WO2005035498A1

WO2005035498A1 - Use of nitrogenous bicyclic compound as feeding control agent

Info

Publication number: WO2005035498A1
Application number: PCT/JP2004/015112
Authority: WO
Inventors: Ryu Nagata; Teruhisa Tokunaga; Tsuyoshi Takasaki; Jun Nagamine; Mutsuo Taiji
Original assignee: Dainippon Sumitomo Pharma Co., Ltd.
Priority date: 2003-10-08
Filing date: 2004-10-06
Publication date: 2005-04-21
Also published as: JPWO2005035498A1

Abstract

Use of a compound represented by the following formula (1), a prodrug thereof, or a pharmaceutically acceptable salt of either as a feeding control agent useful as a therapeutic, preventive, or ameliorating agent for diabetic diseases, etc. (1) [In the formula, R1, R2, R3, and R4 each independently represents hydrogen, optionally substituted alkyl, etc.; R5 represents optionally substituted aryl, etc.; X represents nitrogen, etc.; and W1 represents the formula (2): wherein n is 0, 1, 2, or 3; m is 0, 1, 2, or 3; R7 and R8 each independently represents hydrogen, etc.; and R9 and R10 each independently represents optionally substituted alkyl, etc.]

Description

Specification

Use of nitrogen-containing bicyclic compounds as food intake regulators

The present invention relates to the use of a nitrogen-containing bicyclic compound as a medicament based on the food intake regulating action. Background Technology ·

With the recent changes in eating habits and lifestyles, lifestyle-related diseases such as diabetes, hypertension and hyperlipidemia are increasing and becoming social problems. Obesity is an important risk factor for lifestyle-related diseases, and it is known that obesity and eating activity are closely linked. In recent years, psychogenic eating disorders have also increased. These eating disorders are classified into anorexia nervosa and nervous nervous system, and there is a subtype of anorexia nervosa associated with overeating. In view of the above, the mechanism of regulating feeding has attracted attention.

A recently identified dietary regulator is the gastrointestinal hormone ghrelin, which is secreted from the stomach. Darrelin has been reported to have an energy metabolism-regulating effect such as a food intake-enhancing effect, fat accumulation, and weight gain, and that when administered to rodents and humans, food intake is enhanced (see Current Opinion 'In' Pharmaceuticals (Current O pinionin Pharmacology), 2002, Vol. 2, p. 665-668). In addition, administration of a peptidic darelin antagonist to an animal model can reduce food intake and suppress weight gain.Therefore, drugs that inhibit the action of darelin are used as intake regulators for obesity, diabetes, and other diseases. Potential therapeutic agents have been shown (Gut, 2003, Vol. 52, p. 947-952). As an agent that inhibits the action of ghrelin, compounds having an isoxazole skeleton have been reported ("Bioorganic & Medicinal Chemistry Letters", 2004, No. Vol. 14, p. 5223-5226). The potential and safety in clinical settings is still unknown.

Central nervous nervous depressants such as mazindol and sibutramine are known as drugs used to suppress intake and to treat or prevent obesity. However, habits and concerns, b, blood pressure and other side effects are not satisfactory. WO 00/10975 describes oxyindole / le derivatives as growth hormone secretagogues. However, it is not described as a food intake regulator.

WO 95/18105 pamphlet describes an oxydindonole derivative exhibiting affinity for the vasopressin receptor.

"Chemicale & Pharmaceutical 'Bulletin", 1973, Vol. 21, 960-971, Oxindole in which the benzene ring is unsubstituted. It is described that the derivative has an analgesic action and an anti-inflammatory action.

WO 02/60878 pamphlet describes a benzoimidazolidinone derivative as a growth hormone secretagogue. However, it has not been described as a food intake regulator.

"European Journal of Chemistry" (Eu ropean Journal of Medicine Chemistry; 1997, Vol. 32, .843—868, Neurokyun 1 (K-1) A benzimidazolidinone derivative is described as an antagonist.

As described above, it is desired to provide a food-controlling agent that is effective as a medicine. That is, an object of the present invention is to provide a food intake regulator that is effective as a therapeutic, preventive, and ameliorating agent for diabetes and the like.

The present inventors have conducted intensive studies on food intake regulators and found that the compound represented by the formula (1), a prodrug thereof, or a pharmaceutically acceptable salt thereof can be used as a darrelin antagonist applicable as a medicament. The present invention has been completed by finding that it is a food intake regulator based on action.

That is, the present invention relates to the following.

[1] Equation (1):

[Wherein, R ¹ , ² _s R ³ and R ⁴ are each independently a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkyl, Optionally substituted heteroaryl, optionally substituted heteroaryl, halogen atom, cyano, nitro, force / repoxy, hydroxyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkanoyl, Optionally substituted alkoxyl sulfonyl, optionally substituted sulfamoyl, optionally substituted lumbamoyl, optionally substituted ureido, optionally substituted alkylthio, optionally substituted alkylsulfinyl, substituted Represents an optionally substituted alkylsulfonyl, an optionally substituted alkylsulfonylamino, or an optionally substituted alkanoylamino. . However, all of R ¹ , R ² , R ³ and R ⁴ cannot be hydrogen atoms at the same time.

R ⁵ represents an optionally substituted aryl or an optionally substituted heteroaryl.

X represents C—R ⁶ or a nitrogen atom.

R ⁶ represents _OW ² , —NW ² R ¹³ or a fluorine atom.

When in formula (1), and W ² , one represents a hydrogen atom, an alkyl or one Y ¹ —CONCR ¹ R ¹² , and the other represents a formula (2):

— (CH ₂ ) _n -C- (CH ₂ ) _m -N (2)

R ¹⁰ R ⁸

, Equation (2a):

Or equation (3):

Represents.

