 (3H, s), 4.03 (3H, s), 4.66-4.90 (2H, m), 6.47 (1H, d, J = 2.6 Hz), 6.58 (1H, d, J = 2.6Hz), 6.86 (1H, d, J = 8.8Hz), 7.83 (1H, d, J = 8.8Hz)

１−（２−（２，３−ジヒドロベンゾ［ｂ］［１,４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸0.50gの塩化メチレン5mL溶液に、氷冷下、塩化チオニル2mLおよびＮ，Ｎ−ジメチルホルムアミド1滴を加え、1時間20分間加熱還流した。減圧下で溶媒を留去し、テトラヒドロフラン2mLを加え、氷冷下、25％アンモニア水10mLに滴下し、室温で30分間攪拌した。減圧下で溶媒を留去し、得られた残留物にメタノールを加え、不溶物をろ去し、減圧下で溶媒を留去し、黄褐色固体の１−（２−（２，３−ジヒドロベンゾ［ｂ］［１,４］ベンゾジオキシン−６−イル）エチル）ピペリジン−４−カルボキサミド0.75gを得た。
¹H-NMR(DMSO-d₆)δ値：1.76-1.98(4H,m),2.24-2.42(1H,m),2.71-2.96(4H,m),3.05-3.18(2H,m),3.41-3.54(2H,m),4.21(4H,s),6.70(1H,dd,J=8.2,1.9Hz),6.78(1H,d,J=1.9Hz),6.80(1H,d,J=8.2Hz),7.16-7.46(1H,m),7.42(1H,s)Reference Example 84

1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxylic acid (0.50 g) in methylene chloride (5 mL) was added with ice-cooled thionyl chloride (2 mL). And 1 drop of N, N-dimethylformamide was added and heated to reflux for 1 hour and 20 minutes. The solvent was distilled off under reduced pressure, 2 mL of tetrahydrofuran was added, and the mixture was added dropwise to 10 mL of 25% aqueous ammonia under ice cooling, followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, methanol was added to the obtained residue, the insoluble material was removed by filtration, the solvent was distilled off under reduced pressure, and 1- (2- (2,3-dihydro) of a tan solid was obtained. Benzo [b] [1,4] benzodioxin-6-yl) ethyl) piperidine-4-carboxamide 0.75 g was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.76-1.98 (4H, m), 2.24-2.42 (1H, m), 2.71-2.96 (4H, m), 3.05-3.18 (2H, m), 3.41 -3.54 (2H, m), 4.21 (4H, s), 6.70 (1H, dd, J = 8.2,1.9Hz), 6.78 (1H, d, J = 1.9Hz), 6.80 (1H, d, J = 8.2 Hz), 7.16-7.46 (1H, m), 7.42 (1H, s)

７−メトキシ−４−メチルイソキノリン−１−（２Ｈ）−オン1.8gをオキシ塩化リン12mLに懸濁し、1時間30分間加熱還流した。減圧下で溶媒を留去し、残留物に水および飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルを加えた。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［溶離液；ヘキサン：酢酸エチル＝５：１］で精製し、淡黄色固体の１−クロロ−７−メトキシ−４−メチルイソキノリン1.6gを得た。
¹H-NMR(CDCl₃)δ値：2.56(3H,s),3.99(3H,s),7.41(1H,dd,J=9.1,2.1Hz),7.55(1H,d,J=2.7Hz),7.85(1H,d,J=9.1Hz),8.00(1H,s)Reference Example 85

1.8 g of 7-methoxy-4-methylisoquinolin-1- (2H) -one was suspended in 12 mL of phosphorus oxychloride and heated to reflux for 1 hour 30 minutes. The solvent was distilled off under reduced pressure, water and saturated aqueous sodium hydrogen carbonate solution were added to the residue, and ethyl acetate was added. The organic layer was separated and 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 = 5: 1] to obtain 1.6 g of 1-chloro-7-methoxy-4-methylisoquinoline as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ value: 2.56 (3H, s), 3.99 (3H, s), 7.41 (1H, dd, J = 9.1, 2.1 Hz), 7.55 (1H, d, J = 2.7 Hz) , 7.85 (1H, d, J = 9.1Hz), 8.00 (1H, s)

１−クロロ−７−メトキシ−４−メチルイソキノリン1.7gのベンゼン13mL溶液に、室温でＮ−ブロモスクシンイミド1.4gおよび２，２’−アゾビス（イソブチロニトリル）80mgを加え、6時間加熱還流した。反応混合物を放冷後、水および酢酸エチルを加えた。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、淡黄色固体の４−ブロモメチル−１−クロロ−７−メトキシイソキノリン1.8gを得た。
¹H-NMR(CDCl₃)δ値：4.01(3H,s),4.82(2H,s),7.52(1H,dd,J=9.1,2.7Hz),7.63(1H,d,J=2.7Hz),8.05(1H,d,J=9.2Hz),8.21(1H,s)Reference Example 86

To a solution of 1.7 g of 1-chloro-7-methoxy-4-methylisoquinoline in 13 mL of benzene was added 1.4 g of N-bromosuccinimide and 80 mg of 2,2′-azobis (isobutyronitrile) at room temperature, and the mixture was heated to reflux for 6 hours. . The reaction mixture was allowed to cool, and water and ethyl acetate 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 silica gel column chromatography [eluent: hexane: ethyl acetate = 4: 1] to obtain 1.8 g of 4-bromomethyl-1-chloro-7-methoxyisoquinoline as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ value: 4.01 (3H, s), 4.82 (2H, s), 7.52 (1H, dd, J = 9.1, 2.7 Hz), 7.63 (1H, d, J = 2.7 Hz) , 8.05 (1H, d, J = 9.2Hz), 8.21 (1H, s)

４−ブロモメチル−１−クロロ−７−メトキシイソキノリン1.9gの塩化メチレン7.4mL溶液に、ジメチルスルホキシド15mLおよびトリメチルアミン＝Ｎ−オキシド＝二水和物3.6gを加え、60〜70℃で5時間20分間攪拌した。トリメチルアミン＝Ｎ−オキシド＝二水和物1.4gを加え、65〜75℃で1時間攪拌した。反応混合物に飽和炭酸ナトリウム水溶液、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、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＝１：２］で精製し、淡黄色固体の７−メトキシ−１−オキソ−１，２−ジヒドロイソキノリン−４−カルバルデヒド0.38gを得た。
¹H-NMR(CDCl₃)δ値：3.96(3H,s),7.42(1H,dd,J=9.0,2.9Hz),7.64-7.68(1H,m),7.82(1H,d,J=2.9Hz),9.01(1H,d,J=9.0Hz),9.79(1H,s),10.67(1H,s)Reference Example 87

To a solution of 1.9 mL of 4-bromomethyl-1-chloro-7-methoxyisoquinoline in 7.4 mL of methylene chloride, 15 mL of dimethyl sulfoxide and 3.6 g of trimethylamine = N-oxide = dihydrate were added, and 60-70 ° C. for 5 hours and 20 minutes. Stir. 1.4 g of trimethylamine = N-oxide = dihydrate was added, and the mixture was stirred at 65 to 75 ° C. for 1 hour. Saturated aqueous sodium carbonate solution, 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 silica gel column chromatography [eluent: hexane: ethyl acetate = 1: 2] to give 7-methoxy-1-oxo-1,2-dihydroisoquinoline-4-carbaldehyde as a pale yellow solid. 0.38 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.96 (3H, s), 7.42 (1H, dd, J = 9.0, 2.9 Hz), 7.64-7.68 (1H, m), 7.82 (1H, d, J = 2.9 Hz), 9.01 (1H, d, J = 9.0Hz), 9.79 (1H, s), 10.67 (1H, s)

60％水素化ナトリウム0.35gのＮ，Ｎ−ジメチルホルムアミド5.4mL懸濁液に、氷冷下、ジエチルホスホノ酢酸エチル2.0gを加え、氷冷〜室温で1時間攪拌した。室温で７−メトキシ−１−オキソ−１，２−ジヒドロイソキノリン−４−カルバルデヒド0.36gのＮ，Ｎ−ジメチルホルムアミド3mL溶液を滴下し、60〜70℃で6時間30分間攪拌した。反応混合物を室温まで冷却後、水を加え、飽和塩化アンモニウム水溶液で中和し、酢酸エチルを加えた。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た。得られた残留物に冷ジエチルエーテルを加えて、固形物をろ取し、淡黄白色固体のエチル＝（Ｅ）−３−（７−メトキシ−１−オキソ−１，２−ジヒドロイソキノリン−４−イル）アクリラート0.25gを得た。
¹H-NMR(CDCl₃)δ値：1.36(3H,t,J=7.0Hz),3.97(3H,s),4.29(2H,q,J=7.0Hz),6.33(1H,d,J=15.7Hz),7.39(1H,dd,J=9.0,2.5Hz),7.45(1H,s),7.84(1H,d,J=9.0Hz),7.87(1H,d,J=2.5Hz),8.00(1H,d,J=15.7Hz),11.40(1H,s)Reference Example 88

To a suspension of 0.35 g of 60% sodium hydride in 5.4 mL of N, N-dimethylformamide was added 2.0 g of ethyl diethylphosphonoacetate under ice cooling, and the mixture was stirred from ice cooling to room temperature for 1 hour. At room temperature, a solution of 0.36 g of 7-methoxy-1-oxo-1,2-dihydroisoquinoline-4-carbaldehyde in 3 mL of N, N-dimethylformamide was added dropwise and stirred at 60 to 70 ° C. for 6 hours and 30 minutes. The reaction mixture was cooled to room temperature, water was added, neutralized with saturated aqueous ammonium chloride solution, and ethyl acetate was 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. Cold diethyl ether was added to the resulting residue, and the solid was collected by filtration. Ethyl (E) -3- (7-methoxy-1-oxo-1,2-dihydroisoquinoline-4 as a pale yellowish white solid -Yl) acrylate 0.25 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.36 (3H, t, J = 7.0 Hz), 3.97 (3H, s), 4.29 (2H, q, J = 7.0 Hz), 6.33 (1H, d, J = 15.7Hz), 7.39 (1H, dd, J = 9.0,2.5Hz), 7.45 (1H, s), 7.84 (1H, d, J = 9.0Hz), 7.87 (1H, d, J = 2.5Hz), 8.00 (1H, d, J = 15.7Hz), 11.40 (1H, s)

エチル＝（Ｅ）−３−（７−メトキシ−１−オキソ−１，２−ジヒドロイソキノリン−４−イル）アクリラート0.25gをオキシ塩化リン3.5mLに懸濁し、1時間45分間加熱還流した。減圧下で溶媒を留去し、残留物に水、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た。得られた残留物にヘキサンを加えて、固形物をろ取し、淡黄白色固体のエチル＝（Ｅ）−３−（１−クロロ−７−メトキシイソキノリン−４−イル）アクリラート0.30gを得た。
¹H-NMR(CDCl₃)δ値：1.38(3H,t,J=7.2Hz),4.02(3H,s),4.32(2H,q,J=7.2Hz),6.57(1H,d,J=16.0Hz),7.50(1H,dd,J=9.3,2.7Hz),7.61(1H,d,J=2.7Hz),8.07(1H,d,J=9.3Hz),8.26(1H,d,J=16.0Hz),8.39(1H,s)Reference Example 89

0.25 g of ethyl = (E) -3- (7-methoxy-1-oxo-1,2-dihydroisoquinolin-4-yl) acrylate was suspended in 3.5 mL of phosphorus oxychloride and heated to reflux for 1 hour and 45 minutes. The solvent was distilled off under reduced pressure, and water, saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the residue. 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. Hexane is added to the obtained residue, and the solid matter is collected by filtration to obtain 0.30 g of ethyl = (E) -3- (1-chloro-7-methoxyisoquinolin-4-yl) acrylate as a pale yellowish white solid. It was.
¹ H-NMR (CDCl ₃ ) δ value: 1.38 (3H, t, J = 7.2 Hz), 4.02 (3H, s), 4.32 (2H, q, J = 7.2 Hz), 6.57 (1H, d, J = 16.0Hz), 7.50 (1H, dd, J = 9.3,2.7Hz), 7.61 (1H, d, J = 2.7Hz), 8.07 (1H, d, J = 9.3Hz), 8.26 (1H, d, J = 16.0Hz), 8.39 (1H, s)

窒素気流下、エチル＝（Ｅ）−３−（１−クロロ−７−メトキシイソキノリン−４−イル）アクリラート0.20gのトルエン4mL溶液に、室温でトリブチルビニルスズ0.26gおよびビス（トリ−tｅｒｔ−ブチルホスフィン）パラジウム（０）35mgを加え、100〜105℃で30分間攪拌した。反応混合物を放冷し、水、飽和塩化ナトリウム水溶液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、黄色固体のエチル＝（Ｅ）−３−（７−メトキシ−１−ビニルイソキノリン−４−イル）アクリラート42mgを得た。
¹H-NMR(CDCl₃)δ値：1.38(3H,t,J=7.1Hz),3.98(3H,s),4.32(2H,q,J=7.1Hz),5.75(1H,d,J=10.7Hz),6.56(1H,dd,J=16.8,1.7Hz),6.58(1H,d,J=15.8Hz),7.42(1H,dd,J=9.3,2.4Hz),7.49(1H,d,J=2.4Hz),7.55(1H,dd,J=16.8,10.7Hz),8.07(1H,d,J=9.3Hz),8.33(1H,d,J=15.8Hz),8.65(1H,s)Reference Example 90

Under nitrogen flow, ethyl = (E) -3- (1-chloro-7-methoxyisoquinolin-4-yl) acrylate 0.20 g in toluene 4 mL solution at room temperature with 0.26 g tributylvinyltin and bis (tri-tert-butyl) Phosphine) palladium (0) 35 mg was added, and the mixture was stirred at 100 to 105 ° C. for 30 minutes. The reaction mixture was allowed to cool, and water, saturated aqueous sodium chloride 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, 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 = 3: 1], and yellow solid ethyl = (E) -3- (7-methoxy-1-vinylisoquinoline-4- Yl) 42 mg of acrylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.38 (3H, t, J = 7.1 Hz), 3.98 (3H, s), 4.32 (2H, q, J = 7.1 Hz), 5.75 (1H, d, J = 10.7Hz), 6.56 (1H, dd, J = 16.8,1.7Hz), 6.58 (1H, d, J = 15.8Hz), 7.42 (1H, dd, J = 9.3,2.4Hz), 7.49 (1H, d, J = 2.4Hz), 7.55 (1H, dd, J = 16.8,10.7Hz), 8.07 (1H, d, J = 9.3Hz), 8.33 (1H, d, J = 15.8Hz), 8.65 (1H, s)

５−ブロモ−２−メトキシ−８−（オキシラン−２−イル）キノリン4.1gのＮ，Ｎ−ジメチルホルムアミド25mL溶液に、室温で４−（（ｔｅｒｔ−ブトキシカルボニル）アミノ）ピペリジン4.1gおよび過塩素酸リチウム2.2gを加え、90℃で5時間攪拌した。反応混合物を室温まで冷却し、水50mLおよび酢酸エチル50mLを加えた。有機層を分取し、水層を酢酸エチル20mL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、固形物をろ取し、白色固体のｔｅｒｔ−ブチル＝（１−（２−（５−ブロモ−２−メトキシキノリン−８−イル）−２−ヒドロキシエチル）ピペリジン−４−イル）カルバマート5.7gを得た。
¹H-NMR(CDCl₃)δ値：1.39-1.67(11H,m),1.90-2.10(2H,m),2.15-2.30(1H,m),2.30-2.50(2H,m),2.75-2.85(1H,m),2.94-2.99(1H,m),3.15-3.30(1H,m),3.40-3.60(1H,m),4.03(3H,s),4.20-4.35(1H,m),4.40-4.55(1H,m),5.70(1H,dd,J=9.8,3.1Hz),6.98(1H,d,J=9.0Hz),7.65(1H,d,J=8.1Hz),7.71(1H,d,J=8.1Hz),8.37(1H,d,J=9.0Hz)Reference Example 91

To a solution of 4.1 g of 5-bromo-2-methoxy-8- (oxiran-2-yl) quinoline in 25 mL of N, N-dimethylformamide was added 4.1 g of 4-((tert-butoxycarbonyl) amino) piperidine and perchloric acid at room temperature. 2.2 g of lithium acid was added and stirred at 90 ° C. for 5 hours. The reaction mixture was cooled to room temperature and 50 mL water and 50 mL ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with 20 mL of 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 substance was collected by filtration, and tert-butyl = (1- (2- (5-bromo-2-methoxyquinolin-8-yl) -2-hydroxyethyl as a white solid was collected. 5.7 g of piperidin-4-yl) carbamate were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.39-1.67 (11H, m), 1.90-2.10 (2H, m), 2.15-2.30 (1H, m), 2.30-2.50 (2H, m), 2.75-2.85 (1H, m), 2.94-2.99 (1H, m), 3.15-3.30 (1H, m), 3.40-3.60 (1H, m), 4.03 (3H, s), 4.20-4.35 (1H, m), 4.40 -4.55 (1H, m), 5.70 (1H, dd, J = 9.8,3.1Hz), 6.98 (1H, d, J = 9.0Hz), 7.65 (1H, d, J = 8.1Hz), 7.71 (1H, d, J = 8.1Hz), 8.37 (1H, d, J = 9.0Hz)

ｔｅｒｔ−ブチル＝（１−（２−（５−ブロモ−２−メトキシキノリン−８−イル）−２−ヒドロキシエチル）ピペリジン−４−イル）カルバマート5.4gのＮ，Ｎ−ジメチルホルムアミド27mL溶液に、トリエチルアミン2.3mL、エチル＝アクリラート1.8mLおよびビス（トリ−tｅｒｔ−ブチルホスフィン）パラジウム（０）0.17gを加え、窒素気流下、96〜100℃で1時間30分間攪拌した。反応混合物に水50mLおよび酢酸エチル50mLを加え、不溶物をろ去した。有機層を分取し、水層を酢酸エチル10mL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、黄色油状物のエチル＝（Ｅ）−３−（８−（２−（４−（（ｔｅｒｔ−ブトキシカルボニル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート8.4gを得た。
¹H-NMR(CDCl₃)δ値：
1.30-1.70(2H,m),1.37(3H,t,J=7.1Hz),1.45(9H,s),1.90-2.05(2H,m),2.17-2.25(1H,m),2.35-2.50(2H,m),2.75-2.85(1H,m),2.93-3.03(1H,m),3.15-3.30(1H,m),3.40-3.60(1H,m),4.03(3H,s),4.25-4.50(2H,m),4.36(2H,q,J=7.1Hz),5.76(1H,dd,J=10.0,3.2Hz),6.52(1H,d,J=15.7Hz),6.99(1H,d,J=9.3Hz),7.68(1H,d,J=7.8Hz),7.87(1H,d,J=7.8Hz),8.35(1H,d,J=15.7Hz),8.38(1H,d,J=9.3Hz)Reference Example 92

tert-butyl = (1- (2- (5-bromo-2-methoxyquinolin-8-yl) -2-hydroxyethyl) piperidin-4-yl) carbamate 5.4 g in a solution of N, N-dimethylformamide in 27 mL 2.3 mL of triethylamine, 1.8 mL of ethyl acrylate and 0.17 g of bis (tri-tert-butylphosphine) palladium (0) were added, and the mixture was stirred at 96 to 100 ° C. for 1 hour and 30 minutes under a nitrogen stream. 50 mL of water and 50 mL of ethyl acetate were added to the reaction mixture, and the insoluble material was removed by filtration. The organic layer was separated and the aqueous layer was extracted with 10 mL of 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. Ethyl = (E) -3- (8- (2- 8.4 g of (4-((tert-butoxycarbonyl) amino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value:
1.30-1.70 (2H, m), 1.37 (3H, t, J = 7.1Hz), 1.45 (9H, s), 1.90-2.05 (2H, m), 2.17-2.25 (1H, m), 2.35-2.50 ( 2H, m), 2.75-2.85 (1H, m), 2.93-3.03 (1H, m), 3.15-3.30 (1H, m), 3.40-3.60 (1H, m), 4.03 (3H, s), 4.25- 4.50 (2H, m), 4.36 (2H, q, J = 7.1Hz), 5.76 (1H, dd, J = 10.0,3.2Hz), 6.52 (1H, d, J = 15.7Hz), 6.99 (1H, d , J = 9.3Hz), 7.68 (1H, d, J = 7.8Hz), 7.87 (1H, d, J = 7.8Hz), 8.35 (1H, d, J = 15.7Hz), 8.38 (1H, d, J = 9.3Hz)

エチル＝（Ｅ）−３−（８−（２−（４−（（ｔｅｒｔ−ブトキシカルボニル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート5.4gのエタノール20mL溶液に、10mol/L塩化水素/エタノール溶液を加え、一晩放置した。減圧下で溶媒を留去し、酢酸エチル20mLを加え、固形物をろ取し、白色固体のエチル＝（Ｅ）−３−（８−（２−（４−アミノピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラートの塩酸塩4.8gを得た。
¹H-NMR(DMSO-d₆)δ値：1.30(3H,t,J=7.1Hz),1.90-2.30(4H,m),3.10-3.80(6H,m),3.90-4.00(1H,m),4.08(3H,s),4.24(2H,q,J=7.1Hz),6.05-6.15(1H,m),6.40-6.50(1H,m),6.73(1H,d,J=15.9Hz),7.16(1H,d,J=9.3Hz),7.92(1H,d,J=7.7Hz),8.00(1H,d,J=7.7Hz),8.35(1H,d,J=15.9Hz),8.45-8.60(3H,m),8.62(1H,d,J=9.3Hz),10.22(1H,s)Reference Example 93

Ethyl = (E) -3- (8- (2- (4-((tert-butoxycarbonyl) amino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate 5.4 To a 20 mL solution of g in ethanol, a 10 mol / L hydrogen chloride / ethanol solution was added and left overnight. The solvent was distilled off under reduced pressure, 20 mL of ethyl acetate was added, the solid was collected by filtration, and white solid ethyl = (E) -3- (8- (2- (4-aminopiperidin-1-yl)- 4.8 g of 1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.30 (3H, t, J = 7.1Hz), 1.90-2.30 (4H, m), 3.10-3.80 (6H, m), 3.90-4.00 (1H, m ), 4.08 (3H, s), 4.24 (2H, q, J = 7.1Hz), 6.05-6.15 (1H, m), 6.40-6.50 (1H, m), 6.73 (1H, d, J = 15.9Hz) , 7.16 (1H, d, J = 9.3Hz), 7.92 (1H, d, J = 7.7Hz), 8.00 (1H, d, J = 7.7Hz), 8.35 (1H, d, J = 15.9Hz), 8.45 -8.60 (3H, m), 8.62 (1H, d, J = 9.3Hz), 10.22 (1H, s)

５−ブロモ−２−メトキシ−８−（オキシラン−２−イル）キノリン4.9gおよび１−（ｔｅｒｔ−ブトキシカルボニル）ピペラジン4.6gから参考例９１と同様にして、白色固体のｔｅｒｔ−ブチル＝４−（２−（５−ブロモ−２−メトキシキノリン−８−イル）−２−ヒドロキシエチル）ピペラジン−１−カルボキシラート3.9gを得た。
¹H-NMR(CDCl₃)δ値：1.47(9H,s),2.40-2.55(3H,m),2.60-2.85(2H,m),3.00(1H,dd,J=12.4,3.1Hz),3.35-3.60(4H,m),4.04(3H,s),4.23(1H,s),5.74(1H,dd,J=9.9,3.1Hz),6.99(1H,d,J=9.1Hz),7.66(1H,d,J=7.9Hz),7.72(1H,d,J=7.9Hz),8.38(1H,d,J=9.1Hz)Reference Example 94

In the same manner as in Reference Example 91, from 4.9 g of 5-bromo-2-methoxy-8- (oxiran-2-yl) quinoline and 4.6 g of 1- (tert-butoxycarbonyl) piperazine, tert-butyl = 4- 3.9 g of (2- (5-bromo-2-methoxyquinolin-8-yl) -2-hydroxyethyl) piperazine-1-carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.47 (9H, s), 2.40-2.55 (3H, m), 2.60-2.85 (2H, m), 3.00 (1H, dd, J = 12.4, 3.1 Hz), 3.35-3.60 (4H, m), 4.04 (3H, s), 4.23 (1H, s), 5.74 (1H, dd, J = 9.9,3.1Hz), 6.99 (1H, d, J = 9.1Hz), 7.66 (1H, d, J = 7.9Hz), 7.72 (1H, d, J = 7.9Hz), 8.38 (1H, d, J = 9.1Hz)

ｔｅｒｔ−ブチル＝４−（２−（５−ブロモ−２−メトキシキノリン−８−イル）−２−ヒドロキシエチル）ピペラジン−１−カルボキシラート3.8gから参考例９２と同様にして、褐色油状物の（Ｅ）−エチル＝３−（８−（２−（４−（ｔｅｒｔ−ブトキシカルボニル）ピペラジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート4.5gを得た。
¹H-NMR(CDCl₃)δ値：1.37(3H,t,J=7.1Hz),1.47(9H,s),2.40-2.55(3H,m),2.65-2.85(2H,m),3.02(1H,dd,J=12.4,3.1Hz),3.40-3.60(4H,m),4.04(3H,s),4.25-4.35(1H,m),4.31(2H,q,J=7.1Hz),5.79(1H,dd,J=10.0,2.9Hz),6.52(1H,d,J=15.9Hz),7.00(1H,d,J=9.2Hz),7.69(1H,d,J=7.8Hz),7.87(1H,d,J=7.8Hz),8.35(1H,d,J=15.9Hz),8.39(1H,d,J=9.2Hz)Reference Example 95

tert-butyl 4- (2- (5-bromo-2-methoxyquinolin-8-yl) -2-hydroxyethyl) piperazine-1-carboxylate 4.5 g of (E) -ethyl = 3- (8- (2- (4- (tert-butoxycarbonyl) piperazin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate is obtained. It was.
¹ H-NMR (CDCl ₃ ) δ value: 1.37 (3H, t, J = 7.1 Hz), 1.47 (9H, s), 2.40-2.55 (3H, m), 2.65-2.85 (2H, m), 3.02 ( 1H, dd, J = 12.4,3.1Hz), 3.40-3.60 (4H, m), 4.04 (3H, s), 4.25-4.35 (1H, m), 4.31 (2H, q, J = 7.1Hz), 5.79 (1H, dd, J = 10.0,2.9Hz), 6.52 (1H, d, J = 15.9Hz), 7.00 (1H, d, J = 9.2Hz), 7.69 (1H, d, J = 7.8Hz), 7.87 (1H, d, J = 7.8Hz), 8.35 (1H, d, J = 15.9Hz), 8.39 (1H, d, J = 9.2Hz)

エチル＝（Ｅ）−３−（８−（２−（４−（ｔｅｒｔ−ブトキシカルボニル）ピペラジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート4.0gから参考例９３と同様にして、淡褐色固体のエチル＝（Ｅ）−３−（８−（２−（ピペラジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラートの塩酸塩3.3gを得た。
¹H-NMR(DMSO-d₆)δ値：1.30(3H,t,J=7.1Hz),3.40-4.20(10H,m),4.08(3H,s),4.24(2H,q,J=7.1Hz),6.10-6.20(1H,m),6.25-6.60(1H,broad),6.73(1H,d,J=15.9Hz),7.16(1H,d,J=9.3Hz),7.93(1H,d,J=7.8Hz),8.00(1H,d,J=7.8Hz),8.35(1H,d,J=15.9Hz),8.61(1H,d,J=9.3Hz),10.02(2H,s),11.10-11.60(1H,broad)Reference Example 96

Reference from ethyl = (E) -3- (8- (2- (4- (tert-butoxycarbonyl) piperazin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate 4.0 g Analogously to Example 93, a pale brown solid of ethyl = (E) -3- (8- (2- (piperazin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate 3.3 g of hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.30 (3H, t, J = 7.1 Hz), 3.40-4.20 (10H, m), 4.08 (3H, s), 4.24 (2H, q, J = 7.1 Hz), 6.10-6.20 (1H, m), 6.25-6.60 (1H, broad), 6.73 (1H, d, J = 15.9Hz), 7.16 (1H, d, J = 9.3Hz), 7.93 (1H, d , J = 7.8Hz), 8.00 (1H, d, J = 7.8Hz), 8.35 (1H, d, J = 15.9Hz), 8.61 (1H, d, J = 9.3Hz), 10.02 (2H, s), 11.10-11.60 (1H, broad)

（７−メトキシイソキノリン−４−イル）酢酸の塩酸塩0.80gのメタノール16mL懸濁液に、塩化チオニル0.54mLを加え、1時間加熱還流した。減圧下で溶媒を濃縮した後、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、褐色固体のメチル＝（７−メトキシイソキノリン−４−イル）アセタート0.67gを得た。
¹H-NMR(CDCl₃)δ値：3.69(3H,s),3.96(3H,s),3.99(2H,s),7.25(1H,d,J=2.7Hz),7.40(1H,dd,J=9.3,2.7Hz),7.88(1H,d,J=9.3Hz),8.32(1H,s),9.10(1H,s)Reference Example 97

To a suspension of 0.87 g of hydrochloride salt of (7-methoxyisoquinolin-4-yl) acetic acid in 16 mL of methanol was added 0.54 mL of thionyl chloride, and the mixture was heated to reflux for 1 hour. After concentrating the solvent under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate 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, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Methyl = (7-methoxyisoquinolin-4-yl) acetate as a brown solid 0.67 g Got.
¹ H-NMR (CDCl ₃ ) δ value: 3.69 (3H, s), 3.96 (3H, s), 3.99 (2H, s), 7.25 (1H, d, J = 2.7 Hz), 7.40 (1H, dd, J = 9.3,2.7Hz), 7.88 (1H, d, J = 9.3Hz), 8.32 (1H, s), 9.10 (1H, s)

メチル＝（７−メトキシイソキノリン−４−イル）アセタート0.65gのクロロホルム20mL溶液に、5℃でメタクロロ過安息香酸1.6gを加え、室温で1時間攪拌した。反応混合物に水10mLおよび飽和炭酸水素ナトリウム水溶液10mLを加えた。有機層を分取し、水層をクロロホルム10mL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＝１０：１］で精製し、褐色油状物のメチル＝（７−メトキシイソキノリン−４−イル）アセタート＝Ｎ−オキシド0.70gを得た。
¹H-NMR(CDCl₃)δ値：3.71(3H,s),3.92(2H,s),3.94(3H,s),6.99(1H,d,J=2.4Hz),7.26(1H,dd,J=9.3,2.4Hz),7.77(1H,d,J=9.3Hz),8.01(1H,d,J=1.5Hz),8.62(1H,s)Reference Example 98

To a 20 mL chloroform solution of 0.65 g of methyl = (7-methoxyisoquinolin-4-yl) acetate was added 1.6 g of metachloroperbenzoic acid at 5 ° C., and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, 10 mL of water and 10 mL of a saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated, and the aqueous layer was extracted with 10 mL of 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 = 10: 1] to obtain 0.70 g of methyl = (7-methoxyisoquinolin-4-yl) acetate = N-oxide as a brown oily substance. Obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.71 (3H, s), 3.92 (2H, s), 3.94 (3H, s), 6.99 (1H, d, J = 2.4 Hz), 7.26 (1H, dd, J = 9.3, 2.4Hz), 7.77 (1H, d, J = 9.3Hz), 8.01 (1H, d, J = 1.5Hz), 8.62 (1H, s)

メチル＝（７−メトキシイソキノリン−４−イル）アセタート＝Ｎ−オキシド0.69gのクロロホルム14mL溶液に、オキシ塩化リン0.31mLを加え、室温で1時間30分間、還流下で20分間攪拌した。減圧下で溶媒を留去し、酢酸エチル10mLおよび飽和炭酸水素ナトリウム5mLを加えた。有機層を分取し、水層を酢酸エチル10mL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、褐色固体のメチル＝（１−クロロ−７−メトキシイソキノリン−４−イル）アセタート0.61gを得た。
¹H-NMR(CDCl₃)δ値：3.69(3H,s),3.96(2H,s),4.00(3H,s),7.45(1H,dd,J=9.2,2.6Hz),7.60(1H,d,J=2.6Hz),7.88(1H,d,J=9.2Hz),8.09(1H,s)Reference Example 99

0.31 mL of phosphorus oxychloride was added to a 14 mL chloroform solution of 0.69 g of methyl = (7-methoxyisoquinolin-4-yl) acetate = N-oxide, and the mixture was stirred at room temperature for 1 hour 30 minutes and under reflux for 20 minutes. The solvent was distilled off under reduced pressure, and 10 mL of ethyl acetate and 5 mL of saturated sodium bicarbonate were added. The organic layer was separated and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Methyl = (1-chloro-7-methoxyisoquinolin-4-yl as a brown solid) ) 0.61 g of acetate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.69 (3H, s), 3.96 (2H, s), 4.00 (3H, s), 7.45 (1H, dd, J = 9.2, 2.6 Hz), 7.60 (1H, d, J = 2.6Hz), 7.88 (1H, d, J = 9.2Hz), 8.09 (1H, s)

メチル＝（１−クロロ−７−メトキシイソキノリン−４−イル）アセタート0.20gのトルエン4mL溶液に、トリブチルビニルスズ0.26mLおよびビス（トリ−ｔｅｒｔ−ブチルホスフィン）パラジウム（０）38mgを加え、窒素雰囲気下で30分間加熱還流した。反応混合物をろ過し、ろ滓を酢酸エチルで洗浄した。ろ液および洗液を合わせ、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、褐色油状物のメチル＝（７−メトキシ−１−ビニルイソキノリン−４−イル）アセタート0.13gを得た。
¹H-NMR(CDCl₃)δ値：3.67(3H,s),3.96(3H,s),3.99(2H,s),5.69(1H,dd,J=11.0,2.0Hz),6.47(1H,dd,J=16.9,2.0Hz),7.39(1H,dd,J=9.2,2.6Hz),7.49(1H,d,J=2.6Hz),7.53(1H,dd,J=16.9,11.0Hz),7.88(1H,d,J=9.2Hz),8.33(1H,s)Reference Example 100

To a solution of 0.20 g of methyl = (1-chloro-7-methoxyisoquinolin-4-yl) acetate in 4 mL of toluene were added 0.26 mL of tributylvinyltin and 38 mg of bis (tri-tert-butylphosphine) palladium (0), and a nitrogen atmosphere Under reflux for 30 minutes. The reaction mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate and washings were combined 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 0.13 g of methyl = (7-methoxy-1-vinylisoquinolin-4-yl) acetate as a brown oily substance. Got.
¹ H-NMR (CDCl ₃ ) δ value: 3.67 (3H, s), 3.96 (3H, s), 3.99 (2H, s), 5.69 (1H, dd, J = 11.0, 2.0 Hz), 6.47 (1H, dd, J = 16.9, 2.0Hz), 7.39 (1H, dd, J = 9.2, 2.6Hz), 7.49 (1H, d, J = 2.6Hz), 7.53 (1H, dd, J = 16.9, 11.0Hz), 7.88 (1H, d, J = 9.2Hz), 8.33 (1H, s)

１，２，３，４−テトラヒドロイソキノリン1.0gのジメチルスルホキシド10mL溶液に、炭酸カリウム1.3gおよび１−ブロモ−２−クロロエタン0.94mLを加え、室温で1時間攪拌した。反応混合物に水10mLおよび酢酸エチル10mL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。得られた残留物に酢酸エチルおよび1.0mol/L塩酸を加え、水層を分取した。水層に酢酸エチルおよび炭酸カリウムを加え、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［溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、無色油状物の２−（２−クロロエチル）−１，２，３，４−テトラヒドロイソキノリン0.67gを得た。
¹H-NMR(CDCl₃)δ値：2.82(2H,t,J=5.5Hz),2.88-2.94(4H,m),3.68(2H,t,J=7.1Hz),3.72(2H,s),6.99-7.04(1H,m),7.07-7.16(3H,m)Reference Example 101

To a solution of 1.0 g of 1,2,3,4-tetrahydroisoquinoline in 10 mL of dimethyl sulfoxide were added 1.3 g of potassium carbonate and 0.94 mL of 1-bromo-2-chloroethane, and the mixture was stirred at room temperature for 1 hour. 10 mL of water and 10 mL of ethyl acetate were added to the reaction mixture. 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. Ethyl acetate and 1.0 mol / L hydrochloric acid were added to the obtained residue, and the aqueous layer was separated. Ethyl acetate and potassium carbonate were added to the aqueous layer, 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 [eluent: hexane: ethyl acetate = 10: 1] to give colorless oily 2- (2-chloroethyl) -1,2,3,4-tetrahydroisoquinoline 0.67. g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.82 (2H, t, J = 5.5Hz), 2.88-2.94 (4H, m), 3.68 (2H, t, J = 7.1Hz), 3.72 (2H, s) , 6.99-7.04 (1H, m), 7.07-7.16 (3H, m)

エチル＝３−（８−アミノ−２−メトキシキノリン−５−イル）プロピオナート0.60gおよび１−（ｔｅｒｔ−ブトキシカルボニル）ピペリジン−４−カルボン酸0.55gから実施例１０と同様にして、淡黄色固体のｔｅｒｔ−ブチル＝４−（（（５−（２−（エトキシカルボニル）エチル）−２−メトキシキノリン−８−イル）アミノ）カルボニル）ピペリジン−１−カルボキシラート0.97gを得た。
¹H-NMR(CDCl₃)δ値：1.24(3H,t,J=7.1Hz),1.48(9H,s),1.72-1.88(2H,m),2.00-2.15(2H,m),2.50-2.62(1H,m),2.67(2H,t,J=7.9Hz),2.80-2.95(2H,m),3.30(2H,t,J=7.9Hz),4.09(3H,s),4.10-4.30(2H,m),4.13(2H,q,J=7.1Hz),7.00(1H,d,J=9.0Hz),7.23(1H,d,J=8.0Hz),8.25(1H,d,J=9.0Hz),8.61(1H,d,J=8.0Hz),9.58(1H,s)Reference Example 102

A pale yellow solid in the same manner as in Example 10 using 0.60 g of ethyl 3- (8-amino-2-methoxyquinolin-5-yl) propionate and 0.55 g of 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid Of tert-butyl 4-(((5- (2- (ethoxycarbonyl) ethyl) -2-methoxyquinolin-8-yl) amino) carbonyl) piperidine-1-carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.24 (3H, t, J = 7.1 Hz), 1.48 (9H, s), 1.72-1.88 (2H, m), 2.00-2.15 (2H, m), 2.50- 2.62 (1H, m), 2.67 (2H, t, J = 7.9Hz), 2.80-2.95 (2H, m), 3.30 (2H, t, J = 7.9Hz), 4.09 (3H, s), 4.10-4.30 (2H, m), 4.13 (2H, q, J = 7.1Hz), 7.00 (1H, d, J = 9.0Hz), 7.23 (1H, d, J = 8.0Hz), 8.25 (1H, d, J = 9.0Hz), 8.61 (1H, d, J = 8.0Hz), 9.58 (1H, s)

ｔｅｒｔ−ブチル＝４−（（（５−（２−（エトキシカルボニル）エチル）−２−メトキシキノリン−８−イル）アミノ）カルボニル）ピペリジン−１−カルボキシラート0.96gから参考例１６と同様にして、白色固体のエチル＝３−（２−メトキシ−８−（（ピペリジン−４−イル）カルボニル）アミノキノリン−５−イル）プロピオナート0.89gを得た。
¹H-NMR(CDCl₃)δ値：1.24(3H,t,J=7.2Hz),2.15-2.40(4H,m),2.68(2H,t,J=7.9Hz),2.71-2.80(1H,m),3.07-3.17(2H,m),3.30(2H,t,J=7.9Hz),3.52-3.62(2H,m),4.09(3H,s),4.13(2H,q,J=7.2Hz),7.01(1H,d,J=9.3Hz),7.22-7.27(1H,m),8.26(1H,d,J=9.3Hz),8.57(1H,d,J=8.1Hz),9.59(1H,s)Reference Example 103

tert-Butyl = 4-(((5- (2- (ethoxycarbonyl) ethyl) -2-methoxyquinolin-8-yl) amino) carbonyl) piperidine-1-carboxylate in the same manner as in Reference Example 16 As a white solid, 0.89 g of ethyl 3- (2-methoxy-8-((piperidin-4-yl) carbonyl) aminoquinolin-5-yl) propionate was obtained.
_{^{1 H-NMR (CDCl 3)}} δ value: 1.24 (3H, t, J = 7.2Hz), 2.15-2.40 (4H, m), 2.68 (2H, t, J = 7.9Hz), 2.71-2.80 (1H, m), 3.07-3.17 (2H, m), 3.30 (2H, t, J = 7.9Hz), 3.52-3.62 (2H, m), 4.09 (3H, s), 4.13 (2H, q, J = 7.2Hz ), 7.01 (1H, d, J = 9.3Hz), 7.22-7.27 (1H, m), 8.26 (1H, d, J = 9.3Hz), 8.57 (1H, d, J = 8.1Hz), 9.59 (1H , s)

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0.20gのＮ，Ｎ−ジメチルホルムアミド2.4mL溶液に、４−アミノシクロヘキサンカルボン酸0.35gおよび酢酸0.24mLを加え、室温で15分間攪拌した。水素化トリアセトキシホウ素ナトリウム0.31gを加え、室温で10時間攪拌した。減圧下で溶媒を留去し、得られた残留物をジオキサン5.0mLおよび水3.0mLの溶液に懸濁し、5mol/L水酸化ナトリウム水溶液1.1mLおよびジ−tｅｒｔ−ブチル＝ジカルボナート0.93gを加え、室温で6時間30分間攪拌した。酢酸エチル、水および飽和塩化アンモニウム水溶液を加え、pH8.0に調整した。有機層を分取し、水層を6.0mol/L塩酸でpH4.0に調整し、酢酸エチルで抽出した。有機層および抽出液を合わせ、飽和塩化アンモニ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、白色固体の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）シクロヘキサンカルボン酸0.25gを得た。
¹H-NMR(CDCl₃)δ値：1.32-1.58(13H,m),1.70-1.81(2H,m),2.00-2.10(2H,m),2.15-2.26(1H,m),4.00-4.08(1H,m),4.24-4.45(6H,m),6.78(1H,s),8.06(1H,s)Reference Example 104

To a solution of 0.20 g of 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde in 2.4 mL of N, N-dimethylformamide was added 0.35 g of 4-aminocyclohexanecarboxylic acid and 0.24 mL of acetic acid. And stirred at room temperature for 15 minutes. 0.31 g of sodium triacetoxyborohydride was added and stirred at room temperature for 10 hours. The solvent was distilled off under reduced pressure, the resulting residue was suspended in a solution of 5.0 mL of dioxane and 3.0 mL of water, 1.1 mL of a 5 mol / L aqueous sodium hydroxide solution and 0.93 g of di-tert-butyl dicarbonate were added, The mixture was stirred at room temperature for 6 hours and 30 minutes. Ethyl acetate, water and saturated aqueous ammonium chloride solution were added to adjust to pH 8.0. The organic layer was separated, and the aqueous layer was adjusted to pH 4.0 with 6.0 mol / L hydrochloric acid and extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous ammonium 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 4-((tert-butoxycarbonyl) (2,3-dihydro [1,4] dioxyno 0.25 g of [2,3-c] pyridin-7-ylmethyl) amino) cyclohexanecarboxylic acid was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.32-1.58 (13H, m), 1.70-1.81 (2H, m), 2.00-2.10 (2H, m), 2.15-2.26 (1H, m), 4.00-4.08 (1H, m), 4.24-4.45 (6H, m), 6.78 (1H, s), 8.06 (1H, s)

２−メトキシキノリン−８−アミン0.35gのＮ，Ｎ−ジメチルホルムアミド8.0mL溶液にＳ−トリフルオロメチル−３，７−ジニトロジベンゾチオフェニウム＝トリフルオロメタンスルホナート0.91gを加え、室温で1時間攪拌した。反応混合物に水5mLおよび酢酸エチル5mLを加え、ろ過し、5.0mol/L水酸化ナトリウム水溶液でpH13に調整した。有機層を分取し、水層を酢酸エチル10mL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：トルエン＝３：１］で精製し、ヘキサンを加え、固形物をろ取し、白色固体の２−メトキシ−５−（トリフルオロメチル）キノリン−８−アミン48mgを得た。
¹H-NMR(CDCl₃)δ値：4.07(3H,s),5.00-5.15(2H,m),6.83(1H,d,J=8.1Hz),7.02(1H,d,J=9.3Hz),7.53(1H,d,J=8.1Hz),8.25-8.30(1H,m)Reference Example 105

To a solution of 0.35 g of 2-methoxyquinolin-8-amine in 8.0 mL of N, N-dimethylformamide was added 0.91 g of S-trifluoromethyl-3,7-dinitrodibenzothiophenium = trifluoromethanesulfonate, and 1 hour at room temperature. Stir. 5 mL of water and 5 mL of ethyl acetate were added to the reaction mixture, filtered, and adjusted to pH 13 with 5.0 mol / L aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with 10 mL of 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: toluene = 3: 1], hexane was added, the solid was collected by filtration, and 2-methoxy-5- (trifluoromethyl) as a white solid. ) 48 mg of quinoline-8-amine was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 4.07 (3H, s), 5.00-5.15 (2H, m), 6.83 (1H, d, J = 8.1 Hz), 7.02 (1H, d, J = 9.3 Hz) , 7.53 (1H, d, J = 8.1Hz), 8.25-8.30 (1H, m)

ブチル＝８−ベンジルオキシ−２−メトキシキノリン−５−カルボキシラート0.50gから実施例３３と同様にして、白色固体の８−ベンジルオキシ−２−メトキシキノリン−５−カルボン酸0.34gを得た。
¹H-NMR(CDCl₃)δ値：4.14(3H,s),5.42(2H,s),7.07-7.11(2H,m),7.30-7.45(3H,m),7.56-7.61(2H,m),8.25(1H,d,J=8.8Hz),9.36(1H,d,J=10.0Hz)Reference Example 106

In the same manner as in Example 33, 0.34 g of white solid 8-benzyloxy-2-methoxyquinoline-5-carboxylic acid was obtained from 0.50 g of butyl 8-benzyloxy-2-methoxyquinoline-5-carboxylate.
¹ H-NMR (CDCl ₃ ) δ value: 4.14 (3H, s), 5.42 (2H, s), 7.07-7.11 (2H, m), 7.30-7.45 (3H, m), 7.56-7.61 (2H, m ), 8.25 (1H, d, J = 8.8Hz), 9.36 (1H, d, J = 10.0Hz)

（１）８−ベンジルオキシ−２−メトキシキノリン−５−カルボン酸0.20gの塩化メチレン3.0mL溶液に、塩化オキサリル0.18mLおよびＮ，Ｎ−ジメチルホルムアミド1滴を加え、室温で1時間15分間攪拌した。塩化オキサリル0.18mLを加え、30分間攪拌した。減圧下で溶媒を留去し、８−ベンジルオキシ−２−メトキシキノリン−５−カルボニルクロリドを得た。
（２）水酸化カリウム2.6gの水7.8mL溶液に、ジエチルエーテル7.8mLを加え、氷冷下、Ｎ−ニトロソメチルウレア0.67gを加え、有機層を分取した。氷冷下、８−ベンジルオキシ−２−メトキシキノリン−５−カルボニルクロリドの塩化メチレン5.0mL溶液を加え、室温で30分間攪拌した。減圧下で溶媒を留去し、トルエンを加え、固形物をろ取し、淡褐色固体の１−（８−ベンジルオキシ−２−メトキシキノリン−５−イル）−２−ジアゾエタノン90mgを得た。
¹H-NMR(CDCl₃)δ値：4.13(3H,s),5.40(2H,s),5.75(1H,s),7.01-7.05(2H,m),7.31-7.40(3H,m),7.49(1H,d,J=8.0Hz),7.54-7.59(2H,m),8.94(1H,d,J=9.2Hz)Reference Example 107

(1) To a solution of 0.20 g of 8-benzyloxy-2-methoxyquinoline-5-carboxylic acid in 3.0 mL of methylene chloride, add 0.18 mL of oxalyl chloride and 1 drop of N, N-dimethylformamide and stir at room temperature for 1 hour and 15 minutes. did. 0.18 mL of oxalyl chloride was added and stirred for 30 minutes. The solvent was distilled off under reduced pressure to obtain 8-benzyloxy-2-methoxyquinoline-5-carbonyl chloride.
(2) To a solution of potassium hydroxide (2.6 g) in water (7.8 mL) was added diethyl ether (7.8 mL). Under ice-cooling, N-nitrosomethylurea (0.67 g) was added, and the organic layer was separated. Under ice cooling, 5.0 mL of a methylene chloride solution of 8-benzyloxy-2-methoxyquinoline-5-carbonyl chloride was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, toluene was added, and the solid was collected by filtration to obtain 90 mg of 1- (8-benzyloxy-2-methoxyquinolin-5-yl) -2-diazoethanone as a light brown solid.
¹ H-NMR (CDCl ₃ ) δ value: 4.13 (3H, s), 5.40 (2H, s), 5.75 (1H, s), 7.01-7.05 (2H, m), 7.31-7.40 (3H, m), 7.49 (1H, d, J = 8.0Hz), 7.54-7.59 (2H, m), 8.94 (1H, d, J = 9.2Hz)

トリエチルアミン0.45mLに安息香酸銀31mgを加え、水冷下、１−（８−ベンジルオキシ−２−メトキシキノリン−５−イル）−２−ジアゾエタノン90mgのテトラヒドロフラン0.90mLおよびエタノール0.90mL懸濁液を加え、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、無色油状物のエチル＝（８−ベンジルオキシ−２−メトキシキノリン−５−イル）アセタート63mgを得た。
¹H-NMR(CDCl₃)δ値：1.20(3H,t,J=7.1Hz),3.91(2H,s),4.13(3H,s),4.13(2H,q,J=7.1Hz),5.35(2H,s),6.98(1H,d,J=9.0Hz),7.06(1H,d,J=7.8Hz),7.18(1H,d,J=7.8Hz),7.25-7.42(3H,m),7.58(2H,d,J=7.2Hz),8.18(1H,d,J=9.0Hz)Reference Example 108

Add 31 mg of silver benzoate to 0.45 mL of triethylamine, add 0.90 mL of tetrahydrofuran and 0.90 mL of ethanol suspension of 90 mg of 1- (8-benzyloxy-2-methoxyquinolin-5-yl) -2-diazoethanone under water cooling, Stir at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 10: 1] to give a colorless oily ethyl = (8-benzyloxy-2- 63 mg of methoxyquinolin-5-yl) acetate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.20 (3H, t, J = 7.1 Hz), 3.91 (2H, s), 4.13 (3H, s), 4.13 (2H, q, J = 7.1 Hz), 5.35 (2H, s), 6.98 (1H, d, J = 9.0Hz), 7.06 (1H, d, J = 7.8Hz), 7.18 (1H, d, J = 7.8Hz), 7.25-7.42 (3H, m) 7.58 (2H, d, J = 7.2Hz), 8.18 (1H, d, J = 9.0Hz)

エチル＝（８−ベンジルオキシ−２−メトキシキノリン−５−イル）アセタート60mgから参考例６９と同様にして、無色油状物のエチル＝（８−ヒドロキシ−２−メトキシキノリン−５−イル）アセタート50mgを得た。
¹H-NMR(CDCl₃)δ値：1.21(3H,t,J=7.1Hz),3.90(2H,s),4.08(3H,s),4.12(2H,q,J=7.1Hz),6.99(1H,d,J=9.0Hz),7.09(1H,d,J=8.0Hz),7.21(1H,d,J=8.0Hz),7.68(1H,s),8.21(1H,d,J=9.0Hz)Reference Example 109

In the same manner as in Reference Example 69, from 60 mg of ethyl = (8-benzyloxy-2-methoxyquinolin-5-yl) acetate, 50 mg of ethyl = (8-hydroxy-2-methoxyquinolin-5-yl) acetate as a colorless oily substance. Got.
¹ H-NMR (CDCl ₃ ) δ value: 1.21 (3H, t, J = 7.1 Hz), 3.90 (2H, s), 4.08 (3H, s), 4.12 (2H, q, J = 7.1 Hz), 6.99 (1H, d, J = 9.0Hz), 7.09 (1H, d, J = 8.0Hz), 7.21 (1H, d, J = 8.0Hz), 7.68 (1H, s), 8.21 (1H, d, J = 9.0Hz)

エチル＝（８−ヒドロキシ−２−メトキシキノリン−５−イル）アセタート50mgから参考例７０と同様にして、白色固体のエチル＝（２−メトキシ−８−（（（トリフルオロメチル）スルホニル）オキシ）キノリン−５−イル）アセタート57mgを得た。
¹H-NMR(CDCl₃)δ値：1.23(3H,t,J=7.1Hz),3.98(2H,s),4.14(3H,s),4.15(2H,q,J=7.1Hz),7.05(1H,d,J=9.3Hz),7.30(1H,d,J=7.7Hz),7.46(1H,d,J=7.7Hz),8.23(1H,d,J=9.3Hz)Reference Example 110

From 50 mg of ethyl = (8-hydroxy-2-methoxyquinolin-5-yl) acetate, in the same manner as in Reference Example 70, white solid ethyl = (2-methoxy-8-(((trifluoromethyl) sulfonyl) oxy) 57 mg of quinolin-5-yl) acetate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.23 (3H, t, J = 7.1 Hz), 3.98 (2H, s), 4.14 (3H, s), 4.15 (2H, q, J = 7.1 Hz), 7.05 (1H, d, J = 9.3Hz), 7.30 (1H, d, J = 7.7Hz), 7.46 (1H, d, J = 7.7Hz), 8.23 (1H, d, J = 9.3Hz)

Ｎ−ニトロソメチルウレア0.49gにジエチルエーテル3.9mLを加え、氷冷下、水酸化カリウム1.3gの3.9mL水溶液を加え、有機層を分取した。別途、メチル＝（Ｅ）−３−（８−ベンジルオキシ−２−メトキシキノリン−５−イル）アクリラート60mgのジエチルエーテル0.34mL溶液に、窒素気流下、酢酸パラジウム1.2mgを加え、氷冷下、分取した有機層を滴下し、30分間攪拌した。反応混合物に酢酸0.79mLを加え、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＝１５：１］で精製し、無色油状物のメチル＝２−（８−ベンジルオキシ−２−メトキシキノリン−５−イル）シクロプロパンカルボキシラート35mgを得た。
¹H-NMR(CDCl₃)δ値：1.33-1.40(1H,m),1.63-1.68(1H,m),1.86-1.92(1H,m),2.81-2.87(1H,m),3.79(3H,s),4.13(3H,s),5.34(2H,s),6.98-7.05(3H,m),7.28-7.41(3H,m),7.57(2H,d,J=7.6Hz),8.35(1H,d,J=9.0Hz)Reference Example 111

Diethyl ether (3.9 mL) was added to N-nitrosomethylurea (0.49 g). Under ice-cooling, 3.9 mL aqueous solution of potassium hydroxide (1.3 g) was added to separate the organic layer. Separately, methyl acetate (E) -3- (8-benzyloxy-2-methoxyquinolin-5-yl) acrylate (60 mg) in diethyl ether (0.34 mL) was added with 1.2 mg of palladium acetate under a nitrogen stream, and ice-cooled. The separated organic layer was added dropwise and stirred for 30 minutes. To the reaction mixture was added 0.79 mL of acetic acid, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 15: 1] to give a colorless oily methyl = 35 mg of 2- (8-benzyloxy-2-methoxyquinolin-5-yl) cyclopropanecarboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.33-1.40 (1H, m), 1.63-1.68 (1H, m), 1.86-1.92 (1H, m), 2.81-2.87 (1H, m), 3.79 (3H , s), 4.13 (3H, s), 5.34 (2H, s), 6.98-7.05 (3H, m), 7.28-7.41 (3H, m), 7.57 (2H, d, J = 7.6Hz), 8.35 ( (1H, d, J = 9.0Hz)

メチル＝２−（８−ベンジルオキシ−２−メトキシキノリン−５−イル）シクロプロパンカルボキシラート35mgから参考例６９と同様にして、無色油状物のメチル＝２−（８−ヒドロキシ−２−メトキシキノリン−５−イル）シクロプロパンカルボキシラート23mgを得た。
¹H-NMR(CDCl₃)δ値：1.36-1.41(1H,m),1.62-1.68(1H,m),1.85-1.91(1H,m),2.80-2.86(1H,m),3.78(3H,s),4.08(3H,s),7.01(1H,d,J=9.2Hz),7.03-7.08(2H,m),7.62(1H,s),8.35(1H,d,J=9.2Hz)Reference Example 112

In the same manner as in Reference Example 69, methyl 2- (8-benzyloxy-2-methoxyquinolin-5-yl) cyclopropanecarboxylate was treated in the same manner as in Reference Example 69 and methyl 2- (8-hydroxy-2-methoxyquinoline). 23 mg of -5-yl) cyclopropanecarboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.36-1.41 (1H, m), 1.62-1.68 (1H, m), 1.85-1.91 (1H, m), 2.80-2.86 (1H, m), 3.78 (3H , s), 4.08 (3H, s), 7.01 (1H, d, J = 9.2Hz), 7.03-7.08 (2H, m), 7.62 (1H, s), 8.35 (1H, d, J = 9.2Hz)

メチル＝２−（８−ヒドロキシ−２−メトキシキノリン−５−イル）シクロプロパンカルボキシラート23mgから参考例７０と同様にして、無色油状物のメチル＝２−（２−メトキシー８−（（（トリフルオロメチル）スルホニル）オキシ）キノリン−５−イル）シクロプロパンカルボキシラート26mgを得た。
¹H-NMR(CDCl₃)δ値：1.38-1.44(1H,m),1.70-1.76(1H,m),1.95-2.00(1H,m),2.88-2.94(1H,m),3.80(3H,s),4.14(3H,s),7.07(1H,d,J=9.1Hz),7.12(1H,d,J=8.1Hz),7.41(1H,d,J=8.1Hz),8.38(1H,d,J=9.1Hz)Reference Example 113

In the same manner as in Reference Example 70, from 23 mg of methyl 2- (8-hydroxy-2-methoxyquinolin-5-yl) cyclopropanecarboxylate, methyl 2- (2-methoxy-8-(((tri 26 mg of fluoromethyl) sulfonyl) oxy) quinolin-5-yl) cyclopropanecarboxylate were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.38-1.44 (1H, m), 1.70-1.76 (1H, m), 1.95-2.00 (1H, m), 2.88-2.94 (1H, m), 3.80 (3H , s), 4.14 (3H, s), 7.07 (1H, d, J = 9.1Hz), 7.12 (1H, d, J = 8.1Hz), 7.41 (1H, d, J = 8.1Hz), 8.38 (1H , d, J = 9.1Hz)

５−ヨード−２−メトキシキノリン−８−アミン2.0gの塩化メチレン34mL溶液に、氷冷下、ピリジン0.80mLおよび無水トリフルオロ酢酸1.0mLを加え、室温で35分間攪拌した。反応混合物を飽和塩化アンモニア水に注ぎ、6.0mol/L塩酸でpH1.0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た。得られた残留物にヘキサンを加え、固形物をろ取し、淡褐色固体の２，２，２−トリフルオロ−Ｎ−（５−ヨード−２−メトキシキノリン−８−イル）アセトアミド2.26gを得た。
¹H-NMR(CDCl₃)δ値：4.12(3H,s),7.05(1H,d,J=9.2Hz),7.96(1H,d,J=8.2Hz),8.26(1H,d,J=9.2Hz),8.38(1H,d,J=8.2Hz),10.36(1H,s)Reference Example 114

To a solution of 2.0 g of 5-iodo-2-methoxyquinolin-8-amine in 34 mL of methylene chloride were added 0.80 mL of pyridine and 1.0 mL of trifluoroacetic anhydride under ice cooling, and the mixture was stirred at room temperature for 35 minutes. The reaction mixture was poured into saturated aqueous ammonium chloride and adjusted to pH 1.0 with 6.0 mol / L hydrochloric acid. 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. Hexane was added to the obtained residue, and the solid was collected by filtration to obtain 2.26 g of 2,2,2-trifluoro-N- (5-iodo-2-methoxyquinolin-8-yl) acetamide as a light brown solid. Obtained.
¹ H-NMR (CDCl ₃ ) δ value: 4.12 (3H, s), 7.05 (1H, d, J = 9.2 Hz), 7.96 (1H, d, J = 8.2 Hz), 8.26 (1H, d, J = 9.2Hz), 8.38 (1H, d, J = 8.2Hz), 10.36 (1H, s)

２，２，２−トリフルオロ−Ｎ−（５−ヨード−２−メトキシキノリン−８−イル）アセトアミド1.1gおよびメチル＝２−（トリブチルスタニル）アクリラート1.7gのＮ，Ｎ−ジメチルホルムアミド1.1mL溶液に、窒素雰囲気下、テトラキス（トリフェニルホスフィン）パラジウム0.28gおよびヨウ化銅（I）0.44gを加え、室温で6時間30分間攪拌した。減圧下で溶媒を留去し、得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；トルエン：酢酸エチル＝２０：１］で精製し、褐色固体のメチル＝２−（２−メトキシ−８−（（トリフルオロアセチル）アミノ）キノリン−５−イル）アクリラート0.35gを得た。
¹H-NMR(CDCl₃)δ値：3.75(3H,s),4.10(3H,s),5.91(1H,d,J=1.6Hz),6.74(1H,d,J=1.6Hz),6.99(1H,d,J=8.8Hz),7.31(1H,d,J=8.2Hz),7.95(1H,d,J=8.8Hz),8.61(1H,d,J=8.2Hz),10.44(1H,s)Reference Example 115

1.1 g of N, N-dimethylformamide of 1.1 g of 2,2,2-trifluoro-N- (5-iodo-2-methoxyquinolin-8-yl) acetamide and 1.7 g of methyl 2- (tributylstannyl) acrylate Under a nitrogen atmosphere, 0.28 g of tetrakis (triphenylphosphine) palladium and 0.44 g of copper (I) iodide were added to the solution, and the mixture was stirred at room temperature for 6 hours and 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: toluene: ethyl acetate = 20: 1] to give brown solid methyl = 2- (2-methoxy-8- 0.35 g of ((trifluoroacetyl) amino) quinolin-5-yl) acrylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.75 (3H, s), 4.10 (3H, s), 5.91 (1H, d, J = 1.6 Hz), 6.74 (1H, d, J = 1.6 Hz), 6.99 (1H, d, J = 8.8Hz), 7.31 (1H, d, J = 8.2Hz), 7.95 (1H, d, J = 8.8Hz), 8.61 (1H, d, J = 8.2Hz), 10.44 (1H , s)

メチル＝２−（２−メトキシ−８−（（トリフルオロアセチル）アミノ）キノリン−５−イル）アクリラート0.25gの90％メタノール水溶液10mL懸濁液に、10％パラジウム−炭素50mgおよび炭酸カリウム0.13gを加え、水素雰囲気下、7時間攪拌した。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＝７：１］で精製し、黄色油状物0.13gを得た。得られた黄色油状物を、テトラヒドロフラン2.0mLに溶解し、10％パラジウム−炭素52mgを加え、水素雰囲気下、40℃で5時間攪拌した。減圧下で溶媒を留去し、無色油状物のメチル＝２−（８−アミノ−２−メトキシキノリン−５−イル）プロピオナート0.10gを得た。
¹H-NMR(CDCl₃)δ値：1.59(3H,d,J=7.2Hz),3.62(3H,s),4.06(3H,s),4.24(1H,q,J=7.2Hz),6.89(1H,d,J=7.9Hz),6.94(1H,d,J=9.1Hz),7.15(1H,d,J=7.9Hz),8.23(1H,d,J=9.1Hz)Reference Example 116

To a suspension of 0.25 g of methyl 2- (2-methoxy-8-((trifluoroacetyl) amino) quinolin-5-yl) acrylate in 10 mL of 90% aqueous methanol solution, 50 mg of 10% palladium-carbon and 0.13 g of potassium carbonate And stirred for 7 hours under hydrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 7: 1] to obtain 0.13 g of a yellow oil. The obtained yellow oil was dissolved in 2.0 mL of tetrahydrofuran, 52% of 10% palladium-carbon was added, and the mixture was stirred at 40 ° C. for 5 hours in a hydrogen atmosphere. The solvent was distilled off under reduced pressure to obtain 0.10 g of methyl 2- (8-amino-2-methoxyquinolin-5-yl) propionate as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ value: 1.59 (3H, d, J = 7.2 Hz), 3.62 (3H, s), 4.06 (3H, s), 4.24 (1H, q, J = 7.2 Hz), 6.89 (1H, d, J = 7.9Hz), 6.94 (1H, d, J = 9.1Hz), 7.15 (1H, d, J = 7.9Hz), 8.23 (1H, d, J = 9.1Hz)

エチル＝（Ｅ）−３−（８−アミノ−２−メトキシキノリン−５−イル）アクリラート0.20gおよび１−（ｔｅｒｔ−ブトキシカルボニル）ピペリジン−４−酢酸0.18gから実施例１０と同様にして、淡黄色固体のｔｅｒｔ−ブチル＝４−（２−（（５−（（Ｅ）−２−（エトキシカルボニル）ビニル）−２−メトキシキノリン−８−イル）アミノ）−２−オキソエチル）ピペリジン−１−カルボキシラート0.15gを得た。
¹H-NMR(CDCl₃)δ値：1.15-1.35(2H,m),1.36(3H,t,J=7.2Hz),1.45(9H,s),1.78-1.90(2H,m),2.09-2.20(1H,m),2.40-2.50(2H,m),2.70-2.85(2H,m),4.05-4.20(2H,m),4.11(3H,s),4.30(2H,q,J=7.2Hz),6.51(1H,d,J=15.9Hz),7.06(1H,d,J=9.0Hz),7.72(1H,d,J=8.2Hz),8.30(1H,d,J=15.9Hz),8.44(1H,d,J=9.0Hz),8.73(1H,d,J=8.2Hz),9.50(1H,s)Reference Example 117

In the same manner as in Example 10 from 0.20 g of ethyl = (E) -3- (8-amino-2-methoxyquinolin-5-yl) acrylate and 0.18 g of 1- (tert-butoxycarbonyl) piperidine-4-acetic acid, Light yellow solid tert-butyl 4- (2-((5-((E) -2- (ethoxycarbonyl) vinyl) -2-methoxyquinolin-8-yl) amino) -2-oxoethyl) piperidine-1 -0.15 g of carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.15-1.35 (2H, m), 1.36 (3H, t, J = 7.2 Hz), 1.45 (9H, s), 1.78-1.90 (2H, m), 2.09- 2.20 (1H, m), 2.40-2.50 (2H, m), 2.70-2.85 (2H, m), 4.05-4.20 (2H, m), 4.11 (3H, s), 4.30 (2H, q, J = 7.2 Hz), 6.51 (1H, d, J = 15.9Hz), 7.06 (1H, d, J = 9.0Hz), 7.72 (1H, d, J = 8.2Hz), 8.30 (1H, d, J = 15.9Hz) , 8.44 (1H, d, J = 9.0Hz), 8.73 (1H, d, J = 8.2Hz), 9.50 (1H, s)

ｔｅｒｔ−ブチル＝４−（２−（（５−（（Ｅ）−２−（エトキシカルボニル）ビニル）−２−メトキシキノリン−８−イル）アミノ）−２−オキソエチル）ピペリジン−１−カルボキシラート0.15gから参考例１６と同様にして、淡黄色固体のエチル＝（Ｅ）−３−（２−メトキシ−８−（（ピペリジン−４−イルアセチル）アミノ）キノリン−５−イル）アクリラート0.10gを得た。
¹H-NMR(DMSO-d₆)δ値：1.29(3H,t,J=7.1Hz),1.38-1.50(2H,m),1.86-1.94(2H,m),2.05-2.15(1H,m),2.59-2.63(2H,m),2.86-2.95(2H,m),3.26-3.30(2H,m),4.14(3H,s),4.23(2H,q,J=7.1Hz),6.68(1H,d,J=15.7Hz),7.19(1H,d,J=9.3Hz),7.96(1H,d,J=8.3Hz),8.21-8.29(1H,m),8.30(1H,d,J=15.7Hz),8.54(1H,d,J=8.3Hz),8.64(1H,d,J=9.3Hz),9.74(1H,s)Reference Example 118

tert-butyl 4- (2-((5-((E) -2- (ethoxycarbonyl) vinyl) -2-methoxyquinolin-8-yl) amino) -2-oxoethyl) piperidine-1-carboxylate 0.15 In the same manner as in Reference Example 16, 0.10 g of ethyl = (E) -3- (2-methoxy-8-((piperidin-4-ylacetyl) amino) quinolin-5-yl) acrylate was obtained from g. It was.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.29 (3H, t, J = 7.1 Hz), 1.38-1.50 (2H, m), 1.86-1.94 (2H, m), 2.05-2.15 (1H, m ), 2.59-2.63 (2H, m), 2.86-2.95 (2H, m), 3.26-3.30 (2H, m), 4.14 (3H, s), 4.23 (2H, q, J = 7.1Hz), 6.68 ( 1H, d, J = 15.7Hz), 7.19 (1H, d, J = 9.3Hz), 7.96 (1H, d, J = 8.3Hz), 8.21-8.29 (1H, m), 8.30 (1H, d, J = 15.7Hz), 8.54 (1H, d, J = 8.3Hz), 8.64 (1H, d, J = 9.3Hz), 9.74 (1H, s)

濃硫酸5.0mLに、氷冷下、（Ｅ）−３−エトキシ−Ｎ−（３−フルオロフェニル）アクリルアミド1.5gを分割添加し、室温で20分間攪拌した。反応混合物を氷水に注ぎ、固形物をろ取し、メタノールおよびジエチルエーテルで洗浄し、淡褐色固体の７−フルオロキノリン−２（１Ｈ）−オンおよび５−フルオロキノリン−２（１Ｈ）−オンの混合物0.73gを得た。Reference Example 119

To 5.0 mL of concentrated sulfuric acid, 1.5 g of (E) -3-ethoxy-N- (3-fluorophenyl) acrylamide was added in portions under ice cooling, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into ice water, the solid was collected by filtration, washed with methanol and diethyl ether, and a pale brown solid of 7-fluoroquinolin-2 (1H) -one and 5-fluoroquinolin-2 (1H) -one. 0.73 g of a mixture was obtained.

７−フルオロキノリン−２（１Ｈ）−オンおよび５−フルオロキノリン−２（１Ｈ）−オンの混合物0.70gに、オキシ塩化リン7.0mLを加え、2時間加熱還流した。反応混合物を室温まで冷却し、減圧下で溶媒を留去した。得られた残留物を氷水に注ぎ、酢酸エチルを加え、20％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２−プロパノールを加え、不溶物をろ去し、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＝１０：１］で精製し、白色固体の２−クロロ−７−フルオロキノリンおよび２−クロロ−５−フルオロキノリンの混合物0.25gを得た。Reference Example 120

To 0.70 g of a mixture of 7-fluoroquinolin-2 (1H) -one and 5-fluoroquinolin-2 (1H) -one, 7.0 mL of phosphorus oxychloride was added and heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The obtained residue was poured into ice water, ethyl acetate was added, and the pH was adjusted to 12 with 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 successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 2-Propanol was added to the obtained residue, insolubles were removed by filtration, 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] to give a white solid mixture of 2-chloro-7-fluoroquinoline and 2-chloro-5-fluoroquinoline 0.25. g was obtained.

２−クロロ−７−フルオロキノリンおよび２−クロロ−５−フルオロキノリンの混合物0.25gに、メタノール5mLおよび28％ナトリウムメトキシド/メタノール0.81gを加え、2時間加熱還流した。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、無色油状物の７−フルオロ−２−メトキシキノリンおよび５−フルオロ−２−メトキシキノリンの混合物0.19gを得た。Reference Example 121

5 mL of methanol and 0.81 g of 28% sodium methoxide / methanol were added to 0.25 g of a mixture of 2-chloro-7-fluoroquinoline and 2-chloro-5-fluoroquinoline, and the mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and 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, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate to obtain 0.19 g of a colorless oily mixture of 7-fluoro-2-methoxyquinoline and 5-fluoro-2-methoxyquinoline. It was.