When W ² does not exist in the formula (1), W ¹ is a hydrogen atom, alkyl, —Y ¹ —CON (R ¹¹ ) R ^{X 2} , the formula (2), the formula (2a) or the formula (3) Represents

n represents 0, 1, 2 or 3, and m represents 0, 1, 2 or 3.

Y ¹ represents a single bond or f to C ₃ alkylene.

R ⁷ and R ⁸ each independently represent a hydrogen atom, an optionally substituted alkyl or an optionally substituted cycloalkyl, or together with an adjacent nitrogen atom Represents a saturated heterocyclic group which may be substituted.

R ⁹ and R ¹⁰ independently of ^one another represent a hydrogen atom or an optionally substituted alkyl, or together with an adjacent carbon atom, an optionally substituted cycloalkylene or an optionally substituted Represents a saturated heterocyclic group.

R ^{8 represents a} hydrogen atom, an optionally substituted alkyl or an optionally substituted cycloalkyl, and R ¹ ° represents a hydrogen atom or an optionally substituted alkyl, R ⁷ and R ⁹ are taken together. And, together with the adjacent nitrogen atom, carbon atom and one (CH ₂ ) _m , may represent an optionally substituted saturated heterocyclic group.

R ^{9 a} and R ¹ ° ^a, independently of one another, represent a hydrogen atom or alkyl. R ⁷ and R ^{9 a} is turned over雜adjacent nitrogen atom, a carbon atom and - (CH ₂₎ _m - with, may represent a saturated heterocyclic group which may be substituted.

R ¹¹ and R ¹² independently of ^one another represent a hydrogen atom or an alkyl, or together with a joining nitrogen atom, represent an optionally substituted saturated heterocyclic group.

R ¹³ represents a hydrogen atom or alkyl.

k represents 0 or 1.

Y ² represents cycloanoalkylene, optionally substituted arylene, or optionally substituted heteroarylene.

X represents C-R ^6, when R ⁶ represents an OW ² or a NW ² R ^{1 3,} and W ^2, substituents present in the ortho position of the bond to X of R ⁵ together, Replace new

It may be. ;

Y ³ represents an oxygen atom or NR ¹³ , and Y ⁴ represents CC ₃ alkylene. ]

Or a prodrug thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient.

[2] R ¹ , R ² , R ³ and R ⁴ forces independently of one another, a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted Good canolebamoyl, halogen atom, cyano, nitro, carboxy, optionally substituted a / recoxy, optionally substituted alkanol, optionally substituted alkoxycarboyl, optionally substituted alkylsulfinyl or substituted (But not all of R ¹ , R ² , R ³ and R ^{4 at} the same time are hydrogen atoms), the compound according to [1] or a prodrug thereof, or An eating control agent comprising a pharmaceutically acceptable salt thereof as an active ingredient.

[3] R ¹ , R ² , R ³ and R ⁴ independently of each other a hydrogen atom, an optionally substituted alkyl, an optionally substituted rubamoyl, an optionally substituted propyloxy, a halogen atom, an alkoxy, or One C≡C-one (CH ₂ ) _p — Q (p represents 1 or 2, where Q is a hydroxyl group, an optionally substituted amino, an optionally substituted rubamoyl, an optionally substituted saturated heterocyclic group , Alkylsulphoel, anorecanoynoreamino, alkylsulfuramino or alkylureido), provided that R ¹ , R ² , R.

Not all ³ and R ⁴ can be hydrogen at the same time. And a prodrug thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

[4] The compound or a compound thereof according to [1], wherein R ² and R ⁴ are both hydrogen atoms. An eating control agent comprising a prodrug or a pharmaceutically acceptable salt thereof as an active ingredient.

[5] R ² and R ⁴ are both hydrogen atoms, R ^{1 is} S trifluoromethyl, halogen atom, methyl, or methoxy, and R ³ is hydrogen atom of rubamoyl, carboxy, halogen or 1 C化合物 C— (CH ₂ ) _p -Q (where p and Q have the same meanings as in [3]), a compound according to [3], a prodrug thereof, or a pharmaceutically acceptable salt thereof. Feeding regulator as an active ingredient.

[6] R ² and R ⁴ are both hydrogen atoms, R ¹ is a trifluoromethylinole, a fluorine atom, a chlorine atom or a f-bromine atom, and R ³ is a rubamoyl. A food intake regulator comprising the compound of formula (1) or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[7] R ⁵ force S, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted indolyl, optionally substituted benzofuranyl or optionally substituted benzochel, [1] A food intake regulator comprising, as an active ingredient, the compound according to any one of [1] to [6], a drug therefor, or a pharmaceutically acceptable salt thereof.

[8] R ⁵ force An optionally substituted fuel, an optionally substituted 2-naphthyl or an optionally substituted 7-benzofuranyl, wherein the substituent is substituted with a halogen atom, trifluoromethyl, alkoxy or hydroxyl group Any one of alkyl or alkoxy which may be substituted, and the substituent may be present singly or plurally, which may be the same or different, the substituent according to any one of [1] to [6]. An eating control agent comprising a compound, its prodrug, or a pharmaceutically acceptable salt thereof as an active ingredient.

[9] X is C one R ^6, R ⁶ is an 〇_W ² or a NHW ^2, one of W ¹ and W ² is hydrogen atom or alkyl, and the other has the formula (2 ): 9 R ⁷

— (CH ₂ ) _n -C- (CH ₂ ) _m -N (2)

R ¹⁰ R ⁸

Or equation (3):

(k, n, m, R ⁷ , R ⁸ , R ⁹ and R ¹ are as defined in [1]. The A food-regulating agent comprising, as an active ingredient, the compound according to any one of [1] to [8] or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[10] X is C-R ⁶ , R ^{6 is} -OW ² or NHW ² , W ¹ force S is a hydrogen atom or methyl / re, W ² force Formula (5):

(n and m have the same meanings as in [1]. R ⁷ ′ and R ⁸ ′ are independently of each other an optionally substituted alkyl, or taken together and are adjacent The compound according to any one of [1] to [8], wherein R ⁹ ′ and R ¹⁰ ′ represent a hydrogen atom together with a nitrogen atom. Or a food intake regulator comprising a prodrug thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Is a [1 1] W ¹ 1S formula (2), feeding the [1] to [8] or the compound also properly a prodrug thereof or a pharmaceutically acceptable salt thereof as an active ingredient, a Food regulator.

[12] W ¹ is the force equation (5), [1] to either the compound also properly its prodrugs described in [8] or food intake and their pharmaceutically acceptable salts as an active ingredient, Regulator.

[13] X is C-R ⁶ , R ^{6 is} -OW ² or 1 NHW ² , W ¹ force S is a hydrogen atom or methinole, W ² force S, Formula (6):

(n and m have the same meanings as in [1]. R ⁷ ″ and R ⁸ ″ are, independently of each other, methyl or ethyl, or together form an adjacent nitrogen atom R ⁹ ′ and R ¹⁰ ′ represent a hydrogen atom.), The compound according to any one of [1] to [8], or a prodrug thereof, or a compound thereof. An eating control agent comprising a pharmaceutically acceptable salt as an active ingredient.

[14] W ¹¹ A compound according to any one of [1] to [8], which is represented by the formula (6), or a prodrug thereof, or a pharmaceutically acceptable salt thereof, comprising: Food regulator.

[15] W ¹ force S, equation (7):

(k represents 0 or 1. R ⁷ ′ and R ⁸ ′ are, independently of each other, optionally substituted alkyl or, together with an adjacent nitrogen atom, Y ² ′ represents cyclohexylene, cyclopentylene, cyclobutylene, or f-phenylene.) Is one of [1] to [8]. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient.

[16] W ¹ force formula (8):

(k represents 0 or 1. R ⁷ ″ and R ⁸ ″ are, independently of one another, methyl or ethyl, or together, together with an adjacent nitrogen atom, pyridin or pyrrolidine Y ² ″ represents cyclohexylene or cyclobutylene.) [1] to [8], or a prodrug thereof, or a pharmaceutically acceptable salt thereof. Feeding regulator comprising a salt as an active ingredient.

[17] Equation (9):

[Wherein, R ¹ R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and W ¹ have the same meanings as in [1]. Which comprises an optical isomer of the compound according to any one of [1] to [16] or a prodrug thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient; Regulator. [18] R ¹ is trif / reolomethyl, a chlorine atom or a fluorine atom, R ² is a hydrogen atom, R ³ is canolebamoyl, R ⁴ is a hydrogen atom, X is C—R ⁶ , Wherein R ⁵ is an optionally substituted fuel; and R ⁶ is a hydroxyl group. The compound according to any one of [1] to [17], a prodrug thereof, or a pharmaceutically acceptable salt thereof is effective. Feeding regulator as a component.

[1 9] R ¹ is a chlorine atom or a fluorine atom, R ² is a hydrogen atom, R ³ is a rubamoyl, R ⁴ is a hydrogen atom, X is a nitrogen atom, and R ⁵ is substituted A compound according to any one of [1] to [8], [11], [12] or [14:] to [16], or a prodrug thereof, or a pharmaceutically acceptable derivative thereof; An eating control agent comprising an acceptable salt as an active ingredient.

[20] X is C—R ⁶ , wherein R ⁶ is a fluorine atom, or a dietary control comprising the compound according to [1] or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Agent.

[21] An eating control agent comprising, as an active ingredient, the compound according to [1], which is of the formula (4) or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[22] The food intake regulator according to any one of [1] to [21], which is an agent for treating or preventing diabetes.

[23] The eating control agent according to any one of [1] to [21], which is an agent for treating or preventing an eating disorder.

[24] It is an agent for treating or preventing obesity. [1 :! The food intake regulator according to any one of [21] to [21].

[25] The food intake regulator according to any one of [1] to [21], which is a therapeutic or preventive agent for hyperlipidemia.

[26] Equation (1a):

⁴ , R ⁵ and W ¹ are of significance in [1] Synonymous with 0. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[27] Equation (4):

[In the formula,! ^ ¹ ,! ^ ² ,! ^{^{^{^ 3, R 4, R 5}}} , W 1, Y 3 Contact and Y ⁴ have the same meaning and significance in [1]. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[28] A medicament comprising the compound according to any one of [26] to [27] or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Hereinafter, the compound represented by the formula (1) or a prodrug thereof, or a pharmaceutically acceptable salt thereof will be collectively referred to as “the compound of the present invention” as necessary.

According to the present invention, it is possible to provide a nitrogen-containing bicyclic compound or a prodrug thereof, or a pharmaceutically acceptable salt thereof, which is useful as a food intake regulator. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail.

In the present specification, the number of substituents in the group defined by “may be substituted” or “substituted” is not particularly limited as long as it can be substituted, and is 1 or more. Except where otherwise indicated, the description of each group also applies to the case where the group is part of another group or a substituent.

“Alkyl” includes, for example, straight-chain or branched-chain C ₆ alkyl and the like. Specifically, for example, acetyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methynole Propinole, 1,1-dimethylethyl, pentyl, 1-methinolebutinole, 2-methinolebutinole, 1-ethylpropynole, hexyl, 1-methyl Examples thereof include rupentyl, 2-methylpentyl, and 1-ethylbutyl. “Alkylthio”, “Alkylsnorefiel”, “Alkynolesulfonyl”, “Anolequinoles norehoni / reamino j”, “Alkynoreamino”, “Dialkylamino”, “Alkyl ureide”, “Alkyl force rubamoinole” and “Dialkyl Alkyls in “Lybamoyl” include the same. Preferred alkyls include, for example, straight-chain or branched CC ₄ alkyl.