７−フルオロ−２−メトキシキノリンおよび５−フルオロ−２−メトキシキノリンの混合物0.19gに、濃硫酸2mLおよび発煙硝酸46μLを加え、室温で1時間攪拌した。反応混合物を氷水に注ぎ、固形物をろ取し、水で2回洗浄し、淡黄色固体を得た。得られた淡黄色固体にクロロホルムおよび水を加え、1.0mol/L水酸化ナトリウム水溶液でpH10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、淡黄色固体の７−フルオロ−２−メトキシ−８−ニトロキノリン48mgおよび淡黄色固体の５−フルオロ−２−メトキシ−８−ニトロキノリン20mgを得た。
７−フルオロ−２−メトキシ−８−ニトロキノリン
¹H-NMR(CDCl₃)δ値：4.04(3H,s),6.98(1H,d,J=8.8Hz),7.24-7.28(1H,m),7.83(1H,dd,J=9.0,5.9Hz),8.01(1H,d,J=8.8Hz)
５−フルオロ−２−メトキシ−８−ニトロキノリン
¹H-NMR(CDCl₃)δ値：4.09(3H,s),7.06-7.12(2H,m),8.04(1H,dd,J=8.5,5.4Hz),8.29(1H,d,J=9.3Hz)Reference Example 122

To 0.19 g of a mixture of 7-fluoro-2-methoxyquinoline and 5-fluoro-2-methoxyquinoline, 2 mL of concentrated sulfuric acid and 46 μL of fuming nitric acid were added and stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and the solid was collected by filtration and washed twice with water to give a pale yellow solid. Chloroform and water were added to the obtained pale yellow solid, and the pH was adjusted to 10 with a 1.0 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 silica gel column chromatography [eluent: hexane: ethyl acetate = 2: 1], and 48 mg of a light yellow solid 7-fluoro-2-methoxy-8-nitroquinoline and 5 of a light yellow solid were obtained. 20 mg of fluoro-2-methoxy-8-nitroquinoline was obtained.
7-Fluoro-2-methoxy-8-nitroquinoline
¹ H-NMR (CDCl ₃ ) δ value: 4.04 (3H, s), 6.98 (1H, d, J = 8.8 Hz), 7.24-7.28 (1H, m), 7.83 (1H, dd, J = 9.0, 5.9) Hz), 8.01 (1H, d, J = 8.8Hz)
5-Fluoro-2-methoxy-8-nitroquinoline
¹ H-NMR (CDCl ₃ ) δ value: 4.09 (3H, s), 7.06-7.12 (2H, m), 8.04 (1H, dd, J = 8.5, 5.4 Hz), 8.29 (1H, d, J = 9.3 Hz)

７−フルオロ−２−メトキシ−８−ニトロキノリン45mgに、室温で酢酸4mLおよび10％パラジウム−炭素9mgを加え、水素雰囲気下で1時間攪拌した。不溶物をろ去し、ろ滓を酢酸エチルで3回洗浄した。ろ液および洗液を合わせ、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＝３：１］で精製し、淡褐色固体の７−フルオロ−２−メトキシキノリン−８−アミン33mgを得た。
¹H-NMR(CDCl₃)δ値：4.08(3H,s),6.85(1H,d,J=8.8Hz),7.05(1H,dd,J=8.9,5.7Hz),7.13(1H,dd,J=10.4,8.9Hz),7.92(1H,d,J=8.8Hz)Reference Example 123

To 45 mg of 7-fluoro-2-methoxy-8-nitroquinoline, 4 mL of acetic acid and 9 mg of 10% palladium-carbon were added at room temperature, and the mixture was stirred for 1 hour under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filter cake was washed with ethyl acetate three times. The filtrate and washings were combined 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, 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 = 3: 1] to obtain 33 mg of light brown solid 7-fluoro-2-methoxyquinolin-8-amine.
¹ H-NMR (CDCl ₃ ) δ value: 4.08 (3H, s), 6.85 (1H, d, J = 8.8 Hz), 7.05 (1H, dd, J = 8.9, 5.7 Hz), 7.13 (1H, dd, J = 10.4,8.9Hz), 7.92 (1H, d, J = 8.8Hz)

５−フルオロ−２−メトキシ−８−ニトロキノリン20mgから参考例１２３と同様にして、濃紫色固体の５−フルオロ−２−メトキシキノリン−８−アミン18mgを得た。
¹H-NMR(CDCl₃)δ値：4.07(3H,s),4.56(2H,broad),6.79(1H,dd,J=8.4,5.1Hz),6.88(1H,dd,J=9.6,8.4Hz),6.94(1H,d,J=9.0Hz),8.19(1H,d,J=9.0Hz)Reference Example 124

In the same manner as in Reference Example 123, 20 mg of 5-fluoro-2-methoxy-8-nitroquinoline was obtained in the same manner as in Reference Example 123 to obtain 18 mg of 5-fluoro-2-methoxyquinolin-8-amine as a dark purple solid.
¹ H-NMR (CDCl ₃ ) δ value: 4.07 (3H, s), 4.56 (2H, broad), 6.79 (1H, dd, J = 8.4, 5.1 Hz), 6.88 (1H, dd, J = 9.6, 8.4 Hz), 6.94 (1H, d, J = 9.0Hz), 8.19 (1H, d, J = 9.0Hz)

２−メトキシ−４−メチル−８−ニトロキノリン0.50gのジオキサン5mL溶液に、室温で二酸化セレン0.31gを加え、3時間加熱還流した。減圧下で溶媒を留去し、キシレン5mLを加え、6時間加熱還流した。反応混合物を室温まで冷却した後、不溶物をろ去し、ろ滓をクロロホルムで3回洗浄した。ろ液および洗液を合わせ、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＝３：１］で精製し、淡黄色固体の２−メトキシ−８−ニトロキノリン−４−カルバルデヒド0.15gを得た。
¹H-NMR(CDCl₃)δ値：4.13(3H,s),7.45(1H,s),7.58(1H,dd,J=8.4,7.6Hz),8.02(1H,dd,J=7.6,1.4Hz),9.12(1H,dd,J=8.4,1.4Hz),10.34(1H,s)Reference Example 125

To a solution of 0.50 g of 2-methoxy-4-methyl-8-nitroquinoline in 5 mL of dioxane was added 0.31 g of selenium dioxide at room temperature, and the mixture was heated to reflux for 3 hours. The solvent was distilled off under reduced pressure, 5 mL of xylene was added, and the mixture was heated to reflux for 6 hours. The reaction mixture was cooled to room temperature, insolubles were removed by filtration, and the filter cake was washed with chloroform three times. The filtrate and washings were combined and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 3: 1] to obtain 0.15 g of 2-methoxy-8-nitroquinoline-4-carbaldehyde as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ value: 4.13 (3H, s), 7.45 (1H, s), 7.58 (1H, dd, J = 8.4, 7.6 Hz), 8.02 (1H, dd, J = 7.6, 1.4) Hz), 9.12 (1H, dd, J = 8.4,1.4Hz), 10.34 (1H, s)

ジエチルホスホノ酢酸エチル0.10mLのＮ，Ｎ−ジメチルホルムアミド2mL溶液に、室温で60％水素化ナトリウム19mgを加え、30分間攪拌した。２−メトキシ−８−ニトロキノリン−４−カルバルデヒド0.10gのＮ，Ｎ−ジメチルホルムアミド2mL溶液を加え、30分間攪拌した。反応混合物を氷水および酢酸エチルの混液に注ぎ、1mol/L塩酸でpH3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＝２：１］で精製し、淡褐色固体のエチル＝（Ｅ）−３−（２−メトキシ−８−ニトロキノリン−４−イル）アクリラート85mgを得た。
¹H-NMR(CDCl₃)δ値：1.38(3H,t,J=7.1Hz),4.07(3H,s),4.34(2H,q,J=7.1Hz),6.60(1H,d,J=15.9Hz),7.14(1H,s),7.46-7.51(1H,m),7.97(1H,dd,J=7.6,1.2Hz),8.18(1H,dd,J=8.3,1.2Hz),8.23(1H,d,J=15.9Hz)Reference Example 126

19 mg of 60% sodium hydride was added at room temperature to 2 mL of N, N-dimethylformamide in 0.10 mL of ethyl diethylphosphonoacetate and stirred for 30 minutes. A solution of 0.10 g of 2-methoxy-8-nitroquinoline-4-carbaldehyde in 2 mL of N, N-dimethylformamide was added and stirred for 30 minutes. The reaction mixture was poured into a mixture of ice water and ethyl acetate and adjusted to pH 3 with 1 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 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 = 2: 1] to give a pale brown solid of ethyl = (E) -3- (2-methoxy-8-nitroquinoline-4. -Yl) acrylate 85 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.38 (3H, t, J = 7.1 Hz), 4.07 (3H, s), 4.34 (2H, q, J = 7.1 Hz), 6.60 (1H, d, J = 15.9Hz), 7.14 (1H, s), 7.46-7.51 (1H, m), 7.97 (1H, dd, J = 7.6,1.2Hz), 8.18 (1H, dd, J = 8.3,1.2Hz), 8.23 ( (1H, d, J = 15.9Hz)

エチル＝（Ｅ）−３−（２−メトキシ−８−ニトロキノリン−４−イル）アクリラート80mgに、室温で酢酸3mLおよび10％パラジウム−炭素32mgを加え、水素雰囲気下、40℃で5時間攪拌した。不溶物をろ去し、ろ滓をクロロホルムで3回洗浄した。ろ液および洗液を合わせ、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、褐色油状物のエチル＝３−（８−アミノ−２−メトキシキノリン−４−イル）プロピオナート64mgを得た。
¹H-NMR(CDCl₃)δ値：1.25(3H,t,J=7.2Hz),2.74(2H,t,J=7.9Hz),3.29(2H,t,J=7.9Hz),4.04(3H,s),4.16(2H,q,J=7.2Hz),4.77(2H,s),6.76(1H,s),6.92(1H,dd,J=7.6,1.2Hz),7.20(1H,t,J=7.6Hz),7.24-7.27(1H,m)Reference Example 127

To 80 mg of ethyl = (E) -3- (2-methoxy-8-nitroquinolin-4-yl) acrylate was added 3 mL of acetic acid and 32 mg of 10% palladium-carbon at room temperature, and the mixture was stirred at 40 ° C. for 5 hours in a hydrogen atmosphere. did. The insoluble material was removed by filtration, and the filter cake was washed 3 times with chloroform. The filtrate and washings were combined 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, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl = 3- (8-amino-2-methoxyquinoline- 4-yl) propionate 64 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.25 (3H, t, J = 7.2Hz), 2.74 (2H, t, J = 7.9Hz), 3.29 (2H, t, J = 7.9Hz), 4.04 (3H , s), 4.16 (2H, q, J = 7.2Hz), 4.77 (2H, s), 6.76 (1H, s), 6.92 (1H, dd, J = 7.6, 1.2Hz), 7.20 (1H, t, J = 7.6Hz), 7.24-7.27 (1H, m)

エチル＝（Ｅ）−３−（２−メトキシ−８−ニトロキノリン−４−イル）アクリラート48mgに、室温で酢酸4mLおよびリンドラー触媒9.6mgを加え、水素雰囲気下、同温で30分間、50℃で1時間攪拌した。リンドラー触媒29mgを加え、水素雰囲気下、50℃で6時間攪拌した。不溶物をろ去し、ろ滓をクロロホルムで3回洗浄した。ろ液および洗液を合わせ、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、褐色油状物のエチル＝（Ｅ）−３−（８−アミノ−２−メトキシキノリン−４−イル）アクリラートの43mgを得た。
¹H-NMR(CDCl₃)δ値：1.37(3H,t,J=7.2Hz),4.07(3H,s),4.31(2H,q,J=7.2Hz),4.79(2H,broad),6.55(1H,d,J=15.9Hz),6.96(1H,dd,J=7.6,1.2Hz),7.04(1H,s),7.22-7.28(1H,m),7.35(1H,dd,J=8.3,1.2Hz),8.26(1H,d,J=15.9Hz)Reference Example 128

To 48 mg of ethyl = (E) -3- (2-methoxy-8-nitroquinolin-4-yl) acrylate, 4 mL of acetic acid and 9.6 mg of Lindlar's catalyst were added at room temperature. For 1 hour. Lindlar catalyst (29 mg) was added, and the mixture was stirred at 50 ° C. for 6 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filter cake was washed 3 times with chloroform. The filtrate and washings were combined 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, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl = (E) -3- (8- 43 mg of amino-2-methoxyquinolin-4-yl) acrylate were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.37 (3H, t, J = 7.2 Hz), 4.07 (3H, s), 4.31 (2H, q, J = 7.2 Hz), 4.79 (2H, broad), 6.55 (1H, d, J = 15.9Hz), 6.96 (1H, dd, J = 7.6,1.2Hz), 7.04 (1H, s), 7.22-7.28 (1H, m), 7.35 (1H, dd, J = 8.3 , 1.2Hz), 8.26 (1H, d, J = 15.9Hz)

１−（トリフルオロアセチル）ピペリジン−４−アミンの塩酸塩0.50gの塩化メチレン10mL懸濁液に、２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−スルホニルクロリド0.50gを加え、氷冷下、トリエチルアミン0.59mLを滴下し、室温まで昇温し、1時間攪拌した。反応混合物にクロロホルムおよび水を加えた。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、1.0mol/L塩酸、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、淡褐色泡状物のＮ−（１−（トリフルオロアセチル）ピペリジン−４−イル）−２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−スルホンアミド0.30gを得た。
¹H-NMR(CDCl₃)δ値：1.37-1.53(2H,m),1.86-1.98(2H,m),2.95-3.02(1H,m),3.16-3.24(1H,m),3.39-3.46(1H,m),3.84-3.92(1H,m),4.20-4.40(5H,m),4.48(1H,d,J=7.3Hz),6.97(1H,d,J=8.5Hz),7.36(1H,dd,J=8.5,2.2Hz),7.40(1H,d,J=2.2Hz)Reference Example 129

Add 0.50 g of 2,3-dihydrobenzo [b] [1,4] dioxin-6-sulfonyl chloride to a suspension of 0.50 g of 1- (trifluoroacetyl) piperidin-4-amine hydrochloride in 10 mL of methylene chloride. Under ice-cooling, 0.59 mL of triethylamine was added dropwise, the temperature was raised to room temperature, and the mixture was stirred for 1 hour. 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, washed successively with 1.0 mol / L hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 0.30 g of 1- (trifluoroacetyl) piperidin-4-yl) -2,3-dihydrobenzo [b] [1,4] dioxin-6-sulfonamide was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.37-1.53 (2H, m), 1.86-1.98 (2H, m), 2.95-3.02 (1H, m), 3.16-3.24 (1H, m), 3.39-3.46 (1H, m), 3.84-3.92 (1H, m), 4.20-4.40 (5H, m), 4.48 (1H, d, J = 7.3Hz), 6.97 (1H, d, J = 8.5Hz), 7.36 ( 1H, dd, J = 8.5,2.2Hz), 7.40 (1H, d, J = 2.2Hz)

Ｎ−（１−（トリフルオロアセチル）ピペリジン−４−イル）−２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−スルホンアミド0.29gのメタノール2mL溶液に、水0.5mLおよび炭酸カリウム0.12g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水を加え、1mol/L塩酸で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。得られた残留物にヘキサンを加え、固形物をろ取し、淡褐色固体のＮ−（ピペリジン−４−イル）−２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−スルホンアミド0.11gを得た。
¹H-NMR(DMSO-d₆)δ値：1.12-1.30(2H,m),1.44-1.52(2H,m),2.26-2.35(2H,m),2.74-2.84(2H,m),2.88-2.98(1H,m),4.27-4.38(4H,m),6.98-7.04(1H,m),7.23-7.30(2H,m)Reference Example 130

N- (1- (trifluoroacetyl) piperidin-4-yl) -2,3-dihydrobenzo [b] [1,4] dioxin-6-sulfonamide in 0.2 mL of methanol was added to 0.5 mL of water and carbonic acid. Potassium (0.12 g) was added, and the mixture was stirred at room temperature for 1 hour. Chloroform and water were added to the reaction mixture, and the pH was adjusted to 8.0 with 1 mol / L hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted twice with chloroform. The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane is added to the obtained residue, and the solid is collected by filtration, and light brown solid N- (piperidin-4-yl) -2,3-dihydrobenzo [b] [1,4] dioxin-6-sulfone 0.11 g of amide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.12-1.30 (2H, m), 1.44-1.52 (2H, m), 2.26-2.35 (2H, m), 2.74-2.84 (2H, m), 2.88 -2.98 (1H, m), 4.27-4.38 (4H, m), 6.98-7.04 (1H, m), 7.23-7.30 (2H, m)

ｔｅｒｔ−ブチル＝４−アミノ−４−メチルピペリジン−１−カルボキシラート0.50gの塩化メチレン5mL溶液に、２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−カルバルデヒド0.38gおよび酢酸0.13mLを加え、室温で3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0.74gを加え、同温度で30分間攪拌した。さらに、水素化トリアセトキシホウ素ナトリウム0.74gを加え、同温度で30分間攪拌した後、1時間加熱還流した。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、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ｔｅｒｔ−ブチル＝４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）−４−メチルピペリジン−１−カルボキシラート0.81gを得た。
¹H-NMR(CDCl₃)δ値：1.17(3H,s),1.46(9H,s),1.36-1.60(4H,m),3.35-3.55(3H,m),3.58(2H,s),4.20-4.30(6H,m),6.80-6.90(3H,m)Reference Example 131

To a solution of 0.50 g of tert-butyl 4-amino-4-methylpiperidine-1-carboxylate in 5 mL of methylene chloride was added 0.38 g of 2,3-dihydrobenzo [b] [1,4] dioxin-6-carbaldehyde and acetic acid. 0.13 mL was added and stirred at room temperature for 3 hours. To the reaction mixture, 0.74 g of sodium triacetoxyborohydride was added and stirred at the same temperature for 30 minutes. Further, 0.74 g of sodium triacetoxyborohydride was added, stirred at the same temperature for 30 minutes, and then heated to reflux 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, evaporated under reduced pressure, and tert-butyl 4-((2,3-dihydro 0.81 g of benzo [b] [1,4] dioxin-6-ylmethyl) amino) -4-methylpiperidine-1-carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.17 (3H, s), 1.46 (9H, s), 1.36-1.60 (4H, m), 3.35-3.55 (3H, m), 3.58 (2H, s), 4.20-4.30 (6H, m), 6.80-6.90 (3H, m)

ｔｅｒｔ−ブチル＝４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）−４−メチルピペリジン−１−カルボキシラート0.66gの塩化メチレン5mL溶液に、トリフルオロ酢酸5mL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、水および6mol/L塩酸を加えた。水層を分取し、水層をクロロホルムで洗浄した。水層にクロロホルムを加え、20％水酸化ナトリウム水溶液でpH13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、無色油状物のＮ−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）−４−メチルピペリジン−４−アミン0.26gを得た。
¹H-NMR(CDCl₃)δ値：1.16(3H,s),1.47-1.60(4H,m),2.73-2.79(2H,m),2.93-3.01(2H,m),3.59(2H,s),4.24(4H,s),6.80-6.82(2H,m),6.88-6.90(1H,m)Reference Example 132

tert-butyl = 4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) -4-methylpiperidine-1-carboxylate 5 mL of fluoroacetic acid was added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and chloroform, water and 6 mol / L hydrochloric acid were added. The aqueous layer was separated and the aqueous layer was washed with chloroform. Chloroform was added to the aqueous layer, and the pH was adjusted to 13 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, the solvent was distilled off under reduced pressure, and N- (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl was obtained as a colorless oil. ) -4-6 g piperidin-4-amine 0.26g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.16 (3H, s), 1.47-1.60 (4H, m), 2.73-2.79 (2H, m), 2.93-3.01 (2H, m), 3.59 (2H, s ), 4.24 (4H, s), 6.80-6.82 (2H, m), 6.88-6.90 (1H, m)

１−（トリフルオロアセチル）ピペリジン−４−アミンの塩酸塩1.5gのＮ，Ｎ−ジメチルホルムアミド15mL溶液に、２−ブロモ−Ｎ−（ピリジン−２−イル）アセトアミド1.4gおよび炭酸カリウム1.8gを加え、室温で4時間攪拌した。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＝１０：１］で精製し、淡褐色油状物のＮ−（ピリジン−２−イル）−Ｎ^２−（１−（トリフルオロアセチル）ピペリジン−４−イル）グリシンアミド1.1gを得た。
¹H-NMR(CDCl₃)δ値：1.35-1.55(2H,m),2.00-2.10(2H,m),2.77-2.98(2H,m),3.15-3.23(1H,m),3.48(2H,s),3.97-4.05(1H,m),4.42-4.50(1H,m),7.06(1H,ddd,J=7.3,4.9,1.0Hz),7.72(1H,td,J=7.9,1.9Hz),8.23(1H,d,J=8.3Hz),8.31(1H,ddd,J=4.9,1.9,1.0Hz),9.59(1H,s)Reference Example 133

To a solution of 1.5 g of 1- (trifluoroacetyl) piperidin-4-amine hydrochloride in 15 mL of N, N-dimethylformamide was added 1.4 g of 2-bromo-N- (pyridin-2-yl) acetamide and 1.8 g of potassium carbonate. The mixture was further stirred at room temperature for 4 hours. 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, 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: chloroform: methanol = 10: 1] to give a pale brown oil N- ^{(pyridin-2-yl)} -N 2 - (1- (trifluoromethyl 1.1 g of acetyl) piperidin-4-yl) glycinamide were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.35-1.55 (2H, m), 2.00-2.10 (2H, m), 2.77-2.98 (2H, m), 3.15-3.23 (1H, m), 3.48 (2H , s), 3.97-4.05 (1H, m), 4.42-4.50 (1H, m), 7.06 (1H, ddd, J = 7.3,4.9,1.0Hz), 7.72 (1H, td, J = 7.9,1.9Hz ), 8.23 (1H, d, J = 8.3Hz), 8.31 (1H, ddd, J = 4.9,1.9,1.0Hz), 9.59 (1H, s)

Ｎ−（ピリジン−２−イル）−Ｎ^２−（１−（トリフルオロアセチル）ピペリジン−４−イル）グリシンアミド1.1gの塩化メチレン10mL溶液に、ジ−tｅｒｔ−ブチル＝ジカルボナート0.87gを加え、室温で1時間攪拌した。ジ−tｅｒｔ−ブチル＝ジカルボナート0.87gを加え、2時間加熱還流した。ジ−tｅｒｔ−ブチル＝ジカルボナート1.75gを加え、1時間加熱還流した。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、白色泡状物のｔｅｒｔ−ブチル＝（２−オキソ−２−（ピリジン−２−イルアミノ）エチル）（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0.84gを得た。
¹H-NMR(CDCl₃)δ値：1.47(9H,s),1.55-1.70(2H,m),1.90-2.00(2H,m),2.79(1H,t,J=12.6Hz),3.18(1H,t,J=12.7Hz),3.88(2H,s),4.05-4.13(1H,m),4.15-4.50(1H,m),4.62-4.70(1H,m),7.06(1H,ddd,J=7.3,5.0,0.9Hz),7.69-7.74(1H,m),8.17(1H,d,J=8.3Hz),8.28(1H,ddd,J=5.0,2.0,0.9Hz)Reference Example 134

N- ^{(pyridin-2-yl)} -N 2 - methylene chloride 10mL solution of (1- (trifluoroacetyl) piperidin-4-yl) glycinamide 1.1 g, di -tert- butyl dicarbonate 0.87g in addition, Stir at room temperature for 1 hour. Di-tert-butyl = dicarbonate 0.87g was added, and it heated and refluxed for 2 hours. 1.75 g of di-tert-butyl = dicarbonate was added and heated to reflux for 1 hour. 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 tert-butyl = (2-oxo- There was obtained 0.84 g of 2- (pyridin-2-ylamino) ethyl) (1- (trifluoroacetyl) piperidin-4-yl) carbamate.
¹ H-NMR (CDCl ₃ ) δ value: 1.47 (9H, s), 1.55-1.70 (2H, m), 1.90-2.00 (2H, m), 2.79 (1H, t, J = 12.6 Hz), 3.18 ( 1H, t, J = 12.7Hz), 3.88 (2H, s), 4.05-4.13 (1H, m), 4.15-4.50 (1H, m), 4.62-4.70 (1H, m), 7.06 (1H, ddd, J = 7.3,5.0,0.9Hz), 7.69-7.74 (1H, m), 8.17 (1H, d, J = 8.3Hz), 8.28 (1H, ddd, J = 5.0,2.0,0.9Hz)

ｔｅｒｔ−ブチル＝（２−オキソ−２−（ピリジン−２−イルアミノ）エチル）（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0.80gのメタノール8mL溶液に、水2mLおよび炭酸カリウム0.31g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、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、淡褐色泡状物のｔｅｒｔ−ブチル＝（２−オキソ−２−（ピリジン−２−イルアミノ）エチル）（ピペリジン−４−イル）カルバマート0.61gを得た。
¹H-NMR(CDCl₃)δ値：1.46(9H,s),1.40-1.60(2H,m),1.76-1.83(2H,m),2.65-2.71(2H,m),3.10-3.18(2H,m),3.92(2H,s),4.00-4.25(1H,m),7.04(1H,ddd,J=7.3,4.9,0.9Hz),7.67-7.73(1H,m),8.20(1H,d,J=8.3Hz),8.27(1H,ddd,J=4.9,2.0,0.8Hz)Reference Example 135

tert-Butyl (2-oxo-2- (pyridin-2-ylamino) ethyl) (1- (trifluoroacetyl) piperidin-4-yl) carbamate 0.80 g in methanol 8 mL solution, water 2 mL and potassium carbonate 0.31 g And stirred at room temperature for 1 hour. 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, 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 = (2-oxo-2- ( 0.61 g of pyridin-2-ylamino) ethyl) (piperidin-4-yl) carbamate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.46 (9H, s), 1.40-1.60 (2H, m), 1.76-1.83 (2H, m), 2.65-2.71 (2H, m), 3.10-3.18 (2H , m), 3.92 (2H, s), 4.00-4.25 (1H, m), 7.04 (1H, ddd, J = 7.3,4.9,0.9Hz), 7.67-7.73 (1H, m), 8.20 (1H, d , J = 8.3Hz), 8.27 (1H, ddd, J = 4.9,2.0,0.8Hz)

ｔｅｒｔ−ブチル＝４−（（（ベンジルオキシ）カルボニル）アミノ）−４−（（メチルアミノ）カルボニル）ピペリジン−１−カルボキシラート0.75gのエタノール10mL溶液に、室温で20％水酸化パラジウム−炭素75mgを加え、水素雰囲気下、40℃で2時間攪拌した。20％水酸化パラジウム−炭素75mgを加え、水素雰囲気下、40℃で3時間攪拌した。不溶物をろ去し、ろ滓をクロロホルムで3回洗浄した。ろ液および洗液を合わせ、減圧下で溶媒を留去し、淡灰色泡状物のｔｅｒｔ−ブチル＝４−アミノ−４−（（メチルアミノ）カルボニル）ピペリジン−１−カルボキシラート0.62gを得た。
¹H-NMR(CDCl₃)δ値：1.45(9H,s),1.40-3.80(8H,m),2.84(3H,d,J=4.6Hz),7.75-7.85(1H,broad)Reference Example 136

tert-Butyl 4-(((benzyloxy) carbonyl) amino) -4-((methylamino) carbonyl) piperidine-1-carboxylate 0.75 g in ethanol 10 mL solution at room temperature 20% palladium hydroxide-carbon 75 mg And stirred at 40 ° C. for 2 hours under hydrogen atmosphere. 20% palladium hydroxide-carbon (75 mg) was added, and the mixture was stirred at 40 ° C. for 3 hr under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filter cake was washed 3 times with chloroform. The filtrate and the washing solution were combined and the solvent was distilled off under reduced pressure to obtain 0.62 g of tert-butyl 4-amino-4-((methylamino) carbonyl) piperidine-1-carboxylate as a light gray foam. It was.
¹ H-NMR (CDCl ₃ ) δ value: 1.45 (9H, s), 1.40-3.80 (8H, m), 2.84 (3H, d, J = 4.6 Hz), 7.75-7.85 (1H, broad)

ｔｅｒｔ−ブチル＝４−アミノ−４−（（メチルアミノ）カルボニル）ピペリジン−１−カルボキシラート0.30gの塩化メチレン5mL溶液に、２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−カルバルデヒド0.16gおよび酢酸57μL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0.32gを加え、同温度で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、淡黄色油状物のｔｅｒｔ−ブチル＝４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル)アミノ）−４−（（メチルアミノ）カルボニル）ピペリジン−１−カルボキシラート0.31gを得た。
¹H-NMR(CDCl₃)δ値：1.46(9H,s),1.57-1.67(2H,m),2.03-2.15(2H,m),2.83(3H,d,J=4.9Hz),3.13-3.23(2H,m),3.48(2H,s),3.77-3.88(2H,m),4.26(4H,s),6.75(1H,dd,J=8.3,2.0Hz),6.83-6.90(2H,m),7.21-7.29(1H,m)Reference Example 137

To a solution of 0.30 g of tert-butyl 4-amino-4-((methylamino) carbonyl) piperidine-1-carboxylate in 5 mL of methylene chloride was added 2,3-dihydrobenzo [b] [1,4] dioxin-6- Carbaldehyde 0.16 g and acetic acid 57 μL were added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, 0.32 g of sodium triacetoxyborohydride was added and stirred at the same 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 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: chloroform: methanol = 10: 1], and tert-butyl 4-((2,3-dihydrobenzo [b] [1] , 4] dioxin-6-ylmethyl) amino) -4-((methylamino) carbonyl) piperidine-1-carboxylate 0.31 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.46 (9H, s), 1.57-1.67 (2H, m), 2.03-2.15 (2H, m), 2.83 (3H, d, J = 4.9Hz), 3.13- 3.23 (2H, m), 3.48 (2H, s), 3.77-3.88 (2H, m), 4.26 (4H, s), 6.75 (1H, dd, J = 8.3,2.0Hz), 6.83-6.90 (2H, m), 7.21-7.29 (1H, m)

ｔｅｒｔ−ブチル＝４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）−４−（（メチルアミノ）カルボニル）ピペリジン−１−カルボキシラート0.30gの塩化メチレン3mL溶液に、トリフルオロ酢酸3mLを加え、室温で2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、1.0mol/L水酸化ナトリウム水溶液でpH13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、淡黄色泡状物の４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）−Ｎ−メチルピペリジン−４−カルボキサミド0.22gを得た。
¹H-NMR(CDCl₃)δ値：1.58-1.68(2H,m),2.05-2.14(2H,m),2.76-2.84(2H,m),2.82(3H,d,J=5.1Hz),3.01-3.07(2H,m),3.47(2H,s),4.00-4.20(2H,m),4.27(4H,s),6.77(1H,dd,J=8.0,1.8Hz),6.84-6.87(2H,m),7.32-7.38(1H,m)Reference Example 138

tert-Butyl = 4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) -4-((methylamino) carbonyl) piperidine-1-carboxylate 0.30 g of chloride 3 mL of trifluoroacetic acid was added to 3 mL of methylene, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, chloroform and water were added, and the pH was adjusted to 13 with a 1.0 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 4-((2,3-dihydrobenzo [b] [1,4] dioxin- 0.22 g of 6-ylmethyl) amino) -N-methylpiperidine-4-carboxamide was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.58-1.68 (2H, m), 2.05-2.14 (2H, m), 2.76-2.84 (2H, m), 2.82 (3H, d, J = 5.1 Hz), 3.01-3.07 (2H, m), 3.47 (2H, s), 4.00-4.20 (2H, m), 4.27 (4H, s), 6.77 (1H, dd, J = 8.0,1.8Hz), 6.84-6.87 ( 2H, m), 7.32-7.38 (1H, m)

５−ブロモ−２−メトキシキノリン−８−カルバルデヒド0.10gのＮ，Ｎ−ジメチルホルムアミド2mL溶液に、エチルアクリラート61μL、トリエチルアミン78μLおよびビス（トリ−tｅｒｔ−ブチルホスフィン）パラジウム（０）3.9mgを加え、窒素雰囲気下、90℃で2時間攪拌した後、減圧下で溶媒を留去した。同様にして、５−ブロモ−２−メトキシキノリン−８−カルバルデヒド0.80gのＮ，Ｎ−ジメチルホルムアミド8mL溶液に、エチルアクリラート0.49mL、トリエチルアミン0.62mLおよびビス（トリ−tｅｒｔ−ブチルホスフィン）パラジウム（０）31mgを加え、窒素雰囲気下、90℃で2時間攪拌した後、減圧下で溶媒を留去した。得られた残留物を合わせ、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＝５：１］で精製し、淡褐色固体のエチル＝（Ｅ）−３−（８−ホルミル−２−メトキシキノリン−５−イル）アクリラート0.69gを得た。
¹H-NMR(CDCl₃)δ値：
1.38(3H,t,J=7.1Hz),4.13(3H,s),4.33(2H,q,J=7.1Hz),6.60(1H,d,J=15.9Hz),7.08(1H,d,J=9.1Hz),7.73(1H,d,J=7.8Hz),8.23(1H,d,J=7.8Hz),8.36(1H,d,J=15.9Hz),8.43(1H,d,J=9.1Hz),11.36(1H,s)Reference Example 139

To a solution of 0.10 g of 5-bromo-2-methoxyquinoline-8-carbaldehyde in 2 mL of N, N-dimethylformamide was added 61 μL of ethyl acrylate, 78 μL of triethylamine and 3.9 mg of bis (tri-tert-butylphosphine) palladium (0). In addition, after stirring at 90 ° C. for 2 hours under a nitrogen atmosphere, the solvent was distilled off under reduced pressure. Similarly, in a solution of 0.80 g of 5-bromo-2-methoxyquinoline-8-carbaldehyde in 8 mL of N, N-dimethylformamide, 0.49 mL of ethyl acrylate, 0.62 mL of triethylamine and bis (tri-tert-butylphosphine) palladium. After adding 31 mg of (0) and stirring at 90 ° C. for 2 hours under a nitrogen atmosphere, the solvent was distilled off under reduced pressure. The obtained residues were combined and purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 5: 1] to give a pale brown solid of ethyl = (E) -3- (8-formyl-2-methoxyquinoline). 0.69 g of -5-yl) acrylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value:
1.38 (3H, t, J = 7.1Hz), 4.13 (3H, s), 4.33 (2H, q, J = 7.1Hz), 6.60 (1H, d, J = 15.9Hz), 7.08 (1H, d, J = 9.1Hz), 7.73 (1H, d, J = 7.8Hz), 8.23 (1H, d, J = 7.8Hz), 8.36 (1H, d, J = 15.9Hz), 8.43 (1H, d, J = 9.1) Hz), 11.36 (1H, s)

エチル＝（Ｅ）−３−（８−ホルミル−２−メトキシキノリン−５−イル）アクリラート0.50gのジメチルスルホキシド15mL懸濁液に、室温でトリメチルスルホニウムヨージド0.43gおよび水酸化カリウム0.12gを加え、2時間攪拌した。反応混合物に水およびジエチルエーテルを加えた。有機層を分取し、水層をジエチルエーテルで抽出した。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、ヘキサンを加え、固形物をろ取し、淡褐色固体のエチル＝（Ｅ）−３−（２−メトキシ−８−（オキシラン−２−イル）キノリン−５−イル）アクリラート0.27gを得た。
¹H-NMR(CDCl₃)δ値：1.37(3H,t,J=7.1Hz),2.80(1H,dd,J=5.8,2.5Hz),3.33(1H,dd,J=5.8,4.1Hz),4.09(3H,s),4.31(2H,q,J=7.1Hz),5.00(1H,dd,J=4.1,2.5Hz),6.52(1H,d,J=15.6Hz),7.03(1H,d,J=9.1Hz),7.49(1H,d,J=7.8Hz),7.64(1H,d,J=7.8Hz),8.35(1H,d,J=15.6Hz),8.40(1H,d,9.1Hz)Reference Example 140

To a suspension of ethyl = (E) -3- (8-formyl-2-methoxyquinolin-5-yl) acrylate 0.50 g in dimethyl sulfoxide 15 mL, 0.43 g of trimethylsulfonium iodide and 0.12 g of potassium hydroxide were added at room temperature. And stirred for 2 hours. Water and diethyl ether were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with diethyl ether. 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. Hexane is added to the obtained residue, and the solid is collected by filtration. Ethyl (E) -3- (2-methoxy-8- (oxiran-2-yl) quinolin-5-yl) as a light brown solid 0.27 g of acrylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.37 (3H, t, J = 7.1 Hz), 2.80 (1H, dd, J = 5.8, 2.5 Hz), 3.33 (1H, dd, J = 5.8, 4.1 Hz) , 4.09 (3H, s), 4.31 (2H, q, J = 7.1Hz), 5.00 (1H, dd, J = 4.1,2.5Hz), 6.52 (1H, d, J = 15.6Hz), 7.03 (1H, d, J = 9.1Hz), 7.49 (1H, d, J = 7.8Hz), 7.64 (1H, d, J = 7.8Hz), 8.35 (1H, d, J = 15.6Hz), 8.40 (1H, d, (9.1Hz)

8−アミノ−２−メトキシキノリン0.15gのクロロホルム5.0mL溶液に、４−ジメチルアミノピリジン0.12gおよびＮ，Ｎ’−カルボニルジイミダゾール0.22gを加え、50〜55℃で1時間攪拌した。反応混合物を室温まで冷却し、トリエチルアミン0.24mL、１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペラジンの塩酸塩0.30gを加え、室温で15分間攪拌した。反応混合物に水20mLを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄した。水層をすべて合わせ、酢酸エチル10mL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］で精製した。得られた精製物を酢酸エチル10mLに溶解した後、1.6mol/L塩化水素/酢酸エチル5.0mLを加えた。減圧下で溶媒を留去し、残留物に酢酸エチルを加え、析出物をろ取し、白色固体の４−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）−Ｎ−（２−メトキシキノリン−８−イル）ピペラジン−１−カルボキサミドの塩酸塩0.29gを得た。このうちの0.10gを90％エタノール水5.0mLから再結晶し、白色固体の４−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）−Ｎ−（２−メトキシキノリン−８−イル）ピペラジン−１−カルボキサミドの塩酸塩66mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.90-3.00(2H,m),3.05-3.20(2H,m),3.25-3.40(2H,m),3.45-3.55(2H,m),3.60-3.70(2H,m),4.09(3H,s),4.20-4.24(4H,m),4.20-4.35(2H,m),6.70-6.85(3H,m),7.10(1H,d,J=8.8Hz),7.39(1H,t,J=7.9Hz),7.52(1H,dd,J=7.9,1.1Hz),8.27(1H,d,J=8.8Hz),8.31(1H,dd,J=7.9,1.1Hz),9.06(1H,s),10.85(1H,s)Example 1

4-Dimethylaminopyridine (0.12 g) and N, N′-carbonyldiimidazole (0.22 g) were added to a chloroform (5.0 mL) solution of 8-amino-2-methoxyquinoline (0.15 g), and the mixture was stirred at 50 to 55 ° C. for 1 hour. The reaction mixture was cooled to room temperature, 0.24 mL of triethylamine, 0.30 g of 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperazine hydrochloride was added, and room temperature was added. For 15 minutes. 20 mL of water was added to the reaction mixture. The organic layer was separated and washed with a saturated aqueous sodium chloride solution. All aqueous layers were combined and extracted twice with 10 mL of 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]. The purified product thus obtained was dissolved in 10 mL of ethyl acetate, and then 1.6 mol / L hydrogen chloride / 5.0 mL of ethyl acetate was added. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the precipitate was collected by filtration to give 4- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6 as a white solid. 0.29 g of hydrochloride of -yl) ethyl) -N- (2-methoxyquinolin-8-yl) piperazine-1-carboxamide was obtained. Of these, 0.10 g was recrystallized from 5.0 mL of 90% ethanol water and 4- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) -N as a white solid. 66 mg of hydrochloride salt of-(2-methoxyquinolin-8-yl) piperazine-1-carboxamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.90-3.00 (2H, m), 3.05-3.20 (2H, m), 3.25-3.40 (2H, m), 3.45-3.55 (2H, m), 3.60 -3.70 (2H, m), 4.09 (3H, s), 4.20-4.24 (4H, m), 4.20-4.35 (2H, m), 6.70-6.85 (3H, m), 7.10 (1H, d, J = 8.8Hz), 7.39 (1H, t, J = 7.9Hz), 7.52 (1H, dd, J = 7.9,1.1Hz), 8.27 (1H, d, J = 8.8Hz), 8.31 (1H, dd, J = 7.9, 1.1Hz), 9.06 (1H, s), 10.85 (1H, s)

８−アミノ−２−メチルキノリン0.10gおよび１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペラジンの塩酸塩0.20gから実施例１と同様にして、淡黄色固体の４−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）−Ｎ−（２−メチルキノリン−８−イル）ピペラジン−１−カルボキサミドの塩酸塩0.20gを得た。
¹H-NMR(DMSO-d₆)δ値：2.75(3H,s),2.90-3.00(2H,m),3.10-3.30(2H,m),3.30-3.80(6H,m),4.22(4H,s),4.15-4.40(2H,m),6.75-6.90(3H,m),7.50-7.60(3H,m),8.25-8.35(2H,m)Example 2

Example 1 from 0.10 g of 8-amino-2-methylquinoline and 0.20 g of 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperazine hydrochloride Similarly, light yellow solid 4- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) -N- (2-methylquinolin-8-yl) piperazine 0.20 g of hydrochloride of -1-carboxamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.75 (3H, s), 2.90-3.00 (2H, m), 3.10-3.30 (2H, m), 3.30-3.80 (6H, m), 4.22 (4H , s), 4.15-4.40 (2H, m), 6.75-6.90 (3H, m), 7.50-7.60 (3H, m), 8.25-8.35 (2H, m)

１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸82mgのＮ，Ｎ−ジメチルホルムアミド1.6mL溶液に、Ｎ，Ｎ’−カルボニルジイミダゾール75mgを加え、室温で50分間攪拌した。８−アミノ−２−メトキシキノリン81mgを加え、2時間45分間攪拌した。ジフェニルホスホン酸アジド67μLを加え、60〜70℃で6時間攪拌した。反応混合物に水10mLおよび酢酸エチル10mLを加え、6.0mol/L塩酸でpH1.0に調整した。有機層を分取し、水層に炭酸カルシウムを飽和するまで加え、酢酸エチル10mL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、褐色油状物の１−（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）−３−（２−メトキシキノリン−８−イル）ウレア11mgを得た。
¹H-NMR(CDCl₃)δ値：1.55-1.65(2H,m),2.05-2.25(4H,m),2.50-2.75(4H,m),2.90-3.00(2H,m),3.70-3.80(1H,m),4.09(3H,s),4.23-4.25(4H,m),4.79(1H,d,J=7.6Hz),6.65-6.75(2H,m),6.78(1H,d,J=8.0Hz),6.93(1H,d,J=8.8Hz),7.30-7.40(2H,m),7.99(1H,d,J=8.8Hz),8.40-8.50(2H,m)Example 3

To a solution of 82 mg of 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxylic acid in 1.6 mL of N, N-dimethylformamide was added N, N. 75 mg of '-carbonyldiimidazole was added and stirred at room temperature for 50 minutes. 81 mg of 8-amino-2-methoxyquinoline was added and stirred for 2 hours and 45 minutes. 67 μL of diphenylphosphonic acid azide was added, and the mixture was stirred at 60 to 70 ° C. for 6 hours. 10 mL of water and 10 mL of ethyl acetate were added to the reaction mixture, and the pH was adjusted to 1.0 with 6.0 mol / L hydrochloric acid. The organic layer was separated, calcium carbonate was added to the aqueous layer until saturation, and the mixture was extracted with 10 mL of 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: chloroform: methanol = 20: 1] to give 1- (1- (2- (2,3-dihydrobenzo [b] [1] , 4] dioxin-6-yl) ethyl) piperidin-4-yl) -3- (2-methoxyquinolin-8-yl) urea 11 mg.
¹ H-NMR (CDCl ₃ ) δ value: 1.55-1.65 (2H, m), 2.05-2.25 (4H, m), 2.50-2.75 (4H, m), 2.90-3.00 (2H, m), 3.70-3.80 (1H, m), 4.09 (3H, s), 4.23-4.25 (4H, m), 4.79 (1H, d, J = 7.6Hz), 6.65-6.75 (2H, m), 6.78 (1H, d, J = 8.0Hz), 6.93 (1H, d, J = 8.8Hz), 7.30-7.40 (2H, m), 7.99 (1H, d, J = 8.8Hz), 8.40-8.50 (2H, m)

１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸50mgに塩化チオニル1.0mLを加え、1時間加熱還流した。減圧下で溶媒を留去し、トルエンを加え、再び減圧下で溶媒を留去した。ついで、８−アミノ−２−メトキシキノリン45mgおよびトリエチルアミン35μLの塩化メチレン1.5mL溶液を加え、室温で1時間攪拌した。反応混合物に水10mLおよび酢酸エチル10mLを加えた。有機層を分取し、水層を酢酸エチル10mL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、ジエチルエーテル−ヘキサン混液を加え、析出物をろ取し、白色固体の１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）−Ｎ−（２−メトキシキノリン−８−イル）ピペリジン−４−カルボキサミド24mgを得た。
¹H-NMR(CDCl₃)δ値：1.90-2.10(2H,m),2.10-2.25(4H,m),2.40-2.50(1H,m),2.60-2.70(2H,m),2.70-2.80(2H,m),3.10-3.20(2H,m),4.10(3H,s),4.23-4.28(4H,m),6.65-6.85(3H,m),6.96(1H,d,J=9.0Hz),7.35-7.50(2H,m),8.01(1H,d,J=9.0Hz),8.73(1H,d,J=7.6Hz),9.63(1H,s)Example 4

To 50 mg of 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxylic acid was added 1.0 mL of thionyl chloride, and the mixture was heated to reflux for 1 hour. The solvent was distilled off under reduced pressure, toluene was added, and the solvent was distilled off again under reduced pressure. Subsequently, 45 mg of 8-amino-2-methoxyquinoline and 35 μL of triethylamine in 1.5 mL of methylene chloride were added, and the mixture was stirred at room temperature for 1 hour. 10 mL of water and 10 mL of ethyl acetate were added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted twice with 10 mL of 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: chloroform: methanol = 100: 1], a diethyl ether-hexane mixture was added, and the precipitate was collected by filtration to give a white solid 1- (2- ( 24 mg of 2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) -N- (2-methoxyquinolin-8-yl) piperidine-4-carboxamide was obtained.
_{^{1 H-NMR (CDCl 3)}} δ value: 1.90-2.10 (2H, m), 2.10-2.25 (4H, m), 2.40-2.50 (1H, m), 2.60-2.70 (2H, m), 2.70-2.80 (2H, m), 3.10-3.20 (2H, m), 4.10 (3H, s), 4.23-4.28 (4H, m), 6.65-6.85 (3H, m), 6.96 (1H, d, J = 9.0Hz ), 7.35-7.50 (2H, m), 8.01 (1H, d, J = 9.0Hz), 8.73 (1H, d, J = 7.6Hz), 9.63 (1H, s)

１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸0.83gに塩化チオニル5.4mLおよびＮ，Ｎ−ジメチルホルムアミド30μLを加え、50分間加熱還流した。反応混合物を室温まで冷却し、減圧下で溶媒を留去した。得られた残留物に塩化メチレン5.4mLを加え、氷冷下、５−ブロモ−２−メトキシキノリン−８−アミン0.69gおよびトリエチルアミン0.38mLの塩化メチレン5.4mL溶液を加え、室温で20分間攪拌した。水20mLおよび酢酸エチル20mLを加え、析出物をろ取し、白色固体のＮ−（５−ブロモ−２−メトキシキノリン−８−イル）−１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボキサミド1.3gを得た。
¹H-NMR(DMSO-d₆)δ値：1.95-2.10(2H,m),2.10-2.30(2H,m),2.85-3.15(5H,m),3.20-3.50(2H,m),3.60-3.70(2H,m),4.16(3H,s),4.20-4.25(4H,m),6.70-6.85(3H,m),7.27(1H,d,J=9.0Hz),7.76(1H,d,J=8.4Hz),8.39(1H,d,J=9.0Hz),8.40(1H,d,J=8.4Hz),9.78(1H,s)Example 5

0.83 g of 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxylic acid was charged with 5.4 mL of thionyl chloride and 30 μL of N, N-dimethylformamide. In addition, the mixture was heated to reflux for 50 minutes. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. To the obtained residue, 5.4 mL of methylene chloride was added, and under ice cooling, a solution of 0.69 g of 5-bromo-2-methoxyquinolin-8-amine and 0.38 mL of triethylamine was added to 5.4 mL of methylene chloride, and the mixture was stirred at room temperature for 20 minutes. . Water (20 mL) and ethyl acetate (20 mL) were added, and the precipitate was collected by filtration to give white solid N- (5-bromo-2-methoxyquinolin-8-yl) -1- (2- (2,3-dihydrobenzo [b ] [1,4] Dioxin-6-yl) ethyl) piperidine-4-carboxamide 1.3 g was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.95-2.10 (2H, m), 2.10-2.30 (2H, m), 2.85-3.15 (5H, m), 3.20-3.50 (2H, m), 3.60 -3.70 (2H, m), 4.16 (3H, s), 4.20-4.25 (4H, m), 6.70-6.85 (3H, m), 7.27 (1H, d, J = 9.0Hz), 7.76 (1H, d , J = 8.4Hz), 8.39 (1H, d, J = 9.0Hz), 8.40 (1H, d, J = 8.4Hz), 9.78 (1H, s)

Ｎ−（５−ブロモ−２−メトキシキノリン−８−イル）−１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボキサミド0.10gのヘキサメチルリン酸トリアミド2.0mL溶液に、テトラメチルスズ（IV）53μL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）13mgを加え、窒素気流下、100〜110℃で5時間加熱した。ジクロロビス（トリフェニルホスフィン）パラジウム（II）13mgを加え、100〜110℃で7時間加熱した。反応混合物に水10mLを加え、20％水酸化ナトリウム水溶液でpH11.0に調整し、酢酸エチル20mLを加えた。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た。得られた残留物をアルミナカラムクロマトグラフィー［アルミナ；メルク株式会社、アルミニウムオキシド６０、溶離液；ヘキサン：酢酸エチル＝２：１］および高速液体クロマトグラフィー［担体；株式会社ワイエムシイ、ＯＤＳ ＡＭ、溶離液；アセトニトリル：0.1％トリフルオロ酢酸水溶液＝３：７］で精製した。得られた物質をクロロホルム2.0mLに溶解し、3.2mol/L塩化水素/ジオキサン1.0mLを加えた。減圧下で溶媒を留去し、酢酸エチル5.0mLを加え、減圧下で溶媒を留去した。酢酸エチルを加え、析出物をろ取し、白色固体の１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）−Ｎ−（２−メトキシ−５−メチルキノリン−８−イル）ピペリジン−４−カルボキサミドの塩酸塩6.7mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.90-2.05(2H,m),2.15-2.25(2H,m),2.58(3H,s),2.80-3.10(5H,m),3.20-3.40(2H,m),3.60-3.70(2H,m),4.11(3H,s),4.22(4H,s),6.70-6.85(3H,m),7.13(1H,d,J=8.8Hz),7.25(1H,d,J=7.8Hz),8.33(1H,d,J=7.8Hz),8.38(1H,d,J=8.8Hz),9.67(1H,s)Example 6

N- (5-Bromo-2-methoxyquinolin-8-yl) -1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxamide Tetramethyltin (IV) 53 μL and dichlorobis (triphenylphosphine) palladium (II) 13 mg were added to 0.10 g of hexamethylphosphoric triamide 2.0 mL solution, and heated at 100 to 110 ° C. for 5 hours in a nitrogen stream. 13 mg of dichlorobis (triphenylphosphine) palladium (II) was added, and the mixture was heated at 100 to 110 ° C. for 7 hours. 10 mL of water was added to the reaction mixture, the pH was adjusted to 11.0 with a 20% aqueous sodium hydroxide solution, and 20 mL of ethyl acetate was 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 subjected to alumina column chromatography [alumina; Merck Co., Ltd., aluminum oxide 60, eluent; hexane: ethyl acetate = 2: 1] and high-performance liquid chromatography [carrier: YMC Corporation, ODS AM, eluent] Purified with acetonitrile: 0.1% aqueous trifluoroacetic acid = 3: 7]. The obtained substance was dissolved in 2.0 mL of chloroform, and 1.0 mL of 3.2 mol / L hydrogen chloride / dioxane was added. The solvent was distilled off under reduced pressure, 5.0 mL of ethyl acetate was added, and the solvent was distilled off under reduced pressure. Ethyl acetate was added, the precipitate was collected by filtration, and 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) -N- (2-methoxy) as a white solid. 6.7 mg of the hydrochloride salt of (5-methylquinolin-8-yl) piperidine-4-carboxamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.90-2.05 (2H, m), 2.15-2.25 (2H, m), 2.58 (3H, s), 2.80-3.10 (5H, m), 3.20-3.40 (2H, m), 3.60-3.70 (2H, m), 4.11 (3H, s), 4.22 (4H, s), 6.70-6.85 (3H, m), 7.13 (1H, d, J = 8.8Hz), 7.25 (1H, d, J = 7.8Hz), 8.33 (1H, d, J = 7.8Hz), 8.38 (1H, d, J = 8.8Hz), 9.67 (1H, s)

１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸0.10gおよびｔｅｒｔ−ブチル＝３−（８−アミノ−２−メトキシキノリン−５−イル）プロピオナート0.10gから実施例４と同様にして黄色油状物のｔｅｒｔ−ブチル＝３−（８−（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）プロピオナート0.16gを得た。
¹H-NMR(CDCl₃)δ値：1.43(9H,s),1.50-1.70(2H,m)，1.90-2.05(2H,m),2.10-2.25(2H,m),2.40-2.55(1H,m),2.55-2.70(2H,m),2.59(2H,t,J=7.9Hz),2.70-2.80(2H,m),3.10-3.20(2H,m),3.25(2H,t,J=7.9Hz),4.10(3H,s),4.24(4H,s),6.65-6.80(3H,m),6.99(1H,d,J=9.2Hz),7.15-7.30(1H,m),8.24(1H,d,J=9.2Hz),8.62(1H,d,J=8.0Hz),9.63(1H,s)Example 7

0.10 g of 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxylic acid and tert-butyl = 3- (8-amino-2- In the same manner as in Example 4, from 0.10 g of methoxyquinolin-5-yl) propionate, tert-butyl 3- (8- (1- (2- (2,3-dihydrobenzo [b] [1, 4] Dioxin-6-yl) ethyl) piperidine-4-carboxamido) -2-methoxyquinolin-5-yl) propionate 0.16 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.43 (9H, s), 1.50-1.70 (2H, m), 1.90-2.05 (2H, m), 2.10-2.25 (2H, m), 2.40-2.55 (1H , m), 2.55-2.70 (2H, m), 2.59 (2H, t, J = 7.9Hz), 2.70-2.80 (2H, m), 3.10-3.20 (2H, m), 3.25 (2H, t, J = 7.9Hz), 4.10 (3H, s), 4.24 (4H, s), 6.65 to 6.80 (3H, m), 6.99 (1H, d, J = 9.2Hz), 7.15 to 7.30 (1H, m), 8.24 (1H, d, J = 9.2Hz), 8.62 (1H, d, J = 8.0Hz), 9.63 (1H, s)

ｔｅｒｔ−ブチル＝３−（８−（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）プロピオナート0.16gの塩化メチレン2.0mL溶液に、トリフルオロ酢酸2.0mLを加え、3時間攪拌した。減圧下で溶媒を留去し、得られた残留物をクロロホルム5.0mLに溶解し、3.2mol/L塩化水素/ジオキサン5.0mLを加えた。減圧下で溶媒を留去し、得られた残留物にクロロホルム5.0mL、3.2mol/L塩化水素/ジオキサン5.0mLを加えた。減圧下で溶媒を留去した後、クロロホルム5.0mLおよびジエチルエーテル5.0mLを加え、析出物をろ取し、淡褐色固体の３−（８−（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）プロピオン酸の塩酸塩0.11gを得た。
¹H-NMR(DMSO-d₆)δ値：1.90-2.00(2H,m),2.15-2.30(2H,m),2.40-2.60(2H,m),2.80-3.15(5H,m),3.15-3.40(4H,m),3.60-3.70(2H,m),4.11(3H,s),4.22(4H,s),6.70-6.85(3H,m),7.10-7.15(1H,m),7.25-7.30(1H,m),8.30-8.40(1H,m),8.40-8.50(1H,m),9.70(1H,s),12.20(1H,s)Example 8

tert-butyl = 3- (8- (1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxamide) -2-methoxyquinoline- To a 2.0 mL solution of 5-yl) propionate 0.16 g in methylene chloride was added 2.0 mL trifluoroacetic acid and stirred for 3 hours. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 5.0 mL of chloroform, and 5.0 mL of 3.2 mol / L hydrogen chloride / dioxane was added. The solvent was distilled off under reduced pressure, and 5.0 mL of chloroform and 5.0 mL of 3.2 mol / L hydrogen chloride / dioxane were added to the obtained residue. After distilling off the solvent under reduced pressure, 5.0 mL of chloroform and 5.0 mL of diethyl ether were added, and the precipitate was collected by filtration to give 3- (8- (1- (2- (2,3-dihydrobenzo) as a light brown solid. [B] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxamido) -2-methoxyquinolin-5-yl) propionic acid hydrochloride 0.11 g was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.90-2.00 (2H, m), 2.15-2.30 (2H, m), 2.40-2.60 (2H, m), 2.80-3.15 (5H, m), 3.15 -3.40 (4H, m), 3.60-3.70 (2H, m), 4.11 (3H, s), 4.22 (4H, s), 6.70-6.85 (3H, m), 7.10-7.15 (1H, m), 7.25 -7.30 (1H, m), 8.30-8.40 (1H, m), 8.40-8.50 (1H, m), 9.70 (1H, s), 12.20 (1H, s)

１，４−ベンゾジオキサン−６−アミン26mgのクロロホルム1.8mL溶液に、Ｎ，Ｎ’−カルボニルジイミダゾール44mgを加え、55分間加熱還流した。反応混合物を室温まで冷却し、Ｎ−（２−メトキシキノリン−８−イル）ピペリジン−４−カルボキサミド50mgのクロロホルム1.0mL溶液を加え、室温で20分間攪拌した。反応混合物に水20mLおよび酢酸エチル20mLを加えた。有機層を分取し、塩化アンモニ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。得られた残留物を塩基性アルミナカラムクロマトグラフィー［アルミナ；メルク株式会社、アルミニウムオキシド６０、溶離液；ヘキサン：酢酸エチル＝１：２］で精製し、白色泡状物の１−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）カルバモイル）−Ｎ−（２−メトキシキノリン−８−イル）ピペリジンカルボキサミド26mgを得た。
¹H-NMR(CDCl₃)δ値：1.85-2.00(2H,m),2.15-2.20(2H,m),2.60-2.70(1H,m),3.00-3.10(2H,m),4.10(3H,s),4.10-4.30(6H,m),6.25(1H,s),6.70-6.80(2H,m),6.90-7.00(2H,m),7.35-7.50(2H,m),8.02(1H,d,J=9.2Hz),8.70(1H,dd,J=9.2,1.6Hz),9.62(1H,s)Example 9

To a 1.8 mL chloroform solution of 26 mg 1,4-benzodioxan-6-amine, 44 mg N, N′-carbonyldiimidazole was added and heated to reflux for 55 minutes. The reaction mixture was cooled to room temperature, N- (2-methoxyquinolin-8-yl) piperidine-4-carboxamide (50 mg) in chloroform (1.0 mL) was added, and the mixture was stirred at room temperature for 20 min. 20 mL of water and 20 mL of ethyl acetate were added to the reaction mixture. The organic layer was separated, washed successively with an aqueous ammonium chloride solution 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 alumina column chromatography [alumina; Merck Ltd., aluminum oxide 60, eluent: hexane: ethyl acetate = 1: 2], and white foam 1-((2, 26 mg of 3-dihydrobenzo [b] [1,4] dioxin-6-yl) carbamoyl) -N- (2-methoxyquinolin-8-yl) piperidinecarboxamide were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.85-2.00 (2H, m), 2.15-2.20 (2H, m), 2.60-2.70 (1H, m), 3.00-3.10 (2H, m), 4.10 (3H , s), 4.10-4.30 (6H, m), 6.25 (1H, s), 6.70-6.80 (2H, m), 6.90-7.00 (2H, m), 7.35-7.50 (2H, m), 8.02 (1H , d, J = 9.2Hz), 8.70 (1H, dd, J = 9.2,1.6Hz), 9.62 (1H, s)

１−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）カルバモイル）ピペリジン−４−カルボン酸36mgおよびｔｅｒｔ−ブチル＝３−（８−アミノ−２−メトキシキノリン−５−イル）プロピオナート30mgのＮ，Ｎ−ジメチルホルムアミド0.5mL溶液に、室温でトリエチルアミン56μLおよびＯ−（７−アザベンゾトリアゾール−１−イル）−１，１，３，３−テトラメチルウロニウム＝ヘキサフルオロホスフェート76μgを加え、4時間攪拌した。反応混合物に酢酸エチル10mLおよび水10mLを加えた。有機層を分取し、水層を酢酸エチル10mL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、褐色油状物のｔｅｒｔ−ブチル＝３−（８−（１−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）カルバモイル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）プロピオナート62mgを得た。
¹H-NMR(CDCl₃)δ値：1.43(9H,s),1.90-2.00(2H,m),2.10-2.20(2H,m),2.55-2.70(1H,m),2.59(2H,t,J=8.0Hz),3.00-3.10(2H,m),3.26(2H,t,J=8.0Hz),4.09(3H,s),4.10-4.20(2H,m),4.20-4.30(4H,m),6.21(1H,s),6.75-6.80(2H,m),6.95(1H,d,J=2.2Hz),7.00(1H,d,J=9.2Hz),7.20-7.30(1H,m),8.26(1H,d,J=9.2Hz),8.61(1H,d,J=8.1Hz),9.62(1H,s)Example 10

1-((2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) carbamoyl) piperidine-4-carboxylic acid 36 mg and tert-butyl = 3- (8-amino-2-methoxyquinoline- 5-yl) propionate in a solution of 30 mg of N, N-dimethylformamide in 0.5 mL at room temperature, 56 μL of triethylamine and O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium = 76 μg of hexafluorophosphate was added and stirred for 4 hours. To the reaction mixture, 10 mL of ethyl acetate and 10 mL of water were added. The organic layer was separated and the aqueous layer was extracted with 10 mL of 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: chloroform: methanol = 50: 1], and tert-butyl = 3- (8- (1-((2,3-dihydrobenzo [B] [1,4] dioxin-6-yl) carbamoyl) piperidine-4-carboxamido) -2-methoxyquinolin-5-yl) propionate 62 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.43 (9H, s), 1.90-2.00 (2H, m), 2.10-2.20 (2H, m), 2.55-2.70 (1H, m), 2.59 (2H, t , J = 8.0Hz), 3.00-3.10 (2H, m), 3.26 (2H, t, J = 8.0Hz), 4.09 (3H, s), 4.10-4.20 (2H, m), 4.20-4.30 (4H, m), 6.21 (1H, s), 6.75-6.80 (2H, m), 6.95 (1H, d, J = 2.2Hz), 7.00 (1H, d, J = 9.2Hz), 7.20-7.30 (1H, m ), 8.26 (1H, d, J = 9.2Hz), 8.61 (1H, d, J = 8.1Hz), 9.62 (1H, s)

ｔｅｒｔ−ブチル＝３−（８−（１−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）カルバモイル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）プロピオナート62mgの塩化メチレン0.20mL溶液に、トリフルオロ酢酸0.20mLを加え、1時間10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、析出物をろ取し、暗黄色固体の３−（８−（１−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）カルバモイル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）プロピオン酸のトリフルオロ酢酸塩40mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.55-1.70(2H,m),1.95-2.00(2H,m),2.58(2H,t,J=7.7Hz),2.80-2.95(3H,m),3.20(2H,t,J=7.7Hz),4.10(3H,s),4.10-4.20(6H,m),6.70(1H,d,J=8.7Hz),6.88(1H,dt,J=8.7,2.6Hz),7.06(1H,t,J=2.6Hz),7.12(1H,d,J=9.0Hz),7.26(1H,d,J=8.0Hz),8.32(1H,s),8.38(1H,d,J=8.0Hz),8.44(1H,d,J=9.0Hz),9.64(1H,s)Example 11

tert-butyl = 3- (8- (1-((2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) carbamoyl) piperidine-4-carboxamide) -2-methoxyquinoline-5 I) 0.20 mL of trifluoroacetic acid was added to a solution of 62 mg of propionate in 0.20 mL of methylene chloride, and the mixture was stirred for 1 hour and 10 minutes. The solvent was distilled off under reduced pressure, diethyl ether was added, and the precipitate was collected by filtration to give 3- (8- (1-((2,3-dihydrobenzo [b] [1,4] dioxin) as a dark yellow solid. -6-yl) carbamoyl) piperidine-4-carboxamido) -2-methoxyquinolin-5-yl) propionic acid trifluoroacetate 40 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.55-1.70 (2H, m), 1.95-2.00 (2H, m), 2.58 (2H, t, J = 7.7Hz), 2.80-2.95 (3H, m ), 3.20 (2H, t, J = 7.7Hz), 4.10 (3H, s), 4.10-4.20 (6H, m), 6.70 (1H, d, J = 8.7Hz), 6.88 (1H, dt, J = 8.7, 2.6Hz), 7.06 (1H, t, J = 2.6Hz), 7.12 (1H, d, J = 9.0Hz), 7.26 (1H, d, J = 8.0Hz), 8.32 (1H, s), 8.38 (1H, d, J = 8.0Hz), 8.44 (1H, d, J = 9.0Hz), 9.64 (1H, s)

Ｎ−（２−メトキシキノリン−８−イル）ピペリジン−４−カルボキサミド0.10gのアセトニトリル0.70mL溶液に、Ｎ，Ｎ−ジイソプロピルエチルアミン0.18mLおよび１−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）−２−メチルイソチオウレアのヨウ化水素酸塩0.18gを加え、室温で30分間攪拌後、50分間加熱還流した。さらに、Ｎ，Ｎ−ジメチルホルムアミド2.0mLを加え、120〜130℃で2時間15分間攪拌した。反応混合物を室温まで冷却し、酢酸エチル50mLを加え、20％水酸化ナトリウム水溶液でpH13.0に調整した。有機層を分取し、水層を酢酸エチル10mL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。得られた残留物を塩基性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、シリカゲルＦＬ１００ＤＸ、溶離液；クロロホルム：メタノール＝１０：１］で精製し、無色油状物の１−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルアミノ）（イミノ）メチル）−Ｎ−（２−メトキシキノリン−８−イル）ピペリジン−４−カルボキサミド30mgを得た。
¹H-NMR(CDCl₃)δ値：1.90-2.00(2H,m),2.10-2.20(2H,m),2.60-2.70(1H,m),2.95-3.05(2H,m),4.05-4.15(2H,m),4.10(3H,s),4.20-4.30(4H,m),6.39(1H,dd,J=8.5,2.4Hz),6.43(1H,d,J=2.4Hz),6.78(1H,d,J=8.5Hz),6.97(1H,d,J=8.8Hz),7.35-7.45(2H,m),8.02(1H,d,J=8.8Hz),8.71(1H,dd,J=7.6,1.5Hz),9.64(1H,s)Example 12

To a solution of 0.10 g of N- (2-methoxyquinolin-8-yl) piperidine-4-carboxamide in 0.70 mL of acetonitrile, 0.18 mL of N, N-diisopropylethylamine and 1- (2,3-dihydrobenzo [b] [1, 4] 0.18 g of dioxin-6-yl) -2-methylisothiourea hydroiodide was added, stirred at room temperature for 30 minutes, and then heated to reflux for 50 minutes. Further, 2.0 mL of N, N-dimethylformamide was added, and the mixture was stirred at 120 to 130 ° C. for 2 hours and 15 minutes. The reaction mixture was cooled to room temperature, 50 mL of ethyl acetate was added, and the pH was adjusted to 13.0 with a 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted twice with 10 mL of 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 basic silica gel column chromatography [silica gel; Fuji Silysia Chemical Ltd., silica gel FL100DX, eluent: chloroform: methanol = 10: 1] to give colorless oil 1-((2,3 -Dihydrobenzo [b] [1,4] dioxin-6-ylamino) (imino) methyl) -N- (2-methoxyquinolin-8-yl) piperidine-4-carboxamide was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.90-2.00 (2H, m), 2.10-2.20 (2H, m), 2.60-2.70 (1H, m), 2.95-3.05 (2H, m), 4.05-4.15 (2H, m), 4.10 (3H, s), 4.20-4.30 (4H, m), 6.39 (1H, dd, J = 8.5, 2.4Hz), 6.43 (1H, d, J = 2.4Hz), 6.78 ( 1H, d, J = 8.5Hz), 6.97 (1H, d, J = 8.8Hz), 7.35-7.45 (2H, m), 8.02 (1H, d, J = 8.8Hz), 8.71 (1H, dd, J = 7.6,1.5Hz), 9.64 (1H, s)

１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸0.26gおよびｔｅｒｔ−ブチル＝（Ｅ）−３−（８−アミノ−２−メトキシキノリン−５−イル）アクリラート0.18gから実施例４と同様にして褐色泡状物のｔｅｒｔ−ブチル＝（Ｅ）−３−（８−（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）アクリラート0.26gを得た。
¹H-NMR(CDCl₃)δ値：1.50-1.70(1H,m)，1.56(9H,s),1.90-2.05(2H,m),2.05-2.25(3H,m),2.40-2.50(1H,m),2.55-2.65(2H,m),2.70-2.80(2H,m),3.05-3.15(2H,m),4.11(3H,s),4.24(4H,s),6.44(1H,d,J=15.8Hz),6.68(1H,dd,J=8.0,2.0Hz),6.73(1H,d,J=2.0Hz),6.78(1H,d,J=8.0Hz),7.04(1H,d,J=9.2Hz),7.70(1H,d,J=8.0Hz),8.21(1H,d,J=15.8Hz),8.43(1H,d,J=9.2Hz),8.74(1H,d,J=8.0Hz),9.74(1H,s)Example 13

1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxylic acid 0.26 g and tert-butyl = (E) -3- (8- The brown foam tert-butyl = (E) -3- (8- (1- (2- (2,3,3)) was obtained in the same manner as in Example 4 from 0.18 g of amino-2-methoxyquinolin-5-yl) acrylate. -0.26 g of dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidin-4-carboxamido) -2-methoxyquinolin-5-yl) acrylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.50-1.70 (1H, m), 1.56 (9H, s), 1.90-2.05 (2H, m), 2.05-2.25 (3H, m), 2.40-2.50 (1H , m), 2.55-2.65 (2H, m), 2.70-2.80 (2H, m), 3.05-3.15 (2H, m), 4.11 (3H, s), 4.24 (4H, s), 6.44 (1H, d , J = 15.8Hz), 6.68 (1H, dd, J = 8.0,2.0Hz), 6.73 (1H, d, J = 2.0Hz), 6.78 (1H, d, J = 8.0Hz), 7.04 (1H, d , J = 9.2Hz), 7.70 (1H, d, J = 8.0Hz), 8.21 (1H, d, J = 15.8Hz), 8.43 (1H, d, J = 9.2Hz), 8.74 (1H, d, J = 8.0Hz), 9.74 (1H, s)

ｔｅｒｔ−ブチル＝（Ｅ）−３−（８−（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）アクリラート28mgの塩化メチレン0.20mL溶液に、トリフルオロ酢酸0.20mLを加え、2時間50分間攪拌した。減圧下で溶媒を留去し、得られた残留物を酢酸エチル1.0mLに溶解し、4.0mol/L塩化水素/酢酸エチル1.0mLを加えた。減圧下で溶媒を留去し、酢酸エチルを加え、析出物をろ取し、淡褐色固体の（Ｅ）−３−（８−（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）アクリル酸の塩酸塩23mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.90-2.10(2H,m),2.20-2.30(2H,m),2.50-3.20(7H,m),3.60-3.75(2H,m),4.14(3H,s),4.22(4H,s),6.60(1H,d,J=15.6Hz),6.70-6.85(3H,m),7.20(1H,d,J=9.3Hz),7.94(1H,d,J=8.2Hz),8.25(1H,d,J=15.6Hz),8.54(1H,d,J=8.2Hz),8.64(1H,d,J=9.3Hz),9.87(1H,s)Example 14

tert-butyl = (E) -3- (8- (1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxamide) -2 To a solution of 28 mg of -methoxyquinolin-5-yl) acrylate in 0.20 mL of methylene chloride was added 0.20 mL of trifluoroacetic acid, and the mixture was stirred for 2 hours and 50 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in 1.0 mL of ethyl acetate, and 1.0 mL of 4.0 mol / L hydrogen chloride / ethyl acetate was added. The solvent was distilled off under reduced pressure, ethyl acetate was added, the precipitate was collected by filtration, and a pale brown solid (E) -3- (8- (1- (2- (2,3-dihydrobenzo [b] 23 mg of [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxamido) -2-methoxyquinolin-5-yl) acrylic acid hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.90-2.10 (2H, m), 2.20-2.30 (2H, m), 2.50-3.20 (7H, m), 3.60-3.75 (2H, m), 4.14 (3H, s), 4.22 (4H, s), 6.60 (1H, d, J = 15.6Hz), 6.70-6.85 (3H, m), 7.20 (1H, d, J = 9.3Hz), 7.94 (1H, d, J = 8.2Hz), 8.25 (1H, d, J = 15.6Hz), 8.54 (1H, d, J = 8.2Hz), 8.64 (1H, d, J = 9.3Hz), 9.87 (1H, s)

７−メトキシイソキノリン−１−アミン0.30gのクロロホルム5mL溶液に、室温でＮ，Ｎ−ジメチルアミノピリジン0.23gおよびＮ，Ｎ’−カルボニルジイミダゾール0.45g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Ｎ，Ｎ−ジメチルホルムアミド7mL、１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペラジンの塩酸塩0.61gおよびトリエチルアミン0.53mLを加えた。反応混合物を室温で30分間攪拌した後、酢酸エチル30mLおよび水30mLを加えた。有機層を分取し、水層を酢酸エチル20mL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；クロロホルム：メタノール＝５０：１］で精製し、淡褐色固体の４−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）−Ｎ−（７−メトキシイソキノリン−１−イル）ピペラジン−１−カルボキサミド0.48gを得た。
¹H-NMR(CDCl₃)δ値：2.55-2.65(6H,m),2.70-2.80(2H,m),3.70-3.75(2H,m),3.95(3H,s),4.05-4.10(2H,m),4.24(4H,s),6.65(1H,d,J=6.8Hz),6.69(1H,dd,J=8.2,2.0Hz),6.74(1H,d,J=2.0Hz),6.79(1H,d,J=8.2Hz),7.06-7.09(1H,m),7.30(1H,dd,J=8.5,2.7Hz),7.48(1H,d,J=8.5Hz),8.01(1H,d,J=2.7Hz),14.5(1H,s)Example 15