“Alkenyl” includes, for example, straight-chain or branched-chain C ₂ -C ₆ alkenyl, and specifically, for example, bier, 1-probenyl, 2-propenyl, 1-propyl, 2 —Butenyl, 3-butenyl or 1-pentenyl and the like.

The “alkyl” includes, for example, straight-chain or branched-chain C ₂ -C ₆ alkyl and the like. Specific examples include, for example, ethynyl, 1-propynyl, 2-propynyl, 1-pturyl and 1 pliers and the like.

The “alkoxy” includes, for example, straight-chain or branched-chain C ₆ alkoxy and the like. Specifically, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methyl Propoxy, pentoxy, 1-methylbutoxy, 2-methynolebutoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy or 1-ethylbutoxy. Alkoxy in “alkoxycarbo-norre” includes the same. Preferable alkoxy includes, for example, straight-chain or branched-chain C ₄ -C ₄ alkoxy.

Examples of the "alkanoyl" include, for example, a straight-chain or branched -C ₆ alkanol group and the like, and specific examples include formyl, acetyl, propionyl and butyryl. Alkanol in "Anorecanoylamino" includes the same. Preferred alkanols include, for example, linear or branched C i -C ₄ alkanols and the like.

Examples of C j -C ₃ alkylene include straight-chain or branched -C ₃ alkylene and the like, and specific examples thereof include methylene, ethylene and trimethylene, and preferably methylene or ethylene.

Examples of the cycloalkylene include, for example, c _{3 to} c ₈ cycloa ^^ ylene, and specifically, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexyl, and the like. Rene, cycloheptylene or cyclootylene is mentioned, and preferably cyclobutylene, pentylene or hexylene is used.

The position of two bonds in a cycloalkylene may be two on the same carbon atom or two on separate carbon atoms.

Examples of arylene include C ₆ -C. Examples thereof include divalent aromatic rings such as arylene, and specific examples include: 7-enylene or naphthylene, and preferably phenylene.

Examples of the heteroarylene include, for example, two heteroarylenes such as a monocyclic or bicyclic 5- to 1-membered heteroarylene containing 1 to 3 nitrogen, oxygen, and Z or sulfur atoms. Examples include divalent groups in which a fluorine atom is replaced by a bond, specifically, for example, pyridine di / yl, pyridazine diyl, isothiazol diyl, thiazole diyl, imidazole dinole, pyrimidin diyl, thiaziazole 1 to 3 nitrogen atoms such as dizyl, pyrazolzyl, oxazonoresyl, isoxazolzil, pyrazinezil, triazinzyl, imidazolidinezil, oxazizizilzyl or triazolzyl, oxygen and Monocyclic 5- to 7-membered heteroarylene, indolezyl, chloro containing Z or sulfur atom Benzyl, quinolindinole, isoki / lindinole, benzofurandinoole, benzothiofendiole, benzoxazonoresinole, benzothiazoresinole, benzisoxazonoresole, benzisothiazonoresinole, benzotriazo 2-ring 9 ~ containing 1 to 3 nitrogen, oxygen and / or sulfur atoms, such as resininole or vanes imidazolezyl! _ 0-membered heteroarylene and the like.

Examples of the substituent in the “substituted alkyl” include a halogen atom, an optionally substituted amino, alkoxy, alkoxycarbonyl, an optionally substituted cycloalkylene, an aryl, a hydroxyl group, a carboxy, an optionally substituted rubamoyl, an alkanol , Arylcarbesole, heteroarylcarbonyl, saturated heterocyclic carbole, alkanoylamino, alkylsulfonylamino, ureido which may be substituted, alkoxycarbolamino, saturated heterocyclic group or substituted And sulfamoyl which may be used. Preferred substituted alkyl in R ¹ , R ² , R ³ and R ⁴ include, for example, alkyl substituted with a halogen atom such as triphnoleolomethinole, pentafluoroethyl or 2-cycloethyl. Examples of the substituent in the “substituted alkenyl j” and “substituted alkynyl” include, for example, a halogen atom, an optionally substituted alkyl, an optionally substituted amino, an alkoxy, an alkoxycarbol, an aryl, a hydroxyl group, a carboxy, and an optionally substituted Good carbamoyl, alkanoyl, arylcarbonyl, heteroarylcarbonyl, saturated heterocyclic carbonyl, alkanoylamino, alkylsulfo-lamino, optionally substituted ureido, anorecoxyl propylonylamino, optionally substituted Examples include a heterocyclic group or an optionally substituted sulfamoyl. Examples of the substituent in the optionally substituted alkyl include, for example, a hydroxyl group, an optionally substituted amino, an optionally substituted rubamoyl, an optionally substituted saturated heterocyclic group, an alkylsulfonyl, an anorecanoy / reamino, Examples include alkylsulfonylamino or alkyl peridode.

"Substituted alkoxy", "substituted alkanol", "substituted alkoxycarbonyl", "substituted alkylthio", "substituted alkylsulfiel", "substituted alkylsulfonyl", "substituted alkylsnorefonylamino" and "substituted alkanol" Examples of the substituent in "mino" include a halogen atom, alkoxy, optionally substituted cycloalkyl, aryl, heteroaryl, and hydroxyl.

As the "Ariru", for example C ₆ ~C i. And naphthyl, specifically naphthyl or 2-naphthyl. "The same reel is used in the aryl car J.

Examples of the “heteroaryl” include a monocyclic or bicyclic 5- to 10-membered heteroaryl containing 1 to 3 nitrogen atoms, oxygen atoms and Z or sulfur atoms. Specifically, pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, phenyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, thixazolyl, isosoxazolyl, pyrazinyl, triadiel, triazolyl, imidazolidinolyl, etc. A monocyclic 5- to 7-membered heteroaryl, indolinole, indazolyl, chromele, quinolyl, isoquinolinole, benzofuranole, benzochenii / containing one to three nitrogen, oxygen and Z or sulfur atoms 1 to 3 nitrogen sources such as benzoxazolinole, benzothiazolyl, benzisoxazolinole, benzisothiazolinole, benzotriazolinole or benzimidazolinole , Oxygen atoms and / or sulfate And a 2- to 9-membered heteroaryl having a yellow atom. Heteroaryl in "heteroarylcarbonyl" includes the same

The “cycloalkyl” includes, for example, C ₃ -C ₈ cycloalkyl, and specific examples include cyclopropynole, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

Examples of the “saturated hetero ring” include a monocyclic 5- to 8-membered saturated hetero ring containing 1 to 3 nitrogen atoms, oxygen atoms and / or sulfur atoms. Specifically, for example, a monocyclic 5-membered saturated heterocycle containing 1 to 3 nitrogen atoms, an oxygen atom and a Z or sulfur atom such as tetrahydrofuran, pyrrolidine, pyrazoline, thiazolidine or oxazolidine, piperidine, 1-3 nitrogen atoms such as 1 to 3 nitrogen atoms such as morpholine, thiomorpholine or piperazine, monocyclic 6-membered saturated hetero ring containing oxygen atom and Z or sulfur atom, perhydroazepine, etc. Examples thereof include a monocyclic 7-membered saturated hetero ring containing an oxygen atom and / or a sulfur atom. In addition, the heterocyclic ring of saturate mouth includes, for example, one such as 7-azabicyclo [2.2.1] heptane, 3-azabisik mouth [3.2.1] octane or 3-azabisik mouth [3.2.2] nonane. And a 7- to 9-membered bicyclo-saturated heterocycle containing a nitrogen atom. As the “saturated heterocyclic group”, for example, a monovalent, divalent or trivalent group in which one, two or three hydrogen atoms of a saturated heterocyclic ring are changed into a bond is exemplified. For example, R ⁹ and R ^{1) taken} together, together with adjacent carbon atoms, represent an optionally substituted saturated heterocyclic group are two hydrogen atoms on one carbon atom of a saturated heterocycle. Instead of a bond, it represents bonding with one (CH ₂ ) n— and one (CH ₂ ) m—. For example, when R ⁷ and R ⁹ are linked together to represent an optionally substituted saturated ring group together with an adjacent nitrogen atom, carbon atom and one (CH ₂ ) _m — Two hydrogen atoms on one carbon atom of Te ring and one bromo atom on nitrogen atom turn into a bond, respectively, and bond with one (CH ₂ ) 11-, R ^1Q and R ⁸ etc. Represents Further, for example, it becomes R ⁷ and R ^{9 a} gar cord, the adjacent nitrogen atom, carbon atom and one (CH ₂₎ _ra - together, and represents a saturated heterocyclic group which may be substituted, the saturated two hydrogen atom on one carbon atom of the heterocycle is a double bond, one of the hydrogen atoms on the nitrogen atom changes to a bond denotes the like Rukoto be combined with R ^8. As a saturated heterocyclic group in "saturated heterocyclic carbonyl" Are the same.

"Substituted aryl", "substituted arylene", "substituted file", "substituted naphthyl", "substituted heteroaryl", "substituted heteroarylene", "substituted indazolyl",

Examples of the substituent in "substituted benzofuryl", "substituted benzothenyl", "substituted saturated hetero ring" and "substituted saturated hetero ring group" include, for example, halogen atom, aryl, heteroaryl, alkyl which may be substituted, Alkenyl, alkynyl, optionally substituted diamino, cyano, nitro, hydroxyl, mercapto, alkoxy, alkanol, alkoxypropyl, carboxy, optionally substituted sulfamoyl, optionally substituted carbamoyl, Examples thereof include alkylsulfamoylamino, alkylsulfinyl, alkylsulfoninole, alkylsulfonylamino, and alkanoylamino. Substituents in “substituted saturated heterocycle” and “substituted saturated heterocycle” also include oxo. Examples of the “oxo-saturated heterocycle” and “oxo-saturated heterocycle” include pyrrolidinone (yl, diyl), thiazolidinone (yl, diyl), 2-oxo-1,3-oxazoline (yl, diyl). ), 5-oxo saturated heterocycle (group) such as 2-oxomidazolidine (yl, diyl) or 6-membered saturated heterocycle (group) such as piperidinone (yl, diyl) ' And the like.

Examples of the substituent in the “substituted cycloalkynole” include, for example, a halogen atom, aryl, heteroaryl, optionally substituted alkyl, alkenyl, alkynyl, optionally substituted amino, cyano, nitro, hydroxyl, mercapto, alkoxy, alkynyl And alkoxycanolepoel, sulfoxyl, optionally substituted sulfamoyl, optionally substituted sulfamoyl, alkylsulfamoylamino, alkylsulfinyl, alkylsulfonyl, alkylsulfo-amino and alkanoylamino. Examples of the substituent in the optionally substituted alkyl include, for example, a halogen atom, an amino substituted with an alkyl, an alkoxy, an alkoxycarbonyl, an aryl, a hydroxyl group, a carboxy, a carbamo, an alkamoyl optionally substituted with an alkyl, Aryl carbonyl, heteroaryl carbonyl, saturated heterocyclic carbonyl, alkynylamino, alkylsulfo-amino, ureido optionally substituted with alkyl, alkoxycarbonylamino, saturated heterocyclic or substituted Sulfamoyl and the like.