To a solution of 0.30 g of 7-methoxyisoquinolin-1-amine in 5 mL of chloroform were added 0.23 g of N, N-dimethylaminopyridine and 0.45 g of N, N′-carbonyldiimidazole at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and 7 mL of N, N-dimethylformamide, 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl was added to the obtained residue. ) Piperazine hydrochloride 0.61 g and triethylamine 0.53 mL were added. After the reaction mixture was stirred at room temperature for 30 minutes, 30 mL of ethyl acetate and 30 mL of water were added. The organic layer was separated, and the aqueous layer was extracted with 20 mL of 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: chloroform: methanol = 50: 1] to give 4- (2- (2,3-dihydrobenzo [b] [1,4] as a light brown solid. Dioxin-6-yl) ethyl) -N- (7-methoxyisoquinolin-1-yl) piperazine-1-carboxamide 0.48 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.55-2.65 (6H, m), 2.70-2.80 (2H, m), 3.70-3.75 (2H, m), 3.95 (3H, s), 4.05-4.10 (2H , m), 4.24 (4H, s), 6.65 (1H, d, J = 6.8Hz), 6.69 (1H, dd, J = 8.2, 2.0Hz), 6.74 (1H, d, J = 2.0Hz), 6.79 (1H, d, J = 8.2Hz), 7.06-7.09 (1H, m), 7.30 (1H, dd, J = 8.5,2.7Hz), 7.48 (1H, d, J = 8.5Hz), 8.01 (1H, d, J = 2.7Hz), 14.5 (1H, s)

Ｎ−（７−メトキシイソキノリン−１−イル）ピペリジン−４−カルボキサミド60mgのメタノール2mL溶液に、室温で（２，３−ジヒドロベンゾ［１，４］ジオキシン−６−イル）アセトアルデヒド38mgのメタノール1mL溶液および酢酸40μLを加え、同温度で3時間攪拌した。反応混合物に水素化シアノホウ素ナトリウム13mgを加え、室温で30分間攪拌し、減圧下で溶媒を留去した。水10mLおよびクロロホルム10mLを加えた後、20％水酸化ナトリウム水溶液を加え、pH12.5に調整した。有機層を分取し、水層をクロロホルム10mL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；クロロホルム：メタノール＝１０：１］で精製し、淡褐色固体の１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）−Ｎ−（７−メトキシイソキノリン−１−イル）ピペリジン−４−カルボキサミド10mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.68-1.76(2H,m),1.88-1.91(2H,m),1.99-2.05(2H,m),2.45-2.65(5H,m),2.95-3.05(2H,m),3.86(3H,s),4.20(4H,s),6.65-6.75(3H,m),7.15-7.20(1H,m),7.44(1H,dd,J=8.9,2.4Hz),7.66(1H,d,J=5.5Hz),7.91(1H,d,J=8.9Hz),8.19(1H,d,J=5.5Hz),10.3(1H,s)Example 16

N- (7-methoxyisoquinolin-1-yl) piperidine-4-carboxamide in 60 mL of methanol and 2 mL of (2,3-dihydrobenzo [1,4] dioxin-6-yl) acetaldehyde in 1 mL of methanol at room temperature Then, 40 μL of acetic acid was added and stirred at the same temperature for 3 hours. To the reaction mixture, 13 mg of sodium cyanoborohydride was added, stirred at room temperature for 30 minutes, and the solvent was distilled off under reduced pressure. After adding 10 mL of water and 10 mL of chloroform, 20% aqueous sodium hydroxide solution was added to adjust the pH to 12.5. The organic layer was separated, and the aqueous layer was extracted with 10 mL of 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 silica gel column chromatography [eluent: chloroform: methanol = 10: 1] to give 1- (2- (2,3-dihydrobenzo [b] [1,4] as a light brown solid. 10 mg of dioxin-6-yl) ethyl) -N- (7-methoxyisoquinolin-1-yl) piperidine-4-carboxamide were obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.68-1.76 (2H, m), 1.88-1.91 (2H, m), 1.99-2.05 (2H, m), 2.45-2.65 (5H, m), 2.95 -3.05 (2H, m), 3.86 (3H, s), 4.20 (4H, s), 6.65-6.75 (3H, m), 7.15-7.20 (1H, m), 7.44 (1H, dd, J = 8.9, 2.4Hz), 7.66 (1H, d, J = 5.5Hz), 7.91 (1H, d, J = 8.9Hz), 8.19 (1H, d, J = 5.5Hz), 10.3 (1H, s)

１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸53mgに、室温で２，４−ジメトキシキノリン−８−アミン37mgのＮ，Ｎ−ジメチルホルムアミド3mL溶液を加えた。室温でＯ−（７−アザベンゾトリアゾール−１−イル）−１，１，３，３−テトラメチルウロニウム＝ヘキサフルオロホスフェート0.10gおよびトリエチルアミン76μLを加え、30分間攪拌し、60℃で3時間攪拌した後、室温まで冷却した。反応混合物に酢酸エチル20mLおよび水20mLを加えた。有機層を分取し、水層を酢酸エチル10mL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；クロロホルム：メタノール＝１０：１］で精製し、淡褐色固体の１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）−Ｎ−（２，４−ジメトキシキノリン−８−イル）ピペリジン−４−カルボキサミド40mgを得た。
¹H-NMR(CDCl₃)δ値：1.80-2.90(11H,m),3.10-3.30(2H,m),4.01(3H,s),4.07(3H,s),4.24(4H,s),6.27(1H,s),6.67-6.80(3H,m),7.30-7.34(1H,m),7.74(1H,d,J=8.0Hz),8.68(1H,d,J=7.6Hz),9.65(1H,s)Example 17

To 53 mg of 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxylic acid, 37 mg of 2,4-dimethoxyquinolin-8-amine at room temperature Of N, N-dimethylformamide in 3 mL was added. At room temperature, O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium = 0.10 g of hexafluorophosphate and 76 μL of triethylamine were added, stirred for 30 minutes, and at 60 ° C. for 3 hours. After stirring, it was cooled to room temperature. To the reaction mixture, 20 mL of ethyl acetate and 20 mL of water were added. The organic layer was separated and the aqueous layer was extracted with 10 mL of 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: chloroform: methanol = 10: 1] to give 1- (2- (2,3-dihydrobenzo [b] [1,4] as a light brown solid. 40 mg of dioxin-6-yl) ethyl) -N- (2,4-dimethoxyquinolin-8-yl) piperidine-4-carboxamide were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.80-2.90 (11H, m), 3.10-3.30 (2H, m), 4.01 (3H, s), 4.07 (3H, s), 4.24 (4H, s), 6.27 (1H, s), 6.67-6.80 (3H, m), 7.30-7.34 (1H, m), 7.74 (1H, d, J = 8.0Hz), 8.68 (1H, d, J = 7.6Hz), 9.65 (1H, s)

２−メトキシ−３−メチルキノリン−８−アミン70mgのＮ，Ｎ−ジメチルホルムアミド3mL溶液に、室温で１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸0.11g、Ｏ−（７−アザベンゾトリアゾール−１−イル）−１，１，３，３−テトラメチルウロニウム＝ヘキサフルオロホスフェート0.21gおよびトリエチルアミン0.16mLを加え、60℃で2時間攪拌した。反応混合物を室温まで冷却し、酢酸エチル30mLおよび水20mLを加えた。有機層を分取し、水層を酢酸エチル20mL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；クロロホルム：メタノール＝２０：１］で精製し、淡褐色固体１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）−Ｎ−（２−メトキシ−３−メチルキノリン−８−イル）ピペリジン−４−カルボキサミド85mgを得た。
¹H-NMR(CDCl₃)δ値：1.96-2.05(2H,m),2.14-2.17(4H,m),2.35(3H,s),2.40-2.50(1H,m),2.59-2.61(2H,m),2.71-2.75(2H,m),3.09-3.15(2H,m),4.12(3H,s),4.24(4H,s),6.68(1H,dd,J=8.3,2.0Hz),6.73(1H,d,J=2.0Hz),6.79(1H,d,J=8.3Hz),7.34-7.36(2H,m),7.79(1H,s),8.64-8.66(1H,m),9.63(1H,s)Example 18

To a solution of 70 mg of 2-methoxy-3-methylquinolin-8-amine in 3 mL of N, N-dimethylformamide at room temperature, 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6- Yl) ethyl) piperidine-4-carboxylic acid 0.11 g, O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium = hexafluorophosphate 0.21 g and triethylamine 0.16 mL. The mixture was further stirred at 60 ° C. for 2 hours. The reaction mixture was cooled to room temperature and 30 mL of ethyl acetate and 20 mL of water were added. The organic layer was separated, and the aqueous layer was extracted with 20 mL of 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: chloroform: methanol = 20: 1] to give a light brown solid 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin. 85 mg of -6-yl) ethyl) -N- (2-methoxy-3-methylquinolin-8-yl) piperidine-4-carboxamide was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.96-2.05 (2H, m), 2.14-2.17 (4H, m), 2.35 (3H, s), 2.40-2.50 (1H, m), 2.59-2.61 (2H , m), 2.71-2.75 (2H, m), 3.09-3.15 (2H, m), 4.12 (3H, s), 4.24 (4H, s), 6.68 (1H, dd, J = 8.3,2.0Hz), 6.73 (1H, d, J = 2.0Hz), 6.79 (1H, d, J = 8.3Hz), 7.34-7.36 (2H, m), 7.79 (1H, s), 8.64-8.66 (1H, m), 9.63 (1H, s)

（１）ｔｅｒｔ−ブチル＝1−（２−ヒドロキシ−２−（７−メトキシイソキノリン−１−イル）エチル）ピペリジン−４−イルカルバマート0.45gの塩化メチレン2mL溶液に、室温でトリフルオロ酢酸1mLを加え、1時間攪拌した後、減圧下で溶媒を留去した。得られた残留物に水10mLおよび酢酸エチル20mLを加え、炭酸カリウムを加えてpH9.5に調整した。有機層を分取し、水層を酢酸エチル10mLで4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、黄色泡状物の２−（４−アミノピペリジン−１−イル）−１−（７−メトキシイソキノリン−１−イル）エタノールを得た。
（２）得られた２−（４−アミノピペリジン−１−イル）−１−（７−メトキシイソキノリン−１−イル）エタノールの塩化メチレン9mL懸濁液に、室温でメタノール3mL、１，４−ベンゾジオキサン−６−カルバルデヒド0.14gおよび４Ａモレキュラーシーブス1.5gを加え、終夜攪拌した。反応混合物に水素化ホウ素ナトリウム98mgを加え、室温で2時間攪拌した。水10mLを加え、6mol/L塩酸でpH3.0に調整し、ついで、20％水酸化ナトリウム水溶液でpH10.0に調整した。酢酸エチル10mLを加え、有機層を分取し、水層を酢酸エチル10mL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：イソプロピルアミン＝５０：１：１］で精製し、淡黄色油状物の２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）メチルアミノ）ピペリジン−１−イル）−１−（７−メトキシイソキノリン−１−イル）エタノール20mgを得た。
¹H-NMR(CDCl₃)δ値：1.44-1.58(2H,m),1.93-1.95(2H,m),2.21-2.37(2H,m),2.54-2.59(1H,m),2.76-2.85(2H,m),3.09-3.12(2H,m),3.72(2H,s),3.96(3H,s),4.25(4H,s),5.49(1H,dd,J=8.2,3.4Hz),6.79(1H,dd,J=8.2,1.8Hz),6.82(1H,d,J=8.2Hz),6.84(1H,d,J=1.8Hz),7.36(1H,dd,J=8.8,2.4Hz),7.51-7.53(2H,m),7.76(1H,d,J=8.8Hz),8.36(1H,d,J=5.4Hz)Example 19

(1) tert-butyl = 1- (2-hydroxy-2- (7-methoxyisoquinolin-1-yl) ethyl) piperidin-4-ylcarbamate 0.45 g in methylene chloride 2 mL solution at room temperature with 1 mL trifluoroacetic acid After stirring for 1 hour, the solvent was distilled off under reduced pressure. To the obtained residue, 10 mL of water and 20 mL of ethyl acetate were added, and potassium carbonate was added to adjust to pH 9.5. The organic layer was separated, and the aqueous layer was extracted 4 times with 10 mL of 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 2- (4-aminopiperidin-1-yl)-as a yellow foam. 1- (7-methoxyisoquinolin-1-yl) ethanol was obtained.
(2) To a suspension of the obtained 2- (4-aminopiperidin-1-yl) -1- (7-methoxyisoquinolin-1-yl) ethanol in 9 mL of methylene chloride, 3 mL of methanol, 1,4- Benzodioxane-6-carbaldehyde 0.14g and 4A molecular sieves 1.5g were added and stirred overnight. To the reaction mixture, 98 mg of sodium borohydride was added and stirred at room temperature for 2 hours. 10 mL of water was added, adjusted to pH 3.0 with 6 mol / L hydrochloric acid, and then adjusted to pH 10.0 with 20% aqueous sodium hydroxide solution. 10 mL of ethyl acetate was added, the organic layer was separated, and the aqueous layer was extracted twice with 10 mL of 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: chloroform: methanol: isopropylamine = 50: 1: 1] to give 2- (4-((2,3-dihydrobenzo [ b] [1,4] dioxin-6-yl) methylamino) piperidin-1-yl) -1- (7-methoxyisoquinolin-1-yl) ethanol 20 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ values: 1.44-1.58 (2H, m), 1.93-1.95 (2H, m), 2.21-2.37 (2H, m), 2.54-2.59 (1H, m), 2.76-2.85 (2H, m), 3.09-3.12 (2H, m), 3.72 (2H, s), 3.96 (3H, s), 4.25 (4H, s), 5.49 (1H, dd, J = 8.2,3.4Hz), 6.79 (1H, dd, J = 8.2,1.8Hz), 6.82 (1H, d, J = 8.2Hz), 6.84 (1H, d, J = 1.8Hz), 7.36 (1H, dd, J = 8.8,2.4Hz) ), 7.51-7.53 (2H, m), 7.76 (1H, d, J = 8.8Hz), 8.36 (1H, d, J = 5.4Hz)

２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）メチルアミノ）ピペリジン−１−イル）−１−（７−メトキシイソキノリン−１−イル）エタノール20mgのジオキサン2mL溶液に、室温で3.2mol/L塩化水素/ジオキサン1.0mLを加え、減圧下で溶媒を留去した。残留物に酢酸エチルおよびジエチルエーテルを加え、不溶物をろ取し、白色固体の２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）メチルアミノ）ピペリジン−１−イル）−１−（７−メトキシイソキノリン−１−イル）エタノールの塩酸塩16mgを得た。
¹H-NMR(DMSO-d₆-D₂O)δ値：1.93-2.05(2H,m),2.28-2.35(2H,m),3.15-3.25(2H,m),3.33-3.45(1H,m),3.50-3.68(2H,m),3.75-3.80(1H,m),3.83-3.90(1H,m),3.95(3H,s),3.95-4.10(2H,m),4.19(4H,s),5.97-6.20(1H,m),6.87-7.00(3H,m),7.57-7.60(1H,m),7.66(1H,s),7.97(1H,d,J=6.2Hz),8.03(1H,d,J=9.2Hz),8.33(1H,d,J=6.2Hz)Example 20

2- (4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) methylamino) piperidin-1-yl) -1- (7-methoxyisoquinolin-1-yl) ethanol To 20 mg of dioxane 2 mL solution, 3.2 mol / L hydrogen chloride / dioxane 1.0 mL was added at room temperature, and the solvent was distilled off under reduced pressure. Ethyl acetate and diethyl ether were added to the residue, the insoluble material was collected by filtration, and white solid 2- (4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) methylamino was obtained. 16 mg of hydrochloride of piperidin-1-yl) -1- (7-methoxyisoquinolin-1-yl) ethanol was obtained.
¹ H-NMR (DMSO-d ₆ -D ₂ O) δ value: 1.93-2.05 (2H, m), 2.28-2.35 (2H, m), 3.15-3.25 (2H, m), 3.33-3.45 (1H, m), 3.50-3.68 (2H, m), 3.75-3.80 (1H, m), 3.83-3.90 (1H, m), 3.95 (3H, s), 3.95-4.10 (2H, m), 4.19 (4H, s), 5.97-6.20 (1H, m), 6.87-7.00 (3H, m), 7.57-7.60 (1H, m), 7.66 (1H, s), 7.97 (1H, d, J = 6.2Hz), 8.03 (1H, d, J = 9.2Hz), 8.33 (1H, d, J = 6.2Hz)

１−（７−メトキシイソキノリン−１−イル）−２−（ピペラジン−１−イル）エタノール0.21gの塩化メチレン3mL懸濁液に、室温で酢酸42μL、（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）アセトアルデヒド0.14gおよびトリアセトキシ水素化ホウ素ナトリウム0.15gを加え、室温で2時間攪拌した。さらに、（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）アセトアルデヒド27mgおよびトリアセトキシ水素化ホウ素ナトリウム30mg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10mLおよび水10mLを加え、20％水酸化ナトリウム水溶液でpH11.5に調整した。有機層を分取し、水層をクロロホルム10mL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、淡黄色油状物の２−（４−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペラジン−１−イル）−１−（７−メトキシイソキノリン−１−イル）エタノール0.23gを得た。
¹H-NMR(CDCl₃)δ値：2.55-2.90(14H,m),3.96(3H,s),4.24(4H,s),5.53(1H,dd,J=8.4,3.2Hz),6.68(1H,dd,J=8.2,2.2Hz),6.73(1H,d,J=2.2Hz),6.78(1H,d,J=8.2Hz),7.36(1H,dd,J=9.0,2.2Hz),7.46(1H,d,J=2.2Hz),7.53(1H,d,J=5.6Hz),7.76(1H,d,J=9.0Hz),8.36(1H,d,J=5.6Hz)Example 21

To a suspension of 0.21 g of 1- (7-methoxyisoquinolin-1-yl) -2- (piperazin-1-yl) ethanol in 3 mL of methylene chloride, 42 μL of acetic acid, (2,3-dihydrobenzo [b] [ 1,4] dioxin-6-yl) acetaldehyde (0.14 g) and sodium triacetoxyborohydride (0.15 g) were added, and the mixture was stirred at room temperature for 2 hours. Furthermore, 27 mg of (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) acetaldehyde and 30 mg of sodium triacetoxyborohydride were added and stirred at room temperature for 1 hour. Chloroform 10 mL and water 10 mL were added to the reaction mixture, 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 10 mL of chloroform. The organic layer and the extract were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and a pale yellow oil 2- (4- (2- (2,3-dihydrobenzo [b] [1,4 Dioxin-6-yl) ethyl) piperazin-1-yl) -1- (7-methoxyisoquinolin-1-yl) ethanol 0.23 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.55-2.90 (14H, m), 3.96 (3H, s), 4.24 (4H, s), 5.53 (1H, dd, J = 8.4, 3.2 Hz), 6.68 ( 1H, dd, J = 8.2,2.2Hz), 6.73 (1H, d, J = 2.2Hz), 6.78 (1H, d, J = 8.2Hz), 7.36 (1H, dd, J = 9.0,2.2Hz), 7.46 (1H, d, J = 2.2Hz), 7.53 (1H, d, J = 5.6Hz), 7.76 (1H, d, J = 9.0Hz), 8.36 (1H, d, J = 5.6Hz)

７−メトキシ−１−（オキシラン−２−イル）イソキノリン85mgのＮ，Ｎ−ジメチルホルムアミド5mL溶液に、室温で１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペラジンの塩酸塩0.16g、過塩素酸リチウム45mgおよび炭酸カリウム0.13gを加え、80℃で1時間攪拌した。反応混合物を室温まで冷却し、水10mLおよび酢酸エチル10mLを加えた。有機層を分取し、水層を酢酸エチル5mL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、淡黄色油状物の２−（４−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペラジン−１−イル）−１−（７−メトキシイソキノリン−１−イル）エタノール60mgを得た。
¹H-NMRは、実施例２１のデータと一致した。Example 22

7-Methoxy-1- (oxiran-2-yl) isoquinoline 85 mg in N, N-dimethylformamide 5 mL solution at room temperature with 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin- 6-yl) ethyl) piperazine hydrochloride (0.16 g), lithium perchlorate (45 mg) and potassium carbonate (0.13 g) were added, and the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was cooled to room temperature and 10 mL water and 10 mL ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with 5 mL of 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: chloroform: methanol = 50: 1] to give 2- (4- (2- (2,3-dihydrobenzo [b] [ 60 mg of 1,4] dioxin-6-yl) ethyl) piperazin-1-yl) -1- (7-methoxyisoquinolin-1-yl) ethanol was obtained.
¹ H-NMR was consistent with the data of Example 21.

２−（４−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペラジン−１−イル）−１−（７−メトキシイソキノリン−１−イル）エタノール0.23g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0.55mLを加え、減圧下で溶媒を留去した。残留物に酢酸エチルを加え、不溶物をろ取し、淡黄色固体の２−（４−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペラジン−１−イル）−１−（７−メトキシイソキノリン−１−イル）エタノールの塩酸塩0.23gを得た。
¹H-NMR(DMSO-d₆-D₂O)δ値：2.85-2.90(2H,m),3.00-3.35(12H,m),4.03(3H,s),4.21(4H,s),6.00-6.03(1H,s),6.74-6.84(3H,m),7.74-7.79(2H,m),8.19-8.22(2H,m),8.40(1H,d,J=6.4Hz)Example 23

2- (4- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperazin-1-yl) -1- (7-methoxyisoquinolin-1-yl) To a solution of ethanol 0.23 g in ethyl acetate 3 mL was added 4.0 mol / L hydrogen chloride / ethyl acetate 0.55 mL at room temperature, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, the insoluble material was collected by filtration, and a pale yellow solid 2- (4- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) 0.23 g of hydrochloride of piperazin-1-yl) -1- (7-methoxyisoquinolin-1-yl) ethanol was obtained.
¹ H-NMR (DMSO-d ₆ -D ₂ O) δ value: 2.85-2.90 (2H, m), 3.00-3.35 (12H, m), 4.03 (3H, s), 4.21 (4H, s), 6.00 -6.03 (1H, s), 6.74-6.84 (3H, m), 7.74-7.79 (2H, m), 8.19-8.22 (2H, m), 8.40 (1H, d, J = 6.4Hz)

１−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）メチル）ピペリジン−４−アミンの塩酸塩0.18gのＮ，Ｎ−ジメチルホルムアミド3mL溶液に、炭酸カリウム0.15gを加え、50℃で40分間攪拌した。40℃まで冷却し、過塩素酸リチウム53mgおよび７−メトキシ−１−（オキシラン−２−イル）イソキノリン100mgのＮ，Ｎ−ジメチルホルムアミド2mL溶液を加え、80℃で2時間30分間攪拌した。反応混合物を室温まで冷却し、水5mLおよび酢酸エチル5mL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＝５：１］で精製し、褐色油状物の２−（１−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）メチル）ピペリジン−４−イル）アミノ−１−（７−メトキシイソキノリン−１−イル）エタノール63mgを得た。
¹H-NMR(CDCl₃)δ値：1.45-1.60(2H,m),1.85-2.00(2H,m),2.00-2.10(2H,m),2.55-2.90(4H,m),3.20-3.24(1H,m),3.41(2H,s),3.96(3H,s),4.25(4H,s),5.54(1H,dd,J=8.5,2.7Hz),6.77-6.83(3H,m),7.35-7.38(2H,m),7.55(1H,d,J=5.6Hz),7.77(1H,d,J=9.8Hz),8.34(1H,d,J=5.6Hz)Example 24

1-((2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) methyl) piperidin-4-amine hydrochloride 0.18 g in a solution of N, N-dimethylformamide 3 mL g was added and stirred at 50 ° C. for 40 minutes. After cooling to 40 ° C., 53 mg of lithium perchlorate and 100 mg of 7-methoxy-1- (oxiran-2-yl) isoquinoline in 2 mL of N, N-dimethylformamide were added, and the mixture was stirred at 80 ° C. for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature and 5 mL water and 5 mL 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 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: chloroform: methanol = 5: 1] to give 2- (1-((2,3-dihydrobenzo [b] [1,4 Dioxin-6-yl) methyl) piperidin-4-yl) amino-1- (7-methoxyisoquinolin-1-yl) ethanol (63 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.45-1.60 (2H, m), 1.85-2.00 (2H, m), 2.00-2.10 (2H, m), 2.55-2.90 (4H, m), 3.20-3.24 (1H, m), 3.41 (2H, s), 3.96 (3H, s), 4.25 (4H, s), 5.54 (1H, dd, J = 8.5,2.7Hz), 6.77-6.83 (3H, m), 7.35-7.38 (2H, m), 7.55 (1H, d, J = 5.6Hz), 7.77 (1H, d, J = 9.8Hz), 8.34 (1H, d, J = 5.6Hz)

２−（１−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）メチル）ピペリジン−４−イルアミノ）−１−（７−メトキシイソキノリン−１−イル）エタノール63mgの酢酸エチル2mL溶液に、室温で4.0mol/L塩化水素/酢酸エチル0.12mLを加えた。同温度で1時間10分間攪拌した後、氷冷下で20分間攪拌した。析出物をろ取し、淡黄色固体の２−（１−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）メチル）ピペリジン−４−イルアミノ）−１−（７−メトキシイソキノリン−１−イル）エタノールの塩酸塩52mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.00-2.40(4H,m),2.85-3.00(2H,m),3.20-3.70(4H,m),4.03(3H,s),4.10-4.15(2H,m),4.20-4.30(5H,m),6.05-6.20(1H,m),6.92(1H,d,J=8.2Hz),7.01(1H,d,J=8.2Hz),7.16(1H,s),7.60-7.75(1H,m),7.85-7.95(1H,m),8.00-8.20(2H,m),8.42(1H,d,J=5.9Hz)Example 25

2- (1-((2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) methyl) piperidin-4-ylamino) -1- (7-methoxyisoquinolin-1-yl) ethanol 63 mg To 2 mL of ethyl acetate, 0.12 mL of 4.0 mol / L hydrogen chloride / ethyl acetate was added at room temperature. The mixture was stirred at the same temperature for 1 hour and 10 minutes, and then stirred for 20 minutes under ice cooling. The precipitate was collected by filtration to give 2- (1-((2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) methyl) piperidin-4-ylamino) -1- ( 7 mg of 7-methoxyisoquinolin-1-yl) ethanol hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.00-2.40 (4H, m), 2.85-3.00 (2H, m), 3.20-3.70 (4H, m), 4.03 (3H, s), 4.10-4.15 (2H, m), 4.20-4.30 (5H, m), 6.05-6.20 (1H, m), 6.92 (1H, d, J = 8.2Hz), 7.01 (1H, d, J = 8.2Hz), 7.16 ( 1H, s), 7.60-7.75 (1H, m), 7.85-7.95 (1H, m), 8.00-8.20 (2H, m), 8.42 (1H, d, J = 5.9Hz)

２−（（３−アミノプロピル）（メチル）アミノ）−１−（７−メトキシイソキノリン−１−イル）エタノール97mgの塩化メチレン3mL溶液に、メタノール1mL、４Ａモレキュラーシーブス0.5gおよび１，４−ベンゾジオキサン−６−カルバルデヒド55mgを加え、室温で63時間攪拌した。反応混合物に水素化ホウ素ナトリウム33mgを加え、50分間攪拌した後、不溶物をろ去し、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＝２：１］で精製し、黄色油状物の２−（（３−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）メチルアミノ）プロピル）（メチル）アミノ）−１−（７−メトキシイソキノリン−１−イル）エタノール44mgを得た。
¹H-NMR(CDCl₃)δ値：1.68-1.75(2H,m),2.45(3H,s),2.55-2.67(4H,m),2.81-2.83(2H,m),3.66(2H,s),3.94(3H,s),4.23(4H,s),5.47(1H,dd,J=6.7,4.8Hz),6.76-6.83(3H,m),7.35(1H,dd,J=8.9,2.4Hz),7.51(1H,d,J=2.4Hz),7.52(1H,d,J=5.7Hz),7.76(1H,d,J=8.9Hz),8.36(1H,d,J=5.7Hz)Example 26

2-((3-aminopropyl) (methyl) amino) -1- (7-methoxyisoquinolin-1-yl) ethanol in 97 mg of methylene chloride was added to 1 mL of methanol, 0.5 g of 4A molecular sieves and 1,4-benzoic acid. Dioxane-6-carbaldehyde 55 mg was added, and the mixture was stirred at room temperature for 63 hours. After adding 33 mg of sodium borohydride to the reaction mixture and stirring for 50 minutes, the insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure. Chloroform and water 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. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 2: 1] to give 2-((3-((2,3-dihydrobenzo [b] [1, 4] 44 mg of dioxin-6-yl) methylamino) propyl) (methyl) amino) -1- (7-methoxyisoquinolin-1-yl) ethanol was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.68-1.75 (2H, m), 2.45 (3H, s), 2.55-2.67 (4H, m), 2.81-2.83 (2H, m), 3.66 (2H, s ), 3.94 (3H, s), 4.23 (4H, s), 5.47 (1H, dd, J = 6.7, 4.8Hz), 6.76-6.83 (3H, m), 7.35 (1H, dd, J = 8.9, 2.4) Hz), 7.51 (1H, d, J = 2.4Hz), 7.52 (1H, d, J = 5.7Hz), 7.76 (1H, d, J = 8.9Hz), 8.36 (1H, d, J = 5.7Hz)

２−（（３−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）メチルアミノ）プロピル）（メチル）アミノ）−１−（７−メトキシイソキノリン−１−イル）エタノール44mgの酢酸エチル2mL溶液に、室温で4.0mol/L塩化水素/酢酸エチル88μLを加えた。同温度で30分間攪拌し、エタノールを加え、減圧下で溶媒を留去した。得られた残留物に酢酸エチル、4.0mol/L塩化水素/酢酸エチル88μLおよびエタノールを加え、減圧下で溶媒を留去した。得られた残留物にエタノールおよびジエチルエーテルを加え、減圧下で溶媒を留去し、淡黄色固体の２−（（３−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）メチルアミノ）プロピル）（メチル）アミノ）−１−（７−メトキシイソキノリン−１−イル）エタノールの塩酸塩36mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.15-2.25(2H,m),2.50(3H,s),2.90-3.05(4H,m),3.30-3.60(2H,m),4.00-4.10(5H,m),4.25(4H,s),6.15-6.30(1H,m),6.90(1H,d,J=8.4Hz),7.02(1H,d,J=8.4Hz),7.14(1H,s),7.60-7.70(1H,m),7.90-7.95(1H,m),8.00-8.20(2H,m),8.35-8.45(1H,m)Example 27

2-((3-((2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) methylamino) propyl) (methyl) amino) -1- (7-methoxyisoquinolin-1-yl ) To a solution of ethanol 44 mg in ethyl acetate 2 mL, 4.0 mol / L hydrogen chloride / ethyl acetate 88 μL was added at room temperature. The mixture was stirred at the same temperature for 30 minutes, ethanol was added, and the solvent was distilled off under reduced pressure. Ethyl acetate, 4.0 mol / L hydrogen chloride / ethyl acetate 88 μL and ethanol were added to the obtained residue, and the solvent was distilled off under reduced pressure. Ethanol and diethyl ether were added to the obtained residue, the solvent was distilled off under reduced pressure, and 2-((3-((2,3-dihydrobenzo [b] [1,4] dioxin- 6 mg of hydrochloride of 6-yl) methylamino) propyl) (methyl) amino) -1- (7-methoxyisoquinolin-1-yl) ethanol was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.15-2.25 (2H, m), 2.50 (3H, s), 2.90-3.05 (4H, m), 3.30-3.60 (2H, m), 4.00-4.10 (5H, m), 4.25 (4H, s), 6.15-6.30 (1H, m), 6.90 (1H, d, J = 8.4Hz), 7.02 (1H, d, J = 8.4Hz), 7.14 (1H, s), 7.60-7.70 (1H, m), 7.90-7.95 (1H, m), 8.00-8.20 (2H, m), 8.35-8.45 (1H, m)

１−（２−（チオフェン−２−イルチオ）エチル）ピペリジン−４−アミン70mgのＮ，Ｎ−ジメチルホルムアミド2mL溶液に、７−メトキシ−１−（オキシラン−２−イル）イソキノリン58mgおよび過塩素酸リチウム31mgを加え、85℃で4時間攪拌した。反応混合物を室温まで冷却し、水10mLおよび酢酸エチル10mL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、無色油状物の２−（１−（２−（チオフェン−２−イルチオ）エチル）ピペリジン−４−イルアミノ）−１−（７−メトキシイソキノリン−１−イル）エタノール65mgを得た。
¹H-NMR(CDCl₃)δ値：1.40-1.50(2H,m),1.80-1.95(2H,m),2.00-2.06(2H,m),2.50-2.65(3H,m),2.74-2.92(5H,m),3.17(1H,dd,J=12.0,2.9Hz),3.95(3H,s),5.50(1H,dd,J=8.7,2.8Hz),6.96(1H,dd,J=5.4,3.5Hz),7.11(1H,dd,J=3.5,1.2Hz),7.32(1H,dd,J=5.4,1.2Hz),7.34-7.38(2H,m),7.55(1H,d,J=5.5Hz),7.77(1H,d,J=8.8Hz),8.34(1H,d,J=5.5Hz)Example 28

To a solution of 70 mg of 1- (2- (thiophen-2-ylthio) ethyl) piperidin-4-amine in 2 mL of N, N-dimethylformamide, 58 mg of 7-methoxy-1- (oxiran-2-yl) isoquinoline and perchloric acid 31 mg of lithium was added, and the mixture was stirred at 85 ° C. for 4 hours. The reaction mixture was cooled to room temperature and 10 mL water and 10 mL 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: chloroform: methanol = 5: 1] to give 2- (1- (2- (thiophen-2-ylthio) ethyl) piperidine-4 as a colorless oil. 65 mg of -ylamino) -1- (7-methoxyisoquinolin-1-yl) ethanol was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.40-1.50 (2H, m), 1.80-1.95 (2H, m), 2.00-2.06 (2H, m), 2.50-2.65 (3H, m), 2.74-2.92 (5H, m), 3.17 (1H, dd, J = 12.0,2.9Hz), 3.95 (3H, s), 5.50 (1H, dd, J = 8.7,2.8Hz), 6.96 (1H, dd, J = 5.4 3.5Hz), 7.11 (1H, dd, J = 3.5,1.2Hz), 7.32 (1H, dd, J = 5.4,1.2Hz), 7.34-7.38 (2H, m), 7.55 (1H, d, J = 5.5Hz), 7.77 (1H, d, J = 8.8Hz), 8.34 (1H, d, J = 5.5Hz)

２−（１−（２−（チオフェン−２−イルチオ）エチル）ピペリジン−４−イルアミノ）−１−（７−メトキシイソキノリン−１−イル）エタノール65mgの酢酸エチル2mL溶液に、室温で4.0mol/L塩化水素/酢酸エチル0.13mLを加えた。同温度で30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および4.0mol/L塩化水素/酢酸エチル0.13mLを加え、析出物をろ取し、白色固体の２−（１−（２−（チオフェン−２−イルチオ）エチル）ピペリジン−４−イルアミノ）−１−（７−メトキシイソキノリン−１−イル）エタノールの塩酸塩53mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.95-2.35(6H,m),2.95-3.05(2H,m),3.10-3.80(7H,m),4.07(3H,s),6.20-6.40(1H,m),7.10(1H,dd,J=5.2,3.5Hz),7.31(1H,dd,J=3.5,1.2Hz),7.71(1H,dd,J=5.2,1.2Hz),7.65-7.80(1H,m),7.90-8.05(1H,m),8.10-8.30(2H,m),8.45(1H,d,J=6.1Hz)Example 29

2- (1- (2- (thiophen-2-ylthio) ethyl) piperidin-4-ylamino) -1- (7-methoxyisoquinolin-1-yl) ethanol (65 mg) in ethyl acetate (2 mL) at room temperature at 4.0 mol / L Hydrogen chloride / ethyl acetate 0.13 mL was added. The mixture was stirred at the same temperature for 30 minutes, and the solvent was distilled off under reduced pressure. Ethyl acetate and 0.13 mL of 4.0 mol / L hydrogen chloride / ethyl acetate were added to the obtained residue, and the precipitate was collected by filtration to give 2- (1- (2- (thiophen-2-ylthio) ethyl) as a white solid. 53 mg of hydrochloride of piperidin-4-ylamino) -1- (7-methoxyisoquinolin-1-yl) ethanol was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.95-2.35 (6H, m), 2.95-3.05 (2H, m), 3.10-3.80 (7H, m), 4.07 (3H, s), 6.20-6.40 (1H, m), 7.10 (1H, dd, J = 5.2, 3.5Hz), 7.31 (1H, dd, J = 3.5, 1.2Hz), 7.71 (1H, dd, J = 5.2, 1.2Hz), 7.65 7.80 (1H, m), 7.90-8.05 (1H, m), 8.10-8.30 (2H, m), 8.45 (1H, d, J = 6.1Hz)

Ｎ−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）メチル）ピペリジン−４−カルボキサミド0.12gのジクロロエタン3mL溶液に、室温で７−メトキシイソキノリン−１−カルバルデヒド53mgおよび酢酸24μLを加え、同温度で20分間攪拌した。ついで、同温度でトリアセトキシ水素化ホウ素ナトリウム0.13gを加え、1時間20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＝１０：１］で精製し、無色泡状物のＮ−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）メチル）−１−（（７−メトキシイソキノリン−１−イル）メチル）ピペリジン−４−カルボキサミド0.10gを得た。
¹H-NMR(CDCl₃)δ値：1.70-1.90(4H,m),2.10-2.25(3H,m),2.95-3.05(2H,m),3.96(3H,s),4.05(2H,s),4.23(4H,s),4.31(2H,d,J=5.4Hz),5.55-5.65(1H,m),6.71(1H,dd,J=8.3,2.1Hz),6.75(1H,d,J=2.1Hz),6.80(1H,d,J=8.3Hz),7.34(1H,dd,J=8.9,2.5Hz),7.51(1H,d,J=5.7Hz),7.72(1H,d,J=8.9Hz),7.92(1H,d,J=2.5Hz),8.32(1H,d,J=5.7Hz)Example 30

N-((2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) methyl) piperidine-4-carboxamide in a solution of 0.12 g of dichloroethane at room temperature and 7-methoxyisoquinoline-1-carbaldehyde 53 mg and 24 μL of acetic acid were added and stirred at the same temperature for 20 minutes. Next, 0.13 g of sodium triacetoxyborohydride was added at the same temperature and stirred for 1 hour and 20 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 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 = 10: 1] to give N-((2,3-dihydrobenzo [b] [1,4] dioxin as a colorless foam. 0.10 g of -6-yl) methyl) -1-((7-methoxyisoquinolin-1-yl) methyl) piperidine-4-carboxamide was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.70-1.90 (4H, m), 2.10-2.25 (3H, m), 2.95-3.05 (2H, m), 3.96 (3H, s), 4.05 (2H, s ), 4.23 (4H, s), 4.31 (2H, d, J = 5.4Hz), 5.55-5.65 (1H, m), 6.71 (1H, dd, J = 8.3, 2.1Hz), 6.75 (1H, d, J = 2.1Hz), 6.80 (1H, d, J = 8.3Hz), 7.34 (1H, dd, J = 8.9,2.5Hz), 7.51 (1H, d, J = 5.7Hz), 7.72 (1H, d, J = 8.9Hz), 7.92 (1H, d, J = 2.5Hz), 8.32 (1H, d, J = 5.7Hz)

Ｎ−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）メチル）−１−（（７−メトキシイソキノリン−１−イル）メチル）ピペリジン−４−カルボキサミド0.10g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0.15mLを加え、同温度で35分間攪拌した。析出物をろ取し、淡黄色固体のＮ−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）メチル）−１−（（７−メトキシイソキノリン−１−イル）メチル）ピペリジン−４−カルボキサミドの塩酸塩71mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.95-2.15(4H,m),2.45-2.65(1H,m),3.20-3.35(2H,m),3.60-3.70(2H,m),3.99(3H,s),4.16(2H,d,J=5.6Hz),4.21(4H,s),5.10(2H,s),6.70(1H,dd,J=8.2,2.0Hz),6.73(1H,d,J=2.0Hz),6.79(1H,d,J=8.2Hz),7.50(1H,d,J=2.3Hz),7.54(1H,dd,J=8.9,2.3Hz),7.88(1H,d,J=5.4Hz),8.03(1H,d,J=8.9Hz),8.47(1H,d,J=5.4Hz)Example 31

0.10 g of N-((2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) methyl) -1-((7-methoxyisoquinolin-1-yl) methyl) piperidine-4-carboxamide To a 3 mL solution of ethyl acetate, 4.05 mol / L hydrogen chloride / 0.15 mL of ethyl acetate was added at room temperature, and the mixture was stirred at the same temperature for 35 minutes. The precipitate was collected by filtration, and pale yellow solid N-((2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) methyl) -1-((7-methoxyisoquinolin-1-yl) 71 mg of hydrochloride of methyl) piperidine-4-carboxamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.95-2.15 (4H, m), 2.45-2.65 (1H, m), 3.20-3.35 (2H, m), 3.60-3.70 (2H, m), 3.99 (3H, s), 4.16 (2H, d, J = 5.6Hz), 4.21 (4H, s), 5.10 (2H, s), 6.70 (1H, dd, J = 8.2, 2.0Hz), 6.73 (1H, d, J = 2.0Hz), 6.79 (1H, d, J = 8.2Hz), 7.50 (1H, d, J = 2.3Hz), 7.54 (1H, dd, J = 8.9,2.3Hz), 7.88 (1H, d, J = 5.4Hz), 8.03 (1H, d, J = 8.9Hz), 8.47 (1H, d, J = 5.4Hz)

１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸0.13gの塩化メチレン2mL懸濁液に、塩化チオニル64μLおよびＮ，Ｎ−ジメチルホルムアミド30μLを加え、1時間50分間加熱還流した。さらに、塩化チオニル0.50mLを加え、30分間加熱還流した。反応混合物を室温まで冷却し、減圧下で溶媒を留去した。得られた残留物を塩化メチレン4mLに溶解させ、トリエチルアミン61μLを加え、氷冷下、メチル＝８−アミノ−２−メトキシキノリン−３−カルボキシラート85mgおよびトリエチルアミン61μLの塩化メチレン3mL溶液に加えた。室温で1時間30分間攪拌した後、1時間加熱還流した。反応混合物を室温まで冷却し、水2mLを加え、10分間攪拌した。析出物をろ取し、白色固体のメチル＝８−（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−３−カルボキシラートの塩酸塩82mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.00-2.30(4H,m),2.85-3.10(5H,m),3.20-3.40(2H,m),3.60-3.70(2H,m),3.89(3H,s),4.17(3H,s),4.22(4H,s),6.72-6.74(1H,m),6.78-6.83(2H,m),7.47-7.51(1H,m),7.77-7.79(1H,m),8.50-8.52(1H,m),8.81(1H,s),9.72(1H,s),10.30-10.60(1H,broad)Example 32

To a suspension of 0.13 g of 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxylic acid in 2 mL of methylene chloride, 64 μL of thionyl chloride and N , N-dimethylformamide (30 μL) was added, and the mixture was heated to reflux for 1 hour and 50 minutes. Further, 0.50 mL of thionyl chloride was added, and the mixture was heated to reflux for 30 minutes. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 4 mL of methylene chloride, 61 μL of triethylamine was added, and the mixture was added to a solution of 85 mg of methyl 8-amino-2-methoxyquinoline-3-carboxylate and 61 μL of triethylamine in 3 mL of methylene chloride under ice cooling. After stirring at room temperature for 1 hour and 30 minutes, the mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, 2 mL of water was added and stirred for 10 minutes. The precipitate was collected by filtration, and white solid methyl = 8- (1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxamide)- 82 mg of 2-methoxyquinoline-3-carboxylate hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.00-2.30 (4H, m), 2.85-3.10 (5H, m), 3.20-3.40 (2H, m), 3.60-3.70 (2H, m), 3.89 (3H, s), 4.17 (3H, s), 4.22 (4H, s), 6.72-6.74 (1H, m), 6.78-6.83 (2H, m), 7.47-7.51 (1H, m), 7.77-7.79 (1H, m), 8.50-8.52 (1H, m), 8.81 (1H, s), 9.72 (1H, s), 10.30-10.60 (1H, broad)

メチル＝８−（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−３−カルボキシラート0.10gのメタノール3mL懸濁液に、1.0mol/L水酸化ナトリウム水溶液0.22mLを加え、1時間攪拌した。酢酸エチル3mLおよび20％水酸化ナトリウム水溶液3mLを加え、室温で30分間攪拌した後、1時間加熱還流した。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。水層を分取し、有機層を1.0mol/L水酸化ナトリウム水溶液で抽出した。水層および抽出液を合わせ、酢酸エチルで洗浄し、6.0mol/L塩酸を加え、pH6.8に調整した後、減圧下で溶媒を留去した。得られた残留物にメタノール3mLおよび水3mLを加え、減圧下で溶媒を留去した。得られた残留物に水5mLを加え、析出物をろ取し、淡黄色固体の８−（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−３−カルボン酸31mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.65-1.80(2H,m),1.90-2.00(2H,m),2.00-2.15(2H,m),2.40-2.70(5H,m),2.95-3.05(2H,m),4.07(3H,s),4.20(4H,s),6.66(1H,dd,J=8.2,1.8Hz),6.72-6.75(2H,m),7.34-7.38(1H,m),7.58(1H,d,J=7.6Hz),8.27(1H,s),8.45(1H,d,J=7.6Hz),9.61(1H,s)Example 33

Methyl = 8- (1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxamide) -2-methoxyquinoline-3-carboxylate 0.10 To a 3 mL suspension of g in methanol, 0.22 mL of a 1.0 mol / L aqueous sodium hydroxide solution was added and stirred for 1 hour. 3 mL of ethyl acetate and 3 mL of 20% aqueous sodium hydroxide solution were added, and the mixture was stirred at room temperature for 30 minutes and then heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and water and ethyl acetate were added. The aqueous layer was separated, and the organic layer was extracted with 1.0 mol / L sodium hydroxide aqueous solution. The aqueous layer and the extract were combined, washed with ethyl acetate, 6.0 mol / L hydrochloric acid was added to adjust to pH 6.8, and then the solvent was distilled off under reduced pressure. Methanol 3mL and water 3mL were added to the obtained residue, and the solvent was distilled off under reduced pressure. Water (5 mL) was added to the obtained residue, and the precipitate was collected by filtration, and then collected as a pale yellow solid of 8- (1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl. 31 mg of ethyl) piperidine-4-carboxamide) -2-methoxyquinoline-3-carboxylic acid was obtained.
^{1 H-NMR (DMSO-d} 6) δ value: 1.65-1.80 (2H, m), 1.90-2.00 (2H, m), 2.00-2.15 (2H, m), 2.40-2.70 (5H, m), 2.95 -3.05 (2H, m), 4.07 (3H, s), 4.20 (4H, s), 6.66 (1H, dd, J = 8.2,1.8Hz), 6.72-6.75 (2H, m), 7.34-7.38 (1H , m), 7.58 (1H, d, J = 7.6Hz), 8.27 (1H, s), 8.45 (1H, d, J = 7.6Hz), 9.61 (1H, s)

２，７−ジメトキシキノリン−８−アミン22mgのＮ，Ｎ−ジメチルホルムアミド2mL溶液に、室温で１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸31mg、Ｏ−（７−アザベンゾトリアゾール−１−イル）−１，１，３，３−テトラメチルウロニウム＝ヘキサフルオロホスフェート62mgおよびトリエチルアミン45μLを加え、60℃で1時間、90℃で1時間攪拌した。Ｏ−（７−アザベンゾトリアゾール−１−イル）−１，１，３，３−テトラメチルウロニウム＝ヘキサフルオロホスフェート62mgおよびトリエチルアミン45μLを加え、70℃で1時間攪拌した。反応混合物に酢酸エチル30mLおよび水20mLを加えた。有機層を分取し、水層を酢酸エチル10mLで抽出した。有機層および抽出液を合わせ、水10mLおよび飽和塩化ナトリウム水溶液10mL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、得られた残留物にジエチルエーテルおよびジイソプロピルエーテルを加えた。不溶物をろ取し、淡褐色固体の１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−6−イル）エチル）−Ｎ −（２，７−ジメトキシキノリン−８−イル）ピペリジン−４−カルボキサミド3mgを得た。
¹H-NMR(CDCl₃)δ値：1.95-2.20(6H,m),2.40-2.65(3H,m),2.70-2.80(2H,m),3.05-3.15(2H,m),3.99(3H,s),4.03(3H,s),4.24(4H,s),6.65-6.80(4H,m),7.18(1H,d,J=9.0Hz),7.55(1H,s),7.60(1H,d,J=9.0Hz),7.91(1H,d,J=8.8Hz)Example 34

To a solution of 2,7-dimethoxyquinolin-8-amine 22 mg in 2 mL of N, N-dimethylformamide at room temperature is 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl). Ethyl) piperidine-4-carboxylic acid (31 mg), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium = hexafluorophosphate (62 mg) and triethylamine (45 μL) were added. The mixture was stirred for 1 hour at 90 ° C. 62 mg of O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium = hexafluorophosphate and 45 μL of triethylamine were added and stirred at 70 ° C. for 1 hour. To the reaction mixture, 30 mL of ethyl acetate and 20 mL of water were added. The organic layer was separated and the aqueous layer was extracted with 10 mL of ethyl acetate. The organic layer and the extract were combined, washed with 10 mL of water and 10 mL of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 20: 1], and diethyl ether and diisopropyl ether were added to the obtained residue. The insoluble material was collected by filtration, and 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) -N- (2,7-dimethoxyquinoline- There was obtained 3 mg of 8-yl) piperidine-4-carboxamide.
¹ H-NMR (CDCl ₃ ) δ value: 1.95-2.20 (6H, m), 2.40-2.65 (3H, m), 2.70-2.80 (2H, m), 3.05-3.15 (2H, m), 3.99 (3H , s), 4.03 (3H, s), 4.24 (4H, s), 6.65-6.80 (4H, m), 7.18 (1H, d, J = 9.0Hz), 7.55 (1H, s), 7.60 (1H, d, J = 9.0Hz), 7.91 (1H, d, J = 8.8Hz)

４−アミノ−Ｎ−（７−メトキシイソキノリン−１−イル）シクロヘキサンカルボキサミド80mgのジクロロエタン2mL溶液に、室温で１，４−ベンゾジオキサン−６−カルバルデヒド44mgおよび酢酸16μLを加え、同温度で１時間攪拌した。ついで、同温度でトリアセトキシ水素化ホウ素ナトリウム84mgを加え、3時間攪拌した。反応混合物に水10mLおよび酢酸エチル40mLを加えた。20％水酸化ナトリウム水溶液を加え、pH12.0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；クロロホルム：メタノール＝２０：１］で精製し、白色固体の４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）メチルアミノ）−Ｎ−（７−メトキシイソキノリン−１−イル）シクロヘキサンカルボキサミド17mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.06-1.20(2H,m),1.42-1.74(3H,m),1.96-2.03(4H,m),2.40-2.70(1H,m),3.60-3.70(2H,m),3.85(3H,s),4.21(4H,s),6.76-6.88(3H,m),7.16-7.20(1H,m),7.43(1H,dd,J=9.0,2.4Hz),7.65(1H,d,J=5.5Hz),7.90(1H,d,J=9.0Hz),8.18(1H,d,J=5.5Hz),10.23-10.28(1H,m)Example 35

To a solution of 80 mg of 4-amino-N- (7-methoxyisoquinolin-1-yl) cyclohexanecarboxamide in 2 mL of dichloroethane was added 44 mg of 1,4-benzodioxan-6-carbaldehyde and 16 μL of acetic acid at room temperature, and the mixture was stirred at the same temperature for 1 hour. Stir. Subsequently, 84 mg of sodium triacetoxyborohydride was added at the same temperature and stirred for 3 hours. 10 mL of water and 40 mL of ethyl acetate were added to the reaction mixture. A 20% aqueous sodium hydroxide solution was added to adjust the pH to 12.0. 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: chloroform: methanol = 20: 1] to give 4-((2,3-dihydrobenzo [b] [1,4] dioxin-6 as a white solid. 17 mg of -yl) methylamino) -N- (7-methoxyisoquinolin-1-yl) cyclohexanecarboxamide were obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.06-1.20 (2H, m), 1.42-1.74 (3H, m), 1.96-2.03 (4H, m), 2.40-2.70 (1H, m), 3.60 -3.70 (2H, m), 3.85 (3H, s), 4.21 (4H, s), 6.76-6.88 (3H, m), 7.16-7.20 (1H, m), 7.43 (1H, dd, J = 9.0, 2.4Hz), 7.65 (1H, d, J = 5.5Hz), 7.90 (1H, d, J = 9.0Hz), 8.18 (1H, d, J = 5.5Hz), 10.23-10.28 (1H, m)

８−アミノ−２−メトキシキノリン−５−カルボキサミド13mgのＮ，Ｎ−ジメチルホルムアミド0.60mL溶液に、室温で１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸21mg、トリエチルアミン34μLおよびＯ−（７−アザベンゾトリアゾール−１−イル）−１，１，３，３−テトラメチルウロニウム＝ヘキサフルオロホスフェート46mgを加え、室温で2時間35分間、60〜70℃で40分間攪拌した。反応混合物を室温まで冷却し、Ｏ−（７−アザベンゾトリアゾール−１−イル）−１，１，３，３−テトラメチルウロニウム＝ヘキサフルオロホスフェート46mgおよびトリエチルアミン34μLを加え、室温で55分間、100〜110℃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10mLおよび水10mLを加えた。有機層を分取し、水層を酢酸エチル10mL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＝１０：１］で精製し、褐色固体の８−（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−カルボキサミド5.5mgを得た。
¹H-NMR(CD₃OD)δ値：1.80-3.70(13H,m),4.15(3H,s),4.21(4H,s),6.70-6.80(3H,m),7.10(1H,d,J=9.3Hz),7.67(1H,d,J=8.0Hz),8.57(1H,d,J=8.0Hz),8.74(1H,d,J=9.3Hz)Example 36

To a solution of 13 mg of 8-amino-2-methoxyquinoline-5-carboxamide in 0.60 mL of N, N-dimethylformamide at room temperature is added 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6. -Yl) ethyl) piperidine-4-carboxylic acid 21 mg, triethylamine 34 μL and O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium = hexafluorophosphate 46 mg are added, The mixture was stirred at room temperature for 2 hours and 35 minutes and at 60 to 70 ° C. for 40 minutes. The reaction mixture was cooled to room temperature, O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium = hexafluorophosphate 46 mg and triethylamine 34 μL were added and at room temperature for 55 minutes. It stirred at 100-110 degreeC for 1 hour. The reaction mixture was cooled to room temperature and 10 mL of ethyl acetate and 10 mL of water were added. The organic layer was separated and the aqueous layer was extracted with 10 mL of 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: chloroform: methanol = 10: 1] to give 8- (1- (2- (2,3-dihydrobenzo [b] [1, 4] Dioxin-6-yl) ethyl) piperidine-4-carboxamide) -2-methoxyquinoline-5-carboxamide 5.5 mg was obtained.
¹ H-NMR (CD ₃ OD) δ value: 1.80-3.70 (13H, m), 4.15 (3H, s), 4.21 (4H, s), 6.70-6.80 (3H, m), 7.10 (1H, d, J = 9.3Hz), 7.67 (1H, d, J = 8.0Hz), 8.57 (1H, d, J = 8.0Hz), 8.74 (1H, d, J = 9.3Hz)

８−（（ピペリジン−４−イル）メトキシ）−２−メトキシキノリン24mgおよび（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）アセトアルデヒド17mgのジクロロエタン3mL溶液に、室温で酢酸5μLを加え、同温度で1時間攪拌した。ついで、同温度でトリアセトキシ水素化ホウ素ナトリウム28mgを加え、1時間攪拌した。反応混合物にクロロホルム10mLおよび水10mLを加え、1moL/mL水酸化ナトリウム水溶液を加え、pH11.0に調整した。有機層を分取し、水層をクロロホルム10mL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８−（（1−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）メトキシ）−２−メトキシキノリン19mgを得た。
¹H-NMR(CDCl₃)δ値：1.45-1.58(2H,m),2.00-2.16(5H,m),2.55-2.62(2H,m),2.71-2.77(2H,m),3.05-3.11(2H,m),4.05(2H,d,J=6.6Hz),4.10(3H,s),4.21-4.28(4H,m),6.68(1H,dd,J=8.1,2.1Hz),6.73(1H,d,J=2.1Hz),6.78(1H,d,J=8.1Hz),6.91(1H,d,J=8.9Hz),7.06(1H,dd,J=7.8,1.5Hz),7.28(1H,t,J=7.8Hz),7.32(1H,dd,J=7.8,1.5Hz),7.96(1H,d,J=8.9Hz)Example 37

To a solution of 24 mg of 8-((piperidin-4-yl) methoxy) -2-methoxyquinoline and 17 mg of (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) acetaldehyde in 3 mL of dichloroethane at room temperature. Acetic acid 5 μL was added and stirred at the same temperature for 1 hour. Then, 28 mg of sodium triacetoxyborohydride was added at the same temperature and stirred for 1 hour. Chloroform 10 mL and water 10 mL were added to the reaction mixture, and 1 mol / mL sodium hydroxide aqueous solution was added to adjust the pH to 11.0. The organic layer was separated, and the aqueous layer was extracted with 10 mL of 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] to give 8-((1- (2- (2,3-dihydrobenzo [b] [ 19 mg of 1,4] dioxin-6-yl) ethyl) piperidin-4-yl) methoxy) -2-methoxyquinoline was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.45-1.58 (2H, m), 2.00-2.16 (5H, m), 2.55-2.62 (2H, m), 2.71-2.77 (2H, m), 3.05-3.11 (2H, m), 4.05 (2H, d, J = 6.6Hz), 4.10 (3H, s), 4.21-4.28 (4H, m), 6.68 (1H, dd, J = 8.1,2.1Hz), 6.73 ( 1H, d, J = 2.1Hz), 6.78 (1H, d, J = 8.1Hz), 6.91 (1H, d, J = 8.9Hz), 7.06 (1H, dd, J = 7.8,1.5Hz), 7.28 ( 1H, t, J = 7.8Hz), 7.32 (1H, dd, J = 7.8,1.5Hz), 7.96 (1H, d, J = 8.9Hz)

メチル＝８−アミノ−２−メトキシキノリン−４−カルボキシラート77mgのＮ，Ｎ−ジメチルホルムアミド3mL溶液に、室温で１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸97mg、Ｏ−（７−アザベンゾトリアゾール−１−イル）−１，１，３，３，−テトラメチルウロニウム＝ヘキサフルオロホスフェート0.19gおよびトリエチルアミン0.14mLを加え、60℃で2時間攪拌した後、室温まで冷却した。反応混合物に酢酸エチル20mLおよび水10mLを加えた。有機層を分取し、水層を酢酸エチル10mL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；クロロホルム：メタノール＝２０：１］で精製し、淡褐色固体を得た。この淡褐色固体をイソプロピルエーテルで抽出し、減圧下で溶媒を留去した。得られた固体をメタノールで洗浄し、淡黄白色固体のメチル＝８−（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−４−カルボキシラート10mgを得た。
¹H-NMR(CDCl₃)δ値：1.90-2.04(2H,m),2.10-2.24(4H,m),2.40-2.50(1H,m),2.56-2.64(2H,m),2.70-2.78(2H,m),3.07-3.16(2H,m),4.03(3H,s),4.12(3H,s),4.24(4H,s),6.66-6.82(3H,m),7.44-7.51(2H,m),8.25(1H,d,J=8.5Hz),8.78(1H,d,J=7.6Hz),9.63-9.68(1H,broad)Example 38

1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin) was added to a solution of 77 mg of methyl 8-amino-2-methoxyquinoline-4-carboxylate in 3 mL of N, N-dimethylformamide at room temperature. -6-yl) ethyl) piperidine-4-carboxylic acid 97 mg, O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium 0.19 g hexafluorophosphate and triethylamine 0.14 mL was added, and the mixture was stirred at 60 ° C. for 2 hours, and then cooled to room temperature. To the reaction mixture, 20 mL of ethyl acetate and 10 mL of water were added. The organic layer was separated and the aqueous layer was extracted with 10 mL of 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: chloroform: methanol = 20: 1] to obtain a light brown solid. This light brown solid was extracted with isopropyl ether, and the solvent was distilled off under reduced pressure. The obtained solid was washed with methanol, and a pale yellowish white solid methyl = 8- (1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine- 10 mg of 4-carboxamide) -2-methoxyquinoline-4-carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.90-2.04 (2H, m), 2.10-2.24 (4H, m), 2.40-2.50 (1H, m), 2.56-2.64 (2H, m), 2.70-2.78 (2H, m), 3.07-3.16 (2H, m), 4.03 (3H, s), 4.12 (3H, s), 4.24 (4H, s), 6.66-6.82 (3H, m), 7.44-7.51 (2H , m), 8.25 (1H, d, J = 8.5Hz), 8.78 (1H, d, J = 7.6Hz), 9.63-9.68 (1H, broad)

メチル＝８−（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−４−カルボキシラート44mgのメタノール2mL懸濁液に、テトラヒドロフラン2mLおよび20％水酸化ナトリウム水溶液52μLを加え、室温で1時間攪拌した。ついで20％水酸化ナトリウム水溶液52μLおよび水500μLを追加し、室温で4時間攪拌した。減圧下で溶媒を留去し、水20mLを加え、1.0mol/L塩酸でpH5.5に調整した。析出物をろ取し、水10mLで2回、ジエチルエーテル10mLで洗浄し、淡黄白色固体の８−（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−４−カルボン酸23mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.80-1.95(2H,m),2.00-2.15(2H,m),2.65-2.90(5H,m),3.20-3.50(4H,m),4.07(3H,s),4.21(4H,s),6.67-6.72(1H,m),6.76-6.79(2H,m),7.20(1H,s),7.35-7.43(1H,m),8.18(1H,d,8.5Hz),8.47(1H,d,J=7.8Hz),9.72(1H,s)Example 39

Methyl = 8- (1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxamide) -2-methoxyquinoline-4-carboxylate 44 mg To a 2 mL suspension of methanol was added 2 mL of tetrahydrofuran and 52 μL of 20% aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 1 hour. Subsequently, 52 μL of 20% aqueous sodium hydroxide solution and 500 μL of water were added, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, 20 mL of water was added, and the pH was adjusted to 5.5 with 1.0 mol / L hydrochloric acid. The precipitate was collected by filtration, washed twice with 10 mL of water, and 10 mL of diethyl ether, and turned into 8- (1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin- 6-yl) ethyl) piperidine-4-carboxamide) -2-methoxyquinoline-4-carboxylic acid 23 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.80-1.95 (2H, m), 2.00-2.15 (2H, m), 2.65-2.90 (5H, m), 3.20-3.50 (4H, m), 4.07 (3H, s), 4.21 (4H, s), 6.67-6.72 (1H, m), 6.76-6.79 (2H, m), 7.20 (1H, s), 7.35-7.43 (1H, m), 8.18 (1H , d, 8.5Hz), 8.47 (1H, d, J = 7.8Hz), 9.72 (1H, s)

Ｎ−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）ピペリジン−４−カルボキサミド0.26gのＮ，Ｎ−ジメチルホルムアミド10mL溶液に、室温で７−メトキシ−１−（オキシラン−２−イル）イソキノリン0.20gおよび過塩素酸リチウム0.11gを加え、80℃で2時間攪拌した。反応混合物を室温まで冷却し、水10mLおよび酢酸エチル20mLを加えた。1mol/L塩酸でpH1.1に調整し、水層を分取し、水層を酢酸エチルで洗浄した。水層に酢酸エチル20mLを加え、20％水酸化ナトリウム水溶液を加え、pH11.7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＝９：１］で精製し、淡黄白色固体のＮ−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）−１−（２−ヒドロキシ−２−（７−メトキシイソキノリン−１−イル）エチル）ピペリジン−４−カルボキサミド49mgを得た。
¹H-NMR(CDCl₃)δ値：1.85-2.05(4H,m),2.15-2.40(3H,m),2.75-2.93(2H,m),3.13-3.33(2H,m),3.97(3H,s),4.24(4H,s),5.50-5.52(1H,m),6.80(1H,d,J=8.6Hz),6.90(1H,dd,J=8.6,2.1Hz),7.00-7.12(1H,m),7.16(1H,d,J=2.3Hz),7.37(1H,dd,J=8.9,2.3Hz),7.49-7.53(1H,m),7.54(1H,d,J=5.6Hz),7.77(1H,d,J=8.9Hz),8.36(1H,d,J=5.6Hz)Example 40

To a solution of 0.26 g of N- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) piperidine-4-carboxamide in 10 mL of N, N-dimethylformamide at room temperature was added 7-methoxy-1- ( Oxylan-2-yl) isoquinoline (0.20 g) and lithium perchlorate (0.11 g) were added, and the mixture was stirred at 80 ° C. for 2 hours. The reaction mixture was cooled to room temperature and 10 mL water and 20 mL ethyl acetate were added. The pH was adjusted to 1.1 with 1 mol / L hydrochloric acid, the aqueous layer was separated, and the aqueous layer was washed with ethyl acetate. To the aqueous layer, 20 mL of ethyl acetate was added, and 20% aqueous sodium hydroxide solution was added to adjust the pH to 11.7. 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 silica gel column chromatography [eluent: chloroform: methanol = 9: 1] to give N- (2,3-dihydrobenzo [b] [1,4] dioxin- 49 mg of 6-yl) -1- (2-hydroxy-2- (7-methoxyisoquinolin-1-yl) ethyl) piperidine-4-carboxamide were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.85-2.05 (4H, m), 2.15-2.40 (3H, m), 2.75-2.93 (2H, m), 3.13-3.33 (2H, m), 3.97 (3H , s), 4.24 (4H, s), 5.50-5.52 (1H, m), 6.80 (1H, d, J = 8.6Hz), 6.90 (1H, dd, J = 8.6, 2.1Hz), 7.00-7.12 ( 1H, m), 7.16 (1H, d, J = 2.3Hz), 7.37 (1H, dd, J = 8.9,2.3Hz), 7.49-7.53 (1H, m), 7.54 (1H, d, J = 5.6Hz ), 7.77 (1H, d, J = 8.9Hz), 8.36 (1H, d, J = 5.6Hz)

１−（２−メトキシキノリン−８−イル）−２−（ピペラジン−１−イル）エタノール350mgのクロロホルム5mL溶液に、室温で（２，３−ジヒドロベンゾ［１，４］ジオキシン−６−イル）アセトアルデヒド283mgおよび酢酸0.07mLを加えた後に、トリアセトキシ水素化ほう素ナトリウム327mg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20mLおよび水10mLを加え、さらに20％水酸化ナトリウム水溶液でpH11〜12に調整（pH試験紙）した。有機層を飽和塩化ナトリウム水溶液10mL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＝２０：１：０．１およびシリカゲル；富士シリシア社、シリカゲルChromatorex-NH、溶離液；酢酸エチル］で精製し、黄色油状物の２−（４−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペラジン−１−イル）−１−（２−メトキシキノリン−８−イル）エタノール272mgを得た。
¹H-NMR(CDCl₃)δ値：2.54-2.96(13H,m),3.02(1H,dd,J=12.4,3.1Hz),4.03(3H,s),4.24(4H,s),5.78(1H,dd,J=9.9,3.0Hz),6.65-6.75(2H,m),6.79(1H,d,J=8.1Hz),6.90(1H,d,J=8.9Hz),7.39(1H,t,J=7.8Hz),7.64(1H,dd,J=7.9,1.4Hz),7.84(1H,dd,J=7.2,1.4Hz),7.98(1H,d,J=8.9Hz)Example 41

1- (2-Methoxyquinolin-8-yl) -2- (piperazin-1-yl) ethanol in 350 mg of chloroform at room temperature (2,3-dihydrobenzo [1,4] dioxin-6-yl) After adding 283 mg of acetaldehyde and 0.07 mL of acetic acid, 327 mg of sodium triacetoxyborohydride was added, and the mixture was stirred at room temperature for 2 hours. Chloroform 20mL and water 10mL were added to the reaction mixture, and further adjusted to pH 11-12 with 20% aqueous sodium hydroxide solution (pH test paper). The organic layer was washed with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent; chloroform: methanol: 28% aqueous ammonia = 20: 1: 0.1 and silica gel; Fuji Silysia Ltd., silica gel Chromatorex- NH, eluent: ethyl acetate] and purified as a yellow oil 2- (4- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperazine-1 -Ill) -1- (2-methoxyquinolin-8-yl) ethanol 272 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.54-2.96 (13H, m), 3.02 (1H, dd, J = 12.4, 3.1 Hz), 4.03 (3H, s), 4.24 (4H, s), 5.78 ( 1H, dd, J = 9.9,3.0Hz), 6.65-6.75 (2H, m), 6.79 (1H, d, J = 8.1Hz), 6.90 (1H, d, J = 8.9Hz), 7.39 (1H, t , J = 7.8Hz), 7.64 (1H, dd, J = 7.9,1.4Hz), 7.84 (1H, dd, J = 7.2,1.4Hz), 7.98 (1H, d, J = 8.9Hz)

２−（４−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペラジン−１−イル）−１−（２−メトキシキノリン−８−イル）エタノール47.4mgの酢酸エチル1mL溶液に、室温で4mol/L塩化水素/酢酸エチル0.12mLを加えた。反応混合物を減圧下で濃縮して淡黄色固体２−（４−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペラジン−１−イル）−１−（２−メトキシキノリン−８−イル）エタノールの塩酸塩50.4mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.90-3.04(2H,m),3.14-4.00(12H,m),4.07(3H,s),4.22(4H,s),6.13(1H,d,J=9.8Hz),6.74(1H,dd,J=8.2,1.9Hz),6.79-6.85(2H,m),7.08(1H,d,J=8.9Hz),7.47-7.56(1H,m),7.84-7.93(2H,m),8.29(1H,d,J=8.9Hz)Example 42

2- (4- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperazin-1-yl) -1- (2-methoxyquinolin-8-yl) 0.12 mL of 4 mol / L hydrogen chloride / ethyl acetate was added to 1 mL of ethyl acetate in 47.4 mg of ethanol at room temperature. The reaction mixture was concentrated under reduced pressure to give a pale yellow solid 2- (4- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperazin-1-yl)- 50.4 mg of 1- (2-methoxyquinolin-8-yl) ethanol hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.90-3.04 (2H, m), 3.14-4.00 (12H, m), 4.07 (3H, s), 4.22 (4H, s), 6.13 (1H, d , J = 9.8Hz), 6.74 (1H, dd, J = 8.2,1.9Hz), 6.79-6.85 (2H, m), 7.08 (1H, d, J = 8.9Hz), 7.47-7.56 (1H, m) , 7.84-7.93 (2H, m), 8.29 (1H, d, J = 8.9Hz)

２−メトキシ−８−（２−（ピペリジン−４−イル）エチル）キノリン0.42g、（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）アセトアルデヒド0.36gおよび酢酸0.09mLのジクロロメタン10mL−メタノール1mL溶液に、室温でトリアセトキシ水素化ホウ素ナトリウム0.52gを加え、40分間攪拌した。反応混合物に水10mLおよびクロロホルム20mLを加えた。有機層を分取し、水層をクロロホルム20mL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［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］で精製し、無色油状物の８−（２−（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）エチル）−２−メトキシキノリン0.16gを得た。
¹H-NMR(CDCl₃)δ値：1.30-1.50(2H,m),1.54-2.06(7H,m),2.46-2.61(2H,m),2.63-2.80(2H,m),3.01(2H,d,J=11.0Hz),3.17(2H,t,J=8.1Hz),4.06(3H,s),4.23(4H,s),6.67(1H,dd,J=7.9,2.0Hz),6.71(1H,d,J=1.8Hz),6.78(1H,d,J=8.1Hz),6.88(1H,d,J=8.8Hz),7.30(1H,t,J=7.3Hz),7.47(1H,dd,J=7.0,1.3Hz),7.56(1H,dd,J=7.9,1.5Hz),7.95(1H,d,J=8.8Hz)Example 43

0.42 g of 2-methoxy-8- (2- (piperidin-4-yl) ethyl) quinoline, 0.36 g of (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) acetaldehyde and 0.09 mL of acetic acid To a solution of 10 mL of dichloromethane and 1 mL of methanol was added 0.52 g of sodium triacetoxyborohydride at room temperature, and the mixture was stirred for 40 minutes. 10 mL of water and 20 mL of chloroform were added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted with 20 mL of 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 [silica gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent: ethyl acetate] to give 8- (2- (1- (2- (2 , 3-Dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidin-4-yl) ethyl) -2-methoxyquinoline 0.16 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.30-1.50 (2H, m), 1.54-2.06 (7H, m), 2.46-2.61 (2H, m), 2.63-2.80 (2H, m), 3.01 (2H , d, J = 11.0Hz), 3.17 (2H, t, J = 8.1Hz), 4.06 (3H, s), 4.23 (4H, s), 6.67 (1H, dd, J = 7.9, 2.0Hz), 6.71 (1H, d, J = 1.8Hz), 6.78 (1H, d, J = 8.1Hz), 6.88 (1H, d, J = 8.8Hz), 7.30 (1H, t, J = 7.3Hz), 7.47 (1H , dd, J = 7.0,1.3Hz), 7.56 (1H, dd, J = 7.9,1.5Hz), 7.95 (1H, d, J = 8.8Hz)