Preferred in the "substituted Ariru" and "substituted heteroaryl" in R ⁵ Examples of the substituent include a halogen atom, alkyl, alkoxy, and an alkyl substituted with a halogen atom, and particularly preferably, for example, a chlorine atom, a fluorine atom, methyl, ethyl, methoxy or trifluoromethyl. No.

The “halogen atom” is, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

Examples of the substituent in the “substituted amino” include an alkyl and the like which may be substituted with a hydroxyl group or an alkoxy, and the amino may be substituted with two identical or different substituents. When substituted with two substituents, the two substituents may be taken together to form a saturated heterocycle such as pyrrolidine, piperazine or morpholine with an adjacent nitrogen atom.

Examples of the substituent in the “substituted sulfamoyl”, “substituent rubamoyl” and “substituted ureide” include, for example, alkyl which may be substituted with a hydroxyl group or alkoxy, and the sulfamoyl, levamoyl and ureide are the same. Alternatively, it may be substituted with two different substituents. Also, when sulfamoyl, sorbamoyl or ureido is substituted with two substituents, the two substituents together form a saturated heterocyclic ring such as morpholine with an adjacent nitrogen atom. You may.

"X represents C-R ^6, if representing the R ⁶ force S- OW ² or a NW ² R ^{1 3,} and W ^2, the substituents present on O Z Leto position of binding to X of R ⁵ together The compound which forms a heterocyclic ring which may be newly substituted and has the formula (4) "is specifically exemplified by the following formula:

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , W ¹ and Y ³ are as defined above.] ] And the like.

“Prodrugs” include Chemistry and Industry (1980, 435) or Advanced Drug Discovery. One example is the public drug described in 1-Reviews (Advanced Drug Discovery Reviews 3, 39 (1989)). Specifically, biohydrolyzable esters of carboxyl such as acyloxymethyl ester, glycolate, lactate and morpholinoethyl ester, glutaric acid monoester of phenolic hydroxyl group, N-morpholino methinole amide, N —Acyloxymethylamine or N-acyloxyalkoxycarbo-lamine.

The conjugate in which X is represented by C—R ⁶ or a prodrug thereof may be a separated pure optical isomer, a partially purified optical isomer, a racemic mixture, and a mixture of diastereomers. It may be in a form. Preferred optical isomers include those represented by the formula (9)

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and W ¹ are as defined above. ] And optical isomers having a configuration represented by the formula: These optical isomers usually have a retention time of high performance liquid chromatography (hereinafter abbreviated as HPLC) (Chiralpak 0D (registered trademark, Daicel Chemical Industries, Ltd.), effluent: 2-propanolnohexane). Can be distinguished. Preferred optical isomers usually elute slower than the other isomers.

Examples of the pharmaceutically acceptable salt of the compound represented by the formula (1) or a prodrug thereof include a salt with an inorganic acid or an organic acid. Examples of the salt with an inorganic acid include hydrochloride, hydrobromide, nitrate, sulfate, phosphate and the like. Salts with organic acids include, for example, Rooster salt, acetate, trifluoroacetate, propionate, lactate, tartrate, oxalate, fumarate / maleate, maleate, quaterate, malonate And methanesulfonate and benzenesulfonate. When the compound represented by the formula (1) has an acidic functional group such as a carboxyl group, it can be converted into a salt with a base. As a salt with a base, for example, arginine, lysine or .. is a salt with an organic base such as triethylammonium, an alkali metal (sodium or Salts with inorganic bases such as 8 potassium, etc.) or alkaline earth metals (calcium, barium, etc.), and ammonium salts. The compound represented by the formula (1) or a prodrug thereof, or a pharmaceutically acceptable salt thereof may be in the form of a solvate such as a hydrate thereof. In the formula (1), a derivative in which X is represented by C—R ⁶ can be produced, for example, according to the following method.

Method A

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined above. Z represents a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, toluenesulfonyloxy, trifluoromethanesulfonyloxy or a hydroxyl group. M represents a lithium atom, magnesium bromide, magnesium iodide or magnesium chloride. Li, equation (17a):

— (CH ₂ ) _n -C- (CH ₂ ) _m — 7a)

R ¹⁰

Equation (17b):

Or equation (17c): — (CH ₂ ) _k -Y ^2- (17c)

Represents. In the formula, R ⁹ , R ¹ °, R ^9a , R ¹ ° ^a , Y ² , n, m and k are as defined above. ]

The compound (13) is produced by reacting the isatin derivative (11) with the compound (12) in the presence of a base. The reaction can be carried out according to the usual N-alkylation reaction conditions. Examples of the base include alkali hydrides such as sodium hydride or potassium hydride, alkali amides such as sodium amide or lithium amide, and alkali alkoxides such as potassium t-butoxide or sodium methoxide. . The amount of the base to be used is generally 1 to 10 equivalents, preferably 1.5 to 5 equivalents, relative to the isatin derivative (11). However, when a salt such as the hydrochloride of the compound (12) is used, an excess of a base may be added in a corresponding amount. The amount of compound (12) to be used is generally 1-3 equivalents, preferably 1.2-2 equivalents, relative to isatin derivative (11). Examples of the reaction solvent include an inert organic solvent such as tetrahydrofuran (hereinafter abbreviated as THF) or N, N-dimethylformamide (hereinafter abbreviated as DMF). The reaction temperature is, for example, in the range of 0 ° C to the boiling point of the solvent, preferably in the range of room temperature to 80 ° C. When Z is represented by a hydroxyl group, according to the method of Mitsunobu (Synthesis, 1 (1981)), for example, an azo compound such as acetyldicarboxylate or diisopropyl azodicarboxylate and a phosphorus reagent such as triphenylphenylphosphine are used. Thus, compound (13) can be produced. Examples of the reaction solvent include an inert solvent such as THF, and examples of the reaction temperature include a range of 0 ° C. to the boiling point of the solvent. In Z and L, Arinore - Z or Arukeninore - when forming the Z, reaction using a copper catalyst (.... J. Heterocyclic Chera , 24, 1249 (1987), Org Lett, 5, 3667 (2 003)) Thus, compound (13) can be produced. Examples of the copper catalyst include a monovalent or divalent copper salt such as copper oxide or copper iodide. Further, an inorganic base such as potassium carbonate or cesium carbonate, for example, a rooster ligand such as N, N, -dimethylethylenediamine or 1,10-phenanthroline may be added. Examples of the reaction solvent include an inert solvent such as toluene or DMF, and examples of the reaction temperature include a range of room temperature to the boiling point of the solvent.

Compound (15) is obtained by reacting compound (13) with compound (14). The The reaction between compound (13) and compound (14) can be performed according to ordinary reaction conditions. The amount of compound (14) to be used is generally 1-2 equivalents based on compound (13). Examples of the reaction solvent include ether solvents such as getyl ether and THF. The reaction temperature is, for example, in the range of −78 ° C. to room temperature.

The hydroxyl group of compound (15) can be converted to an amino group or a fluorine atom as required. Chlorination of compound (15) with thionyl chloride, followed by azidation and reduction gives the corresponding amine. Chlorination is usually carried out in the range of room temperature to 50 ° C without solvent. The azidation is carried out, for example, in the presence of a base such as triethylamine, in an inert solvent such as THF or DMF, at room temperature to 80 ° C, using an azidating agent such as sodium azide or trimethylsilyl azide. . Examples of the reducing agent include tin (II) chloride. Examples of the reaction solvent include alcohol solvents such as methanol and ethanol. The reaction temperature ranges from room temperature to the boiling point of the solvent.

If necessary, Compound (1 5) or the corresponding Amin, by introducing an alkyl or a ^{^{Y- CONCR 1 1) R X 2}} (Y, R 1 1 and R ^{1 2} are the same as defined above) The derivative (16) can be produced. Introduction of the group represented by anoalkyl or one Y—CON (R ¹¹ ) R ^{X 2} can be carried out according to a conventional method, for example, in the presence or absence of a base, alkyl halide, Z ¹ -Y- ^{^{^{CONCR 1 1) R 1 2 (}}} Y, R 1 1 and R ^{1 2} are the same as defined above. Z ¹ represents a chlorine atom, a bromine atom, ® © atom, a Metansuru per cent Niruokishi or toluenesulfonyloxy El O carboxymethyl ) Or R ¹¹ -NCO (R ¹¹ is as defined above). Examples of the base include alkali hydrides such as sodium hydride or potassium hydride, alkali amides such as sodium amide and lithium amide, and organic bases such as triethylamine or ethinoresipropylamine. The amount of the base to be used is generally 1 to 10 equivalents relative to compound (15) or the corresponding amine. The amount of the alkyl halide, Z ¹ -Y-CONCR ¹ R ¹² or R ¹¹ -NCO to be used is generally 1 to 10 equivalents relative to compound (15) or the corresponding amine. Examples of the reaction solvent include an inert solvent such as THF or DMF. The reaction temperature is, for example, 0 ° C to the boiling point of the reaction solvent. And preferably in the range of room temperature to 80 ° C. .

The conversion of the hydroxyl group of compound (15) to a fluorine atom can be performed by fluorinating agents such as getylaminosulfur trifluoride, tris (dimethinoleamino) sulfur (trimethinolesilinole) difluoride or pyridiumpolyhydrofluoride. The reaction can be carried out. Further, the hydroxyl group can be converted into a halogen such as a chlorine atom or a sulfonic acid ester such as methanesulfonyl and reacted with a metal fluoride such as silver fluoride or potassium fluoride. The amount of the fluorinating agent to be used is generally 1 to 10 equivalents relative to compound (15). Examples of the reaction solvent include an inert solvent such as dichloromethane or acetonitrile. The reaction temperature is, for example, in the range of −78 ° C. to 50 ° C., and preferably in the range of room temperature to 80 ° C.

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , Y ³ , L, Z and W ¹ are as defined above. ]

Compound (18) is produced by reacting isatin derivative (11) with compound (14) in the same manner as in the reaction of compound (13) with compound (14) in method A. The hydroxyl group of compound (18) can be converted to an amino group in the same manner as in the conversion of the hydroxyl group of compound (15) in Method A. Subsequently, the compound (18) and the compound (12) are reacted in the same manner as in the reaction of the isatin derivative (11) with the compound (12) in Method A, and further, if necessary, alkyl or 1Y- By introducing CONd ^{1 1} ) 1 ^ ² (Y, R ¹¹ and R ¹² are as defined above) The body ((16) and (19)) can be manufactured. In this reaction, an oxindole derivative (19) is mainly obtained.

Method C

[Wherein, I ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , L and Z have the same meanings as described above. Z ² represents a hydroxyl group or a protected form thereof, a chlorine atom or a bromine atom. Z ³ represents methanesulfonyloxy, toluenesulfonyloxy, trifluoromethanesulfonyloxy, a chlorine atom or a bromine atom. ]

In the same manner as in Method A, the isatin derivative (11) is reacted with the compound (20) and the compound (14) sequentially, and Z ² is converted to Z ³ by a general method to give the compound (2 1) Can be obtained. Compound (16) is produced, for example, by reacting compound (21) with compound (22) in an inert solvent such as dichloromethane or DMF in the presence of a base. The reaction temperature is, for example, in the range of 0 ° C. to the boiling point of the solvent. Examples of the base include an organic base such as pyridine, and an inorganic base such as potassium carbonate. The base may be omitted by using the compound (22) having a large excess U.