８−（２−（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）エチル）−２−メトキシキノリン0.14gの酢酸エチル3mL溶液に、室温で4mol/L塩化水素/酢酸エチル0.36mLを加え、減圧下で溶媒を留去した。得られた残留物をジエチルエーテルに懸濁させた後、ろ取し、淡黄色固体の８−（２−（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）エチル）−２−メトキシキノリンの塩酸塩0.12gを得た。
¹H-NMR(DMSO-d₆)δ値：1.44-2.06(6H,m),2.78-3.00(3H,m),3.06-3.24(4H,m),3.40-3.60(4H,m),4.01(3H,s),4.21(4H,s),6.70(1H,dd,J=8.2,2.2Hz),6.78(1H,d,J=2.2Hz),6.81(1H,d,J=8.2Hz),7.02(1H,d,J=8.9Hz),7.37(1H,dd,J=7.9,7.2Hz),7.56(1H,dd,J=7.9,1.4Hz),7.73(1H,dd,J=7.9,1.4Hz),8.22(1H,d,J=8.9Hz)Example 44

8- (2- (1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidin-4-yl) ethyl) -2-methoxyquinoline 0.14 g To a 3 mL solution of ethyl acetate, 0.36 mL of 4 mol / L hydrogen chloride / ethyl acetate was added at room temperature, and the solvent was distilled off under reduced pressure. The obtained residue was suspended in diethyl ether and collected by filtration to give 8- (2- (1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin) as a pale yellow solid. 0.12 g of hydrochloride of -6-yl) ethyl) piperidin-4-yl) ethyl) -2-methoxyquinoline was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.44-2.06 (6H, m), 2.78-3.00 (3H, m), 3.06-3.24 (4H, m), 3.40-3.60 (4H, m), 4.01 (3H, s), 4.21 (4H, s), 6.70 (1H, dd, J = 8.2,2.2Hz), 6.78 (1H, d, J = 2.2Hz), 6.81 (1H, d, J = 8.2Hz) , 7.02 (1H, dd, J = 8.9Hz), 7.37 (1H, dd, J = 7.9, 7.2Hz), 7.56 (1H, dd, J = 7.9, 1.4Hz), 7.73 (1H, dd, J = 7.9 , 1.4Hz), 8.22 (1H, d, J = 8.9Hz)

メチル＝（７−メトキシ−１−ビニルイソキノリン−４−イル）アセタート63mgのトルエン4mL溶液に、ｔｅｒｔ−ブチル＝（２，３−ジヒドロベンゾ［ｂ］［１，４］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96mgを加え、1時間加熱還流した。ｔｅｒｔ−ブチル＝（２，３−ジヒドロベンゾ［ｂ］［１，４］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30mgを加え、1時間30分間攪拌した。減圧下で溶媒を留去し、褐色油状物のメチル＝（１−（２−（４−（（ｔｅｒｔ−ブトキシカルボニル）（２，３−ジヒドロベンゾ［ｂ］［１，４］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−メトキシイソキノリン−４−イル）アセタート0.19gを得た。
¹H-NMR(CDCl₃)δ値：1.35-1.55(9H,m),1.65-1.85(4H,m),2.10-2.30(2H,m),2.85-2.95(2H,m),3.05-3.15(2H,m),3.37-3.45(2H,m),3.67(3H,s),3.94(3H,s),3.94(2H,s),4.05-4.15(1H,m),4.24(4H,s),4.25-4.38(2H,m),6.65-6.80(3H,m),7.35-7.42(2H,m),7.87(1H,d,J=9.8Hz),8.21(1H,s)Example 45

To a solution of 63 mg of methyl = (7-methoxy-1-vinylisoquinolin-4-yl) acetate in 4 mL of toluene, tert-butyl = (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) ( Piperidin-4-yl) carbamate 96 mg was added, and the mixture was heated to reflux for 1 hour. Tert-butyl = (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) (piperidin-4-yl) carbamate 30 mg was added, and the mixture was stirred for 1 hour 30 minutes. The solvent was distilled off under reduced pressure, and the brown oily methyl methyl = (1- (2- (4-((tert-butoxycarbonyl) (2,3-dihydrobenzo [b] [1,4] dioxin-6- 0.19 g of ylmethyl) amino) piperidin-1-yl) ethyl) -7-methoxyisoquinolin-4-yl) acetate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.35-1.55 (9H, m), 1.65-1.85 (4H, m), 2.10-2.30 (2H, m), 2.85-2.95 (2H, m), 3.05-3.15 (2H, m), 3.37-3.45 (2H, m), 3.67 (3H, s), 3.94 (3H, s), 3.94 (2H, s), 4.05-4.15 (1H, m), 4.24 (4H, s ), 4.25-4.38 (2H, m), 6.65-6.80 (3H, m), 7.35-7.42 (2H, m), 7.87 (1H, d, J = 9.8Hz), 8.21 (1H, s)

メチル＝（１−（２−（４−（（ｔｅｒｔ−ブトキシカルボニル）（２，３−ジヒドロベンゾ［ｂ］［１，４］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−メトキシイソキノリン−４−イル）アセタート0.10gの塩化メチレン1mL溶液に、氷冷下、トリフルオロ酢酸1mL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、黄色固体のメチル＝（１−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］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−メトキシイソキノリン−４−イル）アセタート83mgを得た。
¹H-NMR(CDCl₃)δ値：1.50-1.65(2H,m),1.92-2.10(2H,m),2.20-2.50(1H,m),2.53-2.75(2H,m),2.90-3.30(4H,m),3.45-3.63(2H,m),3.68(3H,s),3.71(2H,s),3.95(2H,s),3.97(3H,s),4.25(4H,s),6.76-6.85(3H,m),7.39(1H,dd,J=9.2,2.6Hz),7.43(1H,d,J=2.6Hz),7.87(1H,d,J=9.2Hz),8.21(1H,s)Example 46

Methyl = (1- (2- (4-((tert-butoxycarbonyl) (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) ethyl)- 7 mL of 7-methoxyisoquinolin-4-yl) acetate in 1 mL of methylene chloride was added with 1 mL of trifluoroacetic acid under ice cooling and stirred for 2 hours. The solvent was distilled off under reduced pressure, and ethyl acetate and a 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, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Methyl = (1- (2- (4-((2, 83 mg of 3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) ethyl) -7-methoxyisoquinolin-4-yl) acetate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.50-1.65 (2H, m), 1.92-2.10 (2H, m), 2.20-2.50 (1H, m), 2.53-2.75 (2H, m), 2.90-3.30 (4H, m), 3.45-3.63 (2H, m), 3.68 (3H, s), 3.71 (2H, s), 3.95 (2H, s), 3.97 (3H, s), 4.25 (4H, s), 6.76-6.85 (3H, m), 7.39 (1H, dd, J = 9.2,2.6Hz), 7.43 (1H, d, J = 2.6Hz), 7.87 (1H, d, J = 9.2Hz), 8.21 (1H , s)

５−ブロモ−２−メトキシ−８−（オキシラン−２−イル）キノリン0.20gのＮ，Ｎ−ジメチルホルムアミド5mL溶液に、室温でｔｅｒｔ−ブチル＝（２，３−ジヒドロベンゾ［ｂ］［１，４］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および過塩素酸リチウム98mgを加え、90℃で2時間40分間攪拌した。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＝８０：１］で精製し、淡黄色泡状物のｔｅｒｔ−ブチル＝（１−（２−（５−ブロモ−２−メトキシキノリン−８−イル）−２−ヒドロキシエチル）ピペリジン−４−イル）（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）カルバマート0.30gを得た。
¹H-NMR(CDCl₃)δ値：1.43(9H,s),1.55-1.84(4H,m),2.04-2.20(1H,m),2.22-2.35(1H,m),2.38(1H,dd,J=12.3,10.3Hz),2.79-2.87(1H,m),2.93(1H,dd,J=12.3,2.9Hz),3.28-3.38(1H,m),4.00(3H,s),4.22-4.36(1H,m),4.25(4H,s),4.28-4.36(3H,m),5.67(1H,dd,J=10.3,2.9Hz),6.64-6.74(1H,m),6.76(1H,s),6.80(1H,d,J=8.3Hz),6.97(1H,d,J=9.1Hz),7.64(1H,d,J=7.9Hz),7.70(1H,d,J=7.9Hz),8.36(1H,d,J=9.1Hz)Example 47

To a solution of 0.20 g of 5-bromo-2-methoxy-8- (oxiran-2-yl) quinoline in 5 mL of N, N-dimethylformamide at room temperature is tert-butyl = (2,3-dihydrobenzo [b] [1, 4] 0.32 g of dioxin-6-ylmethyl) (piperidin-4-yl) carbamate and 98 mg of lithium perchlorate were added, and the mixture was stirred at 90 ° C. for 2 hours and 40 minutes. After cooling the reaction mixture 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, 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 = 80: 1], and tert-butyl = (1- (2- (5-bromo-2-methoxy) was obtained as a pale yellow foam. Quinolin-8-yl) -2-hydroxyethyl) piperidin-4-yl) (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) carbamate 0.30 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.43 (9H, s), 1.55-1.84 (4H, m), 2.04-2.20 (1H, m), 2.22-2.35 (1H, m), 2.38 (1H, dd , J = 12.3,10.3Hz), 2.79-2.87 (1H, m), 2.93 (1H, dd, J = 12.3,2.9Hz), 3.28-3.38 (1H, m), 4.00 (3H, s), 4.22- 4.36 (1H, m), 4.25 (4H, s), 4.28-4.36 (3H, m), 5.67 (1H, dd, J = 10.3,2.9Hz), 6.64-6.74 (1H, m), 6.76 (1H, s), 6.80 (1H, d, J = 8.3Hz), 6.97 (1H, d, J = 9.1Hz), 7.64 (1H, d, J = 7.9Hz), 7.70 (1H, d, J = 7.9Hz) , 8.36 (1H, d, J = 9.1Hz)

ｔｅｒｔ−ブチル＝（１−（２−（５−ブロモ−２−メトキシキノリン−８−イル）−２−ヒドロキシエチル）ピペリジン−４−イル）（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）カルバマート0.30gのＮ，Ｎ−ジメチルホルムアミド5mL溶液に、酢酸カリウム0.23g、アクリル酸エチル57μL、トリス（２−メチルフェニル）ホスフィン8.1mgおよび酢酸パラジウム（II）5.4mg、テトラブチルアンモニウムブロミド0.15gを加え、窒素雰囲気下、90〜100℃で3時間攪拌した。アクリル酸エチル26μLを加え、同温度で1時間50分間加熱した後、酢酸パラジウム（II）2.7mgおよびトリス（２−メチルフェニル）ホスフィン4mgを加え、同温度で1時間20分間加熱した。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［富士シリシア、FL100DX、溶離液；ヘキサン：酢酸エチル＝２：１］で精製し、淡黄色泡状物のエチル＝（Ｅ）−３−（８−（２−（４−（（ｔｅｒｔ−ブトキシカルボニル）（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート0.14gを得た。
¹H-NMR(CDCl₃)δ値：1.36(3H,t,J=7.1Hz),1.43(9H,s),1.55-1.85(4H,m),2.06-2.19(1H,m),2.22-2.35(1H,m),2.40(1H,dd,J=12.4,10.1Hz),2.79-2.87(1H,m),2.95(1H,dd,J=12.4,2.9Hz),3.28-3.39(1H,m),4.00(3H,s),4.20-4.34(3H,m),4.25(4H,s),4.30(2H,q,J=7.1Hz),5.72(1H,dd,J=10.1,2.9Hz),6.51(1H,d,J=16.3Hz),6.69-6.81(3H,m),6.98(1H,d,J=9.3Hz),7.67(1H,d,J=7.7Hz),7.86(1H,d,J=7.7Hz),8.34(1H,d,J=16.3Hz),8.37(1H,d,J=9.3Hz)Example 48

tert-butyl = (1- (2- (5-bromo-2-methoxyquinolin-8-yl) -2-hydroxyethyl) piperidin-4-yl) (2,3-dihydrobenzo [b] [1,4 ] To a solution of 0.30 g of dioxin-6-ylmethyl) carbamate in 5 mL of N, N-dimethylformamide, 0.23 g of potassium acetate, 57 μL of ethyl acrylate, 8.1 mg of tris (2-methylphenyl) phosphine and 5.4 mg of palladium (II) acetate, Tetrabutylammonium bromide (0.15 g) was added, and the mixture was stirred at 90 to 100 ° C. for 3 hours under a nitrogen atmosphere. After adding 26 μL of ethyl acrylate and heating at the same temperature for 1 hour and 50 minutes, 2.7 mg of palladium (II) acetate and 4 mg of tris (2-methylphenyl) phosphine were added and heated at the same temperature for 1 hour and 20 minutes. After cooling the reaction mixture to room temperature, water and ethyl acetate 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 silica gel column chromatography [Fuji Silysia, FL100DX, eluent: hexane: ethyl acetate = 2: 1], and light yellow foam ethyl = (E) -3- (8- ( 2- (4-((tert-butoxycarbonyl) (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) -1-hydroxyethyl) -2- 0.14 g of methoxyquinolin-5-yl) acrylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.36 (3H, t, J = 7.1 Hz), 1.43 (9H, s), 1.55-1.85 (4H, m), 2.06-2.19 (1H, m), 2.22- 2.35 (1H, m), 2.40 (1H, dd, J = 12.4,10.1Hz), 2.79-2.87 (1H, m), 2.95 (1H, dd, J = 12.4,2.9Hz), 3.28-3.39 (1H, m), 4.00 (3H, s), 4.20-4.34 (3H, m), 4.25 (4H, s), 4.30 (2H, q, J = 7.1Hz), 5.72 (1H, dd, J = 10.1, 2.9Hz ), 6.51 (1H, d, J = 16.3Hz), 6.69-6.81 (3H, m), 6.98 (1H, d, J = 9.3Hz), 7.67 (1H, d, J = 7.7Hz), 7.86 (1H , d, J = 7.7Hz), 8.34 (1H, d, J = 16.3Hz), 8.37 (1H, d, J = 9.3Hz)

エチル＝（Ｅ）−３−（８−（２−（４−（（ｔｅｒｔ−ブトキシカルボニル）（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート0.14gの塩化メチレン2mL溶液に、氷冷下、トリフルオロ酢酸1mLを滴下し、同温度で40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、1.0mol/L水酸化ナトリウム水溶液でpH11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、黄色泡状物のエチル＝（Ｅ）−３−（８−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート0.11gを得た。
¹H-NMR(CDCl₃)δ値：1.37(3H,t,J=7.1Hz),1.44-1.60(3H,m),1.86-2.00(2H,m),2.10-2.30(1H,m),2.32-2.64(2H,m),2.78-2.90(1H,m),2.98-3.07(1H,m),3.24-3.33(1H,m),3.72(2H,s),4.03(3H,s),4.25(4H,s),4.30(2H,q,J=7.1Hz),5.75-5.82(1H,m),6.52(1H,d,J=15.7Hz),6.74-6.86(3H,m),6.98(1H,d,J=9.3Hz),7.69(1H,d,J=7.7Hz),7.90(1H,d,J=7.7Hz),8.35(1H,d,J=15.7Hz),8.38(1H,d,J=9.3Hz)Example 49

Ethyl = (E) -3- (8- (2- (4-((tert-butoxycarbonyl) (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidine-1 -Il) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate To a solution of 0.14 g of methylene chloride in 2 mL of methylene chloride was added dropwise 1 mL of trifluoroacetic acid and stirred at the same temperature for 40 minutes. The solvent was distilled off under reduced pressure, ethyl acetate and water were added, and the pH was adjusted to 11 with a 1.0 mol / L aqueous sodium hydroxide solution. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and yellow foamy ethyl = (E) -3- (8- (2- (4-((2,3-Dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate 0.11 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.37 (3H, t, J = 7.1 Hz), 1.44-1.60 (3H, m), 1.86-2.00 (2H, m), 2.10-2.30 (1H, m), 2.32-2.64 (2H, m), 2.78-2.90 (1H, m), 2.98-3.07 (1H, m), 3.24-3.33 (1H, m), 3.72 (2H, s), 4.03 (3H, s), 4.25 (4H, s), 4.30 (2H, q, J = 7.1Hz), 5.75-5.82 (1H, m), 6.52 (1H, d, J = 15.7Hz), 6.74-6.86 (3H, m), 6.98 (1H, d, J = 9.3Hz), 7.69 (1H, d, J = 7.7Hz), 7.90 (1H, d, J = 7.7Hz), 8.35 (1H, d, J = 15.7Hz), 8.38 (1H , d, J = 9.3Hz)

エチル＝（Ｅ）−３−（８−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート50mgの90％エタノール水2mL溶液に、氷冷下、20％水酸化ナトリウム水溶液76μLを加え、室温で2時間10分間攪拌した。減圧下で溶媒を留去し、水を加え、炭酸ガスを導入した。固形物をろ取し、淡黄色固体の（Ｅ）−３−（８−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリル酸43mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.20-1.40(2H,m),1.73-1.88(2H,m),2.03-2.20(2H,m),2.40(2H,dd,J=12.5,9.0Hz),2.66(1H,dd,J=12.5,2.6Hz),2.82-2.92(1H,m),3.08-3.16(1H,m),3.61(2H,s),3.99(3H,s),4.20(4H,s),5.80(1H,dd,J=9.0,2.6Hz),6.56(1H,d,J=15.5Hz),6.70-6.85(3H,m),7.08(1H,d,J=9.0Hz),7.80-7.85(2H,m),8.18(1H,d,J=15.5Hz),8.53(1H,d,J=9.0Hz)Example 50

Ethyl = (E) -3- (8- (2- (4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) -1- To a solution of 50 mg of hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate in 2 mL of 90% aqueous ethanol was added 76 μL of a 20% aqueous sodium hydroxide solution under ice cooling, and the mixture was stirred at room temperature for 2 hours and 10 minutes. The solvent was distilled off under reduced pressure, water was added, and carbon dioxide gas was introduced. The solid substance was collected by filtration, and (E) -3- (8- (2- (4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) was obtained as a pale yellow solid. Piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid 43 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.20-1.40 (2H, m), 1.73-1.88 (2H, m), 2.03-2.20 (2H, m), 2.40 (2H, dd, J = 12.5, 9.0Hz), 2.66 (1H, dd, J = 12.5, 2.6Hz), 2.82-2.92 (1H, m), 3.08-3.16 (1H, m), 3.61 (2H, s), 3.99 (3H, s), 4.20 (4H, s), 5.80 (1H, dd, J = 9.0,2.6Hz), 6.56 (1H, d, J = 15.5Hz), 6.70-6.85 (3H, m), 7.08 (1H, d, J = 9.0Hz), 7.80-7.85 (2H, m), 8.18 (1H, d, J = 15.5Hz), 8.53 (1H, d, J = 9.0Hz)

エチル＝（Ｅ）−３−（８−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート52mgの酢酸2mL溶液に、室温で10％パラジウム−炭素12mgを加え、水素雰囲気下、55〜60℃で8時間攪拌した。反応混合物を室温まで冷却後、不溶物をろ去し、減圧下で溶媒を留去した。酢酸エチル、クロロホルムおよび20％水酸化ナトリウム水溶液を加え、pH12.5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、黄色油状物のエチル＝３−（８−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）プロピオナート40mgを得た。
¹H-NMR(CDCl₃)δ値：1.16(3H,t,J=7.2Hz),1.35-1.50(2H,m),1.80-1.92(2H,m),2.04-2.12(1H,m),2.23-2.31(1H,m),2.40(1H,dd,J=12.3,9.9Hz),2.44-2.54(1H,m),2.61(2H,t,J=7.9Hz),2.73-2.82(1H,m),2.89(1H,dd,J=12.3,3.0Hz),3.14-3.28(1H,m),3.24(2H,t,J=7.9Hz),3.64(2H,s),3.95(3H,s),4.06(2H,q,J=7.2Hz),4.17(4H,s),5.66(1H,dd,J=9.9,2.8Hz),6.68-6.80(3H,m),6.86(1H,d,J=9.1Hz),7.18(1H,d,J=7.7Hz),7.69(1H,d,J=7.7Hz),8.14(1H,d,J=9.1Hz)Example 51

Ethyl = (E) -3- (8- (2- (4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) -1- Hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate (52 mg) in acetic acid (2 mL) was added with 10% palladium-carbon (12 mg) at room temperature, and the mixture was stirred at 55 to 60 ° C. for 8 hours in a hydrogen atmosphere. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. Ethyl acetate, chloroform and 20% aqueous sodium hydroxide solution were added to adjust to pH 12.5. 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. Ethyl 3- (8- (2- (4-(( 40 mg of 2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) propionate were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.16 (3H, t, J = 7.2 Hz), 1.35-1.50 (2H, m), 1.80-1.92 (2H, m), 2.04-2.12 (1H, m), 2.23-2.31 (1H, m), 2.40 (1H, dd, J = 12.3,9.9Hz), 2.44-2.54 (1H, m), 2.61 (2H, t, J = 7.9Hz), 2.73-2.82 (1H, m), 2.89 (1H, dd, J = 12.3,3.0Hz), 3.14-3.28 (1H, m), 3.24 (2H, t, J = 7.9Hz), 3.64 (2H, s), 3.95 (3H, s ), 4.06 (2H, q, J = 7.2Hz), 4.17 (4H, s), 5.66 (1H, dd, J = 9.9,2.8Hz), 6.68-6.80 (3H, m), 6.86 (1H, d, J = 9.1Hz), 7.18 (1H, d, J = 7.7Hz), 7.69 (1H, d, J = 7.7Hz), 8.14 (1H, d, J = 9.1Hz)

エチル＝３−（８−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）プロピオナート35mgの90％エタノール水2mL溶液に、氷冷下、20％水酸化ナトリウム水溶液54μLを加え、室温で1時間攪拌した。減圧下で溶媒を留去し、水を加え、炭酸ガスを導入した。減圧下で溶媒を留去し、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；アセトニトリル：水＝３：７］で精製し、白色固体の３−（８−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）プロピオン酸23mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.20-1.36(2H,m),1.72-1.84(2H,m),2.00-2.40(6H,m),2.60-2.70(1H,m),2.81-2.90(1H,m),3.06-3.20(3H,m),3.58(2H,s),3.96(3H,s),4.20(4H,s),5.71-5.79(1H,m),6.72-6.86(3H,m),6.99(1H,d,J=9.1Hz),7.25(1H,d,J=7.3Hz),7.66(1H,d,J=7.3Hz),8.38(1H,d,J=9.1Hz)Example 52

Ethyl = 3- (8- (2- (4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) -1-hydroxyethyl)- To a solution of 2-methoxyquinolin-5-yl) propionate (35 mg) in 90% aqueous ethanol (2 mL) was added 20% aqueous sodium hydroxide solution (54 μL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, water was added, and carbon dioxide gas was introduced. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography [eluent: acetonitrile: water = 3: 7] to give a white solid 3- (8- (2- (4 -((2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) propionic acid 23 mg Got.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.20-1.36 (2H, m), 1.72-1.84 (2H, m), 2.00-2.40 (6H, m), 2.60-2.70 (1H, m), 2.81 -2.90 (1H, m), 3.06-3.20 (3H, m), 3.58 (2H, s), 3.96 (3H, s), 4.20 (4H, s), 5.71-5.79 (1H, m), 6.72-6.86 (3H, m), 6.99 (1H, d, J = 9.1Hz), 7.25 (1H, d, J = 7.3Hz), 7.66 (1H, d, J = 7.3Hz), 8.38 (1H, d, J = (9.1Hz)

５−ブロモ−２−メトキシ−８−（オキシラン−２−イル）キノリン0.13gのＮ，Ｎ−ジメチルホルムアミド2.5mL溶液に、室温で１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペラジン0.11gのＮ，Ｎ−ジメチルホルムアミド2.5mL溶液および過塩素酸リチウム47mgを加え、90〜100℃で10時間攪拌した。反応混合物を室温まで冷却後、酢酸エチルおよび水を加えた。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、橙色油状物の１−（５−ブロモ−２−メトキシキノリン−８−イル）−２−（４−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペラジン−１−イル）エタノール93mgを得た。
¹H-NMR(CDCl₃)δ値：2.44-2.75(9H,m),3.03(1H,dd,J=12.4,3.1Hz),3.40(2H,t,J=5.1Hz),3.58(2H,t,J=5.1Hz),4.04(3H,s),4.24(4H,s),5.74(1H,dd,J=10.2,3.1Hz),6.63-6.80(3H,m),6.98(1H,d,J=9.0Hz),7.66(1H,d,J=7.8Hz),7.74(1H,d,J=7.8Hz),8.37(1H,d,J=9.0Hz)Example 53

To a solution of 0.13 g of 5-bromo-2-methoxy-8- (oxiran-2-yl) quinoline in 2.5 mL of N, N-dimethylformamide at room temperature is 1- (2- (2,3-dihydrobenzo [b] [ 1,4] dioxin-6-yl) ethyl) piperazine (0.11 g) in N, N-dimethylformamide (2.5 mL) and lithium perchlorate (47 mg) were added, and the mixture was stirred at 90 to 100 ° C. for 10 hours. After cooling the reaction mixture to room temperature, ethyl acetate and water 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 silica gel column chromatography [eluent: chloroform: methanol = 100: 1] to give 1- (5-bromo-2-methoxyquinolin-8-yl) -2- ( 93 mg of 4- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperazin-1-yl) ethanol was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.44-2.75 (9H, m), 3.03 (1H, dd, J = 12.4, 3.1 Hz), 3.40 (2H, t, J = 5.1 Hz), 3.58 (2H, t, J = 5.1Hz), 4.04 (3H, s), 4.24 (4H, s), 5.74 (1H, dd, J = 10.2,3.1Hz), 6.63-6.80 (3H, m), 6.98 (1H, d , J = 9.0Hz), 7.66 (1H, d, J = 7.8Hz), 7.74 (1H, d, J = 7.8Hz), 8.37 (1H, d, J = 9.0Hz)

１−（５−ブロモ−２−メトキシキノリン−８−イル）−２−（４−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペラジン−１−イル）エタノール82mgのＮ，Ｎ−ジメチルホルムアミド2mL溶液に、酢酸カリウム76mg、アクリル酸エチル25μL、トリス（２−メチルフェニル）ホスフィン4.7mg、酢酸パラジウム（II）3.5mgおよびテトラブチルアンモニウムブロミド50mgを加え、窒素雰囲気下、90〜95℃で2時間10分間攪拌した。酢酸パラジウム（II）7.0mg、トリス（２−メチルフェニル）ホスフィン9.4mgおよびアクリル酸エチル50μLを分割して加え、95℃で9時間30分間攪拌した。ビス（トリ−tｅｒｔ−ブチルホスフィン）パラジウム（０）4mgを加え、同温で40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。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア、FL100DX、溶離液；クロロホルム］で精製し、褐色泡状物のエチル＝（Ｅ）−３−（８−（２−（４−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペラジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート59mgを得た。
¹H-NMR(CDCl₃)δ値：1.37(3H,t,J=7.0Hz),2.44-2.78(9H,m),3.06(1H,dd,J=12.2,2.8Hz),3.40(2H,t,J=5.0Hz),3.58(2H,t,J=5.0Hz),4.04(3H,s),4.24(4H,s),4.31(2H,q,J=7.0Hz),5.80(1H,dd,J=10.0,2.8Hz),6.52(1H,d,J=15.7Hz),6.64-6.80(3H,m),6.99(1H,d,J=9.1Hz),7.69(1H,d,J=7.7Hz),7.89(1H,d,J=7.7Hz),8.35(1H,d,J=15.7Hz),8.39(1H,d,J=9.1Hz)Example 54

1- (5-Bromo-2-methoxyquinolin-8-yl) -2- (4- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperazine- 1-yl) ethanol 82 mg in N, N-dimethylformamide 2 mL solution, potassium acetate 76 mg, ethyl acrylate 25 μL, tris (2-methylphenyl) phosphine 4.7 mg, palladium (II) acetate 3.5 mg and tetrabutylammonium bromide 50 mg And stirred at 90 to 95 ° C. for 2 hours and 10 minutes under a nitrogen atmosphere. Palladium (II) acetate 7.0 mg, tris (2-methylphenyl) phosphine 9.4 mg and ethyl acrylate 50 μL were added in portions, and the mixture was stirred at 95 ° C. for 9 hours 30 minutes. 4 mg of bis (tri-tert-butylphosphine) palladium (0) was added and stirred at the same temperature for 40 minutes. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia, FL100DX, eluent: chloroform], and the brown foamy substance ethyl = (E) -3- (8- (2- (4- (2- 59 mg of (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperazin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate was obtained. .
¹ H-NMR (CDCl ₃ ) δ value: 1.37 (3H, t, J = 7.0 Hz), 2.44-2.78 (9H, m), 3.06 (1H, dd, J = 12.2, 2.8 Hz), 3.40 (2H, t, J = 5.0Hz), 3.58 (2H, t, J = 5.0Hz), 4.04 (3H, s), 4.24 (4H, s), 4.31 (2H, q, J = 7.0Hz), 5.80 (1H, dd, J = 10.0,2.8Hz), 6.52 (1H, d, J = 15.7Hz), 6.64-6.80 (3H, m), 6.99 (1H, d, J = 9.1Hz), 7.69 (1H, d, J = 7.7Hz), 7.89 (1H, d, J = 7.7Hz), 8.35 (1H, d, J = 15.7Hz), 8.39 (1H, d, J = 9.1Hz)

エチル＝（Ｅ）−３−（８−（２−（４−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペラジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート59mgの90％エタノール水2mL溶液に、氷冷下、20％水酸化ナトリウム水溶液90μLを加え、室温で1時間30分間攪拌した。減圧下で溶媒を留去し、水を加え、炭酸ガスを導入した。反応混合物を減圧下で溶媒を留去し、得られた残留物を1.0mol/L塩酸でpH7.5に調整後、逆相シリカゲルカラムクロマトグラフィー［溶離液；アセトニトリル：水＝１：４］で精製し、黄白色固体の（Ｅ）−３−（８−（２−（４−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）ピペラジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリル酸21mgを得た。
¹H-NMR(CD₃OD)δ値：2.46-2.86(12H,m),3.30(2H,s),4.01(3H,s),4.15(4H,s),5.91-6.00(1H,m),6.52(1H,d,J=15.6Hz),6.58-6.70(3H,m),6.96(1H,d,J=9.3Hz),7.66(1H,d,J=7.7Hz),7.79(1H,d,J=7.7Hz),8.06(1H,d,J=15.6Hz),8.49(1H,d,J=9.3Hz)Example 55

Ethyl = (E) -3- (8- (2- (4- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperazin-1-yl)- To a solution of 59 mg of 1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate in 2 mL of 90% aqueous ethanol was added 90 μL of a 20% aqueous sodium hydroxide solution under ice cooling, and the mixture was stirred at room temperature for 1 hour and 30 minutes. The solvent was distilled off under reduced pressure, water was added, and carbon dioxide gas was introduced. The solvent was distilled off from the reaction mixture under reduced pressure, and the resulting residue was adjusted to pH 7.5 with 1.0 mol / L hydrochloric acid and then subjected to reverse phase silica gel column chromatography [eluent: acetonitrile: water = 1: 4]. (E) -3- (8- (2- (4- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) piperazine-1- Yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid (21 mg) was obtained.
¹ H-NMR (CD ₃ OD) δ value: 2.46-2.86 (12H, m), 3.30 (2H, s), 4.01 (3H, s), 4.15 (4H, s), 5.91-6.00 (1H, m) , 6.52 (1H, d, J = 15.6Hz), 6.58-6.70 (3H, m), 6.96 (1H, d, J = 9.3Hz), 7.66 (1H, d, J = 7.7Hz), 7.79 (1H, d, J = 7.7Hz), 8.06 (1H, d, J = 15.6Hz), 8.49 (1H, d, J = 9.3Hz)

（５−ブロモ−２−メトキシキノリン−８−イル）アセトアルデヒド0.15gの塩化メチレン5mL溶液に、室温でｔｅｒｔ−ブチル＝（２，３−ジヒドロベンゾ［ｂ］［１，４］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0.24gの塩化メチレン1mL溶液および酢酸31μLを加え、同温度で1時間攪拌した。氷冷下、トリアセトキシ水素化ホウ素ナトリウム0.11gを分割添加し、室温で1時間攪拌し、一晩放置した。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、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＝３０：１］で精製し、白色泡状物のｔｅｒｔ−ブチル＝（１−（２−（５−ブロモ−２−メトキシキノリン−８−イル）エチル）ピペリジン−４−イル）（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）カルバマート0.24gを得た。
¹H-NMR(CDCl₃)δ値：1.22-3.70(12H,m),4.05(3H,s),4.18-4.27(1H,m),4.24(4H,s),4.29-4.36(2H,m),6.69-6.80(3H,m),6.99(1H,d,J=9.0Hz),7.37-7.46(1H,m),7.57(1H,d,J=7.9Hz),8.37(1H,d,J=9.0Hz)Example 56

To a solution of 0.15-g (5-bromo-2-methoxyquinolin-8-yl) acetaldehyde in 5 mL of methylene chloride at room temperature is tert-butyl = (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl. ) (Piperidin-4-yl) carbamate 0.24 g in 1 mL of methylene chloride and 31 μL of acetic acid were added and stirred at the same temperature for 1 hour. Under ice cooling, 0.11 g of sodium triacetoxyborohydride was added in portions, stirred at room temperature for 1 hour, and left overnight. Water and ethyl acetate were added to the reaction mixture. 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 silica gel column chromatography [eluent: chloroform: methanol = 30: 1], and white foam tert-butyl = (1- (2- (5-bromo-2-methoxyquinoline) was obtained. There was obtained 0.24 g of -8-yl) ethyl) piperidin-4-yl) (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) carbamate.
¹ H-NMR (CDCl ₃ ) δ value: 1.22-3.70 (12H, m), 4.05 (3H, s), 4.18-4.27 (1H, m), 4.24 (4H, s), 4.29-4.36 (2H, m ), 6.69-6.80 (3H, m), 6.99 (1H, d, J = 9.0Hz), 7.37-7.46 (1H, m), 7.57 (1H, d, J = 7.9Hz), 8.37 (1H, d, (J = 9.0Hz)

ｔｅｒｔ−ブチル＝（１−（２−（５−ブロモ−２−メトキシキノリン−８−イル）エチル）ピペリジン−４−イル）（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）カルバマート0.12gのＮ，Ｎ−ジメチルホルムアミド2mL溶液に、室温でビス（トリ−tｅｒｔ−ブチルホスフィン）パラジウム（０）5mgおよびアクリル酸エチル32μLを加え、窒素雰囲気下、90℃で1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［富士シリシア、FL100DX、溶離液；ヘキサン：酢酸エチル＝２：１］で精製し、褐色泡状物のエチル＝（Ｅ）−３−（８−（２−（４−（（ｔｅｒｔ−ブトキシカルボニル）（２，３−ジヒドロベンゾ［ｂ］［１，４］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）−２−メトキシキノリン−５−イル）アクリラート47mgを得た。
¹H-NMR(CDCl₃)δ値：1.36(3H,t,J=7.1Hz),1.43(9H,s),1.64-1.78(2H,m),1.84-2.06(2H,m),2.20-2.44(2H,m),2.78-3.00(2H,m),3.10-3.56(4H,m),4.05(3H,s),4.24(4H,s),4.26-4.36(3H,m),4.30(2H,q,J=7.1Hz),6.49(1H,d,J=15.7Hz),6.68-6.80(3H,m),6.98(1H,d,J=9.1Hz),7.53(1H,d,J=7.6Hz),7.58(1H,d,J=7.6Hz),8.33(1H,d,J=15.7Hz),8.37(1H,d,J=9.1Hz)Example 57

tert-butyl = (1- (2- (5-bromo-2-methoxyquinolin-8-yl) ethyl) piperidin-4-yl) (2,3-dihydrobenzo [b] [1,4] dioxin-6 To a solution of 0.12 g of -ylmethyl) carbamate in 2 mL of N, N-dimethylformamide was added 5 mg of bis (tri-tert-butylphosphine) palladium (0) and 32 μL of ethyl acrylate at room temperature, and at 90 ° C. for 1 hour under a nitrogen atmosphere. Stir. After cooling the reaction mixture to room temperature, water and ethyl acetate 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 silica gel column chromatography [Fuji Silysia, FL100DX, eluent: hexane: ethyl acetate = 2: 1], and ethyl of brown foam = (E) -3- (8- (2 -(4-((tert-butoxycarbonyl) (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) ethyl) -2-methoxyquinoline-5 Yl) 47 mg of acrylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.36 (3H, t, J = 7.1 Hz), 1.43 (9H, s), 1.64-1.78 (2H, m), 1.84-2.06 (2H, m), 2.20- 2.44 (2H, m), 2.78-3.00 (2H, m), 3.10-3.56 (4H, m), 4.05 (3H, s), 4.24 (4H, s), 4.26-4.36 (3H, m), 4.30 ( 2H, q, J = 7.1Hz), 6.49 (1H, d, J = 15.7Hz), 6.68-6.80 (3H, m), 6.98 (1H, d, J = 9.1Hz), 7.53 (1H, d, J = 7.6Hz), 7.58 (1H, d, J = 7.6Hz), 8.33 (1H, d, J = 15.7Hz), 8.37 (1H, d, J = 9.1Hz)

エチル＝（Ｅ）−３−（８−（２−（４−（（ｔｅｒｔ−ブトキシカルボニル）（２，３−ジヒドロベンゾ［ｂ］［１，４］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）−２−メトキシキノリン−５−イル）アクリラート47mgの塩化メチレン2mL溶液に、氷冷下、トリフルオロ酢酸0.30mLを滴下し、同温度で1時間攪拌した。反応混合物を減圧下で濃縮し、酢酸エチルおよび水を加え、20％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、黄褐色泡状物のエチル＝（Ｅ）−３−（８−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］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）−２−メトキシキノリン−５−イル）アクリラート40mgを得た。
¹H-NMR(CDCl₃)δ値：1.37(3H,t,J=7.2Hz),1.47-1.59(2H,m),1.93-2.02(2H,m),2.18-2.36(2H,m),2.53-2.65(1H,m),2.76-2.88(2H,m),3.06-3.15(2H,m),3.39-3.44(2H,m),3.72(2H,s),4.07(3H,s),4.25(4H,s),4.30(2H,q,J=7.2Hz),6.49(1H,d,J=15.7Hz),6.77-6.85(3H,m),6.98(1H,d,J=9.2Hz),7.52(1H,d,J=7.6Hz),7.58(1H,d,J=7.6Hz),8.34(1H,d,J=15.7Hz),8.37(1H,d,J=9.2Hz)Example 58

Ethyl = (E) -3- (8- (2- (4-((tert-butoxycarbonyl) (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidine-1 -Il) ethyl) -2-methoxyquinolin-5-yl) acrylate To a solution of 47 mg of methylene chloride in 2 mL of methylene chloride was added dropwise 0.30 mL of trifluoroacetic acid, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added, and the pH was adjusted to 12 with 20% 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. Ethyl = (E) -3- (8- (2 40 mg of-(4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) ethyl) -2-methoxyquinolin-5-yl) acrylate are obtained. It was.
¹ H-NMR (CDCl ₃ ) δ value: 1.37 (3H, t, J = 7.2 Hz), 1.47-1.59 (2H, m), 1.93-2.02 (2H, m), 2.18-2.36 (2H, m), 2.53-2.65 (1H, m), 2.76-2.88 (2H, m), 3.06-3.15 (2H, m), 3.39-3.44 (2H, m), 3.72 (2H, s), 4.07 (3H, s), 4.25 (4H, s), 4.30 (2H, q, J = 7.2Hz), 6.49 (1H, d, J = 15.7Hz), 6.77-6.85 (3H, m), 6.98 (1H, d, J = 9.2Hz ), 7.52 (1H, d, J = 7.6Hz), 7.58 (1H, d, J = 7.6Hz), 8.34 (1H, d, J = 15.7Hz), 8.37 (1H, d, J = 9.2Hz)

エチル＝（Ｅ）−３−（８−（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）−２−メトキシキノリン−５−イル）アクリラート40mgの90％エタノール水2mL溶液に、氷冷下、20％水酸化ナトリウム水溶液63μLを加え、水冷〜室温で2時間攪拌した。20％水酸化ナトリウム水溶液31μLを加え、室温で30分間攪拌した。減圧下で溶媒を留去し、水を加え、炭酸ガスを導入した。固形物をろ取し、淡黄色固体の（Ｅ）−３−（８−（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）−２−メトキシキノリン−５−イル）アクリル酸30mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.20-1.33(3H,m),1.75-1.84(2H,m),1.97-2.07(2H,m),2.30-2.40(2H,m),2.58-2.69(2H,m),2.90-2.97(2H,m),3.59(2H,s),4.01(3H,s),4.20(4H,s),6.51(1H,d,J=15.8Hz),6.74-6.84(3H,m),7.07(1H,d,J=9.2Hz),7.57(1H,d,J=7.7Hz),7.70(1H,d,J=7.7Hz),8.07(1H,d,J=15.8Hz),8.50(1H,d,J=9.2Hz)Example 59

Ethyl = (E) -3- (8- (2- (4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl) amino) piperidin-1-yl) ethyl) -2-methoxy To a 2 mL solution of quinolin-5-yl) acrylate 40 mg in 90% aqueous ethanol, 63 μL of a 20% aqueous sodium hydroxide solution was added under ice cooling, and the mixture was stirred from water cooling to room temperature for 2 hours. 31 μL of 20% aqueous sodium hydroxide solution was added and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, water was added, and carbon dioxide gas was introduced. The solid was collected by filtration to give (E) -3- (8- (2- (4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl) amino) piperidine-1 as a pale yellow solid). -Yl) ethyl) -2-methoxyquinolin-5-yl) acrylic acid 30 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.20-1.33 (3H, m), 1.75-1.84 (2H, m), 1.97-2.07 (2H, m), 2.30-2.40 (2H, m), 2.58 -2.69 (2H, m), 2.90-2.97 (2H, m), 3.59 (2H, s), 4.01 (3H, s), 4.20 (4H, s), 6.51 (1H, d, J = 15.8Hz), 6.74-6.84 (3H, m), 7.07 (1H, d, J = 9.2Hz), 7.57 (1H, d, J = 7.7Hz), 7.70 (1H, d, J = 7.7Hz), 8.07 (1H, d , J = 15.8Hz), 8.50 (1H, d, J = 9.2Hz)

（１）５−ブロモ−２−メトキシ−８−（オキシラン−２−イル）キノリン0.69gのＮ，Ｎ−ジメチルホルムアミド9mL溶液に、室温でｔｅｒｔ−ブチル＝（２，３−ジヒドロベンゾ［ｂ］［１，４］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0.94gのＮ，Ｎ−ジメチルホルムアミド3mL溶液および過塩素酸リチウム0.29gを加え、80〜85℃で5時間40分間攪拌した。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＝４０：１］で精製し、淡黄色泡状物のｔｅｒｔ−ブチル＝（１−（１−（５−ブロモ−２−メトキシキノリン−８−イル）−２−ヒドロキシエチル）ピペリジン−４−イル）（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）カルバマートおよびｔｅｒｔ−ブチル＝（１−（２−（５−ブロモ−２−メトキシキノリン−８−イル）−２−ヒドロキシエチル）ピペリジン−４−イル）（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）カルバマートの混合物1.1gを得た。
（２）得られた混合物1.0gのＮ，Ｎ−ジメチルホルムアミド12mL溶液に、ビス（トリ−tｅｒｔ−ブチルホスフィン）パラジウム（０）41mg、アクリル酸エチル0.26mLおよびトリエチルアミン0.33mLを加え、窒素雰囲気下、90℃で1時間30分間攪拌した。反応混合物を室温まで冷却後、酢酸エチルおよび水を加え、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［溶離液；ヘキサン：酢酸エチル＝２：１］で精製し、淡黄色泡状物のエチル＝（Ｅ）−３−（８−（２−（４−（（ｔｅｒｔ−ブトキシカルボニル）（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート0.65gおよび黄色固体のエチル＝（Ｅ）−３−（８−（１−（４−（（ｔｅｒｔ−ブトキシカルボニル）（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−２−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート0.16gを得た。
エチル＝（Ｅ）−３−（８−（２−（４−（（ｔｅｒｔ−ブトキシカルボニル）（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラートの¹H-NMRは、実施例４８のデータと一致した。
エチル＝（Ｅ）−３−（８−（１−（４−（（ｔｅｒｔ−ブトキシカルボニル）（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−２−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート
¹H-NMR(CDCl₃)δ値：1.30-1.90(13H,m),1.38(3H,t,J=7.1Hz),2.00-2.36(2H,m),2.75-3.00(2H,m),3.18-3.26(1H,m),3.58-3.70(1H,m),3.96-4.02(1H,m),4.04(3H,s),4.20-4.35(1H,m),4.24(4H,s),4.25(2H,s),4.31(2H,q,J=7.1Hz),5.22-5.35(1H,m),6.51(1H,d,J=16.6Hz),6.66(1H,d,J=8.3Hz),6.71(1H,s),6.77(1H,d,J=8.3Hz),7.00(1H,d,J=9.2Hz),7.48(1H,d,J=7.8Hz),7.60(1H,d,J=7.8Hz),8.35(1H,d,J=16.6Hz),8.39(1H,d,J=9.2Hz)Example 60

(1) To a solution of 0.69 g of 5-bromo-2-methoxy-8- (oxiran-2-yl) quinoline in 9 mL of N, N-dimethylformamide at room temperature, tert-butyl = (2,3-dihydrobenzo [b] A solution of 0.94 g of [1,4] dioxin-6-ylmethyl) (piperidin-4-yl) carbamate in 3 mL of N, N-dimethylformamide and 0.29 g of lithium perchlorate was added and stirred at 80 to 85 ° C. for 5 hours and 40 minutes. did. After cooling the reaction mixture 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, 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 = 40: 1], and tert-butyl = (1- (1- (5-bromo-2-methoxy) was obtained as a pale yellow foam. Quinolin-8-yl) -2-hydroxyethyl) piperidin-4-yl) (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) carbamate and tert-butyl = (1- (2 -(5-Bromo-2-methoxyquinolin-8-yl) -2-hydroxyethyl) piperidin-4-yl) (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) carbamate 1.1 g of mixture was obtained.
(2) To a solution of 1.0 g of the obtained mixture in 12 mL of N, N-dimethylformamide was added 41 mg of bis (tri-tert-butylphosphine) palladium (0), 0.26 mL of ethyl acrylate and 0.33 mL of triethylamine, and a nitrogen atmosphere. The mixture was stirred at 90 ° C. for 1 hour and 30 minutes. After cooling the reaction mixture to room temperature, ethyl acetate and water were added, 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], and the pale yellow foam ethyl = (E) -3- (8- (2- (4- (4- ((Tert-Butoxycarbonyl) (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinoline-5 Yl) acrylate 0.65 g and yellow solid ethyl = (E) -3- (8- (1- (4-((tert-butoxycarbonyl) (2,3-dihydrobenzo [b] [1,4] dioxin- 0.16 g of 6-ylmethyl) amino) piperidin-1-yl) -2-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate was obtained.
Ethyl = (E) -3- (8- (2- (4-((tert-butoxycarbonyl) (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidine-1 ¹ H-NMR of -yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate was consistent with the data of Example 48.
Ethyl = (E) -3- (8- (1- (4-((tert-butoxycarbonyl) (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidine-1 -Yl) -2-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate
¹ H-NMR (CDCl ₃ ) δ value: 1.30-1.90 (13H, m), 1.38 (3H, t, J = 7.1 Hz), 2.00-2.36 (2H, m), 2.75-3.00 (2H, m), 3.18-3.26 (1H, m), 3.58-3.70 (1H, m), 3.96-4.02 (1H, m), 4.04 (3H, s), 4.20-4.35 (1H, m), 4.24 (4H, s), 4.25 (2H, s), 4.31 (2H, q, J = 7.1Hz), 5.22-5.35 (1H, m), 6.51 (1H, d, J = 16.6Hz), 6.66 (1H, d, J = 8.3Hz ), 6.71 (1H, s), 6.77 (1H, d, J = 8.3Hz), 7.00 (1H, d, J = 9.2Hz), 7.48 (1H, d, J = 7.8Hz), 7.60 (1H, d , J = 7.8Hz), 8.35 (1H, d, J = 16.6Hz), 8.39 (1H, d, J = 9.2Hz)

エチル＝（Ｅ）−３−（８−（１−（４−（（ｔｅｒｔ−ブトキシカルボニル）（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−２−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート0.15gの塩化メチレン4mL溶液に、氷冷下、トリフルオロ酢酸2mLを滴下し、水冷下で50分間攪拌した。反応混合物を減圧下で溶媒を留去し、酢酸エチルおよび水を加え、20％水酸化ナトリウム水溶液でpH10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、橙色泡状物のエチル＝（Ｅ）−３−（８−（１−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−２−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート0.14gを得た。
¹H-NMR(CDCl₃)δ値：1.37(3H,t,J=7.2Hz),1.42-1.56(2H,m),1.82-2.00(3H,m),2.10-2.38(2H,m),2.92-3.00(1H,m),3.12-3.20(1H,m),3.60-3.70(3H,m),4.02-4.08(1H,m),4.07(3H,s),4.21(4H,s),4.31(2H,q,J=7.2Hz),5.35-5.42(1H,m),6.51(1H,d,J=15.8Hz),6.70(1H,dd,J=8.3,2.0Hz),6.75(1H,d,J=2.0Hz),6.75(1H,d,J=8.3Hz),7.00(1H,d,J=9.1Hz),7.51(1H,d,J=7.5Hz),7.61(1H,d,J=7.5Hz),8.35(1H,d,J=15.8Hz),8.39(1H,d,J=9.1Hz)Example 61

Ethyl = (E) -3- (8- (1- (4-((tert-butoxycarbonyl) (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidine-1 -Il) -2-Hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate To a solution of 0.15 g of methylene chloride in 4 mL of methylene chloride was added dropwise 2 mL of trifluoroacetic acid, and the mixture was stirred for 50 minutes under water cooling. The reaction mixture was evaporated under reduced pressure, ethyl acetate and water were added, and the pH was adjusted to 10 with 20% aqueous sodium hydroxide solution. 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 the orange foam ethyl = (E) -3- (8- (1- (4-((2,3-Dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) -2-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate 0.14 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.37 (3H, t, J = 7.2 Hz), 1.42-1.56 (2H, m), 1.82-2.00 (3H, m), 2.10-2.38 (2H, m), 2.92-3.00 (1H, m), 3.12-3.20 (1H, m), 3.60-3.70 (3H, m), 4.02-4.08 (1H, m), 4.07 (3H, s), 4.21 (4H, s), 4.31 (2H, q, J = 7.2Hz), 5.35-5.42 (1H, m), 6.51 (1H, d, J = 15.8Hz), 6.70 (1H, dd, J = 8.3,2.0Hz), 6.75 (1H , d, J = 2.0Hz), 6.75 (1H, d, J = 8.3Hz), 7.00 (1H, d, J = 9.1Hz), 7.51 (1H, d, J = 7.5Hz), 7.61 (1H, d , J = 7.5Hz), 8.35 (1H, d, J = 15.8Hz), 8.39 (1H, d, J = 9.1Hz)

エチル＝（Ｅ）−３−（８−（１−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−２−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート0.14gの90％エタノール水2mL溶液に、氷冷下、20％水酸化ナトリウム水溶液0.2mLを加え、室温で1時間10分間攪拌し、一晩放置した。反応混合物を減圧下で溶媒を留去し、水を加え、6.0mol/L塩酸でpH7.1に調整した。固形物をろ取し、褐色固体の（Ｅ）−３−（８−（１−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−２−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリル酸80mgを得た。
¹H-NMR(CD₃OD)δ値：1.57-1.88(2H,m),1.98-2.14(2H,m),2.16-2.44(2H,m),2.78-2.90(1H,m),3.14-3.24(1H,m),3.46-3.55(1H,m),3.90-4.20(2H,m),3.91(2H,s),4.08(3H,s),4.24(4H,s),5.31-5.40(1H,m),6.57(1H,d,J=15.7Hz),6.80-6.98(3H,m),7.01(1H,d,J=9.1Hz),7.65-7.70(2H,m),8.14(1H,d,J=15.7Hz),8.52(1H,d,J=9.1Hz)Example 62

Ethyl = (E) -3- (8- (1- (4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) -2- Hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate 0.14 g of 90% ethanol water 2 mL solution was added with ice-cooled 20% aqueous sodium hydroxide solution 0.2 mL and stirred at room temperature for 1 hour 10 minutes. Left overnight. The reaction mixture was evaporated under reduced pressure, water was added, and the pH was adjusted to 7.1 with 6.0 mol / L hydrochloric acid. The solid was collected by filtration to give (E) -3- (8- (1- (4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidine as a brown solid). -1-yl) -2-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid 80 mg was obtained.
¹ H-NMR (CD ₃ OD) δ value: 1.57-1.88 (2H, m), 1.98-2.14 (2H, m), 2.16-2.44 (2H, m), 2.78-2.90 (1H, m), 3.14 3.24 (1H, m), 3.46-3.55 (1H, m), 3.90-4.20 (2H, m), 3.91 (2H, s), 4.08 (3H, s), 4.24 (4H, s), 5.31-5.40 ( 1H, m), 6.57 (1H, d, J = 15.7Hz), 6.80-6.98 (3H, m), 7.01 (1H, d, J = 9.1Hz), 7.65-7.70 (2H, m), 8.14 (1H , d, J = 15.7Hz), 8.52 (1H, d, J = 9.1Hz)

メチル＝２−メトキシ−８−（オキシラン−２−イル）キノリン−５−カルボキシラート20mgのＮ，Ｎ−ジメチルホルムアミド1mL溶液に、室温でｔｅｒｔ−ブチル＝（２，３−ジヒドロベンゾ［ｂ］［１，４］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32mg、炭酸カリウム10mgおよび過塩素酸リチウム10mgを加え、75〜85℃で8時間攪拌した。反応混合物を室温まで冷却後、酢酸エチルおよび水を加えた。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、黄色油状物のメチル＝８−（２−（４−（（ｔｅｒｔ−ブトキシカルボニル）（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−カルボキシラート29mgを得た。
¹H-NMR(CDCl₃)δ値：1.44(9H,s),1.56-1.90(5H,m),2.09-2.22(1H,m),2.24-2.43(2H,m),2.80-2.88(1H,m),2.99(1H,dd,J=12.2,2.8Hz),3.30-3.40(1H,m),3.97(3H,s),4.00(3H,s),4.25(4H,s),4.31(2H,s),5.75(1H,dd,J=10.0,2.8Hz),6.62-6.82(3H,m),7.00(1H,d,J=9.3Hz),7.89(1H,d,J=7.7Hz),8.11(1H,d,J=7.7Hz),9.19(1H,d,J=9.3Hz)Example 63

Methyl 2-methoxy-8- (oxiran-2-yl) quinoline-5-carboxylate 20 mg of N, N-dimethylformamide in 1 mL solution at room temperature at tert-butyl = (2,3-dihydrobenzo [b] [ 1,4] dioxin-6-ylmethyl) (piperidin-4-yl) carbamate 32 mg, potassium carbonate 10 mg and lithium perchlorate 10 mg were added, and the mixture was stirred at 75 to 85 ° C. for 8 hours. After cooling the reaction mixture to room temperature, ethyl acetate and water 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 silica gel column chromatography [eluent: chloroform: methanol = 50: 1] to give methyl 8-8- (2- (4-((tert-butoxycarbonyl) (2, There were obtained 29 mg of 3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinoline-5-carboxylate.
¹ H-NMR (CDCl ₃ ) δ value: 1.44 (9H, s), 1.56-1.90 (5H, m), 2.09-2.22 (1H, m), 2.24-2.43 (2H, m), 2.80-2.88 (1H , m), 2.99 (1H, dd, J = 12.2, 2.8Hz), 3.30-3.40 (1H, m), 3.97 (3H, s), 4.00 (3H, s), 4.25 (4H, s), 4.31 ( 2H, s), 5.75 (1H, dd, J = 10.0,2.8Hz), 6.62-6.82 (3H, m), 7.00 (1H, d, J = 9.3Hz), 7.89 (1H, d, J = 7.7Hz ), 8.11 (1H, d, J = 7.7Hz), 9.19 (1H, d, J = 9.3Hz)

メチル＝８−（２−（４−（（ｔｅｒｔ−ブトキシカルボニル）（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−カルボキシラート29mgの塩化メチレン2mL溶液に、氷冷下、トリフルオロ酢酸1mLを滴下し、水冷下で1時間30分間攪拌した。反応混合物を減圧下で溶媒を留去し、酢酸エチルおよび水を加え、20％水酸化ナトリウム水溶液でpH11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、黄色油状物のメチル＝８−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−カルボキシラート12mgを得た。
¹H-NMR(CDCl₃)δ値：1.45-1.65(2H,m),1.85-2.05(2H,m),2.14-2.25(1H,m),2.25-2.50(2H,m),2.54-2.64(1H,m),2.80-2.90(1H,m),3.06(1H,dd,J=12.4,3.0Hz),3.24-3.34(1H,m),3.72(2H,s),3.97(3H,s),4.03(3H,s),4.25(4H,s),5.82(1H,dd,J=10.0,3.0Hz),6.74-6.86(3H,m),7.01(1H,d,J=9.4Hz),7.92(1H,d,J=7.7Hz),8.12(1H,d,J=7.7Hz),9.20(1H,d,J=9.4Hz)Example 64

Methyl = 8- (2- (4-((tert-butoxycarbonyl) (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) -1-hydroxy Ethyl) -2-methoxyquinoline-5-carboxylate To a solution of 29 mg of methylene chloride in 2 mL of methylene chloride was added dropwise 1 mL of trifluoroacetic acid, and the mixture was stirred for 1 hour and 30 minutes under water cooling. The reaction mixture was evaporated under reduced pressure, ethyl acetate and water were added, and the mixture was adjusted to pH 11 with 20% 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. Methyl = 8- (2- (4-((2,3 -12 mg of dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinoline-5-carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.45-1.65 (2H, m), 1.85-2.05 (2H, m), 2.14-2.25 (1H, m), 2.25-2.50 (2H, m), 2.54-2.64 (1H, m), 2.80-2.90 (1H, m), 3.06 (1H, dd, J = 12.4,3.0Hz), 3.24-3.34 (1H, m), 3.72 (2H, s), 3.97 (3H, s ), 4.03 (3H, s), 4.25 (4H, s), 5.82 (1H, dd, J = 10.0, 3.0Hz), 6.74-6.86 (3H, m), 7.01 (1H, d, J = 9.4Hz) , 7.92 (1H, d, J = 7.7Hz), 8.12 (1H, d, J = 7.7Hz), 9.20 (1H, d, J = 9.4Hz)

メチル＝８−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−カルボキシラート11mgの90％エタノール水2mL溶液に、室温で20％水酸化ナトリウム水溶液0.22mLを加え、室温で2時間攪拌し、一晩放置した。減圧下で溶媒を留去し、水を加え、炭酸ガスを導入した。固形物をろ取し、橙色固体の８−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−カルボン酸3.2mgを得た。
¹H-NMR(CD₃OD)δ値：1.50-1.80(2H,m),1.90-2.20(2H,m),2.35-2.60(2H,m),2.70-3.10(3H,m),3.10-3.22(1H,m),3.40-3.60(1H,m),3.87(2H,s),4.03(3H,s),4.23(4H,s),5.92-6.04(1H,m),6.80-7.00(4H,m),7.68(1H,d,J=7.6Hz),7.78(1H,d,J=7.6Hz),8.86(1H,d,J=9.3Hz)Example 65

Methyl = 8- (2- (4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxy To a solution of 11 mg of quinoline-5-carboxylate in 2 mL of 90% aqueous ethanol was added 0.22 mL of 20% aqueous sodium hydroxide at room temperature, stirred at room temperature for 2 hours, and allowed to stand overnight. The solvent was distilled off under reduced pressure, water was added, and carbon dioxide gas was introduced. The solid was collected by filtration to give orange solid 8- (2- (4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) -1 3.2 mg of -hydroxyethyl) -2-methoxyquinoline-5-carboxylic acid was obtained.
¹ H-NMR (CD ₃ OD) δ value: 1.50-1.80 (2H, m), 1.90-2.20 (2H, m), 2.35-2.60 (2H, m), 2.70-3.10 (3H, m), 3.10- 3.22 (1H, m), 3.40-3.60 (1H, m), 3.87 (2H, s), 4.03 (3H, s), 4.23 (4H, s), 5.92-6.04 (1H, m), 6.80-7.00 ( 4H, m), 7.68 (1H, d, J = 7.6Hz), 7.78 (1H, d, J = 7.6Hz), 8.86 (1H, d, J = 9.3Hz)

１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸24mgの塩化メチレン懸濁液2mLに、氷冷下、塩化チオニル0.1mLおよびＮ，Ｎ−ジメチルホルムアミド1滴を加え、1時間15分間加熱還流した。減圧下で溶媒を留去し、クロロホルム2mLを加えた。２，６−ジメトキシキノリン−８−アミン14mgおよびトリエチルアミン0.20mLを加え、室温で2時間10分間攪拌した。
１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸60mgの塩化メチレン溶液2mLに、氷冷下、塩化チオニル0.6mLおよびＮ，Ｎ−ジメチルホルムアミド1滴を加え、30分間加熱還流した。減圧下で溶媒を留去した。得られた残留物、クロロホルム1mLおよびトリエチルアミン0.2mLを上記の反応混合物に加え、室温で2日間放置した。反応混合物に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］で精製し、ジエチルエーテル−ヘキサン混液を加え、固形物をろ取し、白色固体の１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）−Ｎ−（２，６−ジメトキシキノリン−８−イル）ピペリジン−４−カルボキサミド15mgを得た。
¹H-NMR(CDCl₃)δ値：1.90-2.04(2H,m),2.10-2.22(4H,m),2.38-2.50(1H,m),2.57-2.62(2H,m),2.70-2.75(2H,m),3.05-3.14(2H,m),3.89(3H,s),4.06(3H,s),4.24(4H,s),6.68(1H,dd,J=8.2,2.0Hz),6.73(1H,d,J=2.0Hz),6.78(1H,d,J=8.2Hz),6.79(1H,d,J=2.7Hz),6.92(1H,d,J=8.8Hz),7.90(1H,d,J=8.8Hz),8.50(1H,d,J=2.7Hz),9.61(1H,s)Example 66

1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxylic acid 24 mg was added to 2 mL of a methylene chloride suspension under ice cooling and thionyl chloride. 0.1 mL and 1 drop of N, N-dimethylformamide were added, and the mixture was heated to reflux for 1 hour and 15 minutes. The solvent was distilled off under reduced pressure, and 2 mL of chloroform was added. 2,6-Dimethoxyquinolin-8-amine (14 mg) and triethylamine (0.20 mL) were added, and the mixture was stirred at room temperature for 2 hours and 10 minutes.
1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxylic acid 60 mg in 2 mL of methylene chloride solution and ice-cooled thionyl chloride 0.6 mL And 1 drop of N, N-dimethylformamide were added and heated to reflux for 30 minutes. The solvent was distilled off under reduced pressure. The resulting residue, 1 mL of chloroform and 0.2 mL of triethylamine were added to the above reaction mixture and left at room temperature for 2 days. 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 distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform], a diethyl ether-hexane mixture was added, the solid was collected by filtration, and a white solid 1- (2- (2,3-dihydrobenzoic acid) was obtained. [B] 15 mg of [1,4] dioxin-6-yl) ethyl) -N- (2,6-dimethoxyquinolin-8-yl) piperidine-4-carboxamide was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.90-2.04 (2H, m), 2.10-2.22 (4H, m), 2.38-2.50 (1H, m), 2.57-2.62 (2H, m), 2.70-2.75 (2H, m), 3.05-3.14 (2H, m), 3.89 (3H, s), 4.06 (3H, s), 4.24 (4H, s), 6.68 (1H, dd, J = 8.2,2.0Hz), 6.73 (1H, d, J = 2.0Hz), 6.78 (1H, d, J = 8.2Hz), 6.79 (1H, d, J = 2.7Hz), 6.92 (1H, d, J = 8.8Hz), 7.90 ( 1H, d, J = 8.8Hz), 8.50 (1H, d, J = 2.7Hz), 9.61 (1H, s)

１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボキサミド60mg、炭酸セシウム84mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.8mgおよびｒａｃ−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフタレン7.7mgのジオキサン1.8mL溶液を、窒素雰囲気下、10分間、超音波処理した。室温で、ブチル＝２−メトキシ−８−（（（トリフルオロメチル）スルホニル）オキシ）キノリン−５−カルボキシラート84mgを加え、1時間加熱還流した。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；クロロホルム：メタノール＝２００：１］で精製し、黄色固体のブチル＝８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−５−カルボキシラート64mgを得た。
¹H-NMR(CDCl₃)δ値：1.00(3H,t,J=7.3Hz),1.45-1.58(2H,m),1.75-1.85(2H,m),1.92-2.04(2H,m),2.10-2.24(4H,m),2.40-2.52(1H,m),2.60(2H,dd,J=10.2,5.7Hz),2.73(2H,dd,J=10.2,5.7Hz),3.05-3.15(2H,m),4.11(3H,s),4.24(4H,s),4.37(2H,t,J=6.7Hz),6.68(1H,dd,J=8.2,2.0Hz),6.73(1H,d,J=2.0Hz),6.79(1H,d,J=8.2Hz),7.08(1H,d,J=9.3Hz),8.17(1H,d,J=8.4Hz),8.73(1H,d,J=8.4Hz),9.35(1H,d,J=9.3Hz),9.90(1H,s)Example 67

1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxamide 60 mg, cesium carbonate 84 mg, tris (dibenzylideneacetone) dipalladium (0) A solution of 3.8 mg and rac-2,2′-bis (diphenylphosphino) -1,1′-binaphthalene 7.7 mg in dioxane 1.8 mL was sonicated for 10 minutes in a nitrogen atmosphere. At room temperature, 84 mg of butyl = 2-methoxy-8-(((trifluoromethyl) sulfonyl) oxy) quinoline-5-carboxylate was added, and the mixture was heated to reflux for 1 hour. After cooling the reaction mixture 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: chloroform: methanol = 200: 1] to give butyl = 8-(((1- (2- (2,3-dihydrobenzo [b ] [1,4] dioxin-6-yl) ethyl) piperidin-4-yl) carbonyl) amino) -2-methoxyquinoline-5-carboxylate (64 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.00 (3H, t, J = 7.3 Hz), 1.45-1.58 (2H, m), 1.75-1.85 (2H, m), 1.92-2.04 (2H, m), 2.10-2.24 (4H, m), 2.40-2.52 (1H, m), 2.60 (2H, dd, J = 10.2,5.7Hz), 2.73 (2H, dd, J = 10.2,5.7Hz), 3.05-3.15 ( 2H, m), 4.11 (3H, s), 4.24 (4H, s), 4.37 (2H, t, J = 6.7Hz), 6.68 (1H, dd, J = 8.2,2.0Hz), 6.73 (1H, d , J = 2.0Hz), 6.79 (1H, d, J = 8.2Hz), 7.08 (1H, d, J = 9.3Hz), 8.17 (1H, d, J = 8.4Hz), 8.73 (1H, d, J = 8.4Hz), 9.35 (1H, d, J = 9.3Hz), 9.90 (1H, s)

ブチル＝８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−５−カルボキシラート55mgのメタノール1mLおよびテトラヒドロフラン2.0mLの混合溶液に、室温で20％水酸化ナトリウム水溶液0.15mLを加え、室温で4時間30分間攪拌した。20％水酸化ナトリウム水溶液50μLを加え、1時間30分間攪拌した。減圧下で溶媒を留去し、水を加え、2.0mol/L塩酸でpH7.0に調整した。固形物をろ取し、淡黄色固体の８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−５−カルボン酸41mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.65-1.85(2H,m),1.90-2.05(2H,m),2.05-2.20(2H,m),2.40-2.60(2H,m),2.60-2.70(3H,m),2.95-3.08(2H,m),4.12(3H,s),4.20(4H,s),6.67(1H,dd,J=8.1,1.9Hz),6.73(1H,d,J=1.9Hz),6.74(1H,d,J=8.1Hz),7.24(1H,d,J=9.3Hz),8.12(1H,d,J=8.3Hz),8.57(1H,d,J=8.3Hz),9.34(1H,d,J=9.3Hz),9.89(1H,s)Example 68

Butyl = 8-(((1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidin-4-yl) carbonyl) amino) -2-methoxyquinoline To a mixed solution of 55 mg of -5-carboxylate in 1 mL of methanol and 2.0 mL of tetrahydrofuran was added 0.15 mL of 20% aqueous sodium hydroxide at room temperature, and the mixture was stirred at room temperature for 4 hours and 30 minutes. 50 μL of 20% aqueous sodium hydroxide solution was added and stirred for 1 hour 30 minutes. The solvent was distilled off under reduced pressure, water was added, and the pH was adjusted to 7.0 with 2.0 mol / L hydrochloric acid. The solid was collected by filtration to give 8-(((1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidin-4-yl) as a pale yellow solid). 41 mg of carbonyl) amino) -2-methoxyquinoline-5-carboxylic acid were obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.65-1.85 (2H, m), 1.90-2.05 (2H, m), 2.05-2.20 (2H, m), 2.40-2.60 (2H, m), 2.60 -2.70 (3H, m), 2.95-3.08 (2H, m), 4.12 (3H, s), 4.20 (4H, s), 6.67 (1H, dd, J = 8.1,1.9Hz), 6.73 (1H, d , J = 1.9Hz), 6.74 (1H, d, J = 8.1Hz), 7.24 (1H, d, J = 9.3Hz), 8.12 (1H, d, J = 8.3Hz), 8.57 (1H, d, J = 8.3Hz), 9.34 (1H, d, J = 9.3Hz), 9.89 (1H, s)

１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボキサミド50mg、炭酸セシウム66mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.1mgおよびｒａｃ−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフタレン6.4mgのジオキサン1.5mL溶液を、窒素雰囲気下、10分間超音波処理した。室温で２−シアノキノリン−８−イル＝トリフルオロメタンスルホナート51mgを加え、1時間加熱還流した。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；クロロホルム：メタノール＝１０：１］で精製し、淡黄色固体のＮ−（２−シアノキノリン−８−イル）−１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボキサミド52mgを得た。
¹H-NMR(CDCl₃)δ値：1.92-2.24(6H,m),2.48-2.65(3H,m),2.70-2.79(2H,m),3.08-3.17(2H,m),4.24(4H,s),6.70(1H,dd,J=8.2,2.0Hz),6.74(1H,d,J=2.0Hz),6.79(1H,d,J=8.2Hz),7.56(1H,d,J=7.2Hz),7.70(1H,t,J=7.2Hz),7.76(1H,d,J=8.5Hz),8.32(1H,d,J=8.5Hz),8.93(1H,d,J=7.2Hz),9.61(1H,s)Example 69

1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxamide 50 mg, cesium carbonate 66 mg, tris (dibenzylideneacetone) dipalladium (0) 3.1 mg of rac-2,2′-bis (diphenylphosphino) -1,1′-binaphthalene (6.4 mg) in 1.5 mL of dioxane was sonicated in a nitrogen atmosphere for 10 minutes. At room temperature, 51 mg of 2-cyanoquinolin-8-yl = trifluoromethanesulfonate was added, and the mixture was heated to reflux for 1 hour. After cooling the reaction mixture 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: chloroform: methanol = 10: 1], and light yellow solid N- (2-cyanoquinolin-8-yl) -1- (2- (2 , 3-Dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxamide 52 mg.
¹ H-NMR (CDCl ₃ ) δ value: 1.92-2.24 (6H, m), 2.48-2.65 (3H, m), 2.70-2.79 (2H, m), 3.08-3.17 (2H, m), 4.24 (4H , s), 6.70 (1H, dd, J = 8.2,2.0Hz), 6.74 (1H, d, J = 2.0Hz), 6.79 (1H, d, J = 8.2Hz), 7.56 (1H, d, J = 7.2Hz), 7.70 (1H, t, J = 7.2Hz), 7.76 (1H, d, J = 8.5Hz), 8.32 (1H, d, J = 8.5Hz), 8.93 (1H, d, J = 7.2Hz) ), 9.61 (1H, s)

ｔｅｒｔ−ブチル＝（ピペリジン−４−イル）（２−（２−チエニルチオ）エチル）カルバマート43mgのＮ，Ｎ−ジメチルホルムアミド2mL溶液に、室温でエチル＝（Ｅ）−３−（２−メトキシ−８−（オキシラン−２−イル）キノリン−５−イル）アクリラート38mgおよび過塩素酸リチウム15mgを加え、80℃で3時間30分間攪拌した。過塩素酸リチウム5mgを加え、同温度で3時間攪拌した。反応混合物を室温まで冷却後、酢酸エチルおよび水を加えた。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］で精製し、黄色油状物のエチル＝（Ｅ）−３−（８−（２−（４−（（ｔｅｒｔ−ブトキシカルボニル）（２−（２−チエニルチオ）エチル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート52mgを得た。
¹H-NMR(CDCl₃)δ値：1.30-1.46(12H,m),1.52-1.72(4H,m),2.09-2.20(1H,m),2.24-2.36(1H,m),2.42(1H,dd,J=12.3,10.0Hz),2.74-3.02(3H,m),3.18-3.40(3H,m),4.01(3H,s),4.00-4.10(2H,m),4.31(2H,q,J=7.2Hz),5.74(1H,dd,J=10.0,2.8Hz),6.52(1H,d,J=16.3Hz),6.94-7.04(2H,m),7.16-7.20(1H,m),7.35-7.40(1H,m),7.69(1H,d,J=7.6Hz),7.88(1H,d,J=7.6Hz),8.35(1H,d,J=16.3Hz),8.38(1H,d,J=9.3Hz)Example 70

tert-Butyl (piperidin-4-yl) (2- (2-thienylthio) ethyl) carbamate 43 mg in N, N-dimethylformamide 2 mL solution at room temperature with ethyl = (E) -3- (2-methoxy-8) -(Oxiran-2-yl) quinolin-5-yl) acrylate 38 mg and lithium perchlorate 15 mg were added, and the mixture was stirred at 80 ° C. for 3 hours 30 minutes. 5 mg of lithium perchlorate was added and stirred at the same temperature for 3 hours. After cooling the reaction mixture to room temperature, ethyl acetate and water 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 silica gel column chromatography [eluent: chloroform], and ethyl yellow (E) -3- (8- (2- (4-((tert-butoxycarbonyl) (2 -(2-Thienylthio) ethyl) amino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate 52 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.30-1.46 (12H, m), 1.52-1.72 (4H, m), 2.09-2.20 (1H, m), 2.24-2.36 (1H, m), 2.42 (1H , dd, J = 12.3,10.0Hz), 2.74-3.02 (3H, m), 3.18-3.40 (3H, m), 4.01 (3H, s), 4.00-4.10 (2H, m), 4.31 (2H, q , J = 7.2Hz), 5.74 (1H, dd, J = 10.0,2.8Hz), 6.52 (1H, d, J = 16.3Hz), 6.94-7.04 (2H, m), 7.16-7.20 (1H, m) , 7.35-7.40 (1H, m), 7.69 (1H, d, J = 7.6Hz), 7.88 (1H, d, J = 7.6Hz), 8.35 (1H, d, J = 16.3Hz), 8.38 (1H, d, J = 9.3Hz)

エチル＝（Ｅ）−３−（８−（２−（４−（（ｔｅｒｔ−ブトキシカルボニル）（２−（２−チエニルチオ）エチル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート50mgの塩化メチレン1mL溶液に、氷冷下、トリフルオロ酢酸0.35mLを滴下し、室温で一晩放置した。減圧下で溶媒を留去し、酢酸エチルおよび水を加え、20％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、褐色油状物のエチル＝（Ｅ）−３−（８−（１−ヒドロキシ−２−（４−（（２−（２−チエニルチオ）エチル）アミノ）ピペリジン−１−イル）エチル）−２−メトキシキノリン−５−イル）アクリラート42mgを得た。
¹H-NMR(CDCl₃)δ値：1.37(3H,t,J=7.1Hz),1.44-1.75(2H,m),1.80-2.00(2H,m),2.16-2.60(3H,m),2.70-2.96(6H,m),2.98-3.12(1H,m),3.26-3.35(1H,m),4.04(3H,s),4.31(2H,q,J=7.1Hz),5.76-5.86(1H,m),6.52(1H,d,J=15.6Hz),6.95-7.02(2H,m),7.10-7.15(1H,m),7.33-7.37(1H,m),7.69(1H,d,J=7.7Hz),7.90(1H,d,J=7.7Hz),8.35(1H,d,J=15.6Hz),8.39(1H,d,J=9.3Hz)Example 71

Ethyl = (E) -3- (8- (2- (4-((tert-butoxycarbonyl) (2- (2-thienylthio) ethyl) amino) piperidin-1-yl) -1-hydroxyethyl) -2 To a solution of 50 mg of -methoxyquinolin-5-yl) acrylate in 1 mL of methylene chloride was added dropwise 0.35 mL of trifluoroacetic acid under ice cooling, and the mixture was allowed to stand overnight at room temperature. The solvent was distilled off under reduced pressure, ethyl acetate and water were added, and the pH was adjusted to 12 with a 20% 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. Ethyl = (E) -3- (8- (1-hydroxy) as a brown oily substance. 42 mg of -2- (4-((2- (2-thienylthio) ethyl) amino) piperidin-1-yl) ethyl) -2-methoxyquinolin-5-yl) acrylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.37 (3H, t, J = 7.1 Hz), 1.44-1.75 (2H, m), 1.80-2.00 (2H, m), 2.16-2.60 (3H, m), 2.70-2.96 (6H, m), 2.98-3.12 (1H, m), 3.26-3.35 (1H, m), 4.04 (3H, s), 4.31 (2H, q, J = 7.1Hz), 5.76-5.86 ( 1H, m), 6.52 (1H, d, J = 15.6Hz), 6.95-7.02 (2H, m), 7.10-7.15 (1H, m), 7.33-7.37 (1H, m), 7.69 (1H, d, J = 7.7Hz), 7.90 (1H, d, J = 7.7Hz), 8.35 (1H, d, J = 15.6Hz), 8.39 (1H, d, J = 9.3Hz)

エチル＝（Ｅ）−３−（８−（１−ヒドロキシ−２−（４−（（２−（２−チエニルチオ）エチル）アミノ）ピペリジン−１−イル）エチル）−２−メトキシキノリン−５−イル）アクリラート40mgの90％エタノール水1mL溶液に、氷冷下、20％水酸化ナトリウム水溶液62μLを加え、室温で1時間攪拌した。減圧下で溶媒を留去し、水を加え、炭酸ガスを導入した。メタノールを加え、1.0mol/L塩酸でpH7.4に調整し、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；アセトニトリル：水＝３：７］で精製し、淡黄色固体の（Ｅ）−３−（８−（１−ヒドロキシ−２−（４−（（２−（２−チエニルチオ）エチル）アミノ）ピペリジン−１−イル）エチル）−２−メトキシキノリン−５−イル）アクリル酸20mgを得た。
¹H-NMR(CD₃OD)δ値：1.37-1.53(2H,m),1.75-1.91(2H,m),2.25-2.42(2H,m),2.48-2.68(2H,m),2.71-2.88(5H,m),2.98-3.05(1H,m),3.28-3.35(1H,m),3.94(3H,s),5.85-5.92(1H,m),6.46(1H,d,J=15.8Hz),6.86-6.94(2H,m),7.08-7.10(1H,m),7.36-7.41(1H,m),7.57-7.60(1H,m),7.74(1H,d,J=7.8Hz),7.99(1H,d,J=15.8Hz),8.39-8.44(1H,m)Example 72

Ethyl = (E) -3- (8- (1-hydroxy-2- (4-((2- (2-thienylthio) ethyl) amino) piperidin-1-yl) ethyl) -2-methoxyquinoline-5 Yl) To a solution of 40 mg of acrylate in 1 mL of 90% aqueous ethanol, 62 μL of 20% aqueous sodium hydroxide solution was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, water was added, and carbon dioxide gas was introduced. Methanol was added, the pH was adjusted to 7.4 with 1.0 mol / L hydrochloric acid, and the solvent was distilled off under reduced pressure. The obtained residue was purified by reverse phase silica gel column chromatography [eluent: acetonitrile: water = 3: 7] to give (E) -3- (8- (1-hydroxy-2- (4 20 mg of-((2- (2-thienylthio) ethyl) amino) piperidin-1-yl) ethyl) -2-methoxyquinolin-5-yl) acrylic acid was obtained.
¹ H-NMR (CD ₃ OD) δ value: 1.37-1.53 (2H, m), 1.75-1.91 (2H, m), 2.25-2.42 (2H, m), 2.48-2.68 (2H, m), 2.71 2.88 (5H, m), 2.98-3.05 (1H, m), 3.28-3.35 (1H, m), 3.94 (3H, s), 5.85-5.92 (1H, m), 6.46 (1H, d, J = 15.8 Hz), 6.86-6.94 (2H, m), 7.08-7.10 (1H, m), 7.36-7.41 (1H, m), 7.57-7.60 (1H, m), 7.74 (1H, d, J = 7.8Hz) , 7.99 (1H, d, J = 15.8Hz), 8.39-8.44 (1H, m)

エチル＝（Ｅ）−３−（７−メトキシ−１−ビニルイソキノリン−４−イル）アクリラート40mgのトルエン1mL溶液に、ｔｅｒｔ−ブチル＝１−（２，３−ジヒドロベンゾ［ｂ］［１，４］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54mgを加え、80〜100℃で50分間攪拌した。ｔｅｒｔ−ブチル＝１−（２，３−ジヒドロベンゾ［ｂ］［１，４］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40mgのトルエン0.5mL溶液を加え、80〜95℃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、淡褐色油状物のエチル＝（Ｅ）−３−（１−（２−（４−（（ｔｅｒｔ−ブトキシカルボニル）（２，３−ジヒドロベンゾ［ｂ］［１，４］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−メトキシイソキノリン−４−イル）アクリラート56mgを得た。
¹H-NMR(CDCl₃)δ値：1.37(3H,t,J=7.1Hz),1.43(9H,s),1.55-1.85(4H,m),2.10-2.35(2H,m),2.85-3.00(2H,m),3.05-3.20(2H,m),3.40-3.50(2H,m),3.96(3H,s),4.05-4.35(7H,m),4.31(2H,q,J=7.1Hz),6.53(1H,d,J=15.9Hz),6.68-6.80(3H,m),7.40-7.43(2H,m),8.06(1H,d,J=9.8Hz),8.31(1H,d,J=15.9Hz),8.53(1H,s)Example 73

Ethyl = (E) -3- (7-methoxy-1-vinylisoquinolin-4-yl) acrylate In a solution of 40 mg of toluene in 1 mL of toluene, tert-butyl = 1- (2,3-dihydrobenzo [b] [1,4 Dioxin-6-ylmethyl) (piperidin-4-yl) carbamate (54 mg) was added, and the mixture was stirred at 80 to 100 ° C. for 50 minutes. Add tert-butyl = 1- (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) (piperidin-4-yl) carbamate 40 mg in toluene 0.5 mL, Stir for hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 20: 1] to give a pale brown oily ethyl = (E) -3- (1 -(2- (4-((tert-butoxycarbonyl) (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) ethyl) -7-methoxyisoquinoline 56 mg of -4-yl) acrylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.37 (3H, t, J = 7.1 Hz), 1.43 (9H, s), 1.55-1.85 (4H, m), 2.10-2.35 (2H, m), 2.85 3.00 (2H, m), 3.05-3.20 (2H, m), 3.40-3.50 (2H, m), 3.96 (3H, s), 4.05-4.35 (7H, m), 4.31 (2H, q, J = 7.1 Hz), 6.53 (1H, d, J = 15.9Hz), 6.68-6.80 (3H, m), 7.40-7.43 (2H, m), 8.06 (1H, d, J = 9.8Hz), 8.31 (1H, d , J = 15.9Hz), 8.53 (1H, s)

エチル＝（Ｅ）−３−（１−（２−（４−（（ｔｅｒｔ−ブトキシカルボニル）（２，３−ジヒドロベンゾ［ｂ］［１，４］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−メトキシイソキノリン−４−イル）アクリラート0.27gに4mol/L塩化水素/酢酸エチル15mLを加え、6日間放置した。減圧下で溶媒を留去し、得られた残留物に水、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た。有機層を分取し、水層をクロロホルムで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：トリエチルアミン＝１８：２：１］で精製し、淡褐色油状物のエチル＝（Ｅ）−３−（１−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］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−メトキシイソキノリン−４−イル）アクリラート0.17gを得た。
¹H-NMR(CDCl₃)δ値：1.38(3H,t,J=7.1Hz),1.48-1.58(2H,m),1.95-2.02(2H,m),2.22-2.30(2H,m),2.55-2.63(1H,m),2.94-3.00(2H,m),3.06-3.12(2H,m),3.47-3.54(2H,m),3.72(2H,s),3.98(3H,s),4.24(4H,s),4.31(2H,q,J=7.1Hz),6.53(1H,d,J=15.9Hz),6.77-6.86(3H,m),7.41(1H,dd,J=9.3,2.4Hz),7.45(1H,d,J=2.4Hz),8.06(1H,d,J=9.3Hz),8.31(1H,d,J=15.9Hz),8.53(1H,s)Example 74

Ethyl = (E) -3- (1- (2- (4-((tert-butoxycarbonyl) (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidine-1 -Il) ethyl) -7-methoxyisoquinolin-4-yl) acrylate (0.27 g) was added with 4 mol / L hydrogen chloride / ethyl acetate (15 mL) and allowed to stand for 6 days. The solvent was distilled off under reduced pressure, and water, a saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the resulting residue. The organic layer was separated, and the aqueous layer was extracted twice 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: triethylamine = 18: 2: 1] to give a pale brown oily ethyl = (E) -3- (1- (2- ( 0.17 g of 4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) ethyl) -7-methoxyisoquinolin-4-yl) acrylate was obtained. .
¹ H-NMR (CDCl ₃ ) δ value: 1.38 (3H, t, J = 7.1 Hz), 1.48-1.58 (2H, m), 1.95-2.02 (2H, m), 2.22-2.30 (2H, m), 2.55-2.63 (1H, m), 2.94-3.00 (2H, m), 3.06-3.12 (2H, m), 3.47-3.54 (2H, m), 3.72 (2H, s), 3.98 (3H, s), 4.24 (4H, s), 4.31 (2H, q, J = 7.1Hz), 6.53 (1H, d, J = 15.9Hz), 6.77-6.86 (3H, m), 7.41 (1H, dd, J = 9.3, 2.4Hz), 7.45 (1H, d, J = 2.4Hz), 8.06 (1H, d, J = 9.3Hz), 8.31 (1H, d, J = 15.9Hz), 8.53 (1H, s)

エチル＝（Ｅ）−３−（１−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］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−メトキシイソキノリン−４−イル）アクリラート90mgのエタノール3mL溶液に、20％水酸化ナトリウム水溶液0.5mLを加え、室温で2時間攪拌し、一晩放置した。減圧下で溶媒を留去し、得られた残留物に水および塩酸を加え、pH8.0に調整した。２−プロパノールを加え、固形物をろ取し、黄色固体の（Ｅ）−３−（１−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］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−メトキシイソキノリン−４−イル）アクリル酸46mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.26-1.38(2H,m),1.80-1.90(2H,m),2.02-2.12(2H,m),2.40-2.60(1H,m),2.77-2.85(2H,m),2.94-3.04(2H,m),3.15-3.55(2H,m),3.67(2H,s),3.97(3H,s),4.21(4H,s),6.61(1H,d,J=15.9Hz),6.76-6.88(3H,m),7.50(1H,dd,J=9.3,2.4Hz),7.55(1H,d,J=2.4Hz),8.14(1H,d,J=9.3Hz),8.18(1H,d,J=15.9Hz),8.62(1H,s)Example 75

Ethyl = (E) -3- (1- (2- (4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) ethyl)- 7-Methoxyisoquinolin-4-yl) acrylate 90 mg of ethanol 3 mL solution was added with 20% aqueous sodium hydroxide solution 0.5 mL, stirred at room temperature for 2 hours, and allowed to stand overnight. The solvent was distilled off under reduced pressure, and water and hydrochloric acid were added to the resulting residue to adjust to pH 8.0. 2-Propanol was added, and the solid was collected by filtration to give a yellow solid of (E) -3- (1- (2- (4-((2,3-dihydrobenzo [b] [1,4] dioxin-6 46 mg of -ylmethyl) amino) piperidin-1-yl) ethyl) -7-methoxyisoquinolin-4-yl) acrylic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.26-1.38 (2H, m), 1.80-1.90 (2H, m), 2.02-2.12 (2H, m), 2.40-2.60 (1H, m), 2.77 -2.85 (2H, m), 2.94-3.04 (2H, m), 3.15-3.55 (2H, m), 3.67 (2H, s), 3.97 (3H, s), 4.21 (4H, s), 6.61 (1H , d, J = 15.9Hz), 6.76-6.88 (3H, m), 7.50 (1H, dd, J = 9.3,2.4Hz), 7.55 (1H, d, J = 2.4Hz), 8.14 (1H, d, J = 9.3Hz), 8.18 (1H, d, J = 15.9Hz), 8.62 (1H, s)

窒素気流下、ｔｅｒｔ−ブチル＝（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）（１−（２−ヒドロキシ−２−（７−メトキシイソキノリン−１−イル）エチル）ピペリジン−４−イル）カルバマート0.29gのテトラヒドロフラン6mL溶液に、60％水素化ナトリウム22mgおよびｔｅｒｔ−ブチル＝ブロモアセタート80μLを加え、4時間20分間加熱還流した。60％水素化ナトリウム12mgを加え、1時間加熱還流した。反応混合物を放冷後、水および酢酸エチルを加えた。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［富士シリシア、FL1000DX、溶離液；ヘキサン：酢酸エチル＝２：１］で精製し、黄色油状物のｔｅｒｔ−ブチル＝（２−（４−（（ｔｅｒｔ−ブトキシカルボニル）（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−１−（７−メトキシイソキノリン−１−イル）エトキシ）アセタート0.22gを得た。
¹H-NMR(CDCl₃)δ値：1.35-1.45(18H,m),1.55-1.80(4H,m),2.10-2.25(2H,m),2.65-2.80(1H,m),3.05-3.20(2H,m),3.20-3.35(1H,m),3.80-4.15(3H,m),3.93(3H,s),4.20-4.35(2H,broad),4.23(4H,s),5.40-5.50(1H,m),6.60-6.80(3H,m),7.34(1H,dd,J=9.0,2.4Hz),7.52(1H,d,J=5.6Hz),7.73(1H,d,J=9.0Hz),7.92(1H,d,J=2.2Hz),8.37(1H,d,J=5.6Hz)Example 76

Under a nitrogen stream, tert-butyl = (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) (1- (2-hydroxy-2- (7-methoxyisoquinolin-1-yl) ethyl To a solution of 0.29 g of piperidin-4-yl) carbamate in 6 mL of tetrahydrofuran were added 22 mg of 60% sodium hydride and 80 μL of tert-butyl bromoacetate, and the mixture was heated to reflux for 4 hours and 20 minutes. 12 mg of 60% sodium hydride was added, and the mixture was heated to reflux for 1 hour. The reaction mixture was allowed to cool, and water and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia, FL1000DX, eluent; hexane: ethyl acetate = 2: 1], and tert-butyl = (2- (4-((tert- Butoxycarbonyl) (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) -1- (7-methoxyisoquinolin-1-yl) ethoxy) acetate 0.22 g Got.
¹ H-NMR (CDCl ₃ ) δ value: 1.35-1.45 (18H, m), 1.55-1.80 (4H, m), 2.10-2.25 (2H, m), 2.65-2.80 (1H, m), 3.05-3.20 (2H, m), 3.20-3.35 (1H, m), 3.80-4.15 (3H, m), 3.93 (3H, s), 4.20-4.35 (2H, broad), 4.23 (4H, s), 5.40-5.50 (1H, m), 6.60-6.80 (3H, m), 7.34 (1H, dd, J = 9.0,2.4Hz), 7.52 (1H, d, J = 5.6Hz), 7.73 (1H, d, J = 9.0 Hz), 7.92 (1H, d, J = 2.2Hz), 8.37 (1H, d, J = 5.6Hz)

ｔｅｒｔ−ブチル＝（２−（４−（（ｔｅｒｔ−ブトキシカルボニル）（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−１−（７−メトキシイソキノリン−１−イル）エトキシ）アセタート0.22gの4.6mol/L塩化水素/ジオキサン9mL溶液を、室温で7時間攪拌した。減圧下で溶媒を留去し、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［株式会社ワイエムシイ、ODS-AM120-S50、溶離液；水：エタノール＝９：１］で精製した。得られた黄色油状物に20％水酸化ナトリウム水溶液1mLおよびジオキサン4mLを加え、室温で5時間30分間攪拌した。反応混合物に6mol/L塩酸を加えてpH7.8に調整し、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＝５：１］で精製し、精製物に3.6mol/L塩化水素/酢酸エチルを加え、溶媒を留去した。得られた泡状物に酢酸エチルを加え、固形物をろ取し、淡黄色固体の（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）−１−（７−メトキシイソキノリン−１−イル）エトキシ）酢酸の塩酸塩87mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.10-2.30(2H,m),2.30-2.45(2H,m),3.20-3.40(3H,m),3.44-3.90(6H,m),3.95-4.22(2H,m),4.05(3H,s),4.26(4H,s),6.25-6.40(1H,m),6.90(1H,d,J=8.2Hz),7.08(1H,dd,J=8.2,1.9Hz),7.21(1H,d,J=1.9Hz),7.64(1H,dd,J=8.9,1.9Hz),7.89(1H,d,J=1.9Hz),8.07(1H,d,J=5.6Hz),8.12(1H,d,J=8.9Hz),8.48(1H,d,J=5.6Hz)Example 77

tert-butyl = (2- (4-((tert-butoxycarbonyl) (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) -1- ( A solution of 0.22 g of 7-methoxyisoquinolin-1-yl) ethoxy) acetate in 9 mL of 4.6 mol / L hydrogen chloride / dioxane was stirred at room temperature for 7 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography [YMC Co., Ltd., ODS-AM120-S50, eluent: water: ethanol = 9: 1]. To the obtained yellow oil were added 1 mL of 20% aqueous sodium hydroxide solution and 4 mL of dioxane, and the mixture was stirred at room temperature for 5 hours and 30 minutes. 6 mol / L hydrochloric acid was added to the reaction mixture to adjust to pH 7.8, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 5: 1], 3.6 mol / L hydrogen chloride / ethyl acetate was added to the purified product, and the solvent was distilled off. Ethyl acetate was added to the obtained foam, and the solid substance was collected by filtration, and the pale yellow solid (2- (4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl 87 mg of amino) piperidin-1-yl) -1- (7-methoxyisoquinolin-1-yl) ethoxy) acetic acid hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.10-2.30 (2H, m), 2.30-2.45 (2H, m), 3.20-3.40 (3H, m), 3.44-3.90 (6H, m), 3.95 -4.22 (2H, m), 4.05 (3H, s), 4.26 (4H, s), 6.25-6.40 (1H, m), 6.90 (1H, d, J = 8.2Hz), 7.08 (1H, dd, J = 8.2,1.9Hz), 7.21 (1H, d, J = 1.9Hz), 7.64 (1H, dd, J = 8.9,1.9Hz), 7.89 (1H, d, J = 1.9Hz), 8.07 (1H, d , J = 5.6Hz), 8.12 (1H, d, J = 8.9Hz), 8.48 (1H, d, J = 5.6Hz)

メチル＝８−アミノキノリン−２−カルボキシラート0.10gおよび１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸0.17gから実施例４と同様にして、黄色泡状物のメチル＝８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）キノリン−２−カルボキシラート0.16gを得た。
¹H-NMR(CDCl₃)δ値：1.95-2.25(6H,m),2.48-2.63(3H,m),2.70-2.80(2H,m),3.08-3.16(2H,m),4.08(3H,s),4.24(4H,s),6.69(1H,dd,J=8.1,2.0Hz),6.74(1H,d,J=2.0Hz),6.79(1H,d,J=8.1Hz),7.55(1H,d,J=7.3Hz),7.65(1H,t,J=8.1Hz),8.20(1H,d,J=8.1Hz),8.30(1H,d,J=8.1Hz),8.86(1H,d,J=7.3Hz),10.01(1H,s)Example 78

0.10 g of methyl 8-aminoquinoline-2-carboxylate and 0.17 g of 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxylic acid To Example 4 as a yellow foam methyl = 8-(((1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine). 0.16 g of -4-yl) carbonyl) amino) quinoline-2-carboxylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.95-2.25 (6H, m), 2.48-2.63 (3H, m), 2.70-2.80 (2H, m), 3.08-3.16 (2H, m), 4.08 (3H , s), 4.24 (4H, s), 6.69 (1H, dd, J = 8.1, 2.0Hz), 6.74 (1H, d, J = 2.0Hz), 6.79 (1H, d, J = 8.1Hz), 7.55 (1H, d, J = 7.3Hz), 7.65 (1H, t, J = 8.1Hz), 8.20 (1H, d, J = 8.1Hz), 8.30 (1H, d, J = 8.1Hz), 8.86 (1H , d, J = 7.3Hz), 10.01 (1H, s)

メチル＝８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）キノリン−２−カルボキシラート90mgから実施例３３と同様にして、淡黄色固体の８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）キノリン−２−カルボン酸69mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.65-1.80(2H,m),1.83-1.92(2H,m),1.88-2.07(2H,m),2.48-2.74(5H,m),2.95-3.05(2H,m),4.20(4H,s),6.64-6.77(3H,m),7.65(1H,t,J=7.1Hz),7.71(1H,d,J=7.1Hz),8.16(1H,d,J=8.3Hz),8.50(1H,d,J=8.3Hz),8.76(1H,d,J=7.1Hz),10.45(1H,s)Example 79

Methyl = 8-(((1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidin-4-yl) carbonyl) amino) quinoline-2-carboxy The pale yellow solid 8-(((1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine- 69 mg of 4-yl) carbonyl) amino) quinoline-2-carboxylic acid were obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.65-1.80 (2H, m), 1.83-1.92 (2H, m), 1.88-2.07 (2H, m), 2.48-2.74 (5H, m), 2.95 -3.05 (2H, m), 4.20 (4H, s), 6.64-6.77 (3H, m), 7.65 (1H, t, J = 7.1Hz), 7.71 (1H, d, J = 7.1Hz), 8.16 ( 1H, d, J = 8.3Hz), 8.50 (1H, d, J = 8.3Hz), 8.76 (1H, d, J = 7.1Hz), 10.45 (1H, s)

Ｎ−（２−メトキシキノリン−８−イル）ピペリジン−４−カルボキサミド50mgのジメチルスルホキシド0.90mL溶液に、トリエチルアミン29μLおよび２−（２−クロロエチル）−１，２，３，４−テトラヒドロイソキノリン34mgを加え、室温で2時間攪拌した。トリエチルアミン58μLおよび２−（２−クロロエチル）−１，２，３，４−テトラヒドロイソキノリン68mgを加え、室温で1時間攪拌した。トリエチルアミン87μLおよび２−（クロロエチル）−１，２，３，４−テトラヒドロイソキノリン0.10gを加え、室温で1時間攪拌した。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、白色固体の１−（２−（３，４−ジヒドロイソキノリン−２（１Ｈ）−イル）エチル）−Ｎ−（２−メトキシキノリン−８−イル）ピペリジン−４−カルボキサミド25mgを得た。
¹H-NMR(CDCl₃)δ値：1.90-2.25(6H,m),2.40-2.50(1H,m),2.65-2.84(6H,m),2.88-2.94(2H,m),3.05-3.15(2H,m),3.70(2H,s),4.10(3H,s),6.96(1H,d,J=8.9Hz),6.98-7.05(1H,m),7.08-7.14(3H,m),7.38(1H,t,J=7.6Hz),7.41-7.45(1H,m),8.01(1H,d,J=8.9Hz),8.70-8.74(1H,m),9.62(1H,s)Example 80

To a solution of N- (2-methoxyquinolin-8-yl) piperidine-4-carboxamide 50 mg in dimethyl sulfoxide 0.90 mL was added 29 μL of triethylamine and 34 mg of 2- (2-chloroethyl) -1,2,3,4-tetrahydroisoquinoline. And stirred at room temperature for 2 hours. Triethylamine (58 μL) and 2- (2-chloroethyl) -1,2,3,4-tetrahydroisoquinoline (68 mg) were added, and the mixture was stirred at room temperature for 1 hour. 87 μL of triethylamine and 0.10 g of 2- (chloroethyl) -1,2,3,4-tetrahydroisoquinoline were added, and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed 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: chloroform: methanol = 50: 1] to give 1- (2- (3,4-dihydroisoquinolin-2 (1H) -yl) ethyl as a white solid. ) -N- (2-methoxyquinolin-8-yl) piperidine-4-carboxamide (25 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.90-2.25 (6H, m), 2.40-2.50 (1H, m), 2.65-2.84 (6H, m), 2.88-2.94 (2H, m), 3.05-3.15 (2H, m), 3.70 (2H, s), 4.10 (3H, s), 6.96 (1H, d, J = 8.9Hz), 6.98-7.05 (1H, m), 7.08-7.14 (3H, m), 7.38 (1H, t, J = 7.6Hz), 7.41-7.45 (1H, m), 8.01 (1H, d, J = 8.9Hz), 8.70-8.74 (1H, m), 9.62 (1H, s)

Ｎ−（２−メトキシキノリン−８−イル）ピペリジン−４−カルボキサミド35mgのトルエン0.20mL懸濁液に、７−ビニル−２，３−ジヒドロ［１，４］ジオキシノ［２，３−ｃ］ピリジン20mgを加え、2時間30分間加熱還流した。Ｎ，Ｎ−ジメチルホルムアミド0.20mLを加え、1時間加熱還流した。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＝２０：１］で精製し、褐色油状物の１−（２−（２，３−ジヒドロ［１，４］ジオキシノ［２，３−ｃ］ピリジン−７−イル）エチル）−Ｎ−（２−メトキシキノリン−８−イル）ピペリジン−４−カルボキサミド13mgを得た。
¹H-NMR(CDCl₃)δ値：1.90-2.05(2H,m),2.10-2.25(4H,m),2.38-2.48(1H,m),2.70-2.80(2H,m),2.85-2.92(2H,m),3.06-3.14(2H,m),4.10(3H,s),4.25-4.35(4H,m),6.71(1H,s),6.96(1H,d,J=8.8Hz),7.37(1H,t,J=7.8Hz),7.40-7.45(1H,m),8.01(1H,d,J=8.8Hz),8.08(1H,s),8.70-8.76(1H,m),9.62(1H,s)Example 81

To a suspension of N- (2-methoxyquinolin-8-yl) piperidine-4-carboxamide 35 mg in toluene 0.20 mL was added 7-vinyl-2,3-dihydro [1,4] dioxino [2,3-c] pyridine. 20 mg was added and heated to reflux for 2 hours 30 minutes. N, N-dimethylformamide 0.20 mL was added and heated to reflux for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 20: 1] to give 1- (2- (2,3-dihydro) as a brown oily substance. 13 mg of [1,4] dioxyno [2,3-c] pyridin-7-yl) ethyl) -N- (2-methoxyquinolin-8-yl) piperidine-4-carboxamide was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.90-2.05 (2H, m), 2.10-2.25 (4H, m), 2.38-2.48 (1H, m), 2.70-2.80 (2H, m), 2.85-2.92 (2H, m), 3.06-3.14 (2H, m), 4.10 (3H, s), 4.25-4.35 (4H, m), 6.71 (1H, s), 6.96 (1H, d, J = 8.8Hz), 7.37 (1H, t, J = 7.8Hz), 7.40-7.45 (1H, m), 8.01 (1H, d, J = 8.8Hz), 8.08 (1H, s), 8.70-8.76 (1H, m), 9.62 (1H, s)

７−ビニル−２，３−ジヒドロ［１，４］ジオキシノ［２，３−ｃ］ピリジン36mgのクロロベンゼン0.22mL溶液に、エチル＝３−（２−メトキシ−８−（（ピペリジン−４−イルカルボニル）アミノ）キノリン−５−イル）プロピオナート0.11gおよびクロロベンゼン1.1mLを加え、5時間30分間加熱還流した。酢酸13μLを加え、1時間30分間加熱還流した。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＝２５：１］で精製し、褐色油状物のエチル＝３−（８−（（（１−（２−（２，３−ジヒドロ［１，４］ジオキシノ［２，３−ｃ］ピリジン−７−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）プロピオナート35mgを得た。
¹H-NMR(CDCl₃)δ値：1.24(3H,t,J=7.1Hz),1.90-2.25(6H,m),2.38-2.48(1H,m),2.67(2H,t,J=7.9Hz),2.70-2.80(2H,m),2.85-2.95(2H,m),3.05-3.15(2H,m),3.29(2H,t,J=7.9Hz),4.09(3H,s),4.13(2H,q,J=7.1Hz),4.25-4.35(4H,m),6.71(1H,s),7.00(1H,d,J=9.2Hz),7.23(1H,d,J=8.1Hz),8.08(1H,s),8.24(1H,d,J=9.2Hz),8.62(1H,d,J=8.1Hz),9.62(1H,s)Example 82

To a solution of 36 mg of 7-vinyl-2,3-dihydro [1,4] dioxino [2,3-c] pyridine in 0.22 mL of chlorobenzene was added ethyl = 3- (2-methoxy-8-((piperidin-4-ylcarbonyl). ) Amino) quinolin-5-yl) propionate (0.11 g) and chlorobenzene (1.1 mL) were added, and the mixture was heated to reflux for 5 hours and 30 minutes. Acetic acid (13 μL) was added, and the mixture was refluxed for 1 hour and 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 25: 1] to give a brown oily ethyl = 3- (8-(((1 -(2- (2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-yl) ethyl) piperidin-4-yl) carbonyl) amino) -2-methoxyquinolin-5-yl ) Propionate 35mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.24 (3H, t, J = 7.1 Hz), 1.90-2.25 (6H, m), 2.38-2.48 (1H, m), 2.67 (2H, t, J = 7.9 Hz), 2.70-2.80 (2H, m), 2.85-2.95 (2H, m), 3.05-3.15 (2H, m), 3.29 (2H, t, J = 7.9Hz), 4.09 (3H, s), 4.13 (2H, q, J = 7.1Hz), 4.25-4.35 (4H, m), 6.71 (1H, s), 7.00 (1H, d, J = 9.2Hz), 7.23 (1H, d, J = 8.1Hz) , 8.08 (1H, s), 8.24 (1H, d, J = 9.2Hz), 8.62 (1H, d, J = 8.1Hz), 9.62 (1H, s)

エチル＝３−（８−（（（１−（２−（２，３−ジヒドロ［１，４］ジオキシノ［２，３−ｃ］ピリジン−７−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）プロピオナート33mgの90％エタノール水1.0mL溶液に、水酸化ナトリウム2.9mgを加え、室温で1時間攪拌した。1mol/L水酸化ナトリウム水溶液0.12mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、水0.50mLを加え、炭酸ガスを導入した。ジエチルエーテルおよび水を加え、固形物をろ取し、淡褐色固体の３−（８−（（（１−（２−（２，３−ジヒドロ［１，４］ジオキシノ［２，３−ｃ］ピリジン−７−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）プロピオン酸17mgを得た。
¹H-NMR(CD₃OD)δ値：1.94-2.10(2H,m),2.14-2.23(2H,m),2.52-3.10(11H,m),3.20-3.40(2H,m),4.11(3H,s),4.26-4.38(4H,m),6.86(1H,s),7.04(1H,d,J=9.2Hz),7.27(1H,d,J=8.2Hz),7.98(1H,s),8.40(1H,d,J=8.2Hz),8.45(1H,d,J=9.2Hz)Example 83

Ethyl = 3- (8-(((1- (2- (2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-yl) ethyl) piperidin-4-yl) carbonyl) Amino) -2-methoxyquinolin-5-yl) propionate 33 mg of 90% aqueous ethanol 1.0 mL was added with sodium hydroxide 2.9 mg and stirred at room temperature for 1 hour. 0.12 mL of 1 mol / L sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, 0.50 mL of water was added, and carbon dioxide gas was introduced. Diethyl ether and water were added, the solid was collected by filtration, and a pale brown solid 3- (8-(((1- (2- (2,3-dihydro [1,4] dioxino [2,3-c] 17 mg of pyridin-7-yl) ethyl) piperidin-4-yl) carbonyl) amino) -2-methoxyquinolin-5-yl) propionic acid were obtained.
¹ H-NMR (CD ₃ OD) δ value: 1.94-2.10 (2H, m), 2.14-2.23 (2H, m), 2.52-3.10 (11H, m), 3.20-3.40 (2H, m), 4.11 ( 3H, s), 4.26-4.38 (4H, m), 6.86 (1H, s), 7.04 (1H, d, J = 9.2Hz), 7.27 (1H, d, J = 8.2Hz), 7.98 (1H, s ), 8.40 (1H, d, J = 8.2Hz), 8.45 (1H, d, J = 9.2Hz)

Ｎ−（２−メトキシキノリン−８−イル）ピペリジン−４−カルボキサミド50mgおよび（４−ブロモブチル）ベンゼン45mgから参考例１０１と同様にして、白色固体のＮ−（２−メトキシキノリン−８−イル）−１−（４−フェニルブチル）ピペリジン−４−カルボキサミドの塩酸塩29mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.50-1.75(4H,m),1.91-2.04(2H,m),2.07-2.22(2H,m),2.41-2.58(2H,m),2.59-2.68(2H,m),2.80-3.15(3H,m),3.51-3.62(2H,m),4.11(3H,s),7.11(1H,d,J=8.8Hz),7.16-7.34(5H,m),7.41(1H,t,J=7.7Hz),7.62(1H,d,J=7.7Hz),8.28(1H,d,J=8.8Hz),8.45(1H,d,J=7.7Hz),9.45-9.60(1H,m),9.71(1H,s)Example 84

N- (2-methoxyquinolin-8-yl) as a white solid was prepared in the same manner as in Reference Example 101 from 50 mg of N- (2-methoxyquinolin-8-yl) piperidine-4-carboxamide and 45 mg of (4-bromobutyl) benzene. 29 mg of hydrochloride of -1- (4-phenylbutyl) piperidine-4-carboxamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.50-1.75 (4H, m), 1.91-2.04 (2H, m), 2.07-2.22 (2H, m), 2.41-2.58 (2H, m), 2.59 -2.68 (2H, m), 2.80-3.15 (3H, m), 3.51-3.62 (2H, m), 4.11 (3H, s), 7.11 (1H, d, J = 8.8Hz), 7.16-7.34 (5H , m), 7.41 (1H, t, J = 7.7Hz), 7.62 (1H, d, J = 7.7Hz), 8.28 (1H, d, J = 8.8Hz), 8.45 (1H, d, J = 7.7Hz) ), 9.45-9.60 (1H, m), 9.71 (1H, s)

エチル＝３−（２−メトキシ−８−（（ピペリジン−４−イルカルボニル）アミノ）キノリン−５−イル）プロピオナート70mgおよび（４−ブロモブチル）ベンゼン43mgから参考例１０１と同様にして、白色固体のエチル＝３−（２−メトキシ−８−（（（１−（４−フェニルブチル）ピペリジン−４−イル）カルボニル）アミノ）キノリン−５−イル）プロピオナート46mgを得た。
¹H-NMR(CDCl₃)δ値：1.24(3H,t,J=7.1Hz),1.53-1.70(4H,m),1.85-2.15(6H,m),2.35-2.45(3H,m),2.60-2.70(4H,m),2.95-3.05(2H,m),3.29(2H,t,J=7.8Hz),4.08(3H,s),4.13(2H,q,J=7.1Hz),6.99(1H,d,J=9.1Hz),7.16-7.30(6H,m),8.24(1H,d,J=9.1Hz),8.63(1H,d,J=8.0Hz),9.62(1H,s)Example 85

Ethyl = 3- (2-methoxy-8-((piperidin-4-ylcarbonyl) amino) quinolin-5-yl) propionate 70 mg and (4-bromobutyl) benzene 43 mg in the same manner as in Reference Example 101 46 mg of ethyl = 3- (2-methoxy-8-(((1- (4-phenylbutyl) piperidin-4-yl) carbonyl) amino) quinolin-5-yl) propionate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.24 (3H, t, J = 7.1 Hz), 1.53-1.70 (4H, m), 1.85-2.15 (6H, m), 2.35-2.45 (3H, m), 2.60-2.70 (4H, m), 2.95-3.05 (2H, m), 3.29 (2H, t, J = 7.8Hz), 4.08 (3H, s), 4.13 (2H, q, J = 7.1Hz), 6.99 (1H, d, J = 9.1Hz), 7.16-7.30 (6H, m), 8.24 (1H, d, J = 9.1Hz), 8.63 (1H, d, J = 8.0Hz), 9.62 (1H, s)

エチル＝３−（２−メトキシ−８−（（（１−（４−フェニルブチル）ピペリジン−４−イル）カルボニル）アミノ）キノリン−５−イル）プロピオナート40mgから実施例８３と同様にして、白色固体の３−（２−メトキシ−８−（（（１−（４−フェニルブチル）ピペリジンー４−イル）カルボニル）アミノ）キノリンー５−イル）プロピオン酸27mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.40-1.75(6H,m),1.87-2.00(4H,m),2.25-2.35(3H,m),2.45-2.65(4H,m),2.83-2.92(2H,m),3.19(2H,t,J=7.7Hz),4.07(3H,s),7.11(1H,d,J=9.3Hz),7.13-7.30(6H,m),8.38(1H,d,J=8.1Hz),8.43(1H,d,J=9.3Hz),9.59(1H,s)Example 86

Ethyl 3- (2-methoxy-8-(((1- (4-phenylbutyl) piperidin-4-yl) carbonyl) amino) quinolin-5-yl) propionate was used in the same manner as in Example 83 in the same manner as in Example 83. 27 mg of solid 3- (2-methoxy-8-(((1- (4-phenylbutyl) piperidin-4-yl) carbonyl) amino) quinolin-5-yl) propionic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.40-1.75 (6H, m), 1.87-2.00 (4H, m), 2.25-2.35 (3H, m), 2.45-2.65 (4H, m), 2.83 -2.92 (2H, m), 3.19 (2H, t, J = 7.7Hz), 4.07 (3H, s), 7.11 (1H, d, J = 9.3Hz), 7.13-7.30 (6H, m), 8.38 ( 1H, d, J = 8.1Hz), 8.43 (1H, d, J = 9.3Hz), 9.59 (1H, s)

エチル＝３−（８−アミノ−２−メトキシキノリン−５−イル）プロピオナート46mgおよび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）シクロヘキサンカルボン酸66mgから実施例１０と同様にして、無色油状物のエチル＝３−（８−（（（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）シクロヘキシル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）プロピオナート80mgを得た。
¹H-NMR(CDCl₃)δ値：1.23(3H,t,J=7.1Hz),1.33-1.60(11H,m),1.60-1.90(4H,m),2.10-2.35(3H,m),2.66(2H,t,J=7.9Hz),3.28(2H,t,J=7.9Hz),4.10(3H,s),4.13(2H,q,J=7.1Hz),4.20-4.50(7H,m),6.81(1H,s),6.99(1H,d,J=9.0Hz),7.21(1H,d,J=8.0Hz),8.06(1H,s),8.23(1H,d,J=9.0Hz),8.60(1H,d,J=8.0Hz),9.49(1H,s)Example 87

Ethyl = 3- (8-amino-2-methoxyquinolin-5-yl) propionate 46 mg and 4-((tert-butoxycarbonyl) (2,3-dihydro [1,4] dioxino [2,3-c] pyridine In the same manner as in Example 10 from 66 mg of -7-ylmethyl) amino) cyclohexanecarboxylic acid, ethyl = 3- (8-(((4-((tert-butoxycarbonyl) (2,3-dihydro [ 80 mg of 1,4] dioxyno [2,3-c] pyridin-7-ylmethyl) amino) cyclohexyl) carbonyl) amino) -2-methoxyquinolin-5-yl) propionate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.23 (3H, t, J = 7.1 Hz), 1.33-1.60 (11H, m), 1.60-1.90 (4H, m), 2.10-2.35 (3H, m), 2.66 (2H, t, J = 7.9Hz), 3.28 (2H, t, J = 7.9Hz), 4.10 (3H, s), 4.13 (2H, q, J = 7.1Hz), 4.20-4.50 (7H, m ), 6.81 (1H, s), 6.99 (1H, d, J = 9.0Hz), 7.21 (1H, d, J = 8.0Hz), 8.06 (1H, s), 8.23 (1H, d, J = 9.0Hz) ), 8.60 (1H, d, J = 8.0Hz), 9.49 (1H, s)

エチル＝３−（８−（（（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）シクロヘキシル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）プロピオナート80mgの塩化メチレン1.0mL溶液に、トリフルオロ酢酸0.50mL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90％エタノール水溶液1.0mLおよび5.0mol/L水酸化ナトリウム水溶液0.12mLを加え、室温で45分間攪拌した。5.0mol/L水酸化ナトリウム水溶液0.24mLを加え、室温で25分間攪拌した。減圧下で溶媒を留去し、水2.0mLを加え、炭酸ガスを導入した。固形物をろ取し、白色固体の３−（８−（（（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）シクロヘキシル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）プロピオン酸53mgを得た。
¹H-NMR(DMSO-d₆-D₂O)δ値：1.33-1.60(4H,m),2.04-2.18(4H,m),2.34-2.41(2H,m),2.45-2.65(1H,m),2.82-2.91(1H,m),3.12-3.20(2H,m),3.90-4.20(5H,m),4.27-4.40(4H,m),7.06(1H,s),7.13(1H,d,J=9.3Hz),7.27(1H,d,J=8.2Hz),8.12(1H,s),8.29(1H,d,J=8.2Hz),8.47(1H,d,J=9.3Hz),9.67(1H,s)Example 88

Ethyl = 3- (8-(((4-((tert-butoxycarbonyl) (2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino) cyclohexyl) carbonyl) To a solution of amino) -2-methoxyquinolin-5-yl) propionate in 80 mL of methylene chloride was added 0.50 mL of trifluoroacetic acid, and the mixture was stirred for 1 hour. The solvent was distilled off under reduced pressure, and 1.0 mL of 90% ethanol aqueous solution and 0.12 mL of 5.0 mol / L sodium hydroxide aqueous solution were added to the obtained residue, followed by stirring at room temperature for 45 minutes. 5.0 mol / L sodium hydroxide aqueous solution 0.24mL was added, and it stirred at room temperature for 25 minutes. The solvent was distilled off under reduced pressure, 2.0 mL of water was added, and carbon dioxide gas was introduced. The solid was collected by filtration to give 3- (8-(((4-((2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino) cyclohexyl) as a white solid. Carbonyl) amino) -2-methoxyquinolin-5-yl) propionic acid 53 mg was obtained.
¹ H-NMR (DMSO-d ₆ -D ₂ O) δ value: 1.33-1.60 (4H, m), 2.04-2.18 (4H, m), 2.34-2.41 (2H, m), 2.45-2.65 (1H, m), 2.82-2.91 (1H, m), 3.12-3.20 (2H, m), 3.90-4.20 (5H, m), 4.27-4.40 (4H, m), 7.06 (1H, s), 7.13 (1H, d, J = 9.3Hz), 7.27 (1H, d, J = 8.2Hz), 8.12 (1H, s), 8.29 (1H, d, J = 8.2Hz), 8.47 (1H, d, J = 9.3Hz) , 9.67 (1H, s)

２−メトキシ−５−（トリフルオロメチル）キノリン−８−アミン45mgおよび１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸91mgから実施例４と同様にして、固体の１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）−Ｎ−（２−メトキシ−５−（トリフルオロメチル）キノリン−８−イル）ピペリジン−４−カルボキサミド4.3mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.65-1.80(2H,m),1.90-2.00(2H,m),2.00-2.15(2H,m),2.40-2.55(2H,m),2.60-2.70(3H,m),2.95-3.05(2H,m),4.14(3H,s),4.20(4H,s),6.64-6.76(3H,m),7.33(1H,d,J=9.3Hz),7.88(1H,d,J=8.3Hz),8.36-8.40(1H,m),8.63(1H,d,J=8.3Hz),9.87(1H,s)Example 89

45 mg 2-methoxy-5- (trifluoromethyl) quinolin-8-amine and 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4- In the same manner as in Example 4 from 91 mg of carboxylic acid, solid 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) -N- (2-methoxy- 4.3 mg of 5- (trifluoromethyl) quinolin-8-yl) piperidine-4-carboxamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.65-1.80 (2H, m), 1.90-2.00 (2H, m), 2.00-2.15 (2H, m), 2.40-2.55 (2H, m), 2.60 -2.70 (3H, m), 2.95-3.05 (2H, m), 4.14 (3H, s), 4.20 (4H, s), 6.64-6.76 (3H, m), 7.33 (1H, d, J = 9.3Hz ), 7.88 (1H, d, J = 8.3Hz), 8.36-8.40 (1H, m), 8.63 (1H, d, J = 8.3Hz), 9.87 (1H, s)

エチル＝（２−メトキシ−８−（（（トリフルオロメチル）スルホニル）オキシ）キノリン−５−イル）アセタート55mgおよび１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボキサミド45mgから実施例６７と同様にして、黄色油状物のエチル＝（８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）アセタート26mgを得た。
¹H-NMR(CDCl₃)δ値：1.20(3H,t,J=7.1Hz),1.90-2.05(2H,m),2.10-2.25(4H,m),2.40-2.50(1H,m),2.55-2.65(2H,m),2.70-2.80(2H,m),3.05-3.15(2H,m),3.94(2H,s),4.10(3H,s),4.12(2H,q,J=7.1Hz),4.24(4H,s),6.68(1H,dd,J=8.3,1.9Hz),6.73(1H,d,J=1.9Hz),6.79(1H,d,J=8.3Hz),7.00(1H,d,J=9.2Hz),7.29(1H,d,J=8.1Hz),8.24(1H,d,J=9.2Hz),8.67(1H,d,J=8.1Hz),9.66(1H,s)Example 90

Ethyl = (2-methoxy-8-(((trifluoromethyl) sulfonyl) oxy) quinolin-5-yl) acetate 55 mg and 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin In the same manner as in Example 67, from 45 mg of 6-yl) ethyl) piperidine-4-carboxamide, ethyl = (8-(((1- (2- (2,3-dihydrobenzo [b] [ 26 mg of 1,4] dioxin-6-yl) ethyl) piperidin-4-yl) carbonyl) amino) -2-methoxyquinolin-5-yl) acetate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.20 (3H, t, J = 7.1 Hz), 1.90-2.05 (2H, m), 2.10-2.25 (4H, m), 2.40-2.50 (1H, m), 2.55-2.65 (2H, m), 2.70-2.80 (2H, m), 3.05-3.15 (2H, m), 3.94 (2H, s), 4.10 (3H, s), 4.12 (2H, q, J = 7.1 Hz), 4.24 (4H, s), 6.68 (1H, dd, J = 8.3, 1.9Hz), 6.73 (1H, d, J = 1.9Hz), 6.79 (1H, d, J = 8.3Hz), 7.00 ( 1H, d, J = 9.2Hz), 7.29 (1H, d, J = 8.1Hz), 8.24 (1H, d, J = 9.2Hz), 8.67 (1H, d, J = 8.1Hz), 9.66 (1H, s)

エチル＝（８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）アセタート23mgから実施例８３と同様にして、淡褐色固体の（８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）酢酸26mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.65-1.80(2H,m),1.90-2.20(4H,m),2.30-2.40(1H,m),2.40-2.70(4H,m),2.90-3.10(2H,m),3.98(2H,s),4.10(3H,s),4.21(4H,s),6.65-6.80(3H,m),7.14(1H,d,J=9.2Hz),7.30(1H,d,J=8.0Hz),8.34(1H,d,J=9.2Hz),8.42(1H,d,J=8.0Hz),9.66(1H,s)Example 91

Ethyl = (8-(((1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidin-4-yl) carbonyl) amino) -2-methoxy In the same manner as in Example 83, from 23 mg of quinolin-5-yl) acetate, (8-(((1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6 26 mg of -yl) ethyl) piperidin-4-yl) carbonyl) amino) -2-methoxyquinolin-5-yl) acetic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.65-1.80 (2H, m), 1.90-2.20 (4H, m), 2.30-2.40 (1H, m), 2.40-2.70 (4H, m), 2.90 -3.10 (2H, m), 3.98 (2H, s), 4.10 (3H, s), 4.21 (4H, s), 6.65-6.80 (3H, m), 7.14 (1H, d, J = 9.2Hz), 7.30 (1H, d, J = 8.0Hz), 8.34 (1H, d, J = 9.2Hz), 8.42 (1H, d, J = 8.0Hz), 9.66 (1H, s)

メチル＝２−（２−メトキシ−８−（（（トリフルオロメチル）スルホニル）オキシ）キノリン−５−イル）シクロプロパンカルボキシラート26mgおよび１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボキサミド21mgから実施例６７と同様にして、褐色油状物のメチル＝２−（８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）シクロプロパンカルボキシラート15mgを得た。
¹H-NMR(CDCl₃)δ値：1.35-1.45(1H,m),1.50-1.75(1H,m),1.85-2.25(7H,m),2.40-2.50(1H,m),2.50-2.90(5H,m),3.00-3.20(2H,m),3.79(3H,s),4.10(3H,s),4.24(4H,s),6.65-6.74(2H,m),6.79(1H,d,J=8.3Hz),7.03(1H,d,J=9.0Hz),7.13(1H,d,J=8.1Hz),8.39(1H,d,J=9.0Hz),8.55-8.64(1H,m),9.63(1H,s)Example 92

Methyl 2- (2-methoxy-8-(((trifluoromethyl) sulfonyl) oxy) quinolin-5-yl) cyclopropanecarboxylate 26 mg and 1- (2- (2,3-dihydrobenzo [b] [ 1,4] dioxin-6-yl) ethyl) piperidine-4-carboxamide in the same manner as in Example 67, the brown oily methyl 2- (8-(((1- (2- (2,3 -Dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidin-4-yl) carbonyl) amino) -2-methoxyquinolin-5-yl) cyclopropanecarboxylate 15 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.35-1.45 (1H, m), 1.50-1.75 (1H, m), 1.85-2.25 (7H, m), 2.40-2.50 (1H, m), 2.50-2.90 (5H, m), 3.00-3.20 (2H, m), 3.79 (3H, s), 4.10 (3H, s), 4.24 (4H, s), 6.65-6.74 (2H, m), 6.79 (1H, d , J = 8.3Hz), 7.03 (1H, d, J = 9.0Hz), 7.13 (1H, d, J = 8.1Hz), 8.39 (1H, d, J = 9.0Hz), 8.55-8.64 (1H, m ), 9.63 (1H, s)

メチル＝２−（８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）シクロプロパンカルボキシラート15mgから実施例８３と同様にして、黄色固体の２−（８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）シクロプロパンカルボン酸8.0mgを得た。
¹H-NMR(CD₃OD)δ値：1.20-1.35(1H,m),1.48-1.55(1H,m),1.65-1.75(1H,m),1.98-2.10(2H,m),2.17-2.25(2H,m),2.60-3.00(8H,m),3.35-3.50(2H,m),4.11(3H,s),4.20(4H,s),6.70-6.76(3H,m),7.00(1H,d,J=9.0Hz),7.12(1H,d,J=8.2Hz),8.36(1H,d,J=8.2Hz),8.51(1H,d,J=9.0Hz)Example 93

Methyl = 2- (8-((1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidin-4-yl) carbonyl) amino) -2 -Methoxyquinolin-5-yl) cyclopropanecarboxylate 15 mg in the same manner as in Example 83 in the form of a yellow solid 2- (8-(((1- (2- (2,3-dihydrobenzo [b] [1 , 4] dioxin-6-yl) ethyl) piperidin-4-yl) carbonyl) amino) -2-methoxyquinolin-5-yl) cyclopropanecarboxylic acid 8.0 mg.
¹ H-NMR (CD ₃ OD) δ value: 1.20-1.35 (1H, m), 1.48-1.55 (1H, m), 1.65-1.75 (1H, m), 1.98-2.10 (2H, m), 2.17- 2.25 (2H, m), 2.60-3.00 (8H, m), 3.35-3.50 (2H, m), 4.11 (3H, s), 4.20 (4H, s), 6.70-6.76 (3H, m), 7.00 ( 1H, d, J = 9.0Hz), 7.12 (1H, d, J = 8.2Hz), 8.36 (1H, d, J = 8.2Hz), 8.51 (1H, d, J = 9.0Hz)

メチル＝２−（８−アミノ−２−メトキシキノリン−５−イル）プロピオナート50mgおよび１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸67mgから実施例４と同様にして、褐色油状物のメチル＝２−（８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）プロピオナート62mgを得た。
¹H-NMR(CDCl₃)δ値：1.62(3H,d,J=7.1Hz),1.90-2.02(2H,m),2.10-2.20(4H,m),2.38-2.48(1H,m),2.56-2.62(2H,m),2.70-2.75(2H,m),3.06-3.14(2H,m),3.63(3H,s),4.10(3H,s),4.24(4H,s),4.30(1H,q,J=7.1Hz),6.68(1H,dd,J=8.1,2.0Hz),6.73(1H,d,J=2.0Hz),6.78(1H,d,J=8.1Hz),7.01(1H,d,J=9.3Hz),7.34(1H,d,J=8.0Hz),8.31(1H,d,J=9.3Hz),8.69(1H,d,J=8.0Hz),9.66(1H,s)Example 94

50 mg of methyl 2- (8-amino-2-methoxyquinolin-5-yl) propionate and 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine In the same manner as in Example 4 from 67 mg of -4-carboxylic acid, methyl 2- (8-(((1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin) 62 mg of -6-yl) ethyl) piperidin-4-yl) carbonyl) amino) -2-methoxyquinolin-5-yl) propionate were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.62 (3H, d, J = 7.1 Hz), 1.90-2.02 (2H, m), 2.10-2.20 (4H, m), 2.38-2.48 (1H, m), 2.56-2.62 (2H, m), 2.70-2.75 (2H, m), 3.06-3.14 (2H, m), 3.63 (3H, s), 4.10 (3H, s), 4.24 (4H, s), 4.30 ( 1H, q, J = 7.1Hz), 6.68 (1H, dd, J = 8.1,2.0Hz), 6.73 (1H, d, J = 2.0Hz), 6.78 (1H, d, J = 8.1Hz), 7.01 ( 1H, d, J = 9.3Hz), 7.34 (1H, d, J = 8.0Hz), 8.31 (1H, d, J = 9.3Hz), 8.69 (1H, d, J = 8.0Hz), 9.66 (1H, s)

メチル＝２−（８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）プロピオナート62mgから実施例８３と同様にして、淡褐色固体の２−（８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）プロピオン酸40mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.45(3H,d,J=6.8Hz),1.60-1.80(2H,m),1.85-2.00(2H,m),2.00-2.11(2H,m),2.45-2.70(5H,m),2.92-3.02(2H,m),4.09(3H,s),4.20(4H,s),4.32(1H,q,J=6.8Hz),6.62-6.76(3H,m),7.13(1H,d,J=9.0Hz),7.30(1H,d,J=8.3Hz),8.43(1H,d,J=8.3Hz),8.51(1H,d,J=9.0Hz),9.63(1H,s)Example 95

Methyl = 2- (8-((1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidin-4-yl) carbonyl) amino) -2 In the same manner as in Example 83, from 62 mg of -methoxyquinolin-5-yl) propionate, 2- (8-(((1- (2- (2,3-dihydrobenzo [b] [1,4 Dioxin-6-yl) ethyl) piperidin-4-yl) carbonyl) amino) -2-methoxyquinolin-5-yl) propionic acid 40 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.45 (3H, d, J = 6.8Hz), 1.60-1.80 (2H, m), 1.85-2.00 (2H, m), 2.00-2.11 (2H, m ), 2.45-2.70 (5H, m), 2.92-3.02 (2H, m), 4.09 (3H, s), 4.20 (4H, s), 4.32 (1H, q, J = 6.8Hz), 6.62-6.76 ( 3H, m), 7.13 (1H, d, J = 9.0Hz), 7.30 (1H, d, J = 8.3Hz), 8.43 (1H, d, J = 8.3Hz), 8.51 (1H, d, J = 9.0 Hz), 9.63 (1H, s)

エチル＝（Ｅ）−３−（２−メトキシ−８−（（ピペリジン−４−イルアセチル）アミノ）キノリン−５−イル）アクリラート50mgから参考例３６と同様にして、淡褐色固体のエチル＝（Ｅ）−３−（２−メトキシ−８−（（１−（２−（２−チエニルチオ）エチル）ピペリジン−４−イルアセチル）アミノ）キノリン−５−イル）アクリラート36mgを得た。
¹H-NMR(CDCl₃)δ値：1.32-1.46(2H,m),1.36(3H,t,J=7.2Hz),1.80-1.90(2H,m),1.90-2.10(3H,m),2.43(2H,d,J=7.1Hz),2.55-2.65(2H,m),2.85-2.95(4H,m),4.10(3H,s),4.30(2H,q,J=7.2Hz),6.50(1H,d,J=15.6Hz),6.96(1H,dd,J=5.3,3.5Hz),7.05(1H,d,J=9.1Hz),7.11(1H,dd,J=3.5,1.4Hz),7.32(1H,dd,J=5.3,1.4Hz),7.71(1H,d,J=8.3Hz),8.30(1H,d,J=15.6Hz),8.43(1H,d,J=9.1Hz),8.72(1H,d,J=8.3Hz),9.50(1H,s)Example 96

Ethyl = (E) -3- (2-methoxy-8-((piperidin-4-ylacetyl) amino) quinolin-5-yl) acrylate was treated in the same manner as in Reference Example 36 in the same manner as in Reference Example 36. 36 mg of) -3- (2-methoxy-8-((1- (2- (2-thienylthio) ethyl) piperidin-4-ylacetyl) amino) quinolin-5-yl) acrylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.32-1.46 (2H, m), 1.36 (3H, t, J = 7.2Hz), 1.80-1.90 (2H, m), 1.90-2.10 (3H, m), 2.43 (2H, d, J = 7.1Hz), 2.55-2.65 (2H, m), 2.85-2.95 (4H, m), 4.10 (3H, s), 4.30 (2H, q, J = 7.2Hz), 6.50 (1H, d, J = 15.6Hz), 6.96 (1H, dd, J = 5.3,3.5Hz), 7.05 (1H, d, J = 9.1Hz), 7.11 (1H, dd, J = 3.5,1.4Hz) , 7.32 (1H, dd, J = 5.3,1.4Hz), 7.71 (1H, d, J = 8.3Hz), 8.30 (1H, d, J = 15.6Hz), 8.43 (1H, d, J = 9.1Hz) , 8.72 (1H, d, J = 8.3Hz), 9.50 (1H, s)

エチル＝（Ｅ）−３−（２−メトキシ−８−（（１−（２−（２−チエニルチオ）エチル）ピペリジン−４−イルアセチル）アミノ）キノリン−５−イル）アクリラート36mgから実施例８３と同様にして、淡褐色固体の（Ｅ）−３−（２−メトキシ−８−（（１−（２−（２−チエニルチオ）エチル）ピペリジン−４−イルアセチル）アミノ）キノリン−５−イル）アクリル酸23mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.20-1.35(2H,m),1.65-1.85(3H,m),1.85-2.00(2H,m),2.47-2.54(4H,m),2.78-2.85(2H,m),2.90-2.96(2H,m),4.12(3H,s),6.56(1H,d,J=15.5Hz),7.03(1H,dd,J=5.2,3.6Hz),7.15-7.18(2H,m),7.59(1H,dd,J=5.2,1.2Hz),7.89(1H,d,J=8.3Hz),8.19(1H,d,J=15.5Hz),8.54(1H,d,J=8.3Hz),8.60(1H,d,J=9.2Hz),9.66(1H,s)Example 97

Ethyl = (E) -3- (2-methoxy-8-((1- (2- (2-thienylthio) ethyl) piperidin-4-ylacetyl) amino) quinolin-5-yl) acrylate 36 mg from Example 83 Similarly, (E) -3- (2-methoxy-8-((1- (2- (2-thienylthio) ethyl) piperidin-4-ylacetyl) amino) quinolin-5-yl) acrylic is a light brown solid. 23 mg of acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.20-1.35 (2H, m), 1.65-1.85 (3H, m), 1.85-2.00 (2H, m), 2.47-2.54 (4H, m), 2.78 -2.85 (2H, m), 2.90-2.96 (2H, m), 4.12 (3H, s), 6.56 (1H, d, J = 15.5Hz), 7.03 (1H, dd, J = 5.2,3.6Hz), 7.15-7.18 (2H, m), 7.59 (1H, dd, J = 5.2,1.2Hz), 7.89 (1H, d, J = 8.3Hz), 8.19 (1H, d, J = 15.5Hz), 8.54 (1H , d, J = 8.3Hz), 8.60 (1H, d, J = 9.2Hz), 9.66 (1H, s)

エチル＝（Ｅ）−３−（８−アミノ−２−メトキシキノリン−５−イル）アクリラート0.11gおよび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）シクロヘキサンカルボン酸0.15gから実施例１０と同様にして、褐色油状物のエチル＝（Ｅ）−３−（８−（（（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）シクロヘキシル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）アクリラート0.13gを得た。
¹H-NMR(CDCl₃)δ値：1.23-1.53(11H,m),1.36(3H,t,J=7.1Hz),1.65-1.90(4H,m),2.15-2.40(3H,m),4.11(3H,s),4.20-4.55(9H,m),6.50(1H,d,J=15.5Hz),6.81(1H,s),7.05(1H,d,J=9.2Hz),7.70(1H,d,J=8.0Hz),8.06(1H,s),8.30(1H,d,J=15.5Hz),8.43(1H,d,J=9.2Hz),8.72(1H,d,J=8.0Hz),9.60-9.65(1H,broad)Example 98

Ethyl = (E) -3- (8-amino-2-methoxyquinolin-5-yl) acrylate 0.11 g and 4-((tert-butoxycarbonyl) (2,3-dihydro [1,4] dioxyno [2, 3-c] Pyridin-7-ylmethyl) amino) cyclohexanecarboxylic acid was used in the same manner as in Example 10 to obtain a brown oily ethyl = (E) -3- (8-(((4-((tert- Butoxycarbonyl) (2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino) cyclohexyl) carbonyl) amino) -2-methoxyquinolin-5-yl) acrylate 0.13 g Obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.23-1.53 (11H, m), 1.36 (3H, t, J = 7.1 Hz), 1.65-1.90 (4H, m), 2.15-2.40 (3H, m), 4.11 (3H, s), 4.20-4.55 (9H, m), 6.50 (1H, d, J = 15.5Hz), 6.81 (1H, s), 7.05 (1H, d, J = 9.2Hz), 7.70 (1H , d, J = 8.0Hz), 8.06 (1H, s), 8.30 (1H, d, J = 15.5Hz), 8.43 (1H, d, J = 9.2Hz), 8.72 (1H, d, J = 8.0Hz ), 9.60-9.65 (1H, broad)

エチル＝（Ｅ）−３−（８−（（（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）シクロヘキシル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）アクリラート0.13gから実施例８８と同様にして、黄色固体の（Ｅ）−３−（８−（（（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）シクロヘキシル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）アクリル酸43mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.10-1.25(2H,m),1.40-1.60(2H,m),1.95-2.05(4H,m),2.30-2.70(2H,m),3.70(2H,s),4.11(3H,s),4.25-4.40(4H,m),6.52(1H,d,J=15.4Hz),6.95(1H,s),7.16(1H,d,J=9.0Hz),7.75-7.86(1H,m),7.90-8.10(1H,m),8.01(1H,s),8.50-8.60(2H,m),9.70(1H,s)Example 99

Ethyl = (E) -3- (8-(((4-((tert-butoxycarbonyl) (2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino) Cyclohexyl) carbonyl) amino) -2-methoxyquinolin-5-yl) acrylate was used in the same manner as in Example 88 to give (E) -3- (8-(((4-((2,3 -43 mg of dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino) cyclohexyl) carbonyl) amino) -2-methoxyquinolin-5-yl) acrylic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.10-1.25 (2H, m), 1.40-1.60 (2H, m), 1.95-2.05 (4H, m), 2.30-2.70 (2H, m), 3.70 (2H, s), 4.11 (3H, s), 4.25-4.40 (4H, m), 6.52 (1H, d, J = 15.4Hz), 6.95 (1H, s), 7.16 (1H, d, J = 9.0 Hz), 7.75-7.86 (1H, m), 7.90-8.10 (1H, m), 8.01 (1H, s), 8.50-8.60 (2H, m), 9.70 (1H, s)

エチル＝（Ｅ）−３−（２−メトキシ−８−（（ピペリジン−４−イルアセチル）アミノ）キノリン−５−イル）アクリラート50mgから参考例１と同様にして、無色油状物のエチル＝（Ｅ）−３−（８−（（（１−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）ピペリジン−４−イル）アセチル）アミノ）−２−メトキシキノリン−５−イル）アクリラート53mgを得た。
¹H-NMR(CDCl₃)δ値：1.36(3H,t,J=7.1Hz),1.38-1.50(2H,m),1.70-2.05(5H,m),2.44(2H,d,J=7.0Hz),2.85-2.95(2H,m),3.40(2H,s),4.10(3H,s),4.24(4H,s),4.30(2H,q,J=7.1Hz),6.50(1H,d,J=15.7Hz),6.74-6.84(3H,m),7.05(1H,d,J=9.3Hz),7.71(1H,d,J=8.4Hz),8.30(1H,d,J=15.7Hz),8.43(1H,d,J=9.3Hz),8.72(1H,d,J=8.4Hz),9.50(1H,s)Example 100

Ethyl = (E) -3- (2-methoxy-8-((piperidin-4-ylacetyl) amino) quinolin-5-yl) acrylate was prepared in the same manner as in Reference Example 1 in the same manner as in Reference Example 1, and ethyl = (E ) -3- (8-(((1- (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) piperidin-4-yl) acetyl) amino) -2-methoxyquinoline-5 -Yl) 53 mg of acrylate were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.36 (3H, t, J = 7.1 Hz), 1.38-1.50 (2H, m), 1.70-2.05 (5H, m), 2.44 (2H, d, J = 7.0 Hz), 2.85-2.95 (2H, m), 3.40 (2H, s), 4.10 (3H, s), 4.24 (4H, s), 4.30 (2H, q, J = 7.1Hz), 6.50 (1H, d , J = 15.7Hz), 6.74-6.84 (3H, m), 7.05 (1H, d, J = 9.3Hz), 7.71 (1H, d, J = 8.4Hz), 8.30 (1H, d, J = 15.7Hz) ), 8.43 (1H, d, J = 9.3Hz), 8.72 (1H, d, J = 8.4Hz), 9.50 (1H, s)

エチル＝（Ｅ）−３−（８−（（（１−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）ピペリジン−４−イル）アセチル）アミノ）−２−メトキシキノリン−５−イル）アクリラート53mgから実施例８３と同様にして、白色固体の（Ｅ）−３−（８−（（（１−（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）アセチル）アミノ）−２−メトキシキノリン−５−イル）アクリル酸24mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.20-1.36(2H,m),1.65-1.95(5H,m),2.30-2.70(2H,m),2.72-2.80(2H,m),3.25-3.35(2H,m),4.10(3H,s),4.21(4H,s),6.38(1H,d,J=15.5Hz),6.68-6.79(3H,m),7.12(1H,d,J=9.2Hz),7.62(1H,d,J=8.3Hz),7.67(1H,d,J=15.5Hz),8.46(1H,d,J=8.3Hz),8.48(1H,d,J=9.2Hz),9.57(1H,s)Example 101

Ethyl = (E) -3- (8-(((1- (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) piperidin-4-yl) acetyl) amino) -2- (E) -3- (8-(((1- (2,3-dihydro-1,4-benzodioxin-6) was obtained in the same manner as in Example 83 from 53 mg of methoxyquinolin-5-yl) acrylate. 24 mg of -ylmethyl) piperidin-4-yl) acetyl) amino) -2-methoxyquinolin-5-yl) acrylic acid were obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.20-1.36 (2H, m), 1.65-1.95 (5H, m), 2.30-2.70 (2H, m), 2.72-2.80 (2H, m), 3.25 -3.35 (2H, m), 4.10 (3H, s), 4.21 (4H, s), 6.38 (1H, d, J = 15.5Hz), 6.68-6.79 (3H, m), 7.12 (1H, d, J = 9.2Hz), 7.62 (1H, d, J = 8.3Hz), 7.67 (1H, d, J = 15.5Hz), 8.46 (1H, d, J = 8.3Hz), 8.48 (1H, d, J = 9.2 Hz), 9.57 (1H, s)

エチル＝（Ｅ）−３−（８−（２−（４−アミノピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラートの塩酸塩73mgから参考例１と同様にして、無色泡状物のエチル＝（Ｅ）−３−（８−（１−ヒドロキシ−２−（４−（（（２−オキソ−１，２−ジヒドロキノリン−３−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−２−メトキシキノリン−５−イル）アクリラート48mgを得た。
¹H-NMR(CDCl₃)δ値：1.37(3H,t,J=7.1Hz),1.50-2.12(4H,m),2.15-2.25(1H,m),2.35-2.50(2H,m),2.55-2.70(1H,m),2.82-2.90(1H,m),3.00-3.05(1H,m),3.25-3.35(1H,m),3.86(2H,s),4.03(3H,s),4.30(2H,q,J=7.1Hz),5.75-5.85(1H,m),6.52(1H,d,J=16.0Hz),6.98(1H,d,J=9.1Hz),7.15-7.25(2H,m),7.44-7.58(2H,m),7.69(1H,d,J=7.8Hz),7.81(1H,s),7.90(1H,d,J=7.8Hz),8.35(1H,d,J=16.0Hz),8.38(1H,d,J=9.1Hz)Example 102

From Reference Example 1 and 73 mg of hydrochloride of ethyl = (E) -3- (8- (2- (4-aminopiperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate Similarly, colorless foam ethyl = (E) -3- (8- (1-hydroxy-2- (4-(((2-oxo-1,2-dihydroquinolin-3-yl) methyl)) 48 mg of amino) piperidin-1-yl) ethyl) -2-methoxyquinolin-5-yl) acrylate were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.37 (3H, t, J = 7.1 Hz), 1.50-2.12 (4H, m), 2.15-2.25 (1H, m), 2.35-2.50 (2H, m), 2.55-2.70 (1H, m), 2.82-2.90 (1H, m), 3.00-3.05 (1H, m), 3.25-3.35 (1H, m), 3.86 (2H, s), 4.03 (3H, s), 4.30 (2H, q, J = 7.1Hz), 5.75-5.85 (1H, m), 6.52 (1H, d, J = 16.0Hz), 6.98 (1H, d, J = 9.1Hz), 7.15-7.25 (2H , m), 7.44-7.58 (2H, m), 7.69 (1H, d, J = 7.8Hz), 7.81 (1H, s), 7.90 (1H, d, J = 7.8Hz), 8.35 (1H, d, J = 16.0Hz), 8.38 (1H, d, J = 9.1Hz)

エチル＝（Ｅ）−３−（８−（１−ヒドロキシ−２−（４−（（（２−オキソ−１，２−ジヒドロキノリン−３−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−２−メトキシキノリン−５−イル）アクリラート48mgから実施例８３と同様にして、白色固体の（Ｅ）−３−（８−（１−ヒドロキシ−２−（４−（（（２−オキソ−１，２−ジヒドロキノリン−３−イル）メチル）アミノ）ピペリジン−１−イル）エチル）−２−メトキシキノリン−５−イル）アクリル酸33mgを得た。
¹H-NMR(DMSO-d₆-D₂O)δ値：1.60-1.80(2H,m),2.00-2.20(2H,m),2.30-2.90(3H,m),2.95-3.10(2H,m),3.15-3.30(1H,m),3.40-3.52(1H,m),3.94(2H,s),4.03(3H,s),5.90-5.97(1H,m),6.61(1H,d,J=15.7Hz),7.15(1H,d,J=9.4Hz),7.27(1H,t,J=7.8Hz),7.39(1H,d,J=7.8Hz),7.57(1H,t,J=7.8Hz),7.72(1H,d,J=7.8Hz),7.88-7.93(2H,m),8.08(1H,s),8.28(1H,d,J=15.7Hz),8.57(1H,d,J=9.4Hz)Example 103

Ethyl = (E) -3- (8- (1-hydroxy-2- (4-(((2-oxo-1,2-dihydroquinolin-3-yl) methyl) amino) piperidin-1-yl) ethyl ) -2-Methoxyquinolin-5-yl) acrylate was used in the same manner as in Example 83 in the same manner as in Example 83 to obtain (E) -3- (8- (1-hydroxy-2- (4-(((2-oxo 33 mg of -1,2-dihydroquinolin-3-yl) methyl) amino) piperidin-1-yl) ethyl) -2-methoxyquinolin-5-yl) acrylic acid was obtained.
¹ H-NMR (DMSO-d ₆ -D ₂ O) δ value: 1.60-1.80 (2H, m), 2.00-2.20 (2H, m), 2.30-2.90 (3H, m), 2.95-3.10 (2H, m), 3.15-3.30 (1H, m), 3.40-3.52 (1H, m), 3.94 (2H, s), 4.03 (3H, s), 5.90-5.97 (1H, m), 6.61 (1H, d, J = 15.7Hz), 7.15 (1H, d, J = 9.4Hz), 7.27 (1H, t, J = 7.8Hz), 7.39 (1H, d, J = 7.8Hz), 7.57 (1H, t, J = 7.8Hz), 7.72 (1H, d, J = 7.8Hz), 7.88-7.93 (2H, m), 8.08 (1H, s), 8.28 (1H, d, J = 15.7Hz), 8.57 (1H, d, (J = 9.4Hz)

１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸33mgの塩化メチレン2mL溶液に、塩化チオニル1mLおよびＮ，Ｎ−ジメチルホルムアミド20μLを加え、2時間加熱還流した。減圧下で溶媒を留去し、クロロホルム2mL、５−フルオロ−２−メトキシキノリン−８−アミン18mgのクロロホルム3mL溶液およびトリエチルアミン38μLを加え、室温で30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、淡褐色固体の１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）−Ｎ−（５−フルオロ−２−メトキシキノリン−８−イル）ピペリジン−４−カルボキサミド17mgを得た。
¹H-NMR(CDCl₃)δ値：1.90-2.05(2H,m),2.10-2.25(4H,m),2.35-2.50(1H,m),2.55-2.65(2H,m),2.70-2.78(2H,m),3.08-3.17(2H,m),4.11(3H,s),4.24(4H,s),6.68(1H,dd,J=8.1,2.0Hz),6.73(1H,d,J=2.0Hz),6.78(1H,d,J=8.1Hz),6.99-7.07(2H,m),8.27(1H,d,J=9.0Hz),8.66(1H,dd,J=8.8,5.4Hz),9.41(1H,s)Example 104

To a solution of 33 mg of 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxylic acid in 2 mL of methylene chloride was added 1 mL of thionyl chloride and N, N- Dimethylformamide (20 μL) was added and the mixture was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure, chloroform (2 mL), 5-fluoro-2-methoxyquinolin-8-amine (18 mg) in chloroform (3 mL) and triethylamine (38 μL) were added, and the mixture was stirred at room temperature for 30 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 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: chloroform: methanol = 20: 1] to give 1- (2- (2,3-dihydrobenzo [b] [1,4] as a light brown solid. Dioxin-6-yl) ethyl) -N- (5-fluoro-2-methoxyquinolin-8-yl) piperidine-4-carboxamide 17 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.90-2.05 (2H, m), 2.10-2.25 (4H, m), 2.35-2.50 (1H, m), 2.55-2.65 (2H, m), 2.70-2.78 (2H, m), 3.08-3.17 (2H, m), 4.11 (3H, s), 4.24 (4H, s), 6.68 (1H, dd, J = 8.1,2.0Hz), 6.73 (1H, d, J = 2.0Hz), 6.78 (1H, d, J = 8.1Hz), 6.99-7.07 (2H, m), 8.27 (1H, d, J = 9.0Hz), 8.66 (1H, dd, J = 8.8,5.4Hz ), 9.41 (1H, s)

１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸73mgの塩化メチレン2mL溶液に、塩化チオニル1mLおよびＮ，Ｎ−ジメチルホルムアミド20μLを加え、2時間加熱還流した。減圧下で溶媒を留去した。クロロホルム2mL、７−フルオロ−２−メトキシキノリン−８−アミン40mgのクロロホルム3mL溶液およびトリエチルアミン87μLを加え、室温で30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、1.0mol/L水酸化ナトリウム水溶液でpH10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、淡灰色固体の１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）−Ｎ−（７−フルオロ−２−メトキシキノリン−８−イル）ピペリジン−４−カルボキサミド53mgを得た。
¹H-NMR(CDCl₃)δ値：1.80-2.25(6H,m),2.45-2.65(3H,m),2.68-2.78(2H,m),3.06-3.14(2H,m),4.05(3H,s),4.24(4H,s),6.66-6.80(3H,m),6.88(1H,d,J=8.8Hz),7.20-7.30(1H,m),7.54(1H,dd,J=8.8,5.4Hz),7.95-7.97(2H,m)Example 105

To a solution of 73 mg of 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxylic acid in 2 mL of methylene chloride was added 1 mL of thionyl chloride and N, N- Dimethylformamide (20 μL) was added and the mixture was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure. Chloroform (2 mL), 7-fluoro-2-methoxyquinolin-8-amine (40 mg) in chloroform (3 mL) and triethylamine (87 μL) were added, and the mixture was stirred at room temperature for 30 minutes. Water and chloroform were added to the reaction mixture, and the pH was adjusted to 10 with a 1.0 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 silica gel column chromatography [eluent: chloroform: methanol = 20: 1] to give 1- (2- (2,3-dihydrobenzo [b] [1,4] as a light gray solid. Dioxin-6-yl) ethyl) -N- (7-fluoro-2-methoxyquinolin-8-yl) piperidine-4-carboxamide 53 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.80-2.25 (6H, m), 2.45-2.65 (3H, m), 2.68-2.78 (2H, m), 3.06-3.14 (2H, m), 4.05 (3H , s), 4.24 (4H, s), 6.66-6.80 (3H, m), 6.88 (1H, d, J = 8.8Hz), 7.20-7.30 (1H, m), 7.54 (1H, dd, J = 8.8 , 5.4Hz), 7.95-7.97 (2H, m)

７−メトキシ−１−（オキシラン−２−イル）イソキノリン50mgのＮ，Ｎ−ジメチルホルムアミド3mL溶液に、室温でＮ−（２−フェニルエチル）ピペリジン−４−カルボキサミド58mgおよび過塩素酸リチウム27mgを加え、80〜90℃で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、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＝９：１］で精製し、淡褐色固体の１−（２−ヒドロキシ−２−（７−メトキシイソキノリン−１−イル）エチル）−Ｎ−（２−フェニルエチル）ピペリジン−４−カルボキサミド90mgを得た。
¹H-NMR(CDCl₃)δ値：1.70-1.90(4H,m),2.00-2.35(3H,m),2.72-2.87(4H,m),3.11-3.22(2H,m),3.52-3.57(2H,m),3.96(3H,s),5.44-5.54(2H,m),7.15-7.40(6H,m),7.48(1H,d,J=2.4Hz),7.53(1H,d,J=5.9Hz),7.76(1H,d,J=9.0Hz),8.35(1H,d,J=5.6Hz)Example 106

To a solution of 50 mg of 7-methoxy-1- (oxiran-2-yl) isoquinoline in 3 mL of N, N-dimethylformamide was added 58 mg of N- (2-phenylethyl) piperidine-4-carboxamide and 27 mg of lithium perchlorate at room temperature. , And stirred at 80-90 ° C. 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, 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: chloroform: methanol = 9: 1] to give 1- (2-hydroxy-2- (7-methoxyisoquinolin-1-yl) ethyl as a light brown solid. ) -N- (2-phenylethyl) piperidine-4-carboxamide 90 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.70-1.90 (4H, m), 2.00-2.35 (3H, m), 2.72-2.87 (4H, m), 3.11-3.22 (2H, m), 3.52-3.57 (2H, m), 3.96 (3H, s), 5.44-5.54 (2H, m), 7.15-7.40 (6H, m), 7.48 (1H, d, J = 2.4Hz), 7.53 (1H, d, J = 5.9Hz), 7.76 (1H, d, J = 9.0Hz), 8.35 (1H, d, J = 5.6Hz)

８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−４−カルボン酸35mgのＮ，Ｎ−ジメチルホルムアミド2mL懸濁液に、室温でグリシン＝エチル＝エステルの塩酸塩10mg、Ｏ−（７−アザベンゾトリアゾール−１−イル）−１，１，３，３−テトラメチルウロニウム＝ヘキサフルオロホスフェート40mgおよびトリエチルアミン29μLを加え、70℃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、淡褐色固体のＮ−（（８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−４−イル）カルボニル）グリシン＝エチル＝エステル22mgを得た。
¹H-NMR(CDCl₃)δ値：1.34(3H,t,J=7.2Hz),1.90-2.05(2H,m),2.10-2.25(4H,m),2.40-2.50(1H,m),2.58-2.65(2H,m),2.70-2.77(2H,m),3.08-3.16(2H,m),4.10(3H,s),4.24(4H,s),4.29(2H,q,J=7.2Hz),4.30(2H,d,J=5.2Hz),6.63(1H,t,J=5.2Hz),6.68(1H,dd,J=8.2,2.0Hz),6.73(1H,d,J=2.0Hz),6.78(1H,d,J=8.2Hz),7.09(1H,s),7.42(1H,t,J=8.2Hz),7.81(1H,dd,J=8.2,1.1Hz),8.74(1H,dd,J=8.2,1.1Hz),9.58(1H,s)Example 107

8-(((1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidin-4-yl) carbonyl) amino) -2-methoxyquinoline-4 -To a suspension of 35 mg of carboxylic acid in 2 mL of N, N-dimethylformamide, 10 mg of glycine ethyl ester hydrochloride, O- (7-azabenzotriazol-1-yl) -1,1,3,3 at room temperature -Tetramethyluronium = hexafluorophosphate 40 mg and triethylamine 29 μL were added and stirred at 70 ° C. for 1 hour. The reaction mixture was cooled to room temperature 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, 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 light brown solid N-((8-(((1- (2- (2,3-dihydro 22 mg of benzo [b] [1,4] dioxin-6-yl) ethyl) piperidin-4-yl) carbonyl) amino) -2-methoxyquinolin-4-yl) carbonyl) glycine = ethyl ester were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.34 (3H, t, J = 7.2 Hz), 1.90-2.05 (2H, m), 2.10-2.25 (4H, m), 2.40-2.50 (1H, m), 2.58-2.65 (2H, m), 2.70-2.77 (2H, m), 3.08-3.16 (2H, m), 4.10 (3H, s), 4.24 (4H, s), 4.29 (2H, q, J = 7.2 Hz), 4.30 (2H, d, J = 5.2Hz), 6.63 (1H, t, J = 5.2Hz), 6.68 (1H, dd, J = 8.2, 2.0Hz), 6.73 (1H, d, J = 2.0) Hz), 6.78 (1H, d, J = 8.2Hz), 7.09 (1H, s), 7.42 (1H, t, J = 8.2Hz), 7.81 (1H, dd, J = 8.2, 1.1Hz), 8.74 ( 1H, dd, J = 8.2,1.1Hz), 9.58 (1H, s)

Ｎ−（（８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−４−イル）カルボニル）グリシン＝エチル＝エステル18mgのメタノール1mL、テトラヒドロフラン1mLおよび水0.5mL溶液に、20％水酸化ナトリウム水溶液37μLを加え、室温で3時間攪拌した。反応混合物に水を加え、1.0mol/L塩酸でpH5.0に調整した。固形物をろ取し、水およびジエチルエーテルで順次洗浄し、白色固体のＮ−（（８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−４−イル）カルボニル）グリシン6mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.65-1.85(2H,m),1.90-2.05(2H,m),2.05-2.20(2H,m),2.45-2.70(5H,m),2.95-3.10(2H,m),3.97(2H,d,J=5.8Hz),4.13(3H,s),4.20(4H,s),6.65-6.70(1H,m),6.72-6.77(2H,m),7.10(1H,s),7.43(1H,t,J=8.0Hz),7.83(1H,d,J=8.0Hz),8.51(1H,d,J=8.0Hz),9.08(1H,t,J=5.8Hz),9.68(1H,s)Example 108

N-((8-((1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidin-4-yl) carbonyl) amino) -2- Methoxyquinolin-4-yl) carbonyl) glycine = ethyl = 18 mg of methanol (1 mL), tetrahydrofuran (1 mL) and water (0.5 mL) were added with 20% aqueous sodium hydroxide (37 μL) and stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the pH was adjusted to 5.0 with 1.0 mol / L hydrochloric acid. The solid was collected by filtration, washed successively with water and diethyl ether, and white solid N-((8-((1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin- 6 mg of 6-yl) ethyl) piperidin-4-yl) carbonyl) amino) -2-methoxyquinolin-4-yl) carbonyl) glycine were obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.65-1.85 (2H, m), 1.90-2.05 (2H, m), 2.05-2.20 (2H, m), 2.45-2.70 (5H, m), 2.95 -3.10 (2H, m), 3.97 (2H, d, J = 5.8Hz), 4.13 (3H, s), 4.20 (4H, s), 6.65-6.70 (1H, m), 6.72-6.77 (2H, m ), 7.10 (1H, s), 7.43 (1H, t, J = 8.0Hz), 7.83 (1H, d, J = 8.0Hz), 8.51 (1H, d, J = 8.0Hz), 9.08 (1H, t , J = 5.8Hz), 9.68 (1H, s)

１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸0.36gの塩化メチレン4mL懸濁液に、塩化チオニル2mLおよびＮ，Ｎ−ジメチルホルムアミド20μLを加え、3時間加熱還流した。減圧下で溶媒を留去し、クロロホルム5mL、エチル＝３−（８−アミノ−２−メトキシキノリン−５−イル）プロピオナート0.28gおよびトリエチルアミン0.43mLを加え、室温で1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、淡褐色固体のエチル＝３−（８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）プロピオナート0.41gを得た。
¹H-NMR(CDCl₃)δ値：1.24(3H,t,J=7.3Hz),1.90-2.03(2H,m),2.10-2.20(4H,m),2.37-2.48(1H,m),2.56-2.76(6H,m),3.06-3.14(2H,m),3.26-3.33(2H,m),4.10(3H,s),4.13(2H,q,J=7.3Hz),4.24(4H,s),6.68(1H,dd,J=8.2,2.0Hz),6.73(1H,d,J=2.0Hz),6.78(1H,d,J=8.2Hz),7.00(1H,d,J=9.1Hz),7.23(1H,d,J=8.0Hz),8.25(1H,d,J=9.1Hz),8.63(1H,d,J=8.0Hz),9.63(1H,s)Example 109

To a suspension of 0.36 g of 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxylic acid in 4 mL of methylene chloride, 2 mL of thionyl chloride and N , N-dimethylformamide (20 μL) was added, and the mixture was heated to reflux for 3 hours. The solvent was distilled off under reduced pressure, 5 mL of chloroform, 0.28 g of ethyl = 3- (8-amino-2-methoxyquinolin-5-yl) propionate and 0.43 mL of triethylamine were added, and the mixture was stirred at room temperature for 1 hour. 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 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: chloroform: methanol = 20: 1], and light brown solid ethyl = 3- (8-(((1- (2- (2,3- 0.41 g of dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidin-4-yl) carbonyl) amino) -2-methoxyquinolin-5-yl) propionate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.24 (3H, t, J = 7.3 Hz), 1.90-2.03 (2H, m), 2.10-2.20 (4H, m), 2.37-2.48 (1H, m), 2.56-2.76 (6H, m), 3.06-3.14 (2H, m), 3.26-3.33 (2H, m), 4.10 (3H, s), 4.13 (2H, q, J = 7.3Hz), 4.24 (4H, s), 6.68 (1H, dd, J = 8.2,2.0Hz), 6.73 (1H, d, J = 2.0Hz), 6.78 (1H, d, J = 8.2Hz), 7.00 (1H, d, J = 9.1) Hz), 7.23 (1H, d, J = 8.0Hz), 8.25 (1H, d, J = 9.1Hz), 8.63 (1H, d, J = 8.0Hz), 9.63 (1H, s)

３−（８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）プロピオン酸20mgのＮ，Ｎ−ジメチルホルムアミド2mL溶液に、Ｎ，Ｎ’−カルボニルジイミダゾール9.4mgを加え、室温で1時間、35℃で30分間攪拌した。Ｎ，Ｎ’−カルボニルジイミダゾール19mgを加え、40〜50℃で1時間攪拌した。反応混合物を室温まで冷却し、メタンスルホンアミド4.3mgおよび１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン8.5μLを加え、40〜50℃で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、1.0mol/L塩酸でpH7.4に調整した。有機層を分取し、水層を酢酸エチルで3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。得られた残留物にメタノールを加え、固形物をろ取し、白色固体の１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）−Ｎ−（２−メトキシ−５−（３−（（メチルスルホニル）アミノ）−３−オキソプロピル）キノリン−８−イル）ピペリジン−４−カルボキサミド10mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.70-1.85(2H,m),1.95-2.05(2H,m),2.20-2.36(2H,m),2.45-2.75(7H,m),3.09(3H,s),3.05-3.25(4H,m),4.09(3H,s),4.20(4H,s),6.65-6.70(1H,m),6.72-6.78(2H,m),7.13(1H,d,J=9.1Hz),7.24(1H,d,J=8.0Hz),8.38(1H,d,J=8.0Hz),8.45(1H,d,J=9.1Hz),9.63(1H,s)Example 110

3- (8-(((1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidin-4-yl) carbonyl) amino) -2-methoxy To a solution of 20 mg of quinolin-5-yl) propionic acid in 2 mL of N, N-dimethylformamide, 9.4 mg of N, N′-carbonyldiimidazole was added and stirred at room temperature for 1 hour and at 35 ° C. for 30 minutes. 19 mg of N, N′-carbonyldiimidazole was added and stirred at 40-50 ° C. for 1 hour. The reaction mixture was cooled to room temperature, 4.3 mg of methanesulfonamide and 8.5 μL of 1,8-diazabicyclo [5.4.0] undec-7-ene were added, and the mixture was stirred at 40-50 ° C. for 30 minutes. The reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the pH was adjusted to 7.4 with 1.0 mol / L hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted three times 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. Methanol was added to the obtained residue, and the solid was collected by filtration to give 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) -N as a white solid. 10 mg of-(2-methoxy-5- (3-((methylsulfonyl) amino) -3-oxopropyl) quinolin-8-yl) piperidine-4-carboxamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.70-1.85 (2H, m), 1.95-2.05 (2H, m), 2.20-2.36 (2H, m), 2.45-2.75 (7H, m), 3.09 (3H, s), 3.05-3.25 (4H, m), 4.09 (3H, s), 4.20 (4H, s), 6.65-6.70 (1H, m), 6.72-6.78 (2H, m), 7.13 (1H , d, J = 9.1Hz), 7.24 (1H, d, J = 8.0Hz), 8.38 (1H, d, J = 8.0Hz), 8.45 (1H, d, J = 9.1Hz), 9.63 (1H, s )

１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸93mgの塩化メチレン2mL溶液に、塩化チオニル1mLおよびＮ，Ｎ−ジメチルホルムアミド20μLを加え、2時間加熱還流した。減圧下で溶媒を留去し、クロロホルム3mL、２−メトキシ−４−メチルキノリン−８−アミン50mgおよびトリエチルアミン0.11mLを加え、室温で1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、淡褐色固体の１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）−Ｎ−（２−メトキシ−４−メチルキノリン−８−イル）ピペリジン−４−カルボキサミド15mgを得た。
¹H-NMR(CDCl₃)δ値：1.90-2.05(2H,m),2.10-2.20(4H,m),2.38-2.50(1H,m),2.55-2.67(2H,m),2.63(3H,s),2.69-2.78(2H,m),3.06-3.15(2H,m),4.07(3H,s),4.24(4H,s),6.68(1H,dd,J=8.3,2.0Hz),6.73(1H,d,J=2.0Hz),6.78(1H,d,J=8.3Hz),6.81(1H,s),7.39(1H,t,J=8.1Hz),7.57(1H,d,J=8.1Hz),8.73(1H,d,J=8.1Hz),9.74(1H,s)Example 111

To a solution of 93 mg of 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxylic acid in 2 mL of methylene chloride was added 1 mL of thionyl chloride and N, N- Dimethylformamide (20 μL) was added, and the mixture was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure, chloroform (3 mL), 2-methoxy-4-methylquinolin-8-amine (50 mg) and triethylamine (0.11 mL) were added, and the mixture was stirred at room temperature for 1 hour. 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 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: chloroform: methanol = 20: 1] to give 1- (2- (2,3-dihydrobenzo [b] [1,4] as a light brown solid. Dioxin-6-yl) ethyl) -N- (2-methoxy-4-methylquinolin-8-yl) piperidine-4-carboxamide 15 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.90-2.05 (2H, m), 2.10-2.20 (4H, m), 2.38-2.50 (1H, m), 2.55-2.67 (2H, m), 2.63 (3H , s), 2.69-2.78 (2H, m), 3.06-3.15 (2H, m), 4.07 (3H, s), 4.24 (4H, s), 6.68 (1H, dd, J = 8.3, 2.0Hz), 6.73 (1H, d, J = 2.0Hz), 6.78 (1H, d, J = 8.3Hz), 6.81 (1H, s), 7.39 (1H, t, J = 8.1Hz), 7.57 (1H, d, J = 8.1Hz), 8.73 (1H, d, J = 8.1Hz), 9.74 (1H, s)

１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸79mgの塩化メチレン2mL溶液に、塩化チオニル1mLおよびＮ，Ｎ−ジメチルホルムアミド20μLを加え、1時間加熱還流した。減圧下で溶媒を留去し、クロロホルム4mL、エチル＝３−（８−アミノ−２−メトキシキノリン−４−イル）プロピオナート62mgおよびトリエチルアミン96μLを加え、室温で1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、淡褐色油状物のエチル＝３−（８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−４−イル）プロピオナート55mgを得た。
¹H-NMR(CDCl₃)δ値：1.25(3H,t,J=7.3Hz),1.90-2.05(2H,m),2.10-2.23(4H,m),2.35-2.50(1H,m),2.55-2.65(2H,m),2.69-2.81(4H,m),3.06-3.15(2H,m),3.30-3.40(2H,m),4.07(3H,s),4.16(2H,q,J=7.3Hz),4.24(4H,s),6.66-6.84(4H,m),7.40(1H,t,J=8.1Hz),7.60(1H,d,J=8.1Hz),8.73(1H,d,J=8.1Hz),9.74(1H,s)Example 112

1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxylic acid 79 mg in 2 mL of methylene chloride was added to 1 mL of thionyl chloride and N, N- Dimethylformamide (20 μL) was added, and the mixture was heated to reflux for 1 hour. The solvent was distilled off under reduced pressure, 4 mL of chloroform, 62 mg of ethyl 3- (8-amino-2-methoxyquinolin-4-yl) propionate and 96 μL of triethylamine were added, and the mixture was stirred at room temperature for 1 hour. 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 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: chloroform: methanol = 20: 1] to give ethyl 3- (8-(((1- (2- (2,3 -55 mg of dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidin-4-yl) carbonyl) amino) -2-methoxyquinolin-4-yl) propionate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.25 (3H, t, J = 7.3 Hz), 1.90-2.05 (2H, m), 2.10-2.23 (4H, m), 2.35-2.50 (1H, m), 2.55-2.65 (2H, m), 2.69-2.81 (4H, m), 3.06-3.15 (2H, m), 3.30-3.40 (2H, m), 4.07 (3H, s), 4.16 (2H, q, J = 7.3Hz), 4.24 (4H, s), 6.66-6.84 (4H, m), 7.40 (1H, t, J = 8.1Hz), 7.60 (1H, d, J = 8.1Hz), 8.73 (1H, d , J = 8.1Hz), 9.74 (1H, s)

エチル＝３−（８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−４−イル）プロピオナート50mgのエタノール2mL溶液に、20％水酸化ナトリウム水溶液0.11mLおよび水0.2mLを加え、40℃で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。水2mLを加え、1.0mol/L塩酸でpH6.8に調整した。固形物をろ取し、水およびジエチルエーテルで洗浄し、淡褐色固体の３−（８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−４−イル）プロピオン酸30mgを得た。
¹H-NMR(DMSO-d₆)δ値：
1.64-1.78(2H,m),1.91-2.00(2H,m),2.02-2.14(2H,m),2.44-2.72(7H,m),2.94-3.04(2H,m),3.20-3.30(2H,m),4.06(3H,s),4.20(4H,s),6.66(1H,dd,J=8.3,2.0Hz),6.72(1H,d,J=2.0Hz),6.74(1H,d,J=8.3Hz),6.95(1H,s),7.42(1H,t,J=8.0Hz),7.71(1H,dd,J=8.0,1.1Hz),8.51(1H,dd,J=8.0,1.1Hz),9.70(1H,s)Example 113

Ethyl = 3- (8-(((1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidin-4-yl) carbonyl) amino) -2 -Methoxyquinolin-4-yl) propionate 50 mg of ethanol (2 mL) was added with 20% aqueous sodium hydroxide solution (0.11 mL) and water (0.2 mL), and the mixture was stirred at 40 ° C for 30 minutes. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. 2 mL of water was added and adjusted to pH 6.8 with 1.0 mol / L hydrochloric acid. The solid was collected by filtration, washed with water and diethyl ether and washed with 3- (8-(((1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6 30 mg of -yl) ethyl) piperidin-4-yl) carbonyl) amino) -2-methoxyquinolin-4-yl) propionic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value:
1.64-1.78 (2H, m), 1.91-2.00 (2H, m), 2.02-2.14 (2H, m), 2.44-2.72 (7H, m), 2.94-3.04 (2H, m), 3.20-3.30 (2H , m), 4.06 (3H, s), 4.20 (4H, s), 6.66 (1H, dd, J = 8.3,2.0Hz), 6.72 (1H, d, J = 2.0Hz), 6.74 (1H, d, J = 8.3Hz), 6.95 (1H, s), 7.42 (1H, t, J = 8.0Hz), 7.71 (1H, dd, J = 8.0,1.1Hz), 8.51 (1H, dd, J = 8.0,1.1 Hz), 9.70 (1H, s)

１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−カルボン酸51mgの塩化メチレン2mL溶液に、塩化チオニル1mLおよびＮ，Ｎ−ジメチルホルムアミド20μLを加え、1時間30分間加熱還流した。減圧下で溶媒を留去し、クロロホルム2mL、エチル＝（Ｅ）−３−（８−アミノ−２−メトキシキノリン−４−イル）アクリラート40mgのクロロホルム2mL溶液およびトリエチルアミン63μLを加え、室温で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、淡褐色油状物のエチル＝（Ｅ）−３−（８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−４−イル）アクリラート37mgを得た。Example 114

To a solution of 1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidine-4-carboxylic acid 51 mg in 2 mL of methylene chloride was added 1 mL of thionyl chloride and N, N- Dimethylformamide (20 μL) was added, and the mixture was heated to reflux for 1 hour and 30 minutes. The solvent was distilled off under reduced pressure, 2 mL of chloroform, 40 mL of ethyl = (E) -3- (8-amino-2-methoxyquinolin-4-yl) acrylate 40 mg in chloroform and 63 μL of triethylamine were added, and the mixture was stirred at room temperature for 3 hours. Stir. 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 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: chloroform: methanol = 20: 1] to give a pale brown oil of ethyl = (E) -3- (8-(((1- (2- 37 mg of (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidin-4-yl) carbonyl) amino) -2-methoxyquinolin-4-yl) acrylate was obtained.

エチル＝（Ｅ）−３−（８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−４−イル）アクリラート35mgのエタノール1mL、テトラヒドロフラン1mLおよび水0.5mL溶液に、20％水酸化ナトリウム水溶液77μLを加え、40℃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。水10mLを加え、1.0mol/L塩酸でpH6.5に調整した。固形物をろ取し、水およびジエチルエーテルで洗浄し、淡褐色固体の（Ｅ）−３−（８−（（（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）カルボニル）アミノ）−２−メトキシキノリン−４−イル）アクリル酸20mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.67-1.82(2H,m),1.92-2.02(2H,m),2.10-2.20(2H,m),2.46-2.70(5H,m),2.98-3.09(2H,m),4.11(3H,s),4.20(4H,s),6.67(1H,dd,J=8.1,2.0Hz),6.73(1H,d,J=2.0Hz),6.74(1H,d,J=8.1Hz),6.79(1H,d,J=15.7Hz),7.42(1H,s),7.46(1H,t,J=8.0Hz),7.78(1H,d,J=8.0Hz),8.14(1H,d,J=15.7Hz),8.54(1H,d,J=8.0Hz),9.70(1H,s)Example 115

Ethyl = (E) -3- (8-(((1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidin-4-yl) carbonyl) Amino) -2-methoxyquinolin-4-yl) acrylate (35 mg) in ethanol (1 mL), tetrahydrofuran (1 mL) and water (0.5 mL) was added with 20% aqueous sodium hydroxide solution (77 μL) and stirred at 40 ° C. for 1 hour. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. 10 mL of water was added and adjusted to pH 6.5 with 1.0 mol / L hydrochloric acid. The solid was collected by filtration, washed with water and diethyl ether, and (E) -3- (8-(((1- (2- (2,3-dihydrobenzo [b] [1,4 Dioxin-6-yl) ethyl) piperidin-4-yl) carbonyl) amino) -2-methoxyquinolin-4-yl) acrylic acid 20 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.67-1.82 (2H, m), 1.92-2.02 (2H, m), 2.10-2.20 (2H, m), 2.46-2.70 (5H, m), 2.98 -3.09 (2H, m), 4.11 (3H, s), 4.20 (4H, s), 6.67 (1H, dd, J = 8.1,2.0Hz), 6.73 (1H, d, J = 2.0Hz), 6.74 ( 1H, d, J = 8.1Hz), 6.79 (1H, d, J = 15.7Hz), 7.42 (1H, s), 7.46 (1H, t, J = 8.0Hz), 7.78 (1H, d, J = 8.0 Hz), 8.14 (1H, d, J = 15.7Hz), 8.54 (1H, d, J = 8.0Hz), 9.70 (1H, s)

エチル＝（Ｅ）−３−（８−アミノ−２−メトキシキノリン−５−イル）アクリラート70mgのクロロホルム3mL溶液に、Ｎ，Ｎ’−カルボニルジイミダゾール63mgを加え、1時間加熱還流した。反応混合物を室温まで冷却し、ｔｅｒｔ−ブチル＝（２，３−ジヒドロベンゾ［ｂ］［１，４］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0.10gのクロロホルム2mL溶液およびトリエチルアミン72μLを加え、室温で1時間攪拌した後、1時間加熱還流した。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、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＝１：１］で精製し、淡褐色固体のエチル＝（Ｅ）−３−（８−（（（４−（（ｔｅｒｔ−ブトキシカルボニル）（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）アクリラート40mgを得た。
¹H-NMR(CDCl₃)δ値：1.36(3H,t,J=7.0Hz),1.44(9H,s),1.65-1.85(4H,m),2.90-3.05(2H,m),4.01(3H,s),4.10-4.36(5H,m),4.23(4H,s),4.29(2H,q,J=7.0Hz),6.48(1H,d,J=15.6Hz),6.64-6.78(3H,m),7.03(1H,d,J=9.1Hz),7.72(1H,d,J=8.5Hz),8.30(1H,d,J=15.6Hz),8.44(1H,d,J=9.1Hz),8.47(1H,d,J=8.5Hz),9.16(1H,s)Example 116

To a solution of ethyl = (E) -3- (8-amino-2-methoxyquinolin-5-yl) acrylate 70 mg in chloroform 3 mL was added N, N′-carbonyldiimidazole 63 mg and heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, tert-butyl = (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) (piperidin-4-yl) carbamate 0.10 g in chloroform 2 mL and triethylamine 72 μL. And stirred at room temperature for 1 hour, and then heated to reflux for 1 hour. 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 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 = 1: 1] to obtain a pale brown solid of ethyl = (E) -3- (8-(((4-((tert -Butoxycarbonyl) (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) carbonyl) amino) -2-methoxyquinolin-5-yl) acrylate 40 mg Obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.36 (3H, t, J = 7.0 Hz), 1.44 (9H, s), 1.65-1.85 (4H, m), 2.90-3.05 (2H, m), 4.01 ( 3H, s), 4.10-4.36 (5H, m), 4.23 (4H, s), 4.29 (2H, q, J = 7.0Hz), 6.48 (1H, d, J = 15.6Hz), 6.64-6.78 (3H , m), 7.03 (1H, d, J = 9.1Hz), 7.72 (1H, d, J = 8.5Hz), 8.30 (1H, d, J = 15.6Hz), 8.44 (1H, d, J = 9.1Hz) ), 8.47 (1H, d, J = 8.5Hz), 9.16 (1H, s)

エチル＝（Ｅ）−３−（８−（（（４−（（ｔｅｒｔ−ブトキシカルボニル）（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）アクリラート39mgの塩化メチレン2mL溶液に、トリフルオロ酢酸1mLを加え、室温で2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、1.0mol/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、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、淡褐色油状物のエチル＝（Ｅ）−３−（８−（（（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル））カルボニル）アミノ）−２−メトキシキノリン−５−イル）アクリラート33mgを得た。
¹H-NMR(CDCl₃)δ値：1.36(3H,t,J=7.1Hz),1.44-1.56(2H,m),1.96-2.05(2H,m),2.76-2.86(1H,m),3.09-3.19(2H,m),3.75(2H,s),4.06(3H,s),4.13-4.21(2H,m),4.25(4H,s),4.29(2H,q,J=7.1Hz),6.48(1H,d,J=15.6Hz),6.77-6.86(3H,m),7.03(1H,d,J=9.0Hz),7.73(1H,d,J=8.3Hz),8.30(1H,d,J=15.6Hz),8.44(1H,d,J=9.0Hz),8.50(1H,d,J=8.3Hz),9.19(1H,s)Example 117

Ethyl = (E) -3- (8-(((4-((tert-butoxycarbonyl) (2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidine-1- 1 mL of trifluoroacetic acid was added to 2 mL of methylene chloride in 39 mg of yl) carbonyl) amino) -2-methoxyquinolin-5-yl) acrylate, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, chloroform and water were added, and the pH was adjusted to 12 with a 1.0 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 sequentially with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl = (E) -3- (8 -(((4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl)) carbonyl) amino) -2-methoxyquinolin-5-yl ) 33 mg of acrylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.36 (3H, t, J = 7.1 Hz), 1.44-1.56 (2H, m), 1.96-2.05 (2H, m), 2.76-2.86 (1H, m), 3.09-3.19 (2H, m), 3.75 (2H, s), 4.06 (3H, s), 4.13-4.21 (2H, m), 4.25 (4H, s), 4.29 (2H, q, J = 7.1Hz) , 6.48 (1H, d, J = 15.6Hz), 6.77-6.86 (3H, m), 7.03 (1H, d, J = 9.0Hz), 7.73 (1H, d, J = 8.3Hz), 8.30 (1H, d, J = 15.6Hz), 8.44 (1H, d, J = 9.0Hz), 8.50 (1H, d, J = 8.3Hz), 9.19 (1H, s)

エチル＝（Ｅ）−３−（８−（（（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）アクリラート30mgのエタノール1mL、テトラヒドロフラン1mLおよび水0.5mL溶液に、20％水酸化ナトリウム水溶液66μLを加え、40℃で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。水10mLを加え、1.0mol/L塩酸でpH6.8に調整し、固形物をろ取し、水およびジエチルエーテルで洗浄し、淡褐色固体の（Ｅ）−３−（８−（（（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）ピペリジン−１−イル）カルボニル）アミノ）−２−メトキシキノリン−５−イル）アクリル酸9mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.25-1.40(2H,m),1.85-1.95(2H,m),2.60-2.70(1H,m),3.03-3.15(2H,m),3.63(2H,s),3.97-4.06(2H,m),4.07(3H,s),4.20(4H,s),6.54(1H,d,J=15.7Hz),6.75-6.80(2H,m),6.84-6.86(1H,m),7.17(1H,d,J=9.4Hz),7.89(1H,d,J=8.2Hz),8.19(1H,d,J=15.7Hz),8.38(1H,d,J=8.2Hz),8.61(1H,d,J=9.4Hz),9.18(1H,s)Example 118

Ethyl = (E) -3- (8-(((4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) carbonyl) amino) 2-Methoxyquinolin-5-yl) acrylate 30 mg of ethanol 1 mL, tetrahydrofuran 1 mL and water 0.5 mL were added with 66 μL of a 20% aqueous sodium hydroxide solution and stirred at 40 ° C. for 30 minutes. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. 10 mL of water was added, the pH was adjusted to 6.8 with 1.0 mol / L hydrochloric acid, the solid was collected by filtration, washed with water and diethyl ether, and (E) -3- (8-(((4 -((2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) piperidin-1-yl) carbonyl) amino) -2-methoxyquinolin-5-yl) acrylic acid 9 mg is obtained. It was.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.25-1.40 (2H, m), 1.85-1.95 (2H, m), 2.60-2.70 (1H, m), 3.03-3.15 (2H, m), 3.63 (2H, s), 3.97-4.06 (2H, m), 4.07 (3H, s), 4.20 (4H, s), 6.54 (1H, d, J = 15.7Hz), 6.75-6.80 (2H, m), 6.84-6.86 (1H, m), 7.17 (1H, d, J = 9.4Hz), 7.89 (1H, d, J = 8.2Hz), 8.19 (1H, d, J = 15.7Hz), 8.38 (1H, d , J = 8.2Hz), 8.61 (1H, d, J = 9.4Hz), 9.18 (1H, s)

エチル＝（Ｅ）−３−（２−メトキシ−８−（オキシラン−２−イル）キノリン−５−イル）アクリラート75mgのＮ，Ｎ−ジメチルホルムアミド3mL溶液に、室温でＮ−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）ピペリジン−４−カルボキサミド66mgおよび過塩素酸リチウム27mgを加え、90℃で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、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＝９：１］で精製し、褐色泡状物のエチル＝（Ｅ）−３−（８−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルアミノ）カルボニル）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート72mgを得た。
¹H-NMR(CDCl₃)δ値：1.37(3H,t,J=7.1Hz),1.86-2.04(4H,m),2.14-2.42(3H,m),2.44-2.54(1H,m),2.90-3.06(2H,m),3.35-3.45(1H,m),4.03(3H,s),4.23(4H,s),4.30(2H,q,J=7.1Hz),5.75-5.82(1H,m),6.52(1H,d,J=15.7Hz),6.79(1H,d,J=8.7Hz),6.91(1H,dd,J=8.7,2.5Hz),6.99(1H,d,J=9.3Hz),7.16(1H,d,J=2.5Hz),7.23(1H,broad),7.68(1H,d,J=7.8Hz),7.88(1H,d,J=7.8Hz),8.34(1H,d,J=15.7Hz),8.38(1H,d,J=9.3Hz)Example 119

Ethyl = (E) -3- (2-methoxy-8- (oxiran-2-yl) quinolin-5-yl) acrylate 75 mg of N, N-dimethylformamide in 3 mL solution at room temperature with N- (2,3- Dihydrobenzo [b] [1,4] dioxin-6-yl) piperidine-4-carboxamide (66 mg) and lithium perchlorate (27 mg) were added, and the mixture was stirred at 90 ° C. 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, 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: chloroform: methanol = 9: 1], and the brown foamy ethyl = (E) -3- (8- (2- (4-(( 72 mg of 2,3-dihydrobenzo [b] [1,4] dioxin-6-ylamino) carbonyl) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.37 (3H, t, J = 7.1 Hz), 1.86-2.04 (4H, m), 2.14-2.42 (3H, m), 2.44-2.54 (1H, m), 2.90-3.06 (2H, m), 3.35-3.45 (1H, m), 4.03 (3H, s), 4.23 (4H, s), 4.30 (2H, q, J = 7.1Hz), 5.75-5.82 (1H, m), 6.52 (1H, d, J = 15.7Hz), 6.79 (1H, d, J = 8.7Hz), 6.91 (1H, dd, J = 8.7,2.5Hz), 6.99 (1H, d, J = 9.3 Hz), 7.16 (1H, d, J = 2.5Hz), 7.23 (1H, broad), 7.68 (1H, d, J = 7.8Hz), 7.88 (1H, d, J = 7.8Hz), 8.34 (1H, d, J = 15.7Hz), 8.38 (1H, d, J = 9.3Hz)

エチル＝（Ｅ）−３−（８−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルアミノ）カルボニル）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート70mgのエタノール2mL溶液に、20％水酸化ナトリウム水溶液0.15mLを加え、室温で5時間攪拌した。減圧下で溶媒を留去し、水30mLを加え、氷冷下、1.0mol/L塩酸でpH5.0に調整した。固形物をろ取し、水およびジエチルエーテルで洗浄し、淡褐色固体の（Ｅ）−３−（８−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルアミノ）カルボニル）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリル酸49mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.60-1.84(4H,m),2.10-2.35(3H,m),2.70-2.85(1H,m),3.00-3.09(1H,m),3.20-3.50(2H,m),4.02(3H,s),4.15-4.24(4H,m),5.84-5.91(1H,m),6.60(1H,d,J=15.6Hz),6.75(1H,d,J=8.9Hz),6.97(1H,dd,J=8.9,2.4Hz),7.11(1H,d,J=9.3Hz),7.23(1H,d,J=2.4Hz),7.87(1H,d,J=7.8Hz),7.91(1H,d,J=7.8Hz),8.29(1H,d,J=15.6Hz),8.57(1H,d,J=9.3Hz),9.68(1H,s)Example 120

Ethyl = (E) -3- (8- (2- (4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-ylamino) carbonyl) piperidin-1-yl) -1- To a solution of 70 mg of hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate in 2 mL of ethanol was added 0.15 mL of a 20% aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, 30 mL of water was added, and the mixture was adjusted to pH 5.0 with 1.0 mol / L hydrochloric acid under ice cooling. The solid was collected by filtration, washed with water and diethyl ether, and (E) -3- (8- (2- (4-((2,3-dihydrobenzo [b] [1,4]) as a light brown solid. Dioxin-6-ylamino) carbonyl) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid 49 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.60-1.84 (4H, m), 2.10-2.35 (3H, m), 2.70-2.85 (1H, m), 3.00-3.09 (1H, m), 3.20 -3.50 (2H, m), 4.02 (3H, s), 4.15-4.24 (4H, m), 5.84-5.91 (1H, m), 6.60 (1H, d, J = 15.6Hz), 6.75 (1H, d , J = 8.9Hz), 6.97 (1H, dd, J = 8.9,2.4Hz), 7.11 (1H, d, J = 9.3Hz), 7.23 (1H, d, J = 2.4Hz), 7.87 (1H, d , J = 7.8Hz), 7.91 (1H, d, J = 7.8Hz), 8.29 (1H, d, J = 15.6Hz), 8.57 (1H, d, J = 9.3Hz), 9.68 (1H, s)

エチル＝（Ｅ）−３−（２−メトキシ−８−（オキシラン−２−イル）キノリン−５−イル）アクリラート43mgのＮ，Ｎ−ジメチルホルムアミド3mL溶液に、室温でＮ−（ピペリジン−４−イル）−２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルスルホンアミド43mgおよび過塩素酸リチウム15mgを加え、45℃で1時間、80℃で2時間および90℃で1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、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＝１０：１］で精製し、淡褐色油状物のエチル＝（Ｅ）−３−（８−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルスルホニル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート19mgを得た。
¹H-NMR(CDCl₃)δ値：1.36(3H,t,J=7.1Hz),1.45-1.70(2H,m),1.77-1.95(2H,m),2.13-2.23(1H,m),2.33-2.45(1H,m),2.44(1H,dd,J=12.3,10.1Hz),2.69-2.78(1H,m),2.95(1H,dd,J=12.3,3.0Hz),3.08-3.29(2H,m),4.01(3H,s),4.25-4.40(6H,m),5.70(1H,dd,J=10.1,3.0Hz),6.51(1H,d,J=15.9Hz),6.95(1H,d,J=8.5Hz),6.99(1H,d,J=9.1Hz),7.37(1H,dd,J=8.5,2.2Hz),7.41(1H,d,J=2.2Hz),7.67(1H,d,J=7.8Hz),7.84(1H,d,J=7.8Hz),8.34(1H,d,J=15.9Hz),8.38(1H,d,J=9.1Hz)Example 121

Ethyl = (E) -3- (2-methoxy-8- (oxiran-2-yl) quinolin-5-yl) acrylate 43 mg of N, N-dimethylformamide in 3 mL solution at room temperature with N- (piperidine-4- Yl) -2,3-dihydrobenzo [b] [1,4] dioxin-6-ylsulfonamide 43 mg and lithium perchlorate 15 mg are added, 1 hour at 45 ° C., 2 hours at 80 ° C. and 1 at 90 ° C. Stir for 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, 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: chloroform: methanol = 10: 1] to give ethyl = (E) -3- (8- (2- (4-(( 2,3-dihydrobenzo [b] [1,4] dioxin-6-ylsulfonyl) amino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate 19 mg was obtained. .
¹ H-NMR (CDCl ₃ ) δ value: 1.36 (3H, t, J = 7.1 Hz), 1.45-1.70 (2H, m), 1.77-1.95 (2H, m), 2.13-2.23 (1H, m), 2.33-2.45 (1H, m), 2.44 (1H, dd, J = 12.3,10.1Hz), 2.69-2.78 (1H, m), 2.95 (1H, dd, J = 12.3,3.0Hz), 3.08-3.29 ( 2H, m), 4.01 (3H, s), 4.25-4.40 (6H, m), 5.70 (1H, dd, J = 10.1,3.0Hz), 6.51 (1H, d, J = 15.9Hz), 6.95 (1H , d, J = 8.5Hz), 6.99 (1H, d, J = 9.1Hz), 7.37 (1H, dd, J = 8.5,2.2Hz), 7.41 (1H, d, J = 2.2Hz), 7.67 (1H , d, J = 7.8Hz), 7.84 (1H, d, J = 7.8Hz), 8.34 (1H, d, J = 15.9Hz), 8.38 (1H, d, J = 9.1Hz)

エチル＝（Ｅ）−３−（８−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルスルホニル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート19mgのエタノール2mL溶液に、20％水酸化ナトリウム水溶液38μLを加え、室温で1時間攪拌し、一晩静置した。減圧下で溶媒を留去し、水20mLを加え、氷冷下、1.0mol/L塩酸でpH5.0に調整した。固形物をろ取し、水およびジエチルエーテルで洗浄し、淡褐色固体の（Ｅ）−３−（８−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルスルホニル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリル酸7mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.30-1.70(4H,m),2.00-2.30(1H,m),2.40-3.50(6H,m),3.98(3H,s),4.25-4.40(4H,m),5.74-5.84(1H,m),6.59(1H,d,J=15.7Hz),7.03(1H,d,J=8.0Hz),7.09(1H,d,J=9.3Hz),7.26-7.28(2H,m),7.83(1H,d,J=7.7Hz),7.89(1H,d,J=7.7Hz),8.27(1H,d,J=15.7Hz),8.55(1H,d,J=9.3Hz)Example 122

Ethyl = (E) -3- (8- (2- (4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-ylsulfonyl) amino) piperidin-1-yl) -1 -Hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate To a solution of 19 mg of ethanol in 2 mL of ethanol was added 38 μL of a 20% aqueous sodium hydroxide solution, stirred at room temperature for 1 hour, and allowed to stand overnight. The solvent was distilled off under reduced pressure, 20 mL of water was added, and the mixture was adjusted to pH 5.0 with 1.0 mol / L hydrochloric acid under ice cooling. The solid was collected by filtration, washed with water and diethyl ether, and (E) -3- (8- (2- (4-((2,3-dihydrobenzo [b] [1,4]) Dioxin-6-ylsulfonyl) amino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid 7 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.30-1.70 (4H, m), 2.00-2.30 (1H, m), 2.40-3.50 (6H, m), 3.98 (3H, s), 4.25-4.40 (4H, m), 5.74-5.84 (1H, m), 6.59 (1H, d, J = 15.7Hz), 7.03 (1H, d, J = 8.0Hz), 7.09 (1H, d, J = 9.3Hz) , 7.26-7.28 (2H, m), 7.83 (1H, d, J = 7.7Hz), 7.89 (1H, d, J = 7.7Hz), 8.27 (1H, d, J = 15.7Hz), 8.55 (1H, d, J = 9.3Hz)

エチル＝（Ｅ）−３−（２−メトキシ−８−（オキシラン−２−イル）キノリン−５−イル）アクリラート89mgのＮ，Ｎ−ジメチルホルムアミド3mL溶液に、室温でＮ−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）（４−メチルピペリジン−４−イル）アミン78mgおよび過塩素酸リチウム32mgを加え、85〜95℃で5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、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＝５：１］で精製し、淡褐色油状物のエチル＝（Ｅ）−３−（８−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）−４−メチルピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート81mgを得た。
¹H-NMR(CDCl₃)δ値：1.19(3H,s),1.37(3H,t,J=7.1Hz),1.50-1.77(4H,m),2.42-2.53(2H,m),2.55-2.65(1H,m),2.80-2.92(2H,m),3.03-3.09(1H,m),3.59(2H,s),4.04(3H,s),4.24(4H,s),4.31(2H,q,J=7.1Hz),5.77-5.81(1H,m),6.52(1H,d,J=15.9Hz),6.80-6.89(3H,m),6.99(1H,d,J=9.3Hz),7.69(1H,d,J=7.8Hz),7.89(1H,d,J=7.8Hz),8.35(1H,d,J=15.9Hz),8.39(1H,d,J=9.3Hz)Example 123

Ethyl = (E) -3- (2-methoxy-8- (oxiran-2-yl) quinolin-5-yl) acrylate 89 mg of N, N-dimethylformamide in 3 mL solution at room temperature with N- (2,3- Dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) (4-methylpiperidin-4-yl) amine (78 mg) and lithium perchlorate (32 mg) were added, and the mixture was stirred at 85 to 95 ° C. for 5 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, 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: chloroform: methanol = 5: 1] to give ethyl = (E) -3- (8- (2- (4-(( 2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) -4-methylpiperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate 81 mg Got.
¹ H-NMR (CDCl ₃ ) δ value: 1.19 (3H, s), 1.37 (3H, t, J = 7.1 Hz), 1.50-1.77 (4H, m), 2.42-2.53 (2H, m), 2.55- 2.65 (1H, m), 2.80-2.92 (2H, m), 3.03-3.09 (1H, m), 3.59 (2H, s), 4.04 (3H, s), 4.24 (4H, s), 4.31 (2H, q, J = 7.1Hz), 5.77-5.81 (1H, m), 6.52 (1H, d, J = 15.9Hz), 6.80-6.89 (3H, m), 6.99 (1H, d, J = 9.3Hz), 7.69 (1H, d, J = 7.8Hz), 7.89 (1H, d, J = 7.8Hz), 8.35 (1H, d, J = 15.9Hz), 8.39 (1H, d, J = 9.3Hz)

エチル＝（Ｅ）−３−（８−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）−４−メチルピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート65mgのエタノール2mL溶液に、20％水酸化ナトリウム水溶液0.14mLを加え、室温で4時間攪拌した。減圧下で溶媒を留去し、水30mLを加え、1.0mol/L塩酸でpH7.0に調整した。固形物をろ取し、水およびジエチルエーテルで洗浄し、淡褐色固体の（Ｅ）−３−（８−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）−４−メチルピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリル酸45mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.09(3H,s),1.43-1.70(4H,m),2.40-2.55(2H,m),2.61-2.70(2H,m),2.73-2.84(2H,m),3.55(2H,s),4.00(3H,s),4.20(4H,s),5.80-5.87(1H,m),6.58(1H,d,J=15.6Hz),6.76(1H,d,J=8.3Hz),6.78-6.81(1H,m),6.86(1H,d,J=1.7Hz),7.09(1H,d,J=9.1Hz),7.83-7.88(2H,m),8.22(1H,d,J=15.6Hz),8.54(1H,d,J=9.1Hz)Example 124

Ethyl = (E) -3- (8- (2- (4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) -4-methylpiperidin-1-yl ) -1-Hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate To a solution of 65 mg of ethanol in 2 mL of ethanol was added 0.14 mL of 20% aqueous sodium hydroxide, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, 30 mL of water was added, and the pH was adjusted to 7.0 with 1.0 mol / L hydrochloric acid. The solid was collected by filtration, washed with water and diethyl ether, and (E) -3- (8- (2- (4-((2,3-dihydrobenzo [b] [1,4]) Dioxin-6-ylmethyl) amino) -4-methylpiperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid 45 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.09 (3H, s), 1.43-1.70 (4H, m), 2.40-2.55 (2H, m), 2.61-2.70 (2H, m), 2.73-2.84 (2H, m), 3.55 (2H, s), 4.00 (3H, s), 4.20 (4H, s), 5.80-5.87 (1H, m), 6.58 (1H, d, J = 15.6Hz), 6.76 ( 1H, d, J = 8.3Hz), 6.78-6.81 (1H, m), 6.86 (1H, d, J = 1.7Hz), 7.09 (1H, d, J = 9.1Hz), 7.83-7.88 (2H, m ), 8.22 (1H, d, J = 15.6Hz), 8.54 (1H, d, J = 9.1Hz)

エチル＝（Ｅ）−３−（８−（２−（４−アミノピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラートの塩酸塩0.30gの塩化メチレン5mL懸濁液に、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0.12gおよび酢酸42μLを加え、室温で5時間攪拌した。水素化トリアセトキシホウ素ナトリウム0.23gを加え、同温度で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＝１０：１］で精製し、淡褐色油状物のエチル＝（Ｅ）−３−（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）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート0.11gを得た。
¹H-NMR(CDCl₃)δ値：1.37(3H,t,J=7.1Hz),1.45-1.65(2H,m),1.85-2.00(2H,m),2.10-2.20(1H,m),2.30-2.45(1H,m),2.42(1H,dd,J=12.3,10.1Hz),2.51-2.61(1H,m),2.78-2.88(1H,m),3.01(1H,dd,J=12.3,3.2Hz),3.24-3.33(1H,m),3.81(2H,s),4.03(3H,s),4.25-4.35(6H,m),5.78(1H,dd,J=10.1,3,2Hz),6.52(1H,d,J=16.1Hz),6.84(1H,s),6.98(1H,d,J=9.3Hz),7.69(1H,d,J=7.8Hz),7.90(1H,d,J=7.8Hz),8.11(1H,s),8.35(1H,d,J=16.1Hz),8.38(1H,d,J=9.3Hz)Example 125

Ethyl = (E) -3- (8- (2- (4-aminopiperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate hydrochloride 0.30 g methylene chloride 5 mL To the suspension, 0.12 g of 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde and 42 μL of acetic acid were added and stirred at room temperature for 5 hours. 0.23 g of sodium triacetoxyborohydride was added and stirred at the same temperature for 30 minutes. 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 = 10: 1], and ethyl = (E) -3- (8- (2- (4-(( 2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate 0.11 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.37 (3H, t, J = 7.1 Hz), 1.45-1.65 (2H, m), 1.85-2.00 (2H, m), 2.10-2.20 (1H, m), 2.30-2.45 (1H, m), 2.42 (1H, dd, J = 12.3,10.1Hz), 2.51-2.61 (1H, m), 2.78-2.88 (1H, m), 3.01 (1H, dd, J = 12.3 , 3.2Hz), 3.24-3.33 (1H, m), 3.81 (2H, s), 4.03 (3H, s), 4.25-4.35 (6H, m), 5.78 (1H, dd, J = 10.1,3,2Hz ), 6.52 (1H, d, J = 16.1Hz), 6.84 (1H, s), 6.98 (1H, d, J = 9.3Hz), 7.69 (1H, d, J = 7.8Hz), 7.90 (1H, d , J = 7.8Hz), 8.11 (1H, s), 8.35 (1H, d, J = 16.1Hz), 8.38 (1H, d, J = 9.3Hz)

エチル＝（Ｅ）−３−（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）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート0.11gのエタノール2mL溶液に、20％水酸化ナトリウム水溶液0.23mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、水10mLを加え、1.0mol/L塩酸でpH7.5に調整した。固形物をろ取し、水およびジエチルエーテルで洗浄し、淡褐色固体の（Ｅ）−３−（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）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリル酸58mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.35-1.50(2H,m),1.80-1.94(2H,m),2.13-2.30(2H,m),2.44-2.60(2H,m),2.70-2.77(1H,m),2.91-3.00(1H,m),3.16-3.25(1H,m),3.80(2H,s),4.00(3H,s),4.26-4.37(4H,m),5.81-5.87(1H,m),6.59(1H,d,J=15.9Hz),7.00(1H,s),7.08(1H,d,J=9.3Hz),7.84-7.88(2H,m),8.05(1H,s),8.23(1H,d,J=15.9Hz),8.54(1H,d,J=9.3Hz)Example 126

Ethyl = (E) -3- (8- (2- (4-((2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino) piperidin-1-yl ) -1-Hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate 0.12 g of a solution of ethanol 2 mL was added with 20% aqueous sodium hydroxide solution 0.23 mL and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, 10 mL of water was added, and the pH was adjusted to 7.5 with 1.0 mol / L hydrochloric acid. The solid was collected by filtration, washed with water and diethyl ether, and (E) -3- (8- (2- (4-((2,3-dihydro [1,4] dioxino [2, 3-c] pyridin-7-ylmethyl) amino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid 58 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.35-1.50 (2H, m), 1.80-1.94 (2H, m), 2.13-2.30 (2H, m), 2.44-2.60 (2H, m), 2.70 -2.77 (1H, m), 2.91-3.00 (1H, m), 3.16-3.25 (1H, m), 3.80 (2H, s), 4.00 (3H, s), 4.26-4.37 (4H, m), 5.81 -5.87 (1H, m), 6.59 (1H, d, J = 15.9Hz), 7.00 (1H, s), 7.08 (1H, d, J = 9.3Hz), 7.84-7.88 (2H, m), 8.05 ( 1H, s), 8.23 (1H, d, J = 15.9Hz), 8.54 (1H, d, J = 9.3Hz)

エチル＝（Ｅ）−３−（２−メトキシ−８−（オキシラン−２−イル）キノリン−５−イル）アクリラート0.12gのＮ，Ｎ−ジメチルホルムアミド3mL溶液に、室温でｔｅｒｔ−ブチル＝（２−オキソ−２−（ピリジン−２−イルアミノ）エチル）（ピペリジン−４−イル）カルバマート0.13gおよび過塩素酸リチウム43mgを加え、90℃で9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、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＝２０：１］で精製し、淡褐色油状物のエチル＝（Ｅ）−３−（８−（２−（４−（（ｔｅｒｔ−ブトキシカルボニル）（２−オキソ−２−（ピリジン−２−イルアミノ）エチル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート0.24gを得た。
¹H-NMR(CDCl₃)δ値：1.36(3H,t,J=7.2Hz),1.47(9H,s),1.60-1.95(4H,m),2.15-2.55(3H,m),2.87-3.02(2H,m),3.36-3.44(1H,m),3.86-4.07(3H,m),4.01(3H,s),4.30(2H,q,J=7.2Hz),5.70-5.76(1H,m),6.51(1H,d,J=15.6Hz),6.98(1H,d,J=9.1Hz),7.01-7.08(1H,m),7.67(1H,d,J=7.8Hz),7.68-7.75(1H,m),7.86(1H,d,J=7.8Hz),8.20-8.30(2H,m),8.34(1H,d,J=15.6Hz),8.38(1H,d,J=9.1Hz)Example 127

Ethyl = (E) -3- (2-methoxy-8- (oxiran-2-yl) quinolin-5-yl) acrylate 0.12 g of N, N-dimethylformamide in 3 mL solution at room temperature with tert-butyl = (2 -Oxo-2- (pyridin-2-ylamino) ethyl) (piperidin-4-yl) carbamate 0.13 g and lithium perchlorate 43 mg were added, and the mixture was stirred at 90 ° C. for 9 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, 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: chloroform: methanol = 20: 1] to give ethyl = (E) -3- (8- (2- (4-(( tert-butoxycarbonyl) (2-oxo-2- (pyridin-2-ylamino) ethyl) amino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate 0.24 g is obtained. It was.
¹ H-NMR (CDCl ₃ ) δ value: 1.36 (3H, t, J = 7.2 Hz), 1.47 (9H, s), 1.60-1.95 (4H, m), 2.15-2.55 (3H, m), 2.87- 3.02 (2H, m), 3.36-3.44 (1H, m), 3.86-4.07 (3H, m), 4.01 (3H, s), 4.30 (2H, q, J = 7.2Hz), 5.70-5.76 (1H, m), 6.51 (1H, d, J = 15.6Hz), 6.98 (1H, d, J = 9.1Hz), 7.01-7.08 (1H, m), 7.67 (1H, d, J = 7.8Hz), 7.68- 7.75 (1H, m), 7.86 (1H, d, J = 7.8Hz), 8.20-8.30 (2H, m), 8.34 (1H, d, J = 15.6Hz), 8.38 (1H, d, J = 9.1Hz) )

エチル＝（Ｅ）−３−（８−（２−（４−（（ｔｅｒｔ−ブトキシカルボニル）（２−オキソ−２−（ピリジン−２−イルアミノ）エチル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート0.23gの塩化メチレン5mL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。減圧下で溶媒を留去し、酢酸エチルおよび水を加え、20％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、淡褐色油状物のエチル＝（Ｅ）−３−（８−（１−ヒドロキシ−２−（４−（（２−オキソ−２−（ピリジン−２−イルアミノ）エチル）アミノ）ピペリジン−１−イル）エチル）−２−メトキシキノリン−５−イル）アクリラート0.16gを得た。
¹H-NMR(CDCl₃)δ値：1.37(3H,t,J=7.2Hz),1.45-1.70(2H,m),1.85-2.64(6H,m),2.82-3.08(2H,m),3.26-3.40(1H,m),3.46(2H,s),4.02(3H,s),4.30(2H,q,J=7.2Hz),5.74-5.82(1H,m),6.52(1H,d,J=15.9Hz),6.98(1H,d,J=9.3Hz),7.00-7.08(1H,m),7.66-7.74(2H,m),7.88(1H,d,J=7.6Hz),8.24-8.40(4H,m),9.81(1H,s)Example 128

Ethyl = (E) -3- (8- (2- (4-((tert-butoxycarbonyl) (2-oxo-2- (pyridin-2-ylamino) ethyl) amino) piperidin-1-yl) -1 To a solution of 0.23 g of -hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate in 5 mL of methylene chloride was added 5 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, ethyl acetate and water were added, and the pH was adjusted to 12 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 successively with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl = (E) -3- (8 -(1-hydroxy-2- (4-((2-oxo-2- (pyridin-2-ylamino) ethyl) amino) piperidin-1-yl) ethyl) -2-methoxyquinolin-5-yl) acrylate 0.16 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.37 (3H, t, J = 7.2 Hz), 1.45-1.70 (2H, m), 1.85-2.64 (6H, m), 2.82-3.08 (2H, m), 3.26-3.40 (1H, m), 3.46 (2H, s), 4.02 (3H, s), 4.30 (2H, q, J = 7.2Hz), 5.74-5.82 (1H, m), 6.52 (1H, d, J = 15.9Hz), 6.98 (1H, d, J = 9.3Hz), 7.00-7.08 (1H, m), 7.66-7.74 (2H, m), 7.88 (1H, d, J = 7.6Hz), 8.24- 8.40 (4H, m), 9.81 (1H, s)

エチル＝（Ｅ）−３−（８−（１−ヒドロキシ−２−（４−（（２−オキソ−２−（ピリジン−２−イルアミノ）エチル）アミノ）ピペリジン−１−イル）エチル）−２−メトキシキノリン−５−イル）アクリラート0.14gのエタノール2mL溶液に、20％水酸化ナトリウム水溶液0.30mLを加え、室温で2時間攪拌し、一晩静置した。減圧下で溶媒を留去し、水20mLを加え、1.0mol/L塩酸でpH6.0に調整した。固形物をろ取し、水およびジエチルエーテルで洗浄し、淡褐色固体の（Ｅ）−３−（８−（２−（４−（（カルボキシメチル）アミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリル酸48mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.47-1.62(2H,m),1.86-1.97(2H,m),2.06-2.17(2H,m),2.40-2.48(1H,m),2.63-2.70(1H,m),2.80-3.00(2H,m),3.15(2H,s),3.10-3.40(1H,m),4.00(3H,s),5.79-5.84(1H,m),6.60(1H,d,J=15.9Hz),7.09(1H,d,J=9.3Hz),7.84(1H,d,J=7.8Hz),7.88(1H,d,J=7.8Hz),8.26(1H,d,J=15.9Hz),8.55(1H,d,J=9.3Hz)Example 129

Ethyl = (E) -3- (8- (1-hydroxy-2- (4-((2-oxo-2- (pyridin-2-ylamino) ethyl) amino) piperidin-1-yl) ethyl) -2 To a solution of 0.14 g of -methoxyquinolin-5-yl) acrylate in 2 mL of ethanol was added 0.30 mL of 20% aqueous sodium hydroxide solution, stirred at room temperature for 2 hours, and allowed to stand overnight. The solvent was distilled off under reduced pressure, 20 mL of water was added, and the pH was adjusted to 6.0 with 1.0 mol / L hydrochloric acid. The solid was collected by filtration, washed with water and diethyl ether, and (E) -3- (8- (2- (4-((carboxymethyl) amino) piperidin-1-yl) -1- 48 mg of hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid were obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.47-1.62 (2H, m), 1.86-1.97 (2H, m), 2.06-2.17 (2H, m), 2.40-2.48 (1H, m), 2.63 -2.70 (1H, m), 2.80-3.00 (2H, m), 3.15 (2H, s), 3.10-3.40 (1H, m), 4.00 (3H, s), 5.79-5.84 (1H, m), 6.60 (1H, d, J = 15.9Hz), 7.09 (1H, d, J = 9.3Hz), 7.84 (1H, d, J = 7.8Hz), 7.88 (1H, d, J = 7.8Hz), 8.26 (1H , d, J = 15.9Hz), 8.55 (1H, d, J = 9.3Hz)

エチル＝（Ｅ）−３−（２−メトキシ−８−（オキシラン−２−イル）キノリン−５−イル）アクリラート0.11gのＮ，Ｎ−ジメチルホルムアミド3mL溶液に、室温で４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）−Ｎ−メチルピペリジン−４−カルボキサミド0.11gおよび過塩素酸リチウム39mgを加え、95℃で4時間攪拌した。過塩素酸リチウム39mgを加え、95℃で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、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＝１０：１］で精製し、淡褐色油状物のエチル＝（Ｅ）−３−（８−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）−４−（（メチルアミノ）カルボニル）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート0.11gを得た。
¹H-NMR(CDCl₃)δ値：1.37(3H,t,J=7.1Hz),1.65-1.80(2H,m),2.20-2.39(3H,m),2.43-2.62(2H,m),2.75-2.85(1H,m),2.84(3H,d,J=4.9Hz),3.00-3.07(1H,m),3.11-3.19(1H,m),3.48(2H,s),4.03(3H,s),4.26(4H,s),4.30(2H,q,J=7.1Hz),5.75-5.80(1H,m),6.52(1H,d,J=15.7Hz),6.76(1H,dd,J=8.2,2.1Hz),6.83-6.87(2H,m),6.99(1H,d,J=9.3Hz),7.33-7.39(1H,m),7.69(1H,d,J=7.6Hz),7.89(1H,d,J=7.6Hz),8.35(1H,d,J=15.7Hz),8.39(1H,d,J=9.3Hz)Example 130

Ethyl = (E) -3- (2-methoxy-8- (oxiran-2-yl) quinolin-5-yl) acrylate 0.11 g of N, N-dimethylformamide in 3 mL solution at room temperature with 4-((2, 3-Dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) -N-methylpiperidine-4-carboxamide (0.11 g) and lithium perchlorate (39 mg) were added, and the mixture was stirred at 95 ° C. for 4 hours. 39 mg of lithium perchlorate was added and stirred at 95 ° C. 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, 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: chloroform: methanol = 10: 1] to give ethyl = (E) -3- (8- (2- (4-(( 2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) -4-((methylamino) carbonyl) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinoline- 0.11 g of 5-yl) acrylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.37 (3H, t, J = 7.1 Hz), 1.65-1.80 (2H, m), 2.20-2.39 (3H, m), 2.43-2.62 (2H, m), 2.75-2.85 (1H, m), 2.84 (3H, d, J = 4.9Hz), 3.00-3.07 (1H, m), 3.11-3.19 (1H, m), 3.48 (2H, s), 4.03 (3H, s), 4.26 (4H, s), 4.30 (2H, q, J = 7.1Hz), 5.75-5.80 (1H, m), 6.52 (1H, d, J = 15.7Hz), 6.76 (1H, dd, J = 8.2,2.1Hz), 6.83-6.87 (2H, m), 6.99 (1H, d, J = 9.3Hz), 7.33-7.39 (1H, m), 7.69 (1H, d, J = 7.6Hz), 7.89 (1H, d, J = 7.6Hz), 8.35 (1H, d, J = 15.7Hz), 8.39 (1H, d, J = 9.3Hz)

エチル＝（Ｅ）−３−（８−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）−４−（（メチルアミノ）カルボニル）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート0.10gのエタノール3mL、テトラヒドロフラン2mLおよび水0.5mL溶液に、20％水酸化ナトリウム水溶液0.10mLを加え、室温で8時間攪拌した。減圧下で溶媒を留去し、水10mLを加え、1.0mol/L塩酸でpH6.0に調整した。固形物をろ取し、水で洗浄し、淡褐色固体の（Ｅ）−３−（８−（２−（４−（（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イルメチル）アミノ）−４−（（メチルアミノ）カルボニル）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリル酸32mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.52-1.68(2H,m),1.84-1.98(2H,m),2.63(3H,d,J=4.4Hz),2.40-3.50(8H,m),3.99(3H,s),4.20(4H,s),5.80-5.86(1H,m),6.59(1H,d,J=15.6Hz),6.76-6.84(3H,m),7.10(1H,d,J=9.3Hz),7.70-7.76(1H,m),7.85(1H,d,J=7.8Hz),7.89(1H,d,J=7.8Hz),8.26(1H,d,J=15.6Hz),8.55(1H,d,J=9.3Hz)Example 131

Ethyl = (E) -3- (8- (2- (4-((2,3-dihydrobenzo [b] [1,4] dioxin-6-ylmethyl) amino) -4-((methylamino) carbonyl) ) Piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate To 0.10 g of ethanol 3 mL, tetrahydrofuran 2 mL and water 0.5 mL, add 20% aqueous sodium hydroxide solution 0.10 mL, Stir at room temperature for 8 hours. The solvent was distilled off under reduced pressure, 10 mL of water was added, and the pH was adjusted to 6.0 with 1.0 mol / L hydrochloric acid. The solid was collected by filtration, washed with water, and (E) -3- (8- (2- (4-((2,3-dihydrobenzo [b] [1,4] dioxin-6) as a light brown solid. 32 mg of -ylmethyl) amino) -4-((methylamino) carbonyl) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.52-1.68 (2H, m), 1.84-1.98 (2H, m), 2.63 (3H, d, J = 4.4Hz), 2.40-3.50 (8H, m ), 3.99 (3H, s), 4.20 (4H, s), 5.80-5.86 (1H, m), 6.59 (1H, d, J = 15.6Hz), 6.76-6.84 (3H, m), 7.10 (1H, d, J = 9.3Hz), 7.70-7.76 (1H, m), 7.85 (1H, d, J = 7.8Hz), 7.89 (1H, d, J = 7.8Hz), 8.26 (1H, d, J = 15.6 Hz), 8.55 (1H, d, J = 9.3Hz)

エチル＝（Ｅ）−３−（８−（ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）アクリラート85mgのメチルイソブチルケトン4mL溶液に、室温で６−（２−クロロエチル）−２Ｈ−ベンゾ［１，４］オキサジン−３（４Ｈ）−オン61mg、ヨウ化ナトリウム43mgおよび炭酸ナトリウム31mgを加え、120℃で2時間30分間攪拌した。６−（２−クロロエチル）−４Ｈ−ベンゾ［１，４］オキサジン−３−オン61mg、ヨウ化ナトリウム43mgおよび炭酸ナトリウム31mgを加え、4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20mLおよび水20mL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］で精製し、黄色固体のエチル＝（Ｅ）−３−（２−メトキシ−８−（１−（２−（３−オキソ−３，４−ジヒドロ−２Ｈ−ベンゾ［１，４］オキサジン−６−イル）エチル）ピペリジン−４−カルボキサミド）キノリン−５−イル）アクリラート41mgを得た。
¹H-NMR(CDCl₃)δ値：1.36(3H,t,J=7.2Hz),1.92-2.07(2H,m),2.09-2.27(4H,m),2.36-2.53(1H,m),2.53-2.69(2H,m),2.70-2.85(2H,m),3.03-3.19(2H,m),4.12(3H,s),4.30(2H,q,J=7.2Hz),4.59(2H,s),6.51(1H,d,J=15.7Hz),6.66(1H,d,J=1.9Hz),6.82(1H,dd,J=8.2,1.9Hz),6.90(1H,d,J=8.2Hz),7.06(1H,d,J=9.2Hz),7.72(1H,d,J=8.4Hz),7.97(1H,s),8.30(1H,d,J=15.7Hz),8.44(1H,d,J=9.2Hz),8.75(1H,d,J=8.4Hz),9.74(1H,s)Example 132

Ethyl = (E) -3- (8- (piperidin-4-carboxamido) -2-methoxyquinolin-5-yl) acrylate 85 mg of methyl isobutyl ketone in 4 mL solution at room temperature with 6- (2-chloroethyl) -2H- 61 mg of benzo [1,4] oxazin-3 (4H) -one, 43 mg of sodium iodide and 31 mg of sodium carbonate were added, and the mixture was stirred at 120 ° C. for 2 hours and 30 minutes. 61 mg of 6- (2-chloroethyl) -4H-benzo [1,4] oxazin-3-one, 43 mg of sodium iodide and 31 mg of sodium carbonate were added, and the mixture was stirred for 4 hours and 30 minutes. The reaction mixture was cooled to room temperature and 20 mL of ethyl acetate and 20 mL of 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, 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: ethyl acetate], and the yellow solid ethyl = (E) -3- (2-methoxy-8- ( 41 mg of 1- (2- (3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl) ethyl) piperidin-4-carboxamido) quinolin-5-yl) acrylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.36 (3H, t, J = 7.2 Hz), 1.92-2.07 (2H, m), 2.09-2.27 (4H, m), 2.36-2.53 (1H, m), 2.53-2.69 (2H, m), 2.70-2.85 (2H, m), 3.03-3.19 (2H, m), 4.12 (3H, s), 4.30 (2H, q, J = 7.2Hz), 4.59 (2H, s), 6.51 (1H, d, J = 15.7Hz), 6.66 (1H, d, J = 1.9Hz), 6.82 (1H, dd, J = 8.2, 1.9Hz), 6.90 (1H, d, J = 8.2) Hz), 7.06 (1H, d, J = 9.2Hz), 7.72 (1H, d, J = 8.4Hz), 7.97 (1H, s), 8.30 (1H, d, J = 15.7Hz), 8.44 (1H, d, J = 9.2Hz), 8.75 (1H, d, J = 8.4Hz), 9.74 (1H, s)

エチル＝（Ｅ）−３−（２−メトキシ−８−（１−（２−（３−オキソ−３，４−ジヒドロ−２Ｈ−ベンゾ［１，４］オキサジン−６−イル）エチル）ピペリジン−４−カルボキサミド）キノリン−５−イル）アクリラート94mgの70％エタノール8mLおよびテトラヒドロフラン5mL溶液に、5mol/L水酸化ナトリウム水溶液0.17mLを加え、50℃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、1mol/L塩酸でpH7に調整（pH試験紙）した。固形物をろ取し、白色固体の（Ｅ）−３−（２−メトキシ−８−（１−（２−（３−オキソ−３，４−ジヒドロ−２Ｈ−ベンゾ［１，４］オキサジン−６−イル）エチル）ピペリジン−４−カルボキサミド）キノリン−５−イル）アクリル酸79mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.78-2.29(4H,m),2.62-3.80(9H,m),4.14(3H,s),4.54(2H,s),6.59(1H,d,J=15.6Hz),6.78(1H,s),6.83(1H,d,J=7.8Hz),6.92(1H,d,J=7.8Hz),7.19(1H,d,J=9.2Hz),7.94(1H,d,J=8.3Hz),8.24(1H,d,J=15.6Hz),8.54(1H,d,J=8.3Hz),8.64(1H,d,J=9.2Hz),9.86(1H,s),10.77(1H,s)Example 133

Ethyl = (E) -3- (2-methoxy-8- (1- (2- (3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl) ethyl) piperidine- 4-Carboxamido) quinolin-5-yl) acrylate 94 mg 70% ethanol 8 mL and tetrahydrofuran 5 mL solution were added 5 mol / L aqueous sodium hydroxide solution 0.17 mL and stirred at 50 ° C. for 1 hour 30 minutes. The reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the pH was adjusted to 7 with 1 mol / L hydrochloric acid (pH test paper). The solid matter was collected by filtration to give (E) -3- (2-methoxy-8- (1- (2- (3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine- 79 mg of 6-yl) ethyl) piperidine-4-carboxamido) quinolin-5-yl) acrylic acid were obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.78-2.29 (4H, m), 2.62-3.80 (9H, m), 4.14 (3H, s), 4.54 (2H, s), 6.59 (1H, d , J = 15.6Hz), 6.78 (1H, s), 6.83 (1H, d, J = 7.8Hz), 6.92 (1H, d, J = 7.8Hz), 7.19 (1H, d, J = 9.2Hz), 7.94 (1H, d, J = 8.3Hz), 8.24 (1H, d, J = 15.6Hz), 8.54 (1H, d, J = 8.3Hz), 8.64 (1H, d, J = 9.2Hz), 9.86 ( 1H, s), 10.77 (1H, s)

エチル＝（Ｅ）−３−（８−（ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）アクリラートおよび６−（２−クロロエチル）−２Ｈ−ベンゾ［１，４］チアジン−３（４Ｈ）−オンから実施例１３２と同様にして、エチル＝（Ｅ）−３−（２−メトキシ−８−（１−（２−（３−オキソ−３，４−ジヒドロ−２Ｈ−ベンゾ［１，４］チアジン−６−イル）エチル）ピペリジン−４−カルボキサミド）キノリン−５−イル）アクリラートを得た。
¹H-NMR(CDCl₃)δ値：1.36(3H,t,J=7.1Hz),1.88-2.08(2H,m),2.08-2.32(4H,m),2.37-2.54(1H,m),2.55-2.71(2H,m),2.72-2.89(2H,m),3.03-3.20(2H,m),3.42(2H,s),4.11(3H,s),4.30(2H,q,J=7.1Hz),6.51(1H,d,J=15.7Hz),6.72(1H,d,J=1.6Hz),6.88(1H,dd,J=7.9,1.6Hz),7.06(1H,d,J=9.2Hz),7.23(1H,d,J=7.9Hz),7.72(1H,d,J=8.2Hz),8.19(1H,s),8.30(1H,d,J=15.7Hz),8.44(1H,d,J=9.2Hz),8.74(1H,d,J=8.2Hz),9.74(1H,s)Example 134

Ethyl = (E) -3- (8- (piperidine-4-carboxamido) -2-methoxyquinolin-5-yl) acrylate and 6- (2-chloroethyl) -2H-benzo [1,4] thiazine-3 ( 4H) -one in the same manner as in Example 132, ethyl = (E) -3- (2-methoxy-8- (1- (2- (3-oxo-3,4-dihydro-2H-benzo [1 , 4] thiazin-6-yl) ethyl) piperidine-4-carboxamido) quinolin-5-yl) acrylate.
¹ H-NMR (CDCl ₃ ) δ value: 1.36 (3H, t, J = 7.1 Hz), 1.88-2.08 (2H, m), 2.08-2.32 (4H, m), 2.37-2.54 (1H, m), 2.55-2.71 (2H, m), 2.72-2.89 (2H, m), 3.03-3.20 (2H, m), 3.42 (2H, s), 4.11 (3H, s), 4.30 (2H, q, J = 7.1 Hz), 6.51 (1H, d, J = 15.7Hz), 6.72 (1H, d, J = 1.6Hz), 6.88 (1H, dd, J = 7.9,1.6Hz), 7.06 (1H, d, J = 9.2) Hz), 7.23 (1H, d, J = 7.9Hz), 7.72 (1H, d, J = 8.2Hz), 8.19 (1H, s), 8.30 (1H, d, J = 15.7Hz), 8.44 (1H, d, J = 9.2Hz), 8.74 (1H, d, J = 8.2Hz), 9.74 (1H, s)

エチル＝（Ｅ）−３−（２−メトキシ−８−（１−（２−（３−オキソ−３，４−ジヒドロ−２Ｈ−ベンゾ［１，４］チアジン−６−イル）エチル）ピペリジン−４−カルボキサミド）キノリン−５−イル）アクリラートから実施例１３３と同様にして、（Ｅ）−３−（２−メトキシ−８−（１−（２−（３−オキソ−３，４−ジヒドロ−２Ｈ−ベンゾ［１，４］チアジン−６−イル）エチル）ピペリジン−４−カルボキサミド）キノリン−５−イル）アクリル酸を得た。
¹H-NMR(DMSO-d₆)δ値：1.65-1.87(2H,m),1.93-2.08(2H,m),2.43-3.37(9H,m),3.42(2H,s),4.11(3H,s),6.57(1H,d,J=15.6Hz),6.84(1H,s),6.86(1H,d,J=7.8Hz),7.17(1H,d,J=9.2Hz),7.22(1H,d,J=7.8Hz),7.92(1H,d,J=8.3Hz),8.23(1H,d,J=15.6Hz),8.55(1H,d,J=8.3Hz),8.62(1H,d,J=9.2Hz),9.79(1H,s),10.52(1H,s)Example 135

Ethyl = (E) -3- (2-methoxy-8- (1- (2- (3-oxo-3,4-dihydro-2H-benzo [1,4] thiazin-6-yl) ethyl) piperidine- (E) -3- (2-methoxy-8- (1- (2- (3-oxo-3,4-dihydro-)) from 4-carboxamido) quinolin-5-yl) acrylate as in example 133. 2H-benzo [1,4] thiazin-6-yl) ethyl) piperidine-4-carboxamido) quinolin-5-yl) acrylic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.65-1.87 (2H, m), 1.93-2.08 (2H, m), 2.43-3.37 (9H, m), 3.42 (2H, s), 4.11 (3H , s), 6.57 (1H, d, J = 15.6Hz), 6.84 (1H, s), 6.86 (1H, d, J = 7.8Hz), 7.17 (1H, d, J = 9.2Hz), 7.22 (1H , d, J = 7.8Hz), 7.92 (1H, d, J = 8.3Hz), 8.23 (1H, d, J = 15.6Hz), 8.55 (1H, d, J = 8.3Hz), 8.62 (1H, d , J = 9.2Hz), 9.79 (1H, s), 10.52 (1H, s)

エチル＝（Ｅ）−３−（８−（ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）アクリラート280mgおよび７−ブロモ−６−（２−クロロアセチル）−２Ｈ−ピリド［３，２−ｂ］［１，４］チアジン−３（４Ｈ）−オン280mgのメチルイソブチルケトン40mL懸濁液に、炭酸カリウム142mgおよびヨウ化カリウム16mgを加え、室温で一晩攪拌した。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６０、溶離液；クロロホルム：メタノール＝１０：１］で精製し、褐色固体のエチル＝（Ｅ）−３−（８−（１−（２−（７−ブロモ−３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド［３，２−ｂ］［１，４］チアジン−６−イル）−２−オキソエチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）アクリラート264mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.29(3H,t,J=7.3Hz),1.70-1.78(2H,m),1.92-1.97(2H,m),2.38-2.39(1H,m),2.61-2.62(2H,m),2.94-3.02(2H,m),3.68(2H,s),3.86(2H,s),4.12(3H,s),4.22(2H,q,J=7.3Hz),6.68(1H,d,J=16.0Hz),7.19(1H,d,J=9.2Hz),7.97(1H,d,J=8.3Hz),8.24(1H,s),8.29(1H,d,J=16.0Hz),8.56(1H,d,J=8.3Hz),8.64(1H,d,H=9.2Hz),9.78(1H,s),11.27(1H,s)Example 136

Ethyl = (E) -3- (8- (piperidine-4-carboxamido) -2-methoxyquinolin-5-yl) acrylate 280 mg and 7-bromo-6- (2-chloroacetyl) -2H-pyrido [3 To a suspension of 2-b] [1,4] thiazin-3 (4H) -one in 280 mg of methyl isobutyl ketone, 142 mg of potassium carbonate and 16 mg of potassium iodide were added and stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent: chloroform: methanol = 10: 1], and ethyl of brown solid = (E) -3- (8- (1- (2- (7-bromo-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl) -2-oxoethyl) 264 mg of piperidine-4-carboxamide) -2-methoxyquinolin-5-yl) acrylate were obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.29 (3H, t, J = 7.3 Hz), 1.70-1.78 (2H, m), 1.92-1.97 (2H, m), 2.38-2.39 (1H, m ), 2.61-2.62 (2H, m), 2.94-3.02 (2H, m), 3.68 (2H, s), 3.86 (2H, s), 4.12 (3H, s), 4.22 (2H, q, J = 7.3 Hz), 6.68 (1H, d, J = 16.0Hz), 7.19 (1H, d, J = 9.2Hz), 7.97 (1H, d, J = 8.3Hz), 8.24 (1H, s), 8.29 (1H, d, J = 16.0Hz), 8.56 (1H, d, J = 8.3Hz), 8.64 (1H, d, H = 9.2Hz), 9.78 (1H, s), 11.27 (1H, s)

エチル＝（Ｅ）−３−（８−（１−（２−（７−ブロモ−３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド［３，２−ｂ］［１，４］チアジン−６−イル）−２−オキソエチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）アクリラート174mgのクロロホルム15mLおよびメタノール15mL懸濁液に、氷冷下、水素化ホウ素ナトリウム61.3mgを加え、1時間攪拌した。反応混合物を1mol/L塩酸でpH4に調整（pH試験紙）し、飽和炭酸水素ナトリウム水溶液でpH9に調整（pH試験紙）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［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＝１０：１］で精製し、淡褐色固体のエチル＝（Ｅ）−３−（８−（１−（２−（７−ブロモ−３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド［３，２−ｂ］［１，４］チアジン−６−イル）−２−ヒドロキシエチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）アクリラート155mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.29(3H,t,J=6.9Hz),1.71(2H,s),1.91(2H,s),2.20(2H,s),2.37-2.39(1H,m),2.61(2H,s),2.90(1H,s),3.05(1H,s),3.61(2H,s),4.11(3H,s),4.23(2H,q,J=6.9Hz),5.03-5.16(2H,m),6.68(1H,d,J=16.0Hz),7.19(1H,d,J=9.2Hz),7.96(1H,d,J=8.2Hz),8.06(1H,s),8.31(1H,d,J=16.0Hz),8.55(1H,d,J=8.2Hz),8.64(1H,d,J=9.2Hz),9.78(1H,s),11.10(1H,s)Example 137

Ethyl = (E) -3- (8- (1- (2- (7-bromo-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6) -Ile) -2-oxoethyl) piperidin-4-carboxamido) -2-methoxyquinolin-5-yl) acrylate 174 mg of chloroform and 15 mL of methanol were added with 61.3 mg of sodium borohydride under ice cooling, Stir for 1 hour. The reaction mixture was adjusted to pH 4 with 1 mol / L hydrochloric acid (pH test paper), adjusted to pH 9 with saturated aqueous sodium hydrogen carbonate solution (pH test paper), 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 = 10: 1], and light brown solid ethyl = (E) -3- (8 -(1- (2- (7-Bromo-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl) -2-hydroxyethyl) piperidine 155 mg of -4-carboxamido) -2-methoxyquinolin-5-yl) acrylate was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.29 (3H, t, J = 6.9 Hz), 1.71 (2H, s), 1.91 (2H, s), 2.20 (2H, s), 2.37-2.39 ( 1H, m), 2.61 (2H, s), 2.90 (1H, s), 3.05 (1H, s), 3.61 (2H, s), 4.11 (3H, s), 4.23 (2H, q, J = 6.9Hz ), 5.03-5.16 (2H, m), 6.68 (1H, d, J = 16.0Hz), 7.19 (1H, d, J = 9.2Hz), 7.96 (1H, d, J = 8.2Hz), 8.06 (1H , s), 8.31 (1H, d, J = 16.0Hz), 8.55 (1H, d, J = 8.2Hz), 8.64 (1H, d, J = 9.2Hz), 9.78 (1H, s), 11.10 (1H , s)

エチル＝（Ｅ）−３−（８−（１−（２−（７−ブロモ−３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド［３，２−ｂ］［１，４］チアジン−６−イル）−２−ヒドロキシエチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）アクリラート119mgの70％エタノール10mLおよびテトラヒドロフラン5mL懸濁液に、5mol/L水酸化ナトリウム水溶液0.18mLを加え、50℃で1時間攪拌した。反応混合物を室温まで冷却し、水3mLを加え、減圧下で溶媒を留去した。得られた残留物を1mol/L塩酸でpH7に調整（pH試験紙）し、固形物をろ取し、淡褐色固体の（Ｅ）−３−（８−（１−（２−（７−ブロモ−３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド［３，２−ｂ］［１，４］チアジン−６−イル）−２−ヒドロキシエチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）アクリル酸75.7mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.61-1.75(2H,m),1.89-1.94(2H,m),2.18-2.24(2H,m),2.57-2.64(2H,m),2.71-2.73(1H,m),3.02-3.07(2H,m),3.58(2H,s),4.11(3H,s),4.93-4.96(1H,m),5.09-5.12(1H,m),6.56(1H,d,J=15.6Hz),7.18(1H,d,J=9.2Hz),7.92(1H,d,J=8.3Hz),8.06(1H,s),8.22(1H,d,J=15.6Hz),8.56(1H,d,J=8.3Hz),8.59(1H,d,J=9.2Hz),9.76(1H,s),11.09(1H,s)Example 138

Ethyl = (E) -3- (8- (1- (2- (7-bromo-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6) -Il) -2-hydroxyethyl) piperidine-4-carboxamido) -2-methoxyquinolin-5-yl) acrylate 119 mg of 70% ethanol 10 mL and tetrahydrofuran 5 mL suspension with 5 mol / L aqueous sodium hydroxide solution 0.18 mL In addition, the mixture was stirred at 50 ° C. for 1 hour. The reaction mixture was cooled to room temperature, 3 mL of water was added, and the solvent was distilled off under reduced pressure. The obtained residue was adjusted to pH 7 with 1 mol / L hydrochloric acid (pH test paper), the solid substance was collected by filtration, and (E) -3- (8- (1- (2- (7- Bromo-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl) -2-hydroxyethyl) piperidine-4-carboxamide) -2-methoxyquinoline -5-yl) acrylic acid 75.7 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.61-1.75 (2H, m), 1.89-1.94 (2H, m), 2.18-2.24 (2H, m), 2.57-2.64 (2H, m), 2.71 -2.73 (1H, m), 3.02-3.07 (2H, m), 3.58 (2H, s), 4.11 (3H, s), 4.93-4.96 (1H, m), 5.09-5.12 (1H, m), 6.56 (1H, d, J = 15.6Hz), 7.18 (1H, d, J = 9.2Hz), 7.92 (1H, d, J = 8.3Hz), 8.06 (1H, s), 8.22 (1H, d, J = 15.6Hz), 8.56 (1H, d, J = 8.3Hz), 8.59 (1H, d, J = 9.2Hz), 9.76 (1H, s), 11.09 (1H, s)

エチル＝（Ｅ）−３−（８−（ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）アクリラートおよび６−（２−クロロアセチル）−２Ｈ−ピリド［３，２−ｂ］［１，４］チアジン−３（４Ｈ）−オンから実施例１３６と同様にして、エチル＝（Ｅ）−３−（２−メトキシ−８−（１−（２−オキソ−２−（３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド［３，２−ｂ］［１，４］チアジン−６−イル）エチル）ピペリジン−４−カルボキサミド）キノリン−５−イル）アクリラートを得た。
¹H-NMR(DMSO-d₆)δ値：1.28(3H,t,J=6.9Hz),1.75-1.82(2H,m),1.94-1.98(2H,m),2.31-2.42(1H,m),2.60-2.61(2H,m),2.95-3.04(2H,m),3.66(2H,s),4.01(2H,s),4.12(3H,s),4.23(2H,q,J=6.9Hz),6.68(1H,d,J=15.6Hz),7.20(1H,d,J=9.2Hz),7.55-7.59(1H,m),7.91(1H,d,J=8.2Hz),7.96-8.02(1H,m),8.26(1H,d,J=15.6Hz),8.58(1H,d,J=8.2Hz),8.65(1H,d,J=9.2Hz),9.79(1H,s),11.29(1H,s)Example 139

Ethyl = (E) -3- (8- (piperidine-4-carboxamido) -2-methoxyquinolin-5-yl) acrylate and 6- (2-chloroacetyl) -2H-pyrido [3,2-b] [ 1,4] thiazin-3 (4H) -one in the same manner as in Example 136, ethyl = (E) -3- (2-methoxy-8- (1- (2-oxo-2- (3-oxo -3,4-Dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl) ethyl) piperidin-4-carboxamido) quinolin-5-yl) acrylate was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.28 (3H, t, J = 6.9 Hz), 1.75-1.82 (2H, m), 1.94-1.98 (2H, m), 2.31-2.42 (1H, m ), 2.60-2.61 (2H, m), 2.95-3.04 (2H, m), 3.66 (2H, s), 4.01 (2H, s), 4.12 (3H, s), 4.23 (2H, q, J = 6.9 Hz), 6.68 (1H, d, J = 15.6Hz), 7.20 (1H, d, J = 9.2Hz), 7.55-7.59 (1H, m), 7.91 (1H, d, J = 8.2Hz), 7.96- 8.02 (1H, m), 8.26 (1H, d, J = 15.6Hz), 8.58 (1H, d, J = 8.2Hz), 8.65 (1H, d, J = 9.2Hz), 9.79 (1H, s), 11.29 (1H, s)

エチル＝（Ｅ）−３−（２−メトキシ−８−（１−（２−オキソ−２−（３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド［３，２−ｂ］［１，４］チアジン−６−イル）エチル）ピペリジン−４−カルボキサミド）キノリン−５−イル）アクリラート131mgから実施例１３７および実施例１３８と同様にして、（Ｅ）−３−（８−（１−（２−ヒドロキシ−２−（３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド［３，２−ｂ］［１，４］チアジン−６−イル）エチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）アクリル酸を得た。
¹H-NMR(DMSO-d₆)δ値：1.73-1.79(2H,m),1.91-1.95(2H,m),2.24(2H,s),2.61-2.66(3H,m),3.01-3.06(2H,m),3.48(2H,s),4.12(3H,s),4.65-4.69(1H,m),6.58(1H,d,J=15.6Hz),7.14(1H,d,J=7.8Hz),7.18(1H,d,J=8.7Hz),7.77(1H,d,J=7.8Hz),7.92(1H,d,J=8.3Hz),8.24(1H,d,J=15.6Hz),8.57(1H,d,J=8.3Hz),8.65(1H,d,J=8.7Hz),9.78(1H,s),10.87(1H,s)Example 140

Ethyl = (E) -3- (2-methoxy-8- (1- (2-oxo-2- (3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4 ) Thiazin-6-yl) ethyl) piperidin-4-carboxamido) quinolin-5-yl) acrylate in the same manner as in Example 137 and Example 138 as in (E) -3- (8- (1- (2 -Hydroxy-2- (3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl) ethyl) piperidine-4-carboxamido) -2-methoxyquinoline -5-yl) acrylic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.73-1.79 (2H, m), 1.91-1.95 (2H, m), 2.24 (2H, s), 2.61-2.66 (3H, m), 3.01-3.06 (2H, m), 3.48 (2H, s), 4.12 (3H, s), 4.65-4.69 (1H, m), 6.58 (1H, d, J = 15.6Hz), 7.14 (1H, d, J = 7.8 Hz), 7.18 (1H, d, J = 8.7Hz), 7.77 (1H, d, J = 7.8Hz), 7.92 (1H, d, J = 8.3Hz), 8.24 (1H, d, J = 15.6Hz) , 8.57 (1H, d, J = 8.3Hz), 8.65 (1H, d, J = 8.7Hz), 9.78 (1H, s), 10.87 (1H, s)

エチル＝（Ｅ）−３−（８−（ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）アクリラートおよび７−クロロ−６−（２−クロロアセチル）−２Ｈ−ピリド［３，２−ｂ］［１，４］チアジン−３（４Ｈ）−オンから実施例１３６と同様にして、エチル＝（Ｅ）−３−（８−（１−（２−（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−イル）−２−オキソエチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）アクリラートを得た。
¹H-NMR(DMSO-d₆)δ値：1.30(3H,t,J=6.9Hz),1.70-1.76(2H,m),1.90-1.95(2H,m),2.61-2.65(3H,m),2.95-2.97(2H,m),3.70(2H,s),3.86(2H,s),4.11(3H,s),4.23(2H,q,J=6.9Hz),6.68(1H,d,J=15.6Hz),7.19(1H,d,J=9.1Hz),7.97(1H,d,J=8.3Hz),8.12(1H,s),8.29(1H,d,J=15.6Hz),8.57(1H,d,J=8.3Hz),8.65(1H,d,J=9.1Hz),9.78(1H,s)Example 141

Ethyl = (E) -3- (8- (piperidine-4-carboxamido) -2-methoxyquinolin-5-yl) acrylate and 7-chloro-6- (2-chloroacetyl) -2H-pyrido [3,2 -B] [1,4] thiazin-3 (4H) -one in the same manner as in Example 136, ethyl = (E) -3- (8- (1- (2- (7-chloro-3-oxo -3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl) -2-oxoethyl) piperidine-4-carboxamido) -2-methoxyquinolin-5-yl) acrylate Got.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.30 (3H, t, J = 6.9 Hz), 1.70-1.76 (2H, m), 1.90-1.95 (2H, m), 2.61-2.65 (3H, m ), 2.95-2.97 (2H, m), 3.70 (2H, s), 3.86 (2H, s), 4.11 (3H, s), 4.23 (2H, q, J = 6.9Hz), 6.68 (1H, d, J = 15.6Hz), 7.19 (1H, d, J = 9.1Hz), 7.97 (1H, d, J = 8.3Hz), 8.12 (1H, s), 8.29 (1H, d, J = 15.6Hz), 8.57 (1H, d, J = 8.3Hz), 8.65 (1H, d, J = 9.1Hz), 9.78 (1H, s)

エチル＝（Ｅ）−３−（８−（１−（２−（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−イル）−２−オキソエチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）アクリラートから実施例１３７と同様にして、エチル＝（Ｅ）−３−（８−（１−（２−（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−イル）−２−ヒドロキシエチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）アクリラートを得た。
¹H-NMR(DMSO-d₆)δ値：1.29(3H,t,J=6.9Hz),1.74(2H,s),1.94(2H,s),2.22(2H,s),2.73(1H,s),2.90(2H,s),3.04(2H,s),3.59(2H,s),4.12(3H,s),4.23(2H,q,J=6.9Hz),5.13(1H,s),6.68(1H,d,J=15.6Hz),7.20(1H,d,J=9.2Hz),7.99(1H,d,J=8.3Hz),8.29(1H,d,J=15.6Hz),8.32(1H,s),8.55(1H,d,J=8.3Hz),8.65(1H,d,J=9.2Hz),9.79(1H,s),11.16(1H,s)Example 142

Ethyl = (E) -3- (8- (1- (2- (7-chloro-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6) -Yl) -2-oxoethyl) piperidine-4-carboxamido) -2-methoxyquinolin-5-yl) acrylate in the same manner as in Example 137, ethyl = (E) -3- (8- (1- (2 -(7-chloro-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl) -2-hydroxyethyl) piperidine-4-carboxamide)- 2-Methoxyquinolin-5-yl) acrylate was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.29 (3H, t, J = 6.9 Hz), 1.74 (2H, s), 1.94 (2H, s), 2.22 (2H, s), 2.73 (1H, s), 2.90 (2H, s), 3.04 (2H, s), 3.59 (2H, s), 4.12 (3H, s), 4.23 (2H, q, J = 6.9Hz), 5.13 (1H, s), 6.68 (1H, d, J = 15.6Hz), 7.20 (1H, d, J = 9.2Hz), 7.99 (1H, d, J = 8.3Hz), 8.29 (1H, d, J = 15.6Hz), 8.32 ( 1H, s), 8.55 (1H, d, J = 8.3Hz), 8.65 (1H, d, J = 9.2Hz), 9.79 (1H, s), 11.16 (1H, s)

エチル＝（Ｅ）−３−（８−（１−（２−（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−イル）−２−ヒドロキシエチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）アクリラートから実施例１３８と同様にして、（Ｅ）−３−（８−（１−（２−（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−イル）−２−ヒドロキシエチル）ピペリジン−４−カルボキサミド）−２−メトキシキノリン−５−イル）アクリル酸を得た。
¹H-NMR(DMSO-d₆)δ値：1.76-1.90(4H,m),2.00-2.11(3H,m),2.76(2H,s),3.00(2H,s),3.59(2H,s),4.13(3H,s),5.10-5.29(1H,m),6.58(1H,d,J=16.5Hz),7.18(1H,d,J=8.3Hz),7.93(1H,d,J=8.3Hz),8.02(1H,s),8.27(1H,d,J=16.5Hz),8.54(1H,d,J=8.3Hz),8.63(1H,d,J=8.3Hz),9.80(1H,s),11.14(1H,s)Example 143

Ethyl = (E) -3- (8- (1- (2- (7-chloro-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6) (E) -3- (8- (1- (2- (2- (2- (2-ethylethyl)-(2-hydroxyethyl))-(2-hydroxyethyl) piperidine-4-carboxamido) -2-methoxyquinolin-5-yl) acrylate in the same manner as in Example 138. (7-chloro-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl) -2-hydroxyethyl) piperidine-4-carboxamide) -2 -Methoxyquinolin-5-yl) acrylic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.76-1.90 (4H, m), 2.00-2.11 (3H, m), 2.76 (2H, s), 3.00 (2H, s), 3.59 (2H, s ), 4.13 (3H, s), 5.10-5.29 (1H, m), 6.58 (1H, d, J = 16.5Hz), 7.18 (1H, d, J = 8.3Hz), 7.93 (1H, d, J = 8.3Hz), 8.02 (1H, s), 8.27 (1H, d, J = 16.5Hz), 8.54 (1H, d, J = 8.3Hz), 8.63 (1H, d, J = 8.3Hz), 9.80 (1H , s), 11.14 (1H, s)

エチル＝（Ｅ）−３−（８−（１−ヒドロキシ−２−（ピペラジン−１−イル）エチル）−２−メトキシキノリン−５−イル）アクリラートの２塩酸塩0.30gのメチルイソブチルケトン10mL溶液に、室温で６−（２−クロロエチル）−２Ｈ−ベンゾ［１，４］オキサジン−３（４Ｈ）−オン0.35g、ヨウ化ナトリウム0.27gおよび炭酸カリウム0.36gを加え、120℃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＝２０：１］で精製し、白色固体のエチル＝（Ｅ）−３−（８−（１−ヒドロキシ−２−（４−（２−（３−オキソ−３，４−ジヒドロ−２Ｈ−ベンゾ［１，４］オキサジン−６−イル）エチル）ピペラジン−１−イル）エチル）−２−メトキシキノリン−５−イル）アクリラート0.20gを得た。
¹H-NMR(CDCl₃)δ値：1,37(3H,t,J=7.3Hz),2.30-3.02(13H,m),3.07(1H,d,J=11.5Hz),4.04(3H,s),4.31(2H,q,J=7.3Hz),4.59(2H,s),5.80(1H,d,J=8.3Hz),6.52(1H,d,J=15.6Hz),6.65(1H,d,J=1.8Hz),6.82(1H,dd,J=8.3,1.8Hz),6.90(1H,d,J=8.3Hz),7.00(1H,d,J=9.2Hz),7.68(1H,d,J=7.3Hz),7.85(1H,s),7.88(1H,d,J=7.3Hz),8.35(1H,d,J=15.6Hz),8.39(1H,d,J=9.2Hz)Example 144

Ethyl = (E) -3- (8- (1-hydroxy-2- (piperazin-1-yl) ethyl) -2-methoxyquinolin-5-yl) acrylate dihydrochloride 0.30 g of methyl isobutyl ketone 10 mL solution At room temperature were added 0.35 g of 6- (2-chloroethyl) -2H-benzo [1,4] oxazin-3 (4H) -one, 0.27 g of sodium iodide and 0.36 g of potassium carbonate, and the mixture was stirred at 120 ° C. for 5 hours. did. The reaction mixture was cooled to room temperature 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 = 20: 1], and white solid ethyl = (E) -3- (8- (1-Hydroxy-2- (4- (2- (3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl) ethyl) piperazin-1-yl) ethyl) -2 0.20 g of -methoxyquinolin-5-yl) acrylate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1,37 (3H, t, J = 7.3 Hz), 2.30-3.02 (13H, m), 3.07 (1H, d, J = 11.5 Hz), 4.04 (3H, s), 4.31 (2H, q, J = 7.3Hz), 4.59 (2H, s), 5.80 (1H, d, J = 8.3Hz), 6.52 (1H, d, J = 15.6Hz), 6.65 (1H, d, J = 1.8Hz), 6.82 (1H, dd, J = 8.3,1.8Hz), 6.90 (1H, d, J = 8.3Hz), 7.00 (1H, d, J = 9.2Hz), 7.68 (1H, d, J = 7.3Hz), 7.85 (1H, s), 7.88 (1H, d, J = 7.3Hz), 8.35 (1H, d, J = 15.6Hz), 8.39 (1H, d, J = 9.2Hz)

エチル＝（Ｅ）−３−（８−（１−ヒドロキシ−２−（４−（２−（３−オキソ−３，４−ジヒドロ−２Ｈ−ベンゾ［１，４］オキサジン−６−イル）エチル）ピペラジン−１−イル）エチル）−２−メトキシキノリン−５−イル）アクリラート0.15gの70％エタノール10mL、テトラヒドロフラン10mLおよびクロロホルム5mL溶液に、5mol/L水酸化ナトリウム水溶液0.26mLを加え、室温で1時間、50℃で2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、1mol/L塩酸でpH7に調整（pH試験紙）した。固形物をろ取し、酢酸エチルで洗浄し、白色固体の（Ｅ）−３−（８−（１−ヒドロキシ−２−（４−（２−（３−オキソ−３，４−ジヒドロ−２Ｈ−ベンゾ［１，４］オキサジン−６−イル）エチル）ピペラジン−１−イル）エチル）−２−メトキシキノリン−５−イル）アクリル酸61mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.24-3.50(14H,m),4.02(3H,s),4.52(2H,s),5.88(1H,s),6.60(1H,d,J=15.6Hz),6.74(1H,d,J=1.8Hz),6.77(1H,dd,J=7.8,1.8Hz),6.85(1H,d,J=7.8Hz),7.11(1H,d,J=9.2Hz),7.87(1H,d,J=7.8Hz),7.91(1H,d,J=7.8Hz),8.28(1H,d,J=15.6Hz),8.57(1H,d,J=9.2Hz),10.66(1H,s)Example 145

Ethyl = (E) -3- (8- (1-hydroxy-2- (4- (2- (3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl) ethyl) ) Piperazin-1-yl) ethyl) -2-methoxyquinolin-5-yl) acrylate 0.15 g of 70% ethanol 10 mL, tetrahydrofuran 10 mL and chloroform 5 mL are added with 5 mol / L aqueous sodium hydroxide solution 0.26 mL at room temperature. The mixture was stirred for 1 hour at 50 ° C. for 2 hours. The reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the pH was adjusted to 7 with 1 mol / L hydrochloric acid (pH test paper). The solid was collected by filtration, washed with ethyl acetate, and white solid (E) -3- (8- (1-hydroxy-2- (4- (2- (3-oxo-3,4-dihydro-2H -Benzo [1,4] oxazin-6-yl) ethyl) piperazin-1-yl) ethyl) -2-methoxyquinolin-5-yl) acrylic acid 61 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.24-3.50 (14H, m), 4.02 (3H, s), 4.52 (2H, s), 5.88 (1H, s), 6.60 (1H, d, J = 15.6Hz), 6.74 (1H, d, J = 1.8Hz), 6.77 (1H, dd, J = 7.8, 1.8Hz), 6.85 (1H, d, J = 7.8Hz), 7.11 (1H, d, J = 9.2Hz), 7.87 (1H, d, J = 7.8Hz), 7.91 (1H, d, J = 7.8Hz), 8.28 (1H, d, J = 15.6Hz), 8.57 (1H, d, J = 9.2 Hz), 10.66 (1H, s)

エチル＝（Ｅ）−３−（８−（１−ヒドロキシ−２−（ピペラジン−１−イル）エチル）−２−メトキシキノリン−５−イル）アクリラートの２塩酸塩および６−（２−クロロエチル）−２Ｈ−ベンゾ［１，４］チアジン−３（４Ｈ）−オンから実施例１４４と同様にして、エチル＝（Ｅ）−３−（８−（１−ヒドロキシ−２−（４−（２−（３−オキソ−３，４−ジヒドロ−２Ｈ−ベンゾ［１，４］チアジン−６−イル）エチル）ピペラジン−１−イル）エチル）−２−メトキシキノリン−５−イル）アクリラートを得た。
¹H-NMR(CDCl₃)δ値：1.37(3H,t,J=7.2Hz),2.34-3.18(14H,m),3.42(2H,s),4.04(3H,s),4.31(2H,q,J=7.2Hz),5.75-5.84(1H,m),6.52(1H,d,J=15.6Hz),6.69(1H,d,J=1.8Hz),6.88(1H,dd,J=7.8,1.8Hz),7.00(1H,d,J=9.2Hz),7.24(1H,d,J=7.8Hz),7.69(1H,d,J=7.8Hz),7.76(1H,s),7.88(1H,d,J=7.8Hz),8.35(1H,d,J=15.6Hz),8.39(1H,d,J=9.2Hz)Example 146

Ethyl = (E) -3- (8- (1-hydroxy-2- (piperazin-1-yl) ethyl) -2-methoxyquinolin-5-yl) acrylate dihydrochloride and 6- (2-chloroethyl) -H-benzo [1,4] thiazin-3 (4H) -one in the same manner as in Example 144, ethyl = (E) -3- (8- (1-hydroxy-2- (4- (2- (3-Oxo-3,4-dihydro-2H-benzo [1,4] thiazin-6-yl) ethyl) piperazin-1-yl) ethyl) -2-methoxyquinolin-5-yl) acrylate was obtained.
_{^{1 H-NMR (CDCl 3)}} δ value: 1.37 (3H, t, J = 7.2Hz), 2.34-3.18 (14H, m), 3.42 (2H, s), 4.04 (3H, s), 4.31 (2H, q, J = 7.2Hz), 5.75-5.84 (1H, m), 6.52 (1H, d, J = 15.6Hz), 6.69 (1H, d, J = 1.8Hz), 6.88 (1H, dd, J = 7.8 , 1.8Hz), 7.00 (1H, d, J = 9.2Hz), 7.24 (1H, d, J = 7.8Hz), 7.69 (1H, d, J = 7.8Hz), 7.76 (1H, s), 7.88 ( 1H, d, J = 7.8Hz), 8.35 (1H, d, J = 15.6Hz), 8.39 (1H, d, J = 9.2Hz)

エチル＝（Ｅ）−３−（８−（１−ヒドロキシ−２−（４−（２−（３−オキソ−３，４−ジヒドロ−２Ｈ−ベンゾ［１，４］チアジン−６−イル）エチル）ピペラジン−１−イル）エチル）−２−メトキシキノリン−５−イル）アクリラートから実施例１４５と同様にして、（Ｅ）−３−（８−（１−ヒドロキシ−２−（４−（２−（３−オキソ−３，４−ジヒドロ−２Ｈ−ベンゾ［１，４］チアジン−６−イル）エチル）ピペラジン−１−イル）エチル）−２−メトキシキノリン−５−イル）アクリル酸を得た。
¹H-NMR(CD₃OD)δ値：2.81-3.37(13H,m),3.40(2H,s),3.41-3.48(1H,m),4.09(3H,s),6.14(1H,dd,J=9.9,2.5Hz),6.59(1H,d,J=15.6Hz),6.86(1H,d,J=1.8Hz),6.94(1H,dd,J=7.8,1.8Hz),7.10(1H,d,J=9.2Hz),7.25(1H,d,J=7.8Hz),7.85(1H,d,J=7.8Hz),7.96(1H,d,J=7.8Hz),8.40(1H,d,J=15.6Hz),8.53(1H,d,J=9.2Hz)Example 147

Ethyl = (E) -3- (8- (1-hydroxy-2- (4- (2- (3-oxo-3,4-dihydro-2H-benzo [1,4] thiazin-6-yl) ethyl) ) Piperazin-1-yl) ethyl) -2-methoxyquinolin-5-yl) acrylate in the same manner as in Example 145, and (E) -3- (8- (1-hydroxy-2- (4- (2 -(3-Oxo-3,4-dihydro-2H-benzo [1,4] thiazin-6-yl) ethyl) piperazin-1-yl) ethyl) -2-methoxyquinolin-5-yl) acrylic acid It was.
¹ H-NMR (CD ₃ OD) δ value: 2.81-3.37 (13H, m), 3.40 (2H, s), 3.41-3.48 (1H, m), 4.09 (3H, s), 6.14 (1H, dd, J = 9.9, 2.5Hz), 6.59 (1H, d, J = 15.6Hz), 6.86 (1H, d, J = 1.8Hz), 6.94 (1H, dd, J = 7.8, 1.8Hz), 7.10 (1H, d, J = 9.2Hz), 7.25 (1H, d, J = 7.8Hz), 7.85 (1H, d, J = 7.8Hz), 7.96 (1H, d, J = 7.8Hz), 8.40 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz)

エチル＝（Ｅ）−３−（８−（１−ヒドロキシ−２−（ピペラジン−１−イル）エチル）−２−メトキシキノリン−５−イル）アクリラートの２塩酸塩265mgおよび７−ブロモ−６−（２−クロロアセチル）−２Ｈ−ピリド［３，２−ｂ］［１，４］チアジン−３（４Ｈ）−オン221mgのアセトン30mL懸濁液に、炭酸カリウム287mgおよびヨウ化カリウム18.7mgを加え、室温で一晩攪拌した。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６０、溶離液；クロロホルム：メタノール＝１０：１］で精製し、黄色固体のエチル＝（Ｅ）−３−（８−（２−（４−（２−（７−ブロモ−３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド［３，２−ｂ］［１，４］チアジン−６−イル）−２−オキソエチル）ピペラジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート277mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.29(3H,t,J=6.9Hz),2.46-2.75(10H,m),3.66(2H,s),3.82(2H,s),4.01(3H,s),4.24(2H,q,J=6.9Hz),5.81-5.87(1H,m),6.69(1H,d,J=15.6Hz),7.11(1H,d,J=9.2Hz),7.85(1H,d,J=7.8Hz),7.93(1H,d,J=7.8Hz),8.24(1H,s),8.34(1H,d,J=15.6Hz),8.57(1H,d,J=9.2Hz),11.26(1H,s)Example 148

Ethyl = (E) -3- (8- (1-hydroxy-2- (piperazin-1-yl) ethyl) -2-methoxyquinolin-5-yl) acrylate dihydrochloride 265 mg and 7-bromo-6- To a suspension of 221 mg of (2-chloroacetyl) -2H-pyrido [3,2-b] [1,4] thiazin-3 (4H) -one in 30 mL of acetone was added 287 mg of potassium carbonate and 18.7 mg of potassium iodide. Stir at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent: chloroform: methanol = 10: 1], and yellow solid ethyl = (E) -3- (8- (2- (4- (2- (7-Bromo-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl) -2 -Oxoethyl) piperazin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate was obtained 277 mg.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.29 (3H, t, J = 6.9 Hz), 2.46-2.75 (10H, m), 3.66 (2H, s), 3.82 (2H, s), 4.01 ( 3H, s), 4.24 (2H, q, J = 6.9Hz), 5.81-5.87 (1H, m), 6.69 (1H, d, J = 15.6Hz), 7.11 (1H, d, J = 9.2Hz), 7.85 (1H, d, J = 7.8Hz), 7.93 (1H, d, J = 7.8Hz), 8.24 (1H, s), 8.34 (1H, d, J = 15.6Hz), 8.57 (1H, d, J = 9.2Hz), 11.26 (1H, s)

エチル＝（Ｅ）−３−（８−（２−（４−（２−（７−ブロモ−３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド［３，２−ｂ］［１，４］チアジン−６−イル）−２−オキソエチル）ピペラジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート131mgのクロロホルム10mLおよびメタノール10mL懸濁液に、氷冷下、水素化ホウ素ナトリウム88.5mgを加え、2時間攪拌した。反応混合物を1mol/L塩酸でpH4に調整（pH試験紙）し、飽和炭酸水素ナトリウム水溶液でpH9に調整（pH試験紙）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［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＝１０：１］で精製し、黄色固体のエチル＝（Ｅ）−３−（８−（２−（４−（２−（７−ブロモ−３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド［３，２−ｂ］［１，４］チアジン−６−イル）−２−ヒドロキシエチル）ピペラジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート97.4mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.29(3H,t,J=6.9Hz),2.47-2.61(10H,m),3.50-3.52(2H,m),3.58(2H,s),4.03(3H,s),4.24(2H,q,J=6.9Hz),5.04-5.10(1H,m),6.72(1H,d,J=16.1Hz),7.13(1H,d,J=8.7Hz),7.85-8.00(2H,m),8.07(1H,s),8.35(1H,d,J=16.1Hz),8.56-8.64(1H,m),11.09(1H,s)Example 149

Ethyl = (E) -3- (8- (2- (4- (2- (7-bromo-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] To a suspension of thiazin-6-yl) -2-oxoethyl) piperazin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate 131 mg in chloroform 10 mL and methanol 10 mL under ice cooling, 88.5 mg of sodium borohydride was added and stirred for 2 hours. The reaction mixture was adjusted to pH 4 with 1 mol / L hydrochloric acid (pH test paper), adjusted to pH 9 with saturated aqueous sodium hydrogen carbonate solution (pH test paper), 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 = 10: 1], and yellow solid ethyl = (E) -3- (8- (2- (4- (2- (7-Bromo-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl) -2-hydroxyethyl 97.4 mg of piperazin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate were obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.29 (3H, t, J = 6.9 Hz), 2.47-2.61 (10H, m), 3.50-3.52 (2H, m), 3.58 (2H, s), 4.03 (3H, s), 4.24 (2H, q, J = 6.9Hz), 5.04-5.10 (1H, m), 6.72 (1H, d, J = 16.1Hz), 7.13 (1H, d, J = 8.7Hz ), 7.85-8.00 (2H, m), 8.07 (1H, s), 8.35 (1H, d, J = 16.1Hz), 8.56-8.64 (1H, m), 11.09 (1H, s)

エチル＝（Ｅ）−３−（８−（２−（４−（２−（７−ブロモ−３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド［３，２−ｂ］［１，４］チアジン−６−イル）−２−ヒドロキシエチル）ピペラジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート66.7mgのエタノール7mL、テトラヒドロフラン5mLおよび水3mL懸濁液に、5mol/L水酸化ナトリウム水溶液0.1mLを加え、50℃で1時間攪拌した。反応混合物を室温まで冷却し、水3mLを加え、減圧下で溶媒を留去した。得られた残留物を1mol/L塩酸でpH7に調整（pH試験紙）し、固形物をろ取し、淡褐色固体の（Ｅ）−３−（８−（２−（４−（２−（７−ブロモ−３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド［３，２−ｂ］［１，４］チアジン−６−イル）−２−ヒドロキシエチル）ピペラジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリル酸26.0mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.57-2.70(12H,m),3.57(2H,s),4.00(3H,s),5.05-5.09(1H,m),5.79-5.84(1H,m),6.58(1H,d,J=15.5Hz),7.08(1H,d,J=9.2Hz),7.82-7.89(2H,m),8.04(1H,s),8.23(1H,d,J=15.5Hz),8.54(1H,d,J=9.2Hz),11.08(1H,s)Example 150

Ethyl = (E) -3- (8- (2- (4- (2- (7-bromo-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] Thiazin-6-yl) -2-hydroxyethyl) piperazin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate 66.7 mg in ethanol 7 mL, tetrahydrofuran 5 mL and water 3 mL Then, 0.1 mL of 5 mol / L sodium hydroxide aqueous solution was added, and the mixture was stirred at 50 ° C. for 1 hour. The reaction mixture was cooled to room temperature, 3 mL of water was added, and the solvent was distilled off under reduced pressure. The obtained residue was adjusted to pH 7 with 1 mol / L hydrochloric acid (pH test paper), and the solid was collected by filtration to give a pale brown solid of (E) -3- (8- (2- (4- (2- (2- (7-Bromo-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl) -2-hydroxyethyl) piperazin-1-yl) -1 26.0 mg of -hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.57-2.70 (12H, m), 3.57 (2H, s), 4.00 (3H, s), 5.05-5.09 (1H, m), 5.79-5.84 (1H , m), 6.58 (1H, d, J = 15.5Hz), 7.08 (1H, d, J = 9.2Hz), 7.82-7.89 (2H, m), 8.04 (1H, s), 8.23 (1H, d, J = 15.5Hz), 8.54 (1H, d, J = 9.2Hz), 11.08 (1H, s)

エチル＝（Ｅ）−３−（８−（２−（４−アミノピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラートの２塩酸塩0.21gの塩化メチレン3mLおよびメタノール3mL溶液に、７−ブロモ−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0.14g、酢酸0.05mLおよびトリアセトキシ水素化ホウ素ナトリウム0.12g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20mLおよび水10mLを加え、20％水酸化ナトリウム水溶液でpH11に調整（pH試験紙）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＝５：１］で精製し、黄色固体のエチル＝（Ｅ）−３−（８−（２−（４−（（７−ブロモ−３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド［３，２−ｂ］［１，４］チアジン−６−イル）メチルアミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート0.11gを得た。
¹H-NMR(CD₃OD)δ値：1.35(3H,t,J=7.3Hz),1.63-1.81(2H,m),2.02-2.11(1H,m),2.11-2.19(1H,m),2.57-2.93(3H,m),3.12-3.21(1H,m),3.26-3.29(1H,m),3.32-3.35(1H,m),3.55(2H,s),3.56-3.64(1H,m),4.02(2H,s),4.07(3H,s),4.29(2H,q,J=7.3Hz),6.07(1H,dd,J=9.6,2.8Hz),6.62(1H,d,J=16.1Hz),7.07(1H,d,J=9.2Hz),7.83(1H,d,J=7.8Hz),7.93(1H,d,J=7.8Hz),7.96(1H,s),8.41(1H,d,J=16.1Hz),8.51(1H,d,J=9.2Hz)Example 151

Ethyl = (E) -3- (8- (2- (4-aminopiperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate dihydrochloride 0.21 g of methylene chloride To a solution of 3 mL and 3 mL of methanol was added 0.14 g of 7-bromo-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carbaldehyde, 0.05 mL of acetic acid and 0.12 g of sodium acetoxyborohydride was added and stirred at room temperature for 4 hours. Chloroform 20mL and water 10mL were added to the reaction mixture, and it adjusted to pH11 with 20% sodium hydroxide aqueous solution (pH test paper). 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 [silica gel; Kanto Chemical Co., Inc., silica gel 60, eluent: chloroform: methanol = 5: 1], and yellow solid ethyl = (E) -3- (8- (2- (4-((7-Bromo-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl) methylamino) piperidine-1- 0.11 g of yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate was obtained.
¹ H-NMR (CD ₃ OD) δ value: 1.35 (3H, t, J = 7.3 Hz), 1.63-1.81 (2H, m), 2.02-2.11 (1H, m), 2.11-2.19 (1H, m) , 2.57-2.93 (3H, m), 3.12-3.21 (1H, m), 3.26-3.29 (1H, m), 3.32-3.35 (1H, m), 3.55 (2H, s), 3.56-3.64 (1H, m), 4.02 (2H, s), 4.07 (3H, s), 4.29 (2H, q, J = 7.3Hz), 6.07 (1H, dd, J = 9.6, 2.8Hz), 6.62 (1H, d, J = 16.1Hz), 7.07 (1H, d, J = 9.2Hz), 7.83 (1H, d, J = 7.8Hz), 7.93 (1H, d, J = 7.8Hz), 7.96 (1H, s), 8.41 ( 1H, d, J = 16.1Hz), 8.51 (1H, d, J = 9.2Hz)

エチル＝（Ｅ）−３−（８−（２−（４−（（７−ブロモ−３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド［３，２−ｂ］［１，４］チアジン−６−イル）メチルアミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリラート87mgの70％エタノール5mL、テトラヒドロフラン5mLおよびメタノール2mL溶液に、5mol/L水酸化ナトリウム水溶液0.13mLを加え、50℃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、1mol/L塩酸でpH6に調整（pH試験紙）した。固形物をろ取し、酢酸エチルで洗浄し、白色固体の（Ｅ）−３−（８−（２−（４−（（７−ブロモ−３−オキソ−３，４−ジヒドロ−２Ｈ−ピリド［３，２−ｂ］［１，４］チアジン−６−イル）メチルアミノ）ピペリジン−１−イル）−１−ヒドロキシエチル）−２−メトキシキノリン−５−イル）アクリル酸86mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.60-1.88(2H,m),1.91-2.23(2H,m),2.26-3.48(7H,m),3.35(2H,s),3.60(2H,s),4.04(3H,s),5.89-6.08(1H,m),6.62(1H,d,J=15.6Hz),7.14(1H,d,J=9.2Hz),7.90(1H,d,J=7.8Hz),7.95(1H,d,J=7.8Hz),8.15(1H,s),8.29(1H,d,J=15.6Hz),8.60(1H,d,J=9.2Hz)Example 152

Ethyl = (E) -3- (8- (2- (4-((7-bromo-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine- 6-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylate in 5 mL of 70% ethanol, 5 mL tetrahydrofuran and 2 mL methanol in 5 mol / L hydroxylation Sodium aqueous solution 0.13mL was added and it stirred at 50 degreeC for 1 hour. The reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the pH was adjusted to pH 6 with 1 mol / L hydrochloric acid (pH test paper). The solid was collected by filtration, washed with ethyl acetate, (E) -3- (8- (2- (4-((7-bromo-3-oxo-3,4-dihydro-2H-pyrido) as a white solid. 86 mg of [3,2-b] [1,4] thiazin-6-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.60-1.88 (2H, m), 1.91-2.23 (2H, m), 2.26-3.48 (7H, m), 3.35 (2H, s), 3.60 (2H , s), 4.04 (3H, s), 5.89-6.08 (1H, m), 6.62 (1H, d, J = 15.6Hz), 7.14 (1H, d, J = 9.2Hz), 7.90 (1H, d, J = 7.8Hz), 7.95 (1H, d, J = 7.8Hz), 8.15 (1H, s), 8.29 (1H, d, J = 15.6Hz), 8.60 (1H, d, J = 9.2Hz)

Examples 153 to 227
The compounds shown in Tables 10 and 11 were obtained in the same manner as in Example 151 and Example 152.

Example 153
(E) -3- (8- (2- (4- (4-methylbenzylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
^{1 H-NMR (DMSO-d} 6) δ value: 1.22-1.34 (2H, m), 1.75-1.84 (2H, m), 2.04-2.17 (2H, m), 2.27 (3H, s), 2.34-2.43 (2H, m), 2.66 (1H, dd, J = 12.6,3.0Hz), 2.87 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.68 (2H, s) , 3.99 (3H, s), 5.80 (1H, dd, J = 8.9,3.0Hz), 6.56 (1H, d, J = 15.6Hz), 7.08 (1H, d, J = 9.2Hz), 7.10 (2H, d, J = 7.8Hz), 7.21 (2H, d, J = 7.8Hz), 7.82 (1H, d, J = 7.8Hz), 7.84 (1H, d, J = 7.8Hz), 8.19 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz)

Example 154
(E) -3- (8- (2- (4- (3-Fluorobenzylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.22-1.35 (2H, m), 1.75-1.85 (2H, m), 2.06-2.19 (2H, m), 2.33-2.44 (2H, m), 2.66 (1H, dd, J = 12.6,3.0Hz), 2.87 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.74 (2H, s), 3.99 (3H, s) , 5.81 (1H, dd, J = 8.9,3.0Hz), 6.58 (1H, d, J = 15.6Hz), 7.02 (1H, td, J = 8.1,2.8Hz), 7.08 (1H, d, J = 9.2 Hz), 7.17 (2H, t, J = 8.1Hz), 7.33 (1H, td, J = 8.1, 6.2Hz), 7.84 (1H, d, J = 7.8Hz), 7.86 (1H, d, J = 7.8 Hz), 8.22 (1H, d, J = 15.6Hz), 8.54 (1H, d, J = 9.2Hz)

Example 155
(E) -3- (8- (2- (4- (3-vinylbenzylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.28-1.37 (2H, m), 1.77-1.87 (2H, m), 2.05-2.19 (2H, m), 2.37-2.45 (2H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.14 (1H, d, J = 11.5Hz), 3.73 (2H, s), 3.99 (3H, s) , 5.25 (1H, d, J = 11.0Hz), 5.78-5.84 (2H, m), 6.57 (1H, d, J = 15.6Hz), 6.72 (1H, dd, J = 17.9,11.0Hz), 7.09 ( 1H, d, J = 9.2Hz), 7.23-7.34 (3H, m), 7.43 (1H, s), 7.84 (1H, d, J = 7.8Hz), 7.86 (1H, d, J = 7.8Hz), 8.23 (1H, d, J = 15.6Hz), 8.54 (1H, d, J = 9.2Hz)

Example 156
(E) -3- (8- (2- (4- (4-Ethylbenzylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.16 (3H, t, J = 7.6 Hz), 1.28-1.35 (2H, m), 1.76-1.85 (2H, m), 2.04-2.18 (2H, m ), 2.37-2.44 (2H, m), 2.57 (2H, q, J = 7.6Hz), 2.66 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.69 (2H, s), 3.99 (3H, s), 5.81 (1H, dd, J = 8.9,3.0Hz), 6.57 (1H, d, J = 15.6Hz) , 7.08 (1H, d, J = 9.2Hz), 7.13 (2H, d, J = 8.3Hz), 7.24 (2H, d, J = 8.3Hz), 7.83 (1H, d, J = 7.8Hz), 7.85 (1H, d, J = 7.8Hz), 8.20 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz)

Example 157
(E) -3- (8- (2- (4- (3,4-dimethylbenzylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.28-1.34 (2H, m), 1.76-1.84 (2H, m), 2.04-2.15 (2H, m), 2.18 (3H, s), 2.19 (3H , s), 2.35-2.43 (2H, m), 2.66 (1H, dd, J = 12.6, 3.0Hz), 2.87 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz) , 3.65 (2H, s), 3.99 (3H, s), 5.80 (1H, dd, J = 8.9,3.0Hz), 6.55 (1H, d, J = 15.6Hz), 7.01-7.11 (4H, m), 7.80 (1H, d, J = 7.8Hz), 7.82 (1H, d, J = 7.8Hz), 8.11 (1H, d, J = 15.6Hz), 8.51 (1H, d, J = 9.2Hz)

Example 158
(E) -3- (8- (2- (4- (4-methoxybenzylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.27-1.34 (2H, m), 1.71-1.84 (2H, m), 2.04-2.17 (2H, m), 2.34-2.43 (2H, m), 2.65 (1H, dd, J = 12.6,3.0Hz), 2.87 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.66 (2H, s), 3.72 (3H, s) , 3.99 (3H, s), 5.80 (1H, dd, J = 8.9,3.0Hz), 6.55 (1H, d, J = 15.6Hz), 6.86 (2H, d, J = 8.7Hz), 7.08 (1H, d, J = 9.2Hz), 7.24 (2H, d, J = 8.7Hz), 7.82 (2H, s), 8.14 (1H, d, J = 15.6Hz), 8.52 (1H, d, J = 9.2Hz)

Example 159
(E) -3- (8- (2- (4- (3-Fluoro-4-methylbenzylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.26-1.34 (2H, m), 1.74-1.85 (2H, m), 2.05-2.17 (2H, m), 2.19 (3H, s), 2.33-2.44 (2H, m), 2.67 (1H, dd, J = 12.6, 3.0Hz), 2.87 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.70 (2H, s) , 3.99 (3H, s), 5.81 (1H, dd, J = 8.9,3.0Hz), 6.58 (1H, d, J = 15.6Hz), 7.03-7.13 (3H, m), 7.19 (1H, t, J = 8.0Hz), 7.84 (1H, d, J = 7.8Hz), 7.86 (1H, d, J = 7.8Hz), 8.23 (1H, d, J = 15.6Hz), 8.54 (1H, d, J = 9.2) Hz)

Example 160
(E) -3- (8- (2- (4- (3,4-difluorobenzylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.26-1.34 (2H, m), 1.74-1.84 (2H, m), 2.05-2.20 (2H, m), 2.31-2.44 (2H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.70 (2H, s), 3.99 (3H, s) , 5.81 (1H, dd, J = 8.9,3.0Hz), 6.58 (1H, d, J = 15.6Hz), 7.09 (1H, d, J = 9.2Hz), 7.17 (1H, dd, J = 8.5,3.9 Hz), 7.31-7.42 (2H, m), 7.84 (1H, d, J = 7.8Hz), 7.86 (1H, d, J = 7.8Hz), 8.24 (1H, d, J = 15.6Hz), 8.54 ( (1H, d, J = 9.2Hz)

Example 161
(E) -3- (8- (2- (4-((benzofuran-5-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.29-1.39 (2H, m), 1.80-1.90 (2H, m), 2.04-2.17 (2H, m), 2.36-2.43 (2H, m), 2.65 (1H, dd, J = 12.6,3.0Hz), 2.87 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.81 (2H, s), 3.98 (3H, s) , 5.80 (dd, J = 8.9,3.0Hz), 6.54 (1H, d, J = 15.6Hz), 6.91 (1H, d, J = 2.3Hz), 7.07 (1H, d, J = 9.2Hz), 7.29 (1H, dd, J = 8.3,1.6Hz), 7.50 (1H, d, J = 8.3Hz), 7.60 (1H, d, J = 1.6Hz), 7.80 (1H, d, J = 7.8Hz), 7.82 (1H, d, J = 7.8Hz), 7.94 (1H, d, J = 2.3Hz), 8.11 (1H, d, J = 15.6Hz), 8.51 (1H, d, J = 9.2Hz)

Example 162
(E) -3- (8- (2- (4-((1,2,3-benzooxadiazol-5-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2- Methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.29-1.38 (2H, m), 1.79-1.87 (2H, m), 2.06-2.19 (2H, m), 2.37-2.44 (2H, m), 2.66 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.85 (2H, s), 3.99 (3H, s) , 5.81 (1H, dd, J = 8.9,3.0Hz), 6.57 (1H, d, J = 15.6Hz), 7.08 (1H, d, J = 9.2Hz), 7.61 (1H, d, J = 8.3Hz) , 7.82-7.89 (3H, m), 7.97 (1H, d, J = 9.2Hz), 8.22 (1H, d, J = 15.6Hz), 8.54 (1H, d, J = 9.2Hz)

Example 163
(E) -3- (8- (2- (4-((2,3-dihydrobenzo [b] furan-5-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2- Methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.28-1.37 (2H, m), 1.76-1.85 (2H, m), 2.05-2.19 (2H, m), 2.37-2.44 (2H, m), 2.66 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.10-3.17 (3H, m), 3.65 (2H, s), 3.99 (3H, s), 4.49 ( 2H, t, J = 8.7Hz), 5.81 (1H, dd, J = 8.9,3.0Hz), 6.56 (1H, d, J = 15.6Hz), 6.66 (1H, d, J = 8.3Hz), 7.03 ( 1H, d, J = 8.3Hz), 7.08 (1H, d, J = 9.2Hz), 7.20 (1H, s), 7.83 (2H, s), 8.17 (1H, d, J = 15.6Hz), 8.52 ( (1H, d, J = 9.2Hz)

Example 164
(E) -3- (8- (2- (4- (4-acetylbenzylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.27-1.34 (2H, m), 1.75-1.84 (2H, m), 1.99-2.16 (2H, m), 2.31-2.42 (2H, m), 2.56 (3H, s), 2.65 (1H, dd, J = 12.6,3.0Hz), 2.86 (1H, d, J = 11.5Hz), 3.12 (1H, d, J = 11.5Hz), 3.79 (2H, s) , 3.98 (3H, s), 5.80 (1H, dd, J = 8.9,3.0Hz), 6.55 (1H, d, J = 15.6Hz), 7.08 (1H, d, J = 9.2Hz), 7.48 (2H, d, J = 8.3Hz), 7.83 (2H, s), 7.89 (2H, d, J = 8.3Hz), 8.15 (1H, d, J = 15.6Hz), 8.52 (1H, d, J = 9.2Hz)

Example 165
(E) -3- (8- (2- (4- (4- (dimethylamino) benzylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.28-1.34 (2H, m), 1.75-1.85 (2H, m), 2.04-2.16 (2H, m), 2.36-2.43 (2H, m), 2.65 (1H, dd, J = 12.6,3.0Hz), 2.84-2.89 (7H, m), 3.13 (1H, d, J = 11.5Hz), 3.62 (2H, s), 3.99 (3H, s), 5.80 ( 1H, dd, J = 9.2,3.0Hz), 6.53 (1H, d, J = 15.6Hz), 6.66 (2H, d, J = 8.3Hz), 7.07 (1H, d, J = 9.2Hz), 7.14 ( 2H, d, J = 8.3Hz), 7.78 (1H, d, J = 7.8Hz), 7.82 (1H, d, J = 7.8Hz), 8.06 (1H, d, J = 15.6Hz), 8.50 (1H, d, J = 9.2Hz)

Example 166
(E) -3- (8- (2- (4-((benzo [1,3] dioxol-5-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinoline- 5-yl) acrylic acid
^{1 H-NMR (DMSO-d} 6) δ value: 1.28-1.37 (2H, m), 1.74-1.85 (2H, m), 2.02-2.20 (2H, m), 2.33-2.45 (2H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.66 (2H, s), 3.99 (3H, s) , 5.81 (1H, dd, J = 8.9,3.0Hz), 5.97 (2H, s), 6.58 (1H, d, J = 15.6Hz), 6.79 (1H, dd, J = 8.3,1.4Hz), 6.82 ( 1H, d, J = 8.3Hz), 6.94 (1H, d, J = 1.4Hz), 7.08 (1H, d, J = 9.2Hz), 7.84 (1H, d, J = 7.8Hz), 7.86 (1H, d, J = 7.8Hz), 8.20 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz)

Example 167
(E) -3- (8- (2- (4- (4-Ethoxybenzylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.28-1.37 (5H, m), 1.78-1.86 (2H, m), 2.07-2.19 (2H, m), 2.38-2.46 (2H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.89 (1H, d, J = 11.5Hz), 3.14 (1H, d, J = 11.5Hz), 3.69 (2H, s), 3.93-4.04 (5H, m), 5.81 (1H, dd, J = 8.9, 3.0Hz), 6.57 (1H, d, J = 15.6Hz), 6.84 (2H, d, J = 8.7Hz), 7.08 (1H, d, J = 9.2) Hz), 7.24 (2H, d, J = 8.7Hz), 7.83 (1H, d, J = 7.8Hz), 7.85 (1H, d, J = 7.8Hz), 8.20 (1H, d, J = 15.6Hz) , 8.53 (1H, d, J = 9.2Hz)

Example 168
(E) -3- (8- (2- (4- (4-methoxy-3-methylbenzylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.30-1.39 (2H, m), 1.78-1.87 (2H, m), 2.07-2.20 (5H, m), 2.38-2.49 (2H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.89 (1H, d, J = 11.5Hz), 3.14 (1H, d, J = 11.5Hz), 3.66 (2H, s), 3.75 (3H, s) , 3.99 (3H, s), 5.81 (1H, dd, J = 8.9,3.0Hz), 6.57 (1H, d, J = 15.6Hz), 6.85 (1H, d, J = 8.3Hz), 7.08 (1H, d, J = 9.2Hz), 7.10-7.14 (2H, m), 7.84 (2H, s), 8.19 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz)

Example 169
(E) -3- (8- (2- (4- (4-methylsulfanylbenzylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.28-1.37 (2H, m), 1.74-1.85 (2H, m), 2.06-2.19 (2H, m), 2.36-2.43 (2H, m), 2.45 (3H, s), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.69 (2H, s) , 3.99 (3H, s), 5.81 (1H, dd, J = 8.9,3.0Hz), 6.57 (1H, d, J = 15.6Hz), 7.08 (1H, d, J = 9.2Hz), 7.20 (2H, d, J = 8.3Hz), 7.29 (2H, d, J = 8.3Hz), 7.83 (1H, d, J = 7.8Hz), 7.85 (1H, d, J = 7.8Hz), 8.21 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz)

Example 170
(E) -3- (8- (2- (4-((Naphthalen-2-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.30-1.42 (2H, m), 1.81-1.90 (2H, m), 2.06-2.19 (2H, m), 2.37-2.47 (2H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.89 (1H, d, J = 11.5Hz), 3.15 (1H, d, J = 11.5Hz), 3.90 (2H, s), 3.98 (3H, s) , 5.81 (1H, dd, J = 8.9,3.0Hz), 6.57 (1H, d, J = 15.6Hz), 7.08 (1H, d, J = 9.2Hz), 7.44-7.50 (2H, m), 7.53 ( 1H, dd, J = 8.5,1.6Hz), 7.81-7.90 (6H, m), 8.20 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz)

Example 171
(E) -3- (8- (2- (4-((quinolin-6-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.32-1.38 (2H, m), 1.81-1.88 (2H, m), 2.06-2.17 (2H, m), 2.37-2.43 (2H, m), 2.65 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.14 (1H, d, J = 11.5Hz), 3.92 (2H, s), 3.98 (3H, s) , 5.80 (1H, dd, J = 8.9,3.0Hz), 6.54 (1H, d, J = 15.6Hz), 7.07 (1H, d, J = 9.2Hz), 7.50 (1H, dd, J = 8.3,4.1 Hz), 7.77 (1H, dd, J = 8.3,1.4Hz), 7.81 (1H, d, J = 7.8Hz), 7.83 (1H, d, J = 7.8Hz), 7.88 (1H, d, J = 1.4 Hz), 7.95 (1H, d, J = 8.7Hz), 8.12 (1H, d, J = 15.6Hz), 8.32 (1H, dd, J = 8.7, 1.4Hz), 8.52 (1H, d, J = 9.2 Hz), 8.84 (1H, dd, J = 4.1,1.4Hz)

Example 172
(E) -3- (8- (2- (4-((quinoxalin-6-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.30-1.39 (2H, m), 1.80-1.89 (2H, m), 2.06-2.17 (2H, m), 2.36-2.44 (2H, m), 2.66 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.14 (1H, d, J = 11.5Hz), 3.97-4.00 (5H, m), 5.81 (1H, dd, J = 8.9,3.0Hz), 6.56 (1H, d, J = 15.6Hz), 7.08 (1H, d, J = 9.2Hz), 7.81-7.89 (3H, m), 8.02-8.05 (2H, m ), 8.19 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz), 8.91 (2H, dd, J = 13.3,1.8Hz)

Example 173
(E) -3- (8- (2- (4-((1-methyl-1H-1,2,3-benzotriazol-5-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl ) -2-Methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.28-1.37 (2H, m), 1.75-1.87 (2H, m), 2.04-2.16 (2H, m), 2.34-2.43 (2H, m), 2.65 (1H, dd, J = 12.6,3.0Hz), 2.87 (1H, d, J = 11.5Hz), 3.14 (1H, d, J = 11.5Hz), 3.88 (2H, s), 3.98 (3H, s) , 4.28 (3H, s), 5.80 (1H, dd, J = 8.9, 3.0Hz), 6.56 (1H, d, J = 15.6Hz), 7.08 (1H, d, J = 9.2Hz), 7.56 (1H, d, J = 8.3), 7.76 (1H, d, J = 8.3Hz), 7.82 (1H, d, J = 7.8Hz), 7.84 (1H, d, J = 7.8Hz), 7.93 (1H, s), 8.19 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz)

Example 174
(E) -3- (8- (2- (4-((1,2,3-benzothiadiazol-5-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinoline -5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.32-1.41 (2H, m), 1.81-1.89 (2H, m), 2.08-2.20 (2H, m), 2.39-2.46 (2H, m), 2.68 (1H, dd, J = 12.6,3.0Hz), 2.89 (1H, d, J = 11.5Hz), 3.15 (1H, d, J = 11.5Hz), 3.93 (2H, s), 3.98 (3H, s) , 5.82 (1H, dd, J = 8.9,3.0Hz), 6.58 (1H, d, J = 15.6Hz), 7.08 (1H, d, J = 9.2Hz), 7.74 (1H, dd, J = 9.2,1.4 Hz), 7.84 (1H, d, J = 7.8Hz), 7.87 (1H, d, J = 7.8Hz), 7.99 (1H, d, J = 1.4Hz), 8.02 (1H, d, J = 9.2Hz) , 8.24 (1H, d, J = 15.6Hz), 8.54 (1H, d, J = 9.2Hz)

Example 175
(E) -3- (8- (2- (4- (3- (trifluoromethyl) benzylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.29-1.37 (2H, m), 1.77-1.86 (2H, m), 2.08-2.20 (2H, m), 2.35-2.45 (2H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.89 (1H, d, J = 11.5Hz), 3.14 (1H, d, J = 11.5Hz), 3.82 (2H, s), 3.99 (3H, s) , 5.82 (1H, dd, J = 8.9,3.0Hz), 6.58 (1H, d, J = 15.6Hz), 7.08 (1H, d, J = 9.2Hz), 7.53 (1H, t, J = 7.8Hz) , 7.57 (1H, d, J = 7.8Hz), 7.64 (1H, d, J = 7.8Hz), 7.71 (1H, s), 7.84 (1H, d, J = 7.8Hz), 7.87 (1H, d, J = 7.8Hz), 8.23 (1H, d, J = 15.6Hz), 8.54 (1H, d, J = 9.2Hz)

Example 176
(E) -3- (8- (2- (4- (4- (trifluoromethyl) benzylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.27-1.37 (2H, m), 1.75-1.86 (2H, m), 2.06-2.20 (2H, m), 2.33-2.44 (2H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.81 (2H, s), 3.99 (3H, s) , 5.81 (1H, dd, J = 8.9,3.0Hz), 6.58 (1H, d, J = 15.6Hz), 7.09 (1H, d, J = 9.2Hz), 7.57 (2H, d, J = 7.8Hz) , 7.66 (2H, d, J = 7.8Hz), 7.84 (1H, d, J = 7.8Hz), 7.87 (1H, d, J = 7.8Hz), 8.24 (1H, d, J = 15.6Hz), 8.54 (1H, d, J = 9.2Hz)

Example 177
(E) -3- (8- (1-hydroxy-2- (4-((4-methyl-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) methylamino) piperidine- 1-yl) ethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.31-1.40 (2H, m), 1.78-1.86 (2H, m), 2.07-2.19 (2H, m), 2.38-2.48 (2H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.79 (3H, s), 2.89 (1H, d, J = 11.5Hz), 3.14 (1H, d, J = 11.5Hz), 3.16-3.19 (2H, m), 3.62 (2H, s), 3.99 (3H, s), 4.18-4.22 (2H, m), 5.81 (1H, dd, J = 8.9, 3.0Hz), 6.57 (1H, d, J = 15.6Hz) ), 6.62 (1H, d, J = 8.3Hz), 6.68 (1H, d, J = 1.8Hz), 6.74 (1H, dd, J = 8.3, 1.8Hz), 7.07 (1H, d, J = 9.2Hz) ), 7.83 (2H, s), 8.17 (1H, d, J = 15.6Hz), 8.52 (1H, d, J = 9.2Hz)

Example 178
(E) -3- (8- (2- (4-((3,4-dihydro-2H-benzo [b] [1,5] dioxepin-7-yl) methylamino) piperidin-1-yl)- 1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.28-1.34 (2H, m), 1.75-1.85 (2H, m), 2.05-2.19 (4H, m), 2.35-2.44 (2H, m), 2.66 (1H, dd, J = 12.6,3.0Hz), 2.87 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.63 (2H, s), 3.99 (3H, s) , 4.05-4.11 (4H, m), 5.81 (1H, dd, J = 8.9,3.0Hz), 6.57 (1H, d, J = 15.6Hz), 6.85-6.96 (3H, m), 7.08 (1H, d , J = 9.2Hz), 7.83 (2H, s), 8.18 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz)

Example 179
(E) -3- (8- (2- (4- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethylamino) piperidin-1-yl) -1 -Hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.22-1.31 (2H, m), 1.72-1.83 (2H, m), 2.07-2.19 (2H, m), 2.36-2.46 (2H, m), 2.58 (2H, t, J = 7.6Hz), 2.66 (1H, dd, J = 12.6,3.0Hz), 2.74 (2H, t, J = 7.6Hz), 2.87 (1H, d, J = 11.5Hz), 3.12 (1H, d, J = 11.5Hz), 3.99 (3H, s), 4.16-4.23 (4H, m), 5.81 (1H, dd, J = 8.9,3.0Hz), 6.56 (1H, d, J = 15.6 ), 6.65 (1H, dd, J = 7.8, 2.3Hz), 6.70 (1H, d, J = 2.3Hz), 6.74 (1H, d, J = 7.8Hz), 7.08 (1H, d, J = 9.2Hz) ), 7.81-7.87 (2H, m), 8.20 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz)

Example 180
(E) -3- (8- (2- (4- (4- (trifluoromethoxy) benzylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.27-1.38 (2H, m), 1.75-1.86 (2H, m), 2.06-2.20 (2H, m), 2.34-2.44 (2H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.75 (2H, s), 3.99 (3H, s) , 5.81 (1H, dd, J = 8.9,3.0Hz), 6.58 (1H, d, J = 15.6Hz), 7.09 (1H, d, J = 9.2Hz), 7.29 (2H, d, J = 8.3Hz) , 7.46 (2H, d, J = 8.3Hz), 7.84 (1H, d, J = 7.8Hz), 7.87 (1H, d, J = 7.8Hz), 8.24 (1H, d, J = 15.6Hz), 8.54 (1H, d, J = 9.2Hz)

Example 181
(E) -3- (8- (2- (4-((2,2-dimethylchroman-6-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinoline-5 -Yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.25 (6H, s), 1.30-1.40 (2H, m), 1.71-1.76 (2H, m), 1.79-1.88 (2H, m), 2.08-2.20 (2H, m), 2.37-2.46 (2H, m), 2.65-2.73 (3H, m), 2.89 (1H, d, J = 11.5Hz), 3.15 (1H, d, J = 11.5Hz), 3.64 ( 2H, s), 3.99 (3H, s), 5.81 (1H, dd, J = 8.9, 3.0Hz), 6.57 (1H, d, J = 15.6Hz), 6.62 (1H, d, J = 8.3Hz), 7.02 (1H, d, J = 8.3Hz), 7.04 (1H, s), 7.08 (1H, d, J = 9.2Hz), 7.84 (2H, s), 8.19 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz)

Example 182
(E) -3- (8- (2- (4-((benzofuran-2-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.26-1.31 (2H, m), 1.74-1.83 (2H, m), 2.03-2.14 (2H, m), 2.37-2.43 (2H, m), 2.62 (1H, dd, J = 12.6,3.0Hz), 2.84 (1H, d, J = 11.5Hz), 3.10 (1H, d, J = 11.5Hz,), 3.83 (2H, s), 3.95 (3H, s ), 5.77 (1H, dd, J = 8.9,3.0Hz), 6.53 (1H, d, J = 15.6Hz), 6.68 (1H, s), 7.13-7.23 (2H, m), 7.47 (1H, d, J = 8.3Hz), 7.53 (1H, d, J = 6.9Hz), 7.78-7.85 (2H, m), 8.19 (1H, d, J = 15.6Hz), 8.50 (1H, d, J = 9.2Hz)

Example 183
(E) -3- (8- (2- (4-((quinolin-3-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.30-1.40 (2H, m), 1.81-1.89 (2H, m), 2.06-2.19 (2H, m), 2.37-2.46 (2H, m), 2.66 (1H, dd, J = 12.6,3.0Hz), 2.89 (1H, d, J = 11.5Hz), 3.14 (1H, d, J = 11.5Hz), 3.93 (2H, s), 3.98 (3H, s) , 5.81 (1H, dd, J = 8.9,3.0Hz), 6.56 (1H, d, J = 15.6Hz), 7.08 (1H, d, J = 9.2Hz), 7.58 (1H, t, J = 6.9Hz) , 7.70 (1H, t, J = 6.9Hz), 7.83 (2H, s), 7.95 (1H, d, J = 6.9Hz), 7.99 (1H, d, J = 6.9Hz), 8.17 (1H, d, J = 15.6Hz), 8.24 (1H, d, J = 1.4Hz), 8.53 (1H, d, J = 9.2Hz), 8.89 (1H, d, J = 1.4Hz)

Example 184
(E) -3- (8- (2- (4-((quinolin-2-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.33-1.41 (2H, m), 1.80-1.89 (2H, m), 2.06-2.20 (2H, m), 2.37-2.46 (2H, m), 2.66 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.14 (1H, d, J = 11.5Hz), 3.98 (2H, s), 4.02 (3H, s) , 5.81 (1H, dd, J = 8.9,3.0Hz), 6.57 (1H, d, J = 15.6Hz), 7.08 (1H, d, J = 9.2Hz), 7.56 (1H, t, J = 8.3Hz) , 7.64 (1H, d, J = 8.3Hz), 7.72 (1H, t, J = 8.3Hz), 7.84 (1H, d, J = 7.8Hz), 7.87 (1H, d, J = 7.8Hz), 7.95 (2H, t, J = 8.3Hz), 8.22 (1H, d, J = 15.6Hz), 8.30 (1H, d, J = 8.3Hz), 8.53 (1H, d, J = 9.2Hz)

Example 185
(E) -3- (8- (2- (4-((1-methylindol-2-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl Acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.30-1.38 (2H, m), 1.80-1.90 (2H, m), 2.07-2.20 (2H, m), 2.36-2.43 (2H, m), 2.66 (1H, dd, J = 12.6,3.0Hz), 2.87 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.73 (3H, s), 3.88 (2H, s) , 3.99 (3H, s), 5.80 (1H, dd, J = 8.9,3.0Hz), 6.31 (1H, s), 6.49 (1H, d, J = 15.6Hz), 6.97 (1H, t, J = 8.3 Hz), 7.05-7.10 (2H, m), 7.38 (1H, d, J = 8.3Hz), 7.45 (1H, d, J = 8.3Hz), 7.75 (1H, d, J = 7.8Hz), 7.81 ( 1H, d, J = 7.8Hz), 7.99 (1H, d, J = 15.6Hz), 8.49 (1H, d, J = 9.2Hz)

Example 186
(E) -3- (8- (2- (4-((2H-chromen-3-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) Acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.26-1.34 (2H, m), 1.77-1.85 (2H, m), 2.08-2.21 (2H, m), 2.36-2.45 (2H, m), 2.68 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.14 (1H, d, J = 11.5Hz), 3.26 (2H, s), 3.99 (3H, s) , 4.71 (2H, s), 5.82 (1H, dd, J = 8.9,3.0Hz), 6.37 (1H, s), 6.58 (1H, d, J = 15.6Hz), 6.73 (1H, d, J = 7.8 Hz), 6.84 (1H, t, J = 7.8Hz), 7.02 (1H, d, J = 7.8Hz), 7.06 (1H, t, J = 7.8Hz), 7.09 (1H, d, J = 9.2Hz) , 7.84 (1H, d, J = 7.8Hz), 7.87 (1H, d, J = 7.8Hz), 8.24 (1H, d, J = 15.6Hz), 8.54 (1H, d, J = 9.2Hz)

Example 187
(E) -3- (8- (2- (4-((6-methylimidazo [1,2-a] pyridin-2-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl)- 2-Methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.28-1.39 (2H, m), 1.79-1.87 (2H, m), 2.07-2.19 (2H, m), 2.25 (3H, s), 2.35-2.43 (2H, m), 2.66 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.14 (1H, d, J = 11.5Hz), 3.80 (2H, s) , 3.99 (3H, s), 5.81 (1H, dd, J = 8.9,3.0Hz), 7.04 (1H, d, J = 8.7Hz), 7.07 (1H, d, J = 9.2Hz), 7.36 (1H, d, J = 8.7Hz), 7.68 (1H, s), 7.80 (1H, d, J = 7.8Hz), 7.83 (1H, d, J = 7.8Hz), 8.11 (1H, d, J = 15.6Hz) , 8.27 (1H, s), 8.51 (1H, d, J = 9.2Hz)

Example 188
(E) -3- (8- (2- (4-((1-methyl-1H-benzimidazol-2-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinoline -5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.29-1.37 (2H, m), 1.77-1.88 (2H, m), 2.07-2.20 (2H, m), 2.37-2.43 (2H, m), 2.66 (1H, dd, J = 12.6,3.0Hz), 2.86 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.81 (3H, s), 3.98 (3H, s) , 4.00 (2H, s), 5.80 (1H, dd, J = 8.9,3.0Hz), 6.55 (1H, d, J = 15.6Hz), 7.07 (1H, d, J = 9.2Hz), 7.15 (1H, t, J = 7.8Hz), 7.21 (1H, t, J = 7.8Hz), 7.50 (1H, d, J = 7.8Hz), 7.56 (1H, d, J = 7.8Hz), 7.79-7.84 (2H, m), 8.12 (1H, d, J = 15.6Hz), 8.52 (1H, d, J = 9.2Hz)

Example 189
(E) -3- (8- (2- (4-((benzo [b] thiophen-2-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinoline-5 Il) Acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.28-1.37 (2H, m), 1.78-1.87 (2H, m), 2.05-2.17 (2H, m), 2.37-2.45 (2H, m), 2.65 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.98 (3H, s), 4.02 (2H, s) , 5.80 (1H, dd, J = 8.9,3.0Hz), 6.56 (1H, d, J = 15.6Hz), 7.08 (1H, d, J = 9.2Hz), 7.24-7.33 (3H, m), 7.72 ( 1H, d, J = 7.3Hz), 7.81-7.89 (3H, m), 8.21 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz)

Example 190
(E) -3- (8- (2- (4-((benzothiazol-2-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.30-1.39 (2H, m), 1.78-1.88 (2H, m), 2.07-2.20 (2H, m), 2.36-2.43 (2H, m), 2.66 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.14 (1H, d, J = 11.5Hz), 3.98 (3H, s), 4.13 (2H, s) , 5.80 (1H, dd, J = 8.9,3.0Hz), 6.56 (1H, d, J = 15.6Hz), 7.08 (1H, d, J = 9.2Hz), 7.38 (1H, t, J = 8.3Hz) , 7.46 (1H, t, J = 8.3Hz), 7.81-7.91 (3H, m), 8.03 (1H, d, J = 8.3Hz), 8.21 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz)

Example 191
(E) -3- (8- (2- (4-((thieno [3,2-b] thiophen-2-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxy Quinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.28-1.38 (2H, m), 1.77-1.86 (2H, m), 2.05-2.19 (2H, m), 2.37-2.45 (2H, m), 2.66 (1H, dd, J = 12.6,3.0Hz), 2.87 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.98 (2H, s), 3.99 (3H, s) , 5.81 (1H, dd, J = 8.9,3.0Hz), 6.57 (1H, d, J = 15.6Hz), 7.08 (1H, d, J = 9.2Hz), 7.27 (1H, s), 7.35 (1H, d, J = 5.0Hz), 7.54 (1H, d, J = 5.0Hz), 7.84 (1H, d, J = 7.8Hz), 7.87 (1H, d, J = 7.8Hz), 8.23 (1H, d, J = 15.6Hz), 8.54 (1H, d, J = 9.2Hz)

Example 192
(E) -3- (8- (2- (4-((8-hydroxyquinolin-2-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl Acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.37-1.44 (2H, m), 1.82-1.92 (2H, m), 2.08-2.19 (2H, m), 2.37-2.44 (2H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.91 (1H, d, J = 11.5Hz), 3.16 (1H, d, J = 11.5Hz), 3.99 (3H, s), 4.05 (2H, s) , 5.82 (1H, dd, J = 8.9,3.0Hz), 6.57 (1H, d, J = 15.6Hz), 7.04-7.11 (2H, m), 7.33-7.42 (2H, m), 7.56 (1H, d , J = 8.3Hz), 7.84 (1H, d, J = 7.8Hz), 7.87 (1H, d, J = 7.8Hz), 8.20-8.26 (2H, m), 8.54 (1H, d, J = 9.2Hz )

Example 193
(E) -3- (8- (2- (4-((3-methylbenzo [b] thiophen-2-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinoline- 5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.30-1.38 (2H, m), 1.76-1.88 (2H, m), 2.06-2.19 (2H, m), 2.30 (3H, s), 2.40-2.45 (2H, m), 2.66 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.14 (1H, d, J = 11.5Hz), 3.99 (5H, s) , 5.80 (1H, dd, J = 8.9,3.0Hz), 6.55 (1H, d, J = 15.6Hz), 7.08 (1H, d, J = 9.2Hz), 7.28 (1H, t, J = 8.3Hz) , 7.35 (1H, t, J = 8.3Hz), 7.67 (1H, d, J = 8.3Hz), 7.81-7.88 (3H, m), 8.18 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz)

Example 194
(E) -3- (8- (2- (4-((6-Chlorobenzo [1,3] dioxol-5-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxy Quinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.28-1.40 (2H, m), 1.75-1.85 (2H, m), 2.10-2.23 (2H, m), 2.34-2.45 (2H, m), 2.68 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.14 (1H, d, J = 11.5Hz), 3.69 (2H, s), 3.99 (3H, s) , 5.82 (1H, dd, J = 8.9,3.0Hz), 6.04 (2H, s), 6.58 (1H, d, J = 15.6Hz), 7.02 (1H, s), 7.09 (1H, d, J = 9.2 Hz), 7.11 (1H, s), 7.84 (1H, d, J = 7.8Hz), 7.87 (1H, d, J = 7.8Hz), 8.24 (1H, d, J = 15.6Hz), 8.54 (1H, d, J = 9.2Hz)

Example 195
(E) -3- (8- (2- (4-((1-chloro-3,4-dihydronaphthalen-2-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2- Methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.28-1.40 (2H, m), 1.78-1.88 (2H, m), 2.08-2.23 (2H, m), 2.35-2.42 (2H, m), 2.44 -2.48 (2H, m), 2.68 (1H, dd, J = 12.6,3.0Hz), 2.74-2.80 (2H, m), 2.88 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.55 (2H, s), 3.99 (3H, s), 5.81 (1H, dd, J = 8.9, 3.0Hz), 6.58 (1H, d, J = 15.6Hz), 7.08 (1H, d , J = 9.2Hz), 7.17-7.30 (3H, m), 7.48 (1H, d, J = 7.3Hz), 7.84 (1H, d, J = 7.8Hz), 7.87 (1H, d, J = 7.8Hz ), 8.24 (1H, d, J = 15.6Hz), 54 (1H, d, J = 9.2Hz)

Example 196
(E) -3- (8- (2- (4-((3,4-dimethylthieno [2,3-b] thiophen-2-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl ) -2-Methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.29-1.38 (2H, m), 1.76-1.88 (2H, m), 2.08-2.24 (2H, m), 2.35-2.42 (8H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.15 (1H, d, J = 11.5Hz), 3.88 (2H, s), 3.99 (3H, s) , 5.81 (1H, dd, J = 8.9,3.0Hz), 6.58 (1H, d, J = 15.6Hz), 7.07 (1H, s), 7.09 (1H, d, J = 9.2Hz), 7.84 (1H, d, J = 7.8Hz), 7.87 (1H, d, J = 7.8Hz), 8.26 (1H, d, J = 15.6Hz), 8.55 (1H, d, J = 9.2Hz)

Example 197
(E) -3- (8- (2- (4-((3-chlorobenzo [b] thiophen-2-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinoline- 5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.30-1.40 (2H, m), 1.77-1.87 (2H, m), 2.07-2.18 (2H, m), 2.35-2.43 (2H, m), 2.65 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.98 (3H, s), 4.06 (2H, s) , 5.80 (1H, dd, J = 8.9,3.0Hz), 6.55 (1H, d, J = 15.6Hz), 7.08 (1H, d, J = 9.2Hz), 7.42 (1H, t, J = 8.3Hz) , 7.48 (1H, t, J = 8.3Hz), 7.71 (1H, d, J = 8.3Hz), 7.83 (2H, s), 7.98 (1H, d, J = 8.3Hz), 8.17 (1H, d, J = 15.6Hz), 8.52 (1H, d, J = 9.2Hz)

Example 198
(E) -3- (8- (2- (4-((2- (dimethylamino) quinolin-3-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinoline- 5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.29-1.40 (2H, m), 1.82-1.91 (2H, m), 2.09-2.21 (2H, m), 2.37-2.47 (2H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.90 (1H, d, J = 11.5Hz), 2.95 (6H, s), 3.15 (1H, d, J = 11.5Hz), 3.83 (2H, s) , 3.99 (3H, s), 5.82 (1H, dd, J = 8.9,3.0Hz), 6.57 (1H, d, J = 15.6Hz), 7.08 (1H, d, J = 9.2Hz), 7.32 (1H, t, J = 7.8Hz), 7.54 (1H, t, J = 7.8Hz), 7.68 (1H, d, J = 7.8Hz), 7.76 (1H, d, J = 7.8Hz), 7.86 (2H, s) , 8.17-8.23 (2H, m), 8.53 (1H, d, J = 9.2Hz)

Example 199
(E) -3- (8- (2- (4-((2-chloro-6-methylquinolin-3-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinoline -5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.34-1.42 (2H, m), 1.83-1.91 (2H, m), 2.09 (3H, s), 2.10-2.23 (2H, m), 2.37-2.47 (2H, m), 2.68 (1H, dd, J = 12.6,3.0Hz), 2.91 (1H, d, J = 11.5Hz), 3.16 (1H, d, J = 11.5Hz), 3.91 (2H, s) , 3.99 (3H, s), 5.82 (1H, dd, J = 8.9,3.0Hz), 6.58 (1H, d, J = 15.6Hz), 7.09 (1H, d, J = 9.2Hz), 7.61 (1H, dd, J = 8.7,1.8Hz), 7.78-7.90 (4H, m), 8.25 (1H, d, J = 15.6Hz), 8.37 (1H, s), 8.54 (1H, d, J = 9.2Hz)

Example 200
(E) -3- (8- (2- (4-((2-chloro-6-methoxyquinolin-3-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinoline -5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.33-1.44 (2H, m), 1.83-1.93 (2H, m), 2.12-2.24 (2H, m), 2.37-2.46 (2H, m), 2.69 (1H, d, J = 12.6,3.0Hz), 2.92 (1H, d, J = 11.5Hz), 3.17 (1H, d, J = 11.5Hz), 3.90 (3H, s), 3.91 (2H, s) , 4.00 (3H, s), 5.83 (1H, dd, J = 8.9,3.0Hz), 6.58 (1H, d, J = 15.6Hz), 7.09 (1H, d, J = 9.2Hz), 7.40 (1H, dd, J = 9.2,2.8Hz), 7.46 (1H, d, J = 2.8Hz), 7.81-7.91 (3H, m), 8.25 (1H, d, J = 15.6Hz), 8.39 (1H, s), 8.55 (1H, d, J = 9.2Hz)

Example 201
(E) -3- (8- (2- (4-((4-chloro-6-fluoro-2H-thiochromen-3-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2 -Methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.33-1.44 (2H, m), 1.83-1.93 (2H, m), 2.12-2.24 (2H, m), 2.37-2.46 (2H, m), 2.69 (1H, dd, J = 12.6,3.0Hz), 2.92 (1H, d, J = 11.5Hz), 3.17 (1H, d, J = 11.5Hz), 3.64 (2H, s), 3.66 (2H, s) , 4.00 (3H, s), 5.87 (1H, dd, J = 8.9,3.0Hz), 6.59 (1H, d, J = 15.6Hz), 7.08-7.17 (2H, m), 7.35-7.42 (2H, m ), 7.83-7.92 (2H, m), 8.28 (1H, d, J = 15.6Hz), 8.56 (1H, d, J = 9.2Hz)

Example 202
(E) -3- (8- (2- (4-((6-Bromobenzo [1,3] dioxol-5-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxy Quinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.29-1.37 (2H, m), 1.72-1.85 (2H, m), 2.07-2.21 (2H, m), 2.33-2.44 (2H, m), 2.66 (1H, dd, J = 12.6,3.0Hz), 2.87 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.67 (2H, s), 3.99 (3H, s) , 5.81 (1H, dd, J = 8.9,3.0Hz), 6.04 (2H, s), 6.57 (1H, d, J = 15.6Hz), 7.08 (1H, d, J = 9.2Hz), 7.12 (1H, s), 7.15 (1H, s), 7.81-7.88 (2H, m), 8.20 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz)

Example 203
(E) -3- (8- (2- (4-((E, E) -2,4-hexadienylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinoline-5 -Yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.22-1.33 (2H, m), 1.68-1.83 (5H, m), 2.06-2.20 (2H, m), 2.37-2.45 (2H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.85-2.90 (1H, m), 3.10-3.14 (1H, m), 3.21-3.23 (2H, m), 4.00 (3H, s), 5.54-5.67 (2H, m), 5.78-5.84 (1H, m), 5.98-6.16 (2H, m), 6.56 (1H, d, J = 15.6Hz), 7.08 (1H, d, J = 9.2Hz), 7.83 ( 2H, s), 8.19 (1H, d, J = 15.6Hz), 8.52 (1H, d, J = 9.2Hz)

Example 204
(E) -3- (8- (2- (4- (heptylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 0.86 (3H, t, J = 7.3 Hz), 1.21-1.31 (10H, m), 1.37-1.42 (2H, m), 1.73-1.82 (2H, m ), 2.07-2.19 (2H, m), 2.37-2.48 (4H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.87 (1H, d, J = 11.5Hz), 3.12 (1H, d, J = 11.5Hz), 4.00 (3H, s), 5.80 (1H, dd, J = 8.9,3.0Hz), 6.53 (1H, d, J = 15.6Hz), 7.07 (1H, d, J = 9.2 Hz), 7.80 (1H, d, J = 7.8Hz), 7.83 (1H, d, J = 7.8Hz), 8.12 (1H, d, J = 15.6Hz), 8.51 (1H, d, J = 9.2Hz)

Example 205
(E) -3- (8- (2- (4-((E) -3- (2-furyl) allylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl Acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.22-1.34 (2H, m), 1.75-1.86 (2H, m), 2.07-2.21 (2H, m), 2.37-2.46 (2H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.87 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.50-3.60 (2H, m), 4.00 (3H, s), 5.81 (1H, dd, J = 8.9,3.0Hz), 6.08-6.15 (1H, m), 6.33-6.46 (3H, m), 6.55 (1H, d, J = 15.6Hz), 7.08 (1H , d, J = 9.2Hz), 7.57 (1H, s), 7.82-7.84 (2H, m), 8.16 (1H, d, J = 15.6Hz), 8.52 (1H, d, J = 9.2Hz)

Example 206
(E) -3- (8- (2- (4- (octane-2-ynylamino) -piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 0.86 (3H, t, J = 7.3 Hz), 1.21-1.37 (6H, m), 1.38-1.46 (2H, m), 1.68-1.79 (2H, m ), 2.05-2.21 (4H, m), 2.37-2.45 (2H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.86 (1H, d, J = 11.5Hz), 3.12 (1H, d, J = 11.5Hz), 3.30 (2H, s), 4.00 (3H, s), 5.81 (1H, dd, J = 8.9,3.0Hz), 6.57 (1H, d, J = 15.6Hz), 7.08 ( 1H, d, J = 9.2Hz), 7.81-7.88 (2H, m), 8.23 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz)

Example 207
(E) -3- (8- (2- (4- (3-phenylpropan-2-ynylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.21-1.37 (2H, m), 1.74-1.85 (2H, m), 2.12-2.25 (2H, m), 2.35-2.45 (2H, m), 2.68 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.12 (1H, d, J = 11.5Hz), 3.57 (2H, s), 4.00 (3H, s) , 5.82 (1H, dd, J = 8.9,3.0Hz), 6.56 (1H, d, J = 15.6Hz), 7.08 (1H, d, J = 9.2Hz), 7.32-7.42 (5H, m), 7.85 ( 2H, s), 8.21 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz)

Example 208
(E) -3- (8- (2- (4-((E) -3-phenylallylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.28-1.34 (2H, m), 1.78-1.87 (2H, m), 2.08-2.21 (2H, m), 2.37-2.48 (2H, m), 2.68 (1H, dd, J = 12.6,3.0Hz), 2.89 (1H, d, J = 11.5Hz), 3.14 (1H, d, J = 11.5Hz), 3.35-3.37 (2H, m), 4.00 (3H, s), 5.81 (1H, dd, J = 8.9, 3.0Hz), 6.29-6.35 (1H, m), 6.50-6.59 (2H, m), 7.08 (1H, d, J = 9.2Hz), 7.21 (1H , t, J = 7.3Hz), 7.31 (2H, t, J = 7.3Hz), 7.40 (2H, d, J = 7.3Hz), 7.83 (2H, s), 8.18 (1H, d, J = 15.6Hz ), 8.52 (1H, d, J = 9.2Hz)

Example 209
(E) -3- (8- (2- (4- (3-phenylpropylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.22-1.32 (2H, m), 1.66-1.83 (4H, m), 2.06-2.20 (2H, m), 2.38-2.44 (2H, m), 2.54 -2.63 (4H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.12 (1H, d, J = 11.5Hz), 3.99 (3H, s), 5.80 (1H, dd, J = 8.9, 3.0Hz), 6.54 (1H, d, J = 15.6Hz), 7.07 (1H, d, J = 9.2Hz), 7.14-7.21 (3H, m), 7.27 (1H, t, J = 7.6Hz), 7.80 (2H, d, J = 7.8Hz), 7.83 (1H, d, J = 7.8Hz), 8.13 (1H, d, J = 15.6Hz), 8.51 ( (1H, d, J = 9.2Hz)

Example 210
E) -3- (8- (2- (4-((E) -2-methyl-3- (2-furyl) allylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinoline- 5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.27-1.34 (2H, m), 1.73-1.84 (2H, m), 1.92 (3H, s), 2.07-2.21 (2H, m), 2.33-2.44 (2H, m), 2.68 (1H, dd, J = 12.6,3.0Hz), 2.87 (1H, d, J = 11.5Hz), 3.12 (1H, d, J = 11.5Hz), 3.23 (2H, s) , 3.99 (3H, s), 5.80 (1H, dd, J = 8.9,3.0Hz), 6.28 (1H, s), 6.33 (1H, d, J = 3.2Hz), 6.47 (1H, dd, J = 3.2 , 1.8Hz), 6.55 (1H, d, J = 15.6Hz), 7.07 (1H, d, J = 9.2Hz), 7.58 (1H, d, J = 1.8Hz), 7.80 (1H, d, J = 7.8 Hz), 7.83 (1H, d, J = 7.8Hz), 8.14 (1H, d, J = 15.6Hz), 8.51 (1H, d, J = 9.2Hz)

Example 211
(E) -3- (8- (2- (4-((E) -2-methyl-3-phenylallylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinoline-5 Il) Acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.29-1.38 (2H, m), 1.79-1.89 (5H, m), 2.10-2.24 (2H, m), 2.40-2.46 (2H, m), 2.68 (1H, dd, J = 12.6,3.0Hz), 2.90 (1H, d, J = 11.5Hz), 3.15 (1H, d, J = 11.5Hz), 3.27 (2H, s), 4.00 (3H, s) , 5.82 (1H, dd, J = 8.9,3.0Hz), 6.44 (1H, s), 6.58 (1H, d, J = 15.6Hz), 7.09 (1H, d, J = 9.2Hz), 7.15-7.28 ( 3H, m), 7.34 (2H, t, J = 7.6Hz), 7.84 (1H, d, J = 7.8Hz), 7.87 (1H, d, J = 7.8Hz), 8.23 (1H, d, J = 15.6) Hz), 8.54 (1H, d, J = 9.2Hz)

Example 212
(E) -3- (8- (2- (4- (3-Phenylbutylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.15-1.26 (5H, m), 1.62-1.73 (4H, m), 2.03-2.15 (2H, m), 2.27-2.34 (1H, m), 2.35 -2.45 (3H, m), 2.65 (1H, dd, J = 12.6,3.0Hz), 2.76-2.86 (2H, m), 3.08 (1H, d, J = 11.5Hz), 3.98 (3H, s), 5.78 (1H, dd, J = 8.9,3.0Hz), 6.50 (1H, d, J = 15.6Hz), 7.06 (1H, d, J = 9.2Hz), 7.16 (1H, t, J = 7.3Hz), 7.20 (2H, d, J = 7.3Hz), 7.27 (2H, t, J = 7.3Hz), 7.75 (1H, d, J = 7.8Hz), 7.80 (1H, d, J = 7.8Hz), 8.02 ( 1H, d, J = 15.6Hz), 8.49 (1H, d, J = 9.2Hz)

Example 213
(E) -3- (8- (2- (4- (2- (benzyloxy) ethylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid ¹ H-NMR (DMSO-d ₆ ) δ value: 1.21-1.30 (2H, m), 1.71-1.81 (2H, m), 2.07-2.20 (2H, m), 2.37-2.44 (2H, m), 2.67 ( 1H, dd, J = 12.6,3.0Hz), 2.73 (2H, t, J = 5.7Hz), 2.86 (1H, d, J = 11.5Hz), 3.11 (1H, d, J = 11.5Hz), 3.48 ( 2H, t, J = 5.7Hz), 3.99 (3H, s), 4.47 (2H, s), 5.80 (1H, dd, J = 8.9,3.0Hz), 6.56 (1H, d, J = 15.6Hz), 7.08 (1H, d, J = 9.2Hz), 7.24-7.39 (5H, m), 7.84 (2H, s), 8.20 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz )

Example 214
(E) -3- (8- (2- (4-((Naphthalen-1-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.34-1.41 (2H, m), 1.86-1.94 (2H, m), 2.11-2.22 (2H, m), 2.37-2.46 (2H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.90 (1H, d, J = 11.5Hz), 3.16 (1H, d, J = 11.5Hz), 4.00 (3H, s), 4.17 (2H, s) , 5.82 (1H, dd, J = 8.9,3.0Hz), 6.56 (1H, d, J = 15.6Hz), 7.09 (1H, d, J = 9.2Hz), 7.43-7.55 (4H, m), 7.80 ( 1H, d, J = 7.8Hz), 7.85 (2H, s), 7.91 (1H, d, J = 7.8Hz), 8.16-8.21 (2H, m), 8.54 (1H, d, J = 9.2Hz)

Example 215
(E) -3- (8- (2- (4-decylaminopiperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 0.86 (3H, t, J = 7.3 Hz), 1.21-1.31 (16H, m), 1.37-1.42 (2H, m), 1.73-1.82 (2H, m ), 2.07-2.19 (2H, m), 2.37-2.48 (4H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.87 (1H, d, J = 11.5Hz), 3.12 (1H, d, J = 11.5Hz), 4.00 (3H, s), 5.80 (1H, dd, J = 8.9,3.0Hz), 6.53 (1H, d, J = 15.6Hz), 7.07 (1H, d, J = 9.2 Hz), 7.80 (1H, d, J = 7.8Hz), 7.83 (1H, d, J = 7.8Hz), 8.12 (1H, d, J = 15.6Hz), 8.51 (1H, d, J = 9.2Hz)

Example 216
(E) -3- (8- (2- (4-((5-phenylfuran-2-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl Acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.29-1.34 (2H, m), 1.78-1.87 (2H, m), 2.08-2.20 (2H, m), 2.37-2.46 (2H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.89 (1H, d, J = 11.5Hz), 3.15 (1H, d, J = 11.5Hz), 3.77 (2H, s), 3.99 (3H, s) , 5.81 (1H, dd, J = 8.9,3.0Hz), 6.34 (1H, d, J = 3.2Hz), 6.57 (1H, d, J = 15.6Hz), 6.84 (1H, d, J = 3.2Hz) , 7.08 (1H, d, J = 9.2Hz), 7.26 (1H, t, J = 7.3Hz), 7.40 (2H, t, J = 7.3Hz), 7.66 (2H, d, J = 7.3Hz), 7.84 (2H, s), 8.19 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz)

Example 217
(E) -3- (8- (2- (4-((5- (thiophen-2-yl) isoxazol-3-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2 -Methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.26-1.34 (2H, m), 1.74-1.85 (2H, m), 2.08-2.20 (2H, m), 2.36-2.43 (2H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.87 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.77 (2H, s), 3.99 (3H, s) , 5.81 (1H, dd, J = 8.9,3.0Hz), 6.57 (1H, d, J = 15.6Hz), 6.82 (1H, s), 7.08 (1H, d, J = 9.2Hz), 7.23 (1H, dd, J = 5.0,3.7Hz), 7.68 (1H, d, J = 3.7Hz), 7.80 (1H, d, J = 5.0Hz), 7.82-7.87 (2H, m), 8.21 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz)

Example 218
(E) -3- (8- (2- (4-((5-phenylthiophen-2-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl Acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.29-1.34 (2H, m), 1.78-1.87 (2H, m), 2.05-2.21 (2H, m), 2.36-2.46 (2H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.14 (1H, d, J = 11.5Hz), 3.91 (2H, s), 3.99 (3H, s) , 5.81 (1H, dd, J = 8.9,3.0Hz), 6.57 (1H, d, J = 15.6Hz), 6.94 (1H, d, J = 3.7Hz), 7.08 (1H, d, J = 9.2Hz) , 7.27 (1H, t, J = 7.3Hz), 7.32 (1H, d, J = 3.7Hz), 7.39 (2H, t, J = 7.3Hz), 7.60 (2H, d, J = 7.3Hz), 7.84 (2H, s), 8.19 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz)

Example 219
(E) -3- (8- (2- (4- (2-Fluoro-5- (trifluoromethyl) benzylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinoline-5 Il) Acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.30-1.36 (2H, m), 1.75-1.86 (2H, m), 2.08-2.20 (2H, m), 2.36-2.44 (2H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.14 (1H, d, J = 11.5Hz), 3.81 (2H, s), 3.99 (3H, s) , 5.82 (1H, dd, J = 8.9,3.0Hz), 6.58 (1H, d, J = 15.6Hz), 7.09 (1H, d, J = 9.2Hz), 7.38 (1H, t, J = 9.2Hz) , 7.63-7.69 (1H, m), 7.84 (1H, d, J = 7.8Hz), 7.87 (1H, d, J = 7.8Hz), 7.88-7.91 (1H, m), 8.24 (1H, d, J = 15.6Hz), 8.54 (1H, d, J = 9.2Hz)

Example 220
(E) -3- (8- (2- (4-((9H-fluoren-2-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) Acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.31-1.38 (2H, m), 1.80-1.88 (2H, m), 2.07-2.18 (2H, m), 2.37-2.45 (2H, m), 2.66 (1H, dd, J = 12.6,3.0Hz), 2.89 (1H, d, J = 11.5Hz), 3.14 (1H, d, J = 11.5Hz), 3.80 (2H, s), 3.89 (2H, s) , 3.99 (3H, s), 5.81 (1H, dd, J = 8.9,3.0Hz), 6.56 (1H, d, J = 15.6Hz), 7.08 (1H, d, J = 9.2Hz), 7.29 (1H, t, J = 6.9Hz), 7.33-7.38 (2H, m), 7.54-7.62 (2H, m), 7.81 (1H, d, J = 7.8Hz), 7.83 (2H, s), 7.85 (1H, d , J = 7.8Hz), 8.16 (1H, d, J = 15.6Hz), 8.52 (1H, d, J = 9.2Hz)

Example 221
(E) -3- (8- (2- (4-((2,2′-bithiophen-5-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinoline-5 -Yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.29-1.34 (2H, m), 1.77-1.85 (2H, m), 2.07-2.19 (2H, m), 2.38-2.46 (2H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.89 (1H, d, J = 11.5Hz), 3.14 (1H, d, J = 11.5Hz), 3.89 (2H, s), 3.99 (3H, s) , 5.81 (1H, dd, J = 8.9,3.0Hz), 6.58 (1H, d, J = 15.6Hz), 6.89 (1H, d, J = 3.2Hz), 7.05-7.11 (3H, m), 7.22 ( 1H, d, J = 3.2Hz), 7.45 (1H, d, J = 5.0Hz), 7.84 (1H, d, J = 7.8Hz), 7.87 (1H, d, J = 7.8Hz), 8.23 (1H, J = 15.6Hz), 8.54 (1H, d, J = 9.2Hz)

Example 222
(E) -3- (8- (2- (4- (3- (4-tert-butylphenyl) -2-methylpropylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinoline -5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 0.81 (3H, d, J = 6.9 Hz), 1.23-1.31 (11H, m), 1.71-1.82 (3H, m), 2.07-2.19 (2H, m ), 2.24-2.30 (1H, m), 2.34-2.54 (4H, m), 2.64-2.70 (2H, m), 2.88 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5) Hz), 4.00 (3H, s), 5.81 (1H, dd, J = 9.2,3.0Hz), 6.57 (1H, d, J = 15.6Hz), 7.04-7.11 (3H, m), 7.28 (2H, d , J = 8.3Hz), 7.80-7.87 (2H, m), 8.19 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz)

Example 223
(E) -3- (8- (2- (4-((phenanthren-9-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.36-1.45 (2H, m), 1.87-1.99 (2H, m), 2.08-2.23 (2H, m), 2.33-2.43 (2H, m), 2.66 (1H, dd, J = 12.6,3.0Hz), 2.89 (1H, d, J = 11.5Hz), 3.15 (1H, d, J = 11.5Hz), 3.97 (3H, s), 4.19 (2H, s) , 5.80 (1H, dd, J = 8.9,3.0Hz), 6.55 (1H, d, J = 15.6Hz), 7.05 (1H, d, J = 9.2Hz), 7.55-7.70 (4H, m), 7.78- 7.86 (3H, m), 7.92 (1H, d, J = 7.8Hz), 8.19 (1H, d, J = 15.6Hz), 8.24 (1H, d, J = 9.6Hz), 8.51 (1H, d, J = 9.2Hz), 8.76 (1H, d, J = 8.3Hz), 8.82 (1H, d, J = 8.3Hz)

Example 224
(E) -3- (8- (2- (4- (4- (benzyloxy) benzylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.29-1.34 (2H, m), 1.75-1.85 (2H, m), 2.05-2.17 (2H, m), 2.35-2.44 (2H, m), 2.66 (1H, dd, J = 12.6,3.0Hz), 2.87 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.66 (2H, s), 3.99 (3H, s) , 5.08 (2H, s), 5.80 (1H, dd, J = 8.9,3.0Hz), 6.56 (1H, d, J = 15.6Hz), 6.94 (2H, d, J = 8.7Hz), 7.07 (1H, d, J = 9.2Hz), 7.24 (2H, d, J = 8.7Hz), 7.32 (1H, t, J = 7.3Hz), 7.38 (2H, t, J = 7.6Hz), 7.43 (2H, d, J = 7.3Hz), 7.83 (2H, s), 8.15 (1H, d, J = 15.6Hz), 8.52 (1H, d, J = 9.2Hz)

Example 225
(E) -3- (8- (2- (4-((5- (phenylethynyl) thiophen-2-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinoline- 5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.27-1.34 (2H, m), 1.75-1.84 (2H, m), 2.07-2.19 (2H, m), 2.36-2.44 (2H, m), 2.66 (1H, dd, J = 12.6,3.0Hz), 2.88 (1H, d, J = 11.5Hz), 3.13 (1H, d, J = 11.5Hz), 3.92 (2H, s), 4.00 (3H, s) , 5.81 (1H, dd, J = 8.9,3.0Hz), 6.57 (1H, d, J = 15.6Hz), 6.93 (1H, d, J = 3.7Hz), 7.08 (1H, d, J = 9.2Hz) , 7.24 (1H, d, J = 3.7Hz), 7.39-7.45 (3H, m), 7.48-7.55 (2H, m), 7.84 (2H, s), 8.19 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz)

Example 226
(E) -3- (8- (2- (4-((9-ethylcarbazol-3-yl) methylamino) piperidin-1-yl) -1-hydroxyethyl) -2-methoxyquinolin-5-yl Acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.30 (3H, t, J = 7.3 Hz), 1.37-1.44 (2H, m), 1.85-1.94 (2H, m), 2.08-2.19 (2H, m ), 2.36-2.47 (2H, m), 2.67 (1H, dd, J = 12.6,3.0Hz), 2.91 (1H, d, J = 11.5Hz), 3.17 (1H, d, J = 11.5Hz), 3.94 (2H, s), 3.99 (3H, s), 4.43 (2H, q, J = 7.3Hz), 5.82 (1H, dd, J = 8.9,3.0Hz), 6.57 (1H, d, J = 15.6Hz) , 7.07 (1H, d, J = 9.2Hz), 7.18 (1H, t, J = 8.3Hz), 7.41-7.48 (2H, m), 7.54 (1H, d, J = 8.3Hz), 7.58 (1H, d, J = 8.3Hz), 7.84 (2H, s), 8.09-8.13 (2H, m), 8.19 (1H, d, J = 15.6Hz), 8.52 (1H, d, J = 9.2Hz)

Example 227
(E) -3- (8- (1-hydroxy-2- (4-((5,5,8a-trimethyl-1-((phenylsulfinyl) methyl) -3,4,4a, 5,6,7 , 8,8a-Octahydronaphthalen-2-yl) methylamino) piperidin-1-yl) ethyl) -2-methoxyquinolin-5-yl) acrylic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 0.82-0.87 (3H, m), 0.89-0.93 (3H, m), 0.98 (3H, s), 1.12-1.46 (6H, m), 1.50-1.81 (5H, m), 1.88-2.45 (7H, m), 2.59-2.70 (1H, m), 2.84-3.30 (4H, m), 3.49-3.62 (2H, m), 3.70-3.85 (1H, m) , 4.00 (3H, s), 5.81 (1H, d, J = 9.2Hz), 6.57 (1H, d, J = 15.6Hz), 7.09 (1H, d, J = 9.2Hz), 7.51-7.73 (5H, m), 7.81-7.89 (2H, m), 8.20 (1H, d, J = 15.6Hz), 8.53 (1H, d, J = 9.2Hz)

１−（２−メトキシキノリン−８−イル）−２−（ピペリジン−４−イル）エタノール80mgの塩化メチレン3mL溶液に、室温で（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）アセトアルデヒド65mg、酢酸0.02mLおよびトリアセトキシ水素化ホウ素ナトリウム93mg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10mLおよび水5mLを加え、10％水酸化ナトリウム水溶液でpH11に調整（pH試験紙）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10mL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；ヘキサン：酢酸エチル＝１：１］で精製し、黄色油状の２−（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）−１−（２−メトキシキノリン−８−イル）エタノール80mgを得た。
¹H-NMR(CDCl₃)δ値：1.20-2.22(6H,m),2.41-2.86(4H,m),2.89-3.10(2H,m),3.71-3.92(3H,m),4.05(3H,s),4.23(4H,s),5.37-5.49(1H,m),6.59-6.87(3H,m),6.93(1H,d,J=8.8Hz),7.36(1H,t,J=7.7Hz),7.43-7.54(1H,m),7.63(1H,dd,J=7.7,1.5Hz),8.03(1H,d,J=8.8Hz)Example 228

To a solution of 80 mg of 1- (2-methoxyquinolin-8-yl) -2- (piperidin-4-yl) ethanol in 3 mL of methylene chloride is added (2,3-dihydrobenzo [b] [1,4] dioxin- 6-yl) acetaldehyde 65 mg, acetic acid 0.02 mL and sodium triacetoxyborohydride 93 mg were added and stirred for 1 hour 30 minutes. Chloroform 10 mL and water 5 mL were added to the reaction mixture, and the pH was adjusted to pH 11 with 10% aqueous sodium hydroxide (pH test paper). The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, washed with 10 mL of 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; hexane: ethyl acetate = 1: 1] to give 2- (1- (2- (2 , 3-Dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidin-4-yl) -1- (2-methoxyquinolin-8-yl) ethanol 80 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.20-2.22 (6H, m), 2.41-2.86 (4H, m), 2.89-3.10 (2H, m), 3.71-3.92 (3H, m), 4.05 (3H , s), 4.23 (4H, s), 5.37-5.49 (1H, m), 6.59-6.87 (3H, m), 6.93 (1H, d, J = 8.8Hz), 7.36 (1H, t, J = 7.7 Hz), 7.43-7.54 (1H, m), 7.63 (1H, dd, J = 7.7,1.5Hz), 8.03 (1H, d, J = 8.8Hz)

２−（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）−１−（２−メトキシキノリン−８−イル）エタノール80mgの酢酸エチル3mL溶液に、室温で4mol／L塩化水素／酢酸エチル0.14mLを加え、減圧下で溶媒を留去した。得られた残留物をジエチルエーテル15mLに懸濁させ、固形物をろ取し、淡黄色固体の２−（１−（２−（２，３−ジヒドロベンゾ［ｂ］［１，４］ジオキシン−６−イル）エチル）ピペリジン−４−イル）−１−（２−メトキシキノリン−８−イル）エタノールの塩酸塩26mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.37-1.97(5H,m),2.12-2.31(1H,m),2.80-3.02(4H,m),3.10-3.65(5H,m),4.00(3H,s),4.22(4H,s),5.71(1H,dd,J=9.8,2.8Hz),6.67-6.75(1H,m),6.76-6.86(2H,m),7.02(1H,d,J=8.9Hz),7.36-7.51(1H,m),7.76(1H,dd,J=8.2,1.4Hz),7.82(1H,dd,J=7.1,1.4Hz),8.23(1H,d,J=8.9Hz),9.99(1H,s)Example 229

2- (1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) ethyl) piperidin-4-yl) -1- (2-methoxyquinolin-8-yl) To a solution of 80 mg of ethanol in 3 mL of ethyl acetate was added 4 mol / L hydrogen chloride / ethyl acetate 0.14 mL at room temperature, and the solvent was distilled off under reduced pressure. The obtained residue was suspended in 15 mL of diethyl ether, and the solid was collected by filtration to give 2- (1- (2- (2,3-dihydrobenzo [b] [1,4] dioxin- 26 mg of 6-yl) ethyl) piperidin-4-yl) -1- (2-methoxyquinolin-8-yl) ethanol hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.37-1.97 (5H, m), 2.12-2.31 (1H, m), 2.80-3.02 (4H, m), 3.10-3.65 (5H, m), 4.00 (3H, s), 4.22 (4H, s), 5.71 (1H, dd, J = 9.8,2.8Hz), 6.67-6.75 (1H, m), 6.76-6.86 (2H, m), 7.02 (1H, d , J = 8.9Hz), 7.36-7.51 (1H, m), 7.76 (1H, dd, J = 8.2,1.4Hz), 7.82 (1H, dd, J = 7.1,1.4Hz), 8.23 (1H, d, J = 8.9Hz), 9.99 (1H, s)

Ｎ−（２−メトキシキノリン−８−イル）ピペリジン−４−カルボキサミド101mgのメチルイソブチルケトン4mL溶液に、室温で６−（２−クロロエチル）−２Ｈ−ベンゾ［１，４］オキサジン−３（４Ｈ）−オン97mg、ヨウ化ナトリウム69mgおよび炭酸ナトリウム49mgを加え、窒素雰囲気下、120℃で5時間攪拌した。反応混合物を室温まで冷却し、酢酸エチル20mLおよび水20mLを加え、不溶物をろ去した。有機層を分取し、飽和塩化ナトリウム水溶液20mL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；富士シリシア社、シリカゲルChromatorex-NH、溶離液；ヘキサン：酢酸エチル＝１：１］で精製し、白色固体のＮ−（２−メトキシキノリン−８−イル）−１−（２−（３−オキソ−３，４−ジヒドロ−２Ｈ−ベンゾ［１，４］オキサジン−６−イル）エチル）ピペリジン−４−カルボキサミド65mgを得た。
¹H-NMR(CDCl₃)δ値：1.89-2.07(2H,m),2.08-2.26(4H,m),2.37-2.53(1H,m),2.54-2.65(2H,m),2.69-2.84(2H,m),3.01-3.16(2H,m),4.10(3H,s),4.59(2H,s),6.69(1H,d,J=1.9Hz),6.82(1H,dd,J=8.2,1.9Hz),6.89(1H,d,J=8.2Hz),6.96(1H,d,J=8.9Hz),7.34-7.42(1H,m),7.44(1H,dd,J=8.1,1.7Hz),8.01(1H,d,J=8.9Hz),8.43(1H,s),8.73(1H,dd,J=7.5,1.7Hz),9.62(1H,s)Example 230

To a solution of 101 mg of N- (2-methoxyquinolin-8-yl) piperidine-4-carboxamide in 4 mL of methyl isobutyl ketone is added 6- (2-chloroethyl) -2H-benzo [1,4] oxazine-3 (4H) at room temperature. -97 mg of ON, 69 mg of sodium iodide and 49 mg of sodium carbonate were added, and the mixture was stirred at 120 ° C for 5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, 20 mL of ethyl acetate and 20 mL of water were added, and the insoluble material was removed by filtration. The organic layer was separated, washed with 20 mL of 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; Fuji Silysia, silica gel Chromatorex-NH, eluent; hexane: ethyl acetate = 1: 1], and white solid N- (2-methoxyquinoline-8). There was obtained 65 mg of -yl) -1- (2- (3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl) ethyl) piperidine-4-carboxamide.
¹ H-NMR (CDCl ₃ ) δ value: 1.89-2.07 (2H, m), 2.08-2.26 (4H, m), 2.37-2.53 (1H, m), 2.54-2.65 (2H, m), 2.69-2.84 (2H, m), 3.01-3.16 (2H, m), 4.10 (3H, s), 4.59 (2H, s), 6.69 (1H, d, J = 1.9Hz), 6.82 (1H, dd, J = 8.2 , 1.9Hz), 6.89 (1H, d, J = 8.2Hz), 6.96 (1H, d, J = 8.9Hz), 7.34-7.42 (1H, m), 7.44 (1H, dd, J = 8.1,1.7Hz) ), 8.01 (1H, d, J = 8.9Hz), 8.43 (1H, s), 8.73 (1H, dd, J = 7.5,1.7Hz), 9.62 (1H, s)

Ｎ−（２−メトキシキノリン−８−イル）ピペリジン−４−カルボキサミドと６−（２−クロロエチル）−２Ｈ−ベンゾ［１，４］チアジン−３（４Ｈ）−オンから実施例２３０と同様にして、Ｎ−（２−メトキシキノリン−８−イル）−１−（２−（３−オキソ−３，４−ジヒドロ−２Ｈ−ベンゾ［１，４］チアジン−６−イル）エチル）ピペリジン−４−カルボキサミドを得た。
¹H-NMR(CDCl₃)δ値：1.93-2.07(2H,m),2.08-2.28(4H,m),2.39-2.53(1H,m),2.55-2.68(2H,m),2.72-2.86(2H,m),3.04-3.17(2H,m),3.42(2H,s),4.10(3H,s),6.72(1H,d,J=1.6Hz),6.88(1H,dd,J=7.9,1.6Hz),6.96(1H,d,J=8.9Hz),7.23(1H,d,J=7.9Hz),7.33-7.41(1H,m),7.44(1H,dd,J=8.2,1.7Hz),8.01(1H,d,J=8.9Hz),8.17(1H,s),8.72(1H,dd,J=7.4,1.7Hz),9.62(1H,s)Example 231

N- (2-methoxyquinolin-8-yl) piperidine-4-carboxamide and 6- (2-chloroethyl) -2H-benzo [1,4] thiazin-3 (4H) -one as in Example 230 , N- (2-methoxyquinolin-8-yl) -1- (2- (3-oxo-3,4-dihydro-2H-benzo [1,4] thiazin-6-yl) ethyl) piperidine-4- Carboxamide was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.93-2.07 (2H, m), 2.08-2.28 (4H, m), 2.39-2.53 (1H, m), 2.55-2.68 (2H, m), 2.72-2.86 (2H, m), 3.04-3.17 (2H, m), 3.42 (2H, s), 4.10 (3H, s), 6.72 (1H, d, J = 1.6Hz), 6.88 (1H, dd, J = 7.9 , 1.6Hz), 6.96 (1H, d, J = 8.9Hz), 7.23 (1H, d, J = 7.9Hz), 7.33-7.41 (1H, m), 7.44 (1H, dd, J = 8.2, 1.7Hz) ), 8.01 (1H, d, J = 8.9Hz), 8.17 (1H, s), 8.72 (1H, dd, J = 7.4, 1.7Hz), 9.62 (1H, s)

１−（２−メトキシキノリン−８−イル）−２−（ピペラジン−１−イル）エタノール184mgのメチルイソブチルケトン8mL溶液に、室温で６−（２−クロロエチル）−２Ｈ−ベンゾ［１，４］オキサジン−３（４Ｈ）−オン176mg、ヨウ化ナトリウム125mgおよび炭酸ナトリウム88mgを加え、120℃にて5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30mLおよび水30mL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［シリカゲル；富士シリシア社、シリカゲルChromatorex-NH、溶離液；酢酸エチル］で精製し、酢酸エチルで再結晶し、淡黄色固体の１−（２−メトキシキノリン−８−イル）−２−（４−（２−（３−オキソ−３，４−ジヒドロ−２Ｈ−ベンゾ［１，４］オキサジン−６−イル）エチル）ピペラジン−１−イル）エタノール76mgを得た。
¹H-NMR(CDCl₃)δ値：2.52-2.69(9H,m),2.70-2.80(2H,m),2.81-2.96(2H,m),3.01(1H,dd,J=12.4,3.3Hz),4.03(3H,s),4.59(2H,s),5.76(1H,dd,J=10.1,3.0Hz),6.65(1H,d,J=1.9Hz),6.82(1H,dd,J=8.2,1.9Hz),6.89(1H,d,J=8.2Hz),6.90(1H,d,J=9.0Hz),7.40(1H,dd,J=7.9,7.3Hz),7.63(1H,dd,J=7.9,1.5Hz),7.80-7.86(1H,m),7.99(1H,d,J=9.0Hz),8.20(1H,s)Example 232

To a solution of 184 mg of 1- (2-methoxyquinolin-8-yl) -2- (piperazin-1-yl) ethanol in 8 mL of methyl isobutyl ketone is added 6- (2-chloroethyl) -2H-benzo [1,4] at room temperature. 176 mg of oxazine-3 (4H) -one, 125 mg of sodium iodide and 88 mg of sodium carbonate were added, and the mixture was stirred at 120 ° C. for 5 hours and 30 minutes. The reaction mixture was cooled to room temperature and 30 mL chloroform and 30 mL 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 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; Fuji Silysia, silica gel Chromatorex-NH, eluent: ethyl acetate], recrystallized from ethyl acetate, and 1- (2-methoxyquinoline as a pale yellow solid. 76 mg of -8-yl) -2- (4- (2- (3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl) ethyl) piperazin-1-yl) ethanol Obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.52-2.69 (9H, m), 2.70-2.80 (2H, m), 2.81-2.96 (2H, m), 3.01 (1H, dd, J = 12.4,3.3Hz ), 4.03 (3H, s), 4.59 (2H, s), 5.76 (1H, dd, J = 10.1,3.0Hz), 6.65 (1H, d, J = 1.9Hz), 6.82 (1H, dd, J = 8.2,1.9Hz), 6.89 (1H, d, J = 8.2Hz), 6.90 (1H, d, J = 9.0Hz), 7.40 (1H, dd, J = 7.9,7.3Hz), 7.63 (1H, dd, J = 7.9,1.5Hz), 7.80-7.86 (1H, m), 7.99 (1H, d, J = 9.0Hz), 8.20 (1H, s)

１−（２−メトキシキノリン−８−イル）−２−（ピペラジン−１−イル）エタノールと６−（２−クロロエチル）−２Ｈ−ベンゾ［１，４］チアジン−３（４Ｈ）−オンから実施例２３２と同様にして、１−（２−メトキシキノリン−８−イル）−２−（４−（２−（３−オキソ−３，４−ジヒドロ−２Ｈ−ベンゾ［１，４］チアジン−６−イル）エチル）ピペラジン−１−イル）エタノールを得た。
¹H-NMR(CDCl₃)δ値：2.52-2.70(9H,m),2.72-2.81(2H,m),2.82-2.95(2H,m),3.02(1H,dd,J=12.5,3.2Hz),3.42(2H,s),4.03(3H,s),5.76(1H,dd,J=10.2,2.9Hz),6.69(1H,d,J=1.6Hz),6.88(1H,dd,J=7.9,1.6Hz),6.91(1H,d,J=8.9Hz),7.23(1H,d,J=7.9Hz),7.40(1H,dd,J=7.9,7.5Hz),7.63(1H,dd,J=7.9,1.6Hz),7.80-7.86(1H,m),7.91-7.96(1H,s),7.99(1H,d,J=8.9Hz)Example 233

Performed from 1- (2-methoxyquinolin-8-yl) -2- (piperazin-1-yl) ethanol and 6- (2-chloroethyl) -2H-benzo [1,4] thiazin-3 (4H) -one Analogously to Example 232, 1- (2-methoxyquinolin-8-yl) -2- (4- (2- (3-oxo-3,4-dihydro-2H-benzo [1,4] thiazine-6 -Yl) ethyl) piperazin-1-yl) ethanol was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.52-2.70 (9H, m), 2.72-2.81 (2H, m), 2.82-2.95 (2H, m), 3.02 (1H, dd, J = 12.5, 3.2 Hz ), 3.42 (2H, s), 4.03 (3H, s), 5.76 (1H, dd, J = 10.2,2.9Hz), 6.69 (1H, d, J = 1.6Hz), 6.88 (1H, dd, J = 7.9, 1.6Hz), 6.91 (1H, d, J = 8.9Hz), 7.23 (1H, d, J = 7.9Hz), 7.40 (1H, dd, J = 7.9, 7.5Hz), 7.63 (1H, dd, J = 7.9,1.6Hz), 7.80-7.86 (1H, m), 7.91-7.96 (1H, s), 7.99 (1H, d, J = 8.9Hz)

  The compound of the general formula [1] or a salt thereof is useful as an excellent antibacterial agent because it has strong antibacterial activity and high safety.

Claims (11)

General formula

“Wherein R ¹ represents a halogen atom, a cyano group, an optionally protected carboxyl group or an optionally substituted alkyl, alkoxy or acyloxy group; R ² , R ³ , R ⁴ and R ⁵ are A hydrogen atom, a halogen atom, a cyano group, an optionally protected carboxyl group or an optionally substituted alkyl, alkenyl, alkoxy, cycloalkyl, amino or carbamoyl group; Z ¹ and Z ² are the same or different; Nitrogen atom or CR ⁷ wherein R ⁷ represents a hydrogen atom, a halogen atom, a cyano group, an optionally protected carboxyl group or an optionally substituted alkyl, alkenyl, alkoxy, amino or carbamoyl group. . it is "and, at least one of the nitrogen atoms of the ^{Z 1} and ^{Z 2; X 1} An oxygen atom, a sulfur atom, a sulfinyl group, ^{"wherein R 8a} denotes a hydrogen atom or an optionally substituted alkyl or aryl group." Sulfonyl group, ^{NR 8a} or ^CR 9 ^{R 10} "in the formula, R ⁹ and R ¹⁰ are the same or different and each represents a hydrogen atom or an optionally substituted alkyl, hydroxyl, amino or mercapto group. ”; X ² represents a carbonyl group, NR ^8b “ wherein R ^8b Represents a hydrogen atom or an optionally substituted alkyl or aryl group. ”Or a bond; X ³ represents a C _1-4 alkylene group or a bond; and R ⁶ represents a general formula.

"Wherein R ¹¹ represents one or more hydrogen atoms, halogen atoms, an optionally protected hydroxyl or carboxyl group or an optionally substituted amino, lower alkyl, alkoxy or carbamoyl group; R ^11a , R ^11b and R ^11c are the same or different and each represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl or carboxyl group or an optionally substituted amino, lower alkyl, alkoxy or carbamoyl group; R ¹² represents a general formula;

"Wherein R ¹⁴ represents a hydrogen atom, an optionally protected carboxyl group or an optionally substituted cycloalkyl, cycloalkenyl, aralkyl, aryl or heterocyclic group; X ⁴ represents an oxygen atom, A sulfur atom, a carbonyl group or a bond; X ⁵ represents an optionally substituted alkylene group or a bond; X ⁶ represents an optionally substituted alkylene, alkenylene or alkynylene group or a sulfonyl group; X ⁷ ., the mean an alkylene group or a bond may be substituted with group represented by "; R ¹³ is a hydrogen atom, means a protecting group or an optionally substituted alkyl or aryl group of an amino group To do. "Means. Or a salt thereof. Z ¹ and Z ² are a nitrogen atom or CR ⁷ wherein R ⁷ is a hydrogen atom, a halogen atom, a cyano group, an optionally protected carboxyl group or an optionally substituted alkyl, alkenyl, alkoxy, . refers to an amino or carbamoyl group is "and, at least one of the nitrogen atoms of the Z ¹ and Z ^2; R ⁶ has the general formula

"Wherein R ¹¹ represents one or more hydrogen atoms, halogen atoms, an optionally protected hydroxyl or carboxyl group or an optionally substituted amino, lower alkyl, alkoxy or carbamoyl group; R ^11a , R ^11b and R ^11c are the same or different and each represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl or carboxyl group, or an optionally substituted amino, lower alkyl, alkoxy or carbamoyl group; R ^12a is a group represented by the general formula:

“Wherein R ^14a represents an optionally substituted aralkyl, monocyclic heterocyclic or bicyclic heterocyclic group; X ⁴ represents an oxygen atom, sulfur atom, carbonyl group or bond. X ⁵ represents an optionally substituted alkylene group or a bond; X ^6a represents an alkylene group; R ¹³ represents a hydrogen atom, an amino group protecting group or a substituent; Means an alkyl or aryl group which may be substituted. A group represented by the formula: However, when Z ² is CR ⁷ , R ⁶ is

"Wherein R ¹¹ represents one or more hydrogen atoms, halogen atoms, an optionally protected hydroxyl or carboxyl group or an optionally substituted amino, lower alkyl, alkoxy or carbamoyl group; R ^11a , R ^11b and R ^11c are the same or different and each represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl or carboxyl group, or an optionally substituted amino, lower alkyl, alkoxy or carbamoyl group; R ^12a is a group represented by the general formula:

“Wherein R ^14a represents an optionally substituted aralkyl, monocyclic heterocyclic or bicyclic heterocyclic group; X ⁴ represents an oxygen atom, sulfur atom, carbonyl group or bond. X ⁵ represents an optionally substituted alkylene group or a bond; X ^6a represents an alkylene group; and R ¹³ represents a hydrogen atom, an amino group protecting group, or It means an alkyl or aryl group which may be substituted. The nitrogen-containing heterocyclic compound or a salt thereof according to claim 1, which is a group represented by: R ¹ is a halogen atom, a cyano group or an optionally substituted alkyl, alkoxy or acyloxy group; R ² , R ³ , R ⁴ and R ⁵ are the same or different and are a hydrogen atom, halogen atom, cyano group, protection An optionally substituted carboxyl group or an optionally substituted alkyl, alkenyl, alkoxy, amino or carbamoyl group; Z ¹ and Z ² are a nitrogen atom or CR ⁷ , wherein R ⁷ is a hydrogen atom, a halogen atom , A cyano group, an optionally protected carboxyl group or an optionally substituted alkyl, alkenyl, alkoxy, amino or carbamoyl group. ”And at least one of Z ¹ and Z ² is a nitrogen atom ; ^{X 1} is an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, ^{NR 8a} " ^{Among, R 8a} denotes a hydrogen atom or an optionally substituted alkyl or aryl group. "Or a ^CR 9a ^{R 10a 'formula, R 9a} and ^{R 10a} are being hydrogen atom or a substituent identical or different Means an optionally hydroxyl, amino or mercapto group. "; R ⁶ is of the general formula

"Wherein R ¹¹ represents one or more hydrogen atoms, halogen atoms, an optionally protected hydroxyl or carboxyl group or an optionally substituted amino, lower alkyl, alkoxy or carbamoyl group; R ^11a , R ^11b and R ^11c are the same or different and each represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl or carboxyl group, or an optionally substituted amino, lower alkyl, alkoxy or carbamoyl group; R ^12b represents a general formula;

“Wherein R ^14b represents a monocyclic heterocyclic or bicyclic heterocyclic group which may be substituted; X ^4a represents an oxygen atom, a sulfur atom or a bond; A group represented by “represents an integer of 4.”; R ^13a represents a hydrogen atom or an optionally substituted alkyl or aryl group; A group represented by the formula: However, when Z ² is CR ⁷ , R ⁶ is

"Wherein R ¹¹ represents one or more hydrogen atoms, halogen atoms, an optionally protected hydroxyl or carboxyl group or an optionally substituted amino, lower alkyl, alkoxy or carbamoyl group; R ^11a , R ^11b and R ^11c are the same or different and each represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl or carboxyl group, or an optionally substituted amino, lower alkyl, alkoxy or carbamoyl group; R ^12b represents a general formula;

“Wherein R ^14b represents a monocyclic heterocyclic or bicyclic heterocyclic group which may be substituted; X ^4a represents an oxygen atom, a sulfur atom or a bond; A group represented by “represents an integer of 4.”; R ^13a represents a hydrogen atom or an optionally substituted alkyl or aryl group; The nitrogen-containing heterocyclic compound or a salt thereof according to claim 1 or 2, which is a group represented by the formula: One of Z ¹ and Z ² is a nitrogen atom; the other is CR ⁷ , wherein R ⁷ is a hydrogen atom, a halogen atom, a cyano group, an optionally protected carboxyl group or a substituted group It means a good alkyl, alkenyl, alkoxy, amino or carbamoyl group. ”The nitrogen-containing heterocyclic compound or a salt thereof according to claim 1. R ⁶ represents the general formula

Wherein R ^12b is a general formula

“Wherein R ^14b represents a monocyclic heterocyclic or bicyclic heterocyclic group which may be substituted; X ^4a represents an oxygen atom, a sulfur atom or a bond; Means an integer of 4. " The nitrogen-containing heterocyclic compound or a salt thereof according to claim 1, which is a group represented by the formula: X ¹ is NR ^8a [wherein R ^8a represents a hydrogen atom or an optionally substituted alkyl or aryl group.] Or CR ^9a R ^10a “wherein R ^9a and R ^10a are the same or Differently represents a hydrogen atom or an optionally substituted hydroxyl, amino or mercapto group. "; X ² is a carbonyl group or a bond; R ¹ is an optionally substituted alkoxy group; R ² , R ³ , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, an optionally protected carboxyl group, or an optionally substituted alkyl or alkenyl group, Its salt. At least one of R ^{3 and} R ⁴ is a halogen atom, an optionally protected carboxyl group or an optionally substituted carbamoyl, alkyl, alkenyl or cycloalkyl group; Z ¹ is a nitrogen atom; Z ² is CR ⁷ wherein R ⁷ represents a hydrogen atom, a halogen atom, a cyano group, an optionally protected carboxyl group or an optionally substituted alkyl, alkenyl, alkoxy, amino or carbamoyl group; ⁶ is the general formula

“Wherein R ¹¹ represents one or more hydrogen atoms, halogen atoms, an optionally protected hydroxyl or carboxyl group or an optionally substituted amino, lower alkyl, alkoxy or carbamoyl group;
R ¹² is a general formula

"Wherein R ¹⁴ represents a hydrogen atom, an optionally protected carboxyl group or an optionally substituted cycloalkyl, cycloalkenyl, aralkyl, aryl or heterocyclic group; X ⁴ represents an oxygen atom, A sulfur atom, a carbonyl group or a bond; X ⁵ represents an optionally substituted alkylene group or a bond; X ⁶ represents an optionally substituted alkylene, alkenylene or alkynylene group or a sulfonyl group; X ⁷ ., the mean an alkylene group or a bond may be substituted with group represented by "; R ¹³ is a hydrogen atom, means a protecting group or an optionally substituted alkyl or aryl group of an amino group To do. The nitrogen-containing heterocyclic compound or a salt thereof according to claim 1, which is a group represented by: R ³ is a hydrogen atom; R ⁴ is an optionally protected carboxyl group, an alkyl, alkenyl or cycloalkyl group substituted with an optionally protected carboxyl group, or an optionally substituted carbamoyl group The nitrogen-containing heterocyclic compound or a salt thereof according to claim 1 or 7, which is represented by a substituted alkyl or alkenyl group. R ⁴ is an alkenyl group substituted with an optionally protected carboxyl group; R ⁶ is a group of the general formula

"Wherein R ¹¹ represents one or more hydrogen atoms, halogen atoms, an optionally protected hydroxyl or carboxyl group or an optionally substituted amino, lower alkyl, alkoxy or carbamoyl group; R ^12c is General formula

"Wherein R ^14c represents an optionally substituted aryl, monocyclic heterocyclic or bicyclic heterocyclic group; X ^4a represents an oxygen atom, a sulfur atom or a bond; X ^6b represents Represents an optionally substituted alkylene, alkenylene or alkynylene group; a group represented by: R ^13a represents a hydrogen atom or an optionally substituted alkyl or aryl group. The nitrogen-containing heterocyclic compound or a salt thereof according to claim 1, 7 or 8, which is represented by: R ¹ is an alkoxy group; R ² and R ⁵ are hydrogen atoms; R ⁶ is a general formula

"Wherein R ¹¹ represents one or more hydrogen atoms, halogen atoms, an optionally protected hydroxyl or carboxyl group or an optionally substituted amino, lower alkyl, alkoxy or carbamoyl group; R ^14c is An optionally substituted aryl, monocyclic heterocyclic or bicyclic heterocyclic group; X ^6c represents an optionally substituted alkylene group. Item 10. The nitrogen-containing heterocyclic compound or a salt thereof according to item 1 or 7-9. The antibacterial agent containing the nitrogen-containing heterocyclic compound of Claims 1-10.