The isatin derivative (11) can be produced, for example, as follows. Isatin ¾Conductor manufacturing method (Method D)

And R ⁴ are as defined above. ]

The isatin derivative (11) can be produced according to the method of Sandmeyer (Org. Synth., Coll. Vol. I, 321 (1941)). The isatin derivative (11) is obtained by reacting an aniline derivative (23) with saturated chloral and hydroxylamine in water under heating to reflux to give a compound (24), followed by treatment with an acid and treatment with water. By being manufactured. Examples of the acid include concentrated sulfuric acid and polyphosphoric acid, and it is preferable to use these as a reaction solvent. Examples of the temperature of the acid treatment include a range of 50 ° C to 100 ° C. Can be carried out, for example, by adding a reaction solution to water. The temperature of the treatment with water is preferably in the range of 0 ° C to room temperature. The fever is so intense that the ice may be hot.

The isatin derivative (11) can also be produced by reacting an oxaniline derivative (23) with oxalyl chloride, followed by an intramolecular Friedenolekrafts reaction. These two reactions can be performed at the same time in the same reaction vessel. Examples of the reaction solvent include a halogen-based solvent such as dichloromethane or 1,2-dichloroethane, and may be solvent-free. In the Friedel-Crafts reaction, it is preferable to add a Lewis acid. Examples of the Lewis acid include (for example, aluminum chloride and the like).

Preparation of Isatin Derivatives (Method—E)

(11)

[Wherein, R ¹ , R ² , R ³ and R ⁴ are as defined above. R ²¹ and R ²² ′ independently represent alkyl. ]

The isatin derivative (11) can be produced according to the method of Gassman (J. Am. Chem. Soc., 96, 5508 (1974)). Compound (25) is to chlorinating Anirin derivative conductor ^{(23), R 2 1 SCH} 2 C0 2 R 2 2 was added, obtained by treatment with a base. Examples of the reaction solvent include, for example, a halogen-based solvent such as dichloromethane or 1,2-dichloromethane. Examples of the chlorinating agent include sulfuryl chloride and t-butoxycyclolide. The temperature of the chlorination reaction and R ^{2 1} reaction with _{_{^{S CH 2 C0 2 R 2 2}}} , - 78 range ° C~- 20 ° C is exemplified et be. Examples of the base include an organic base such as triethylamine. The treatment with a base can be performed, for example, by warming the reaction mixture to room temperature and keeping the temperature at that temperature.

Compound (26) is obtained by treating compound (25) with an acid. Examples of the acid include hydrochloric acid, sulfuric acid, methanesulfonic acid, and the like, and examples of the reaction temperature include room temperature. This reaction f can be carried out successively in the same vessel of the previous reaction.

Compound (11) is obtained by oxidizing compound (26). Examples of the oxidizing agent include cupric oxide. The reaction temperature ranges, for example, from room temperature to the boiling point of the solvent, and the reaction solvent includes, for example, an inert solvent such as acetone or acetate.

How to make Satin body (Method F)

[Wherein, R ¹ , R ² , R ³ and R ⁴ are as defined above. R ^{2 3} and R ^{2 4} represents independently alkyl. ]

The isatin derivative (11) can also be obtained by the Risert reaction. For example, nitrotoluene (27) is reacted with a dialkyl oxalate in an alcoholic solvent in the presence of a metal alkoxide to give ketoestenole (28) (J. Am. Chem. So, 78). , 221 (1956)). Preferred combinations of the dialkyl oxalate, the metal anorecoside and the alcohol solvent include dimethyl oxalate-sodium methoxide-methanol, dimethyl oxalate-potassium methoxide-methanol, or ethynoleate sodium ethoxylate. Ethanol. The reaction temperature is, for example, in the range of o ° C to the boiling point of the solvent. Ketoester (28) is treated with hydrogen peroxide in the presence of an acid such as perchloric acid (J. Org. Chem., 16, 1785 (1951)). Methylation using Thioel gives the ester (29). The reaction temperature ranges, for example, from room temperature to the boiling point of the solvent. The ethoxy group (30) can be obtained by reducing the etro group with iron acetic acid, an aqueous solution of titanium trichloride or tin (II) chloride (Synthesis, 1993, 51). The reaction temperature is, for example, in the range of 0 ° C. to the boiling point of the solvent. Isatin (11) is obtained by a two-step reaction of treating hydroxyindole (30) with pyridinium tribromide and hydrolyzing with an acid such as hydrobromic acid (Tetrahedron Lett., 39, 7679 (1998)). In the reaction with pyridinium tribromide, examples of the reaction solvent include t-butanol, and the reaction temperature includes, for example, a range of O ° C to 50 ° C. In the hydrolysis reaction, the reaction temperature may be, for example, in the range of 0 ° C to the boiling point of the solvent. May be added according to the requirements.

Isachin's Wife (Method GJ_

[Wherein, R ¹ , R ² , R ³ and R ⁴ are as defined above. R ²⁵ and R ²⁶ independently represent alkyl. ]

The isatin derivative (11) can be obtained by the above-mentioned reaction via indole. The compound (27) was reacted with tris (dianolequinoleamino) methane in a DMF solvent under heating conditions to convert it into (31) (Heterocycles, 51, 1119 (1981)). Similarly to Method F, reduction with iron Z-acetic acid, aqueous solution of titanium trichloride or tin (II) chloride gives indole (32) (Tetrahedron Lett., 24, 4561 (1983)). Examples of tris (diaquinolamino) methane include tris (dimethylamino) methane and tripiperidinomethane. Indole (32) is treated with pyridinium tribromide (Tetrahedron Lett., 28, 4027 (1987)), and hydrolyzed with an acid such as hydrobromic acid. (1 1) is obtained. The reaction with the pyridendribromide and the hydrolysis reaction can be carried out in the same manner as in the above-mentioned Method F.

Method for preparing isatin derivatives (method Η)

[Wherein, R ¹ , R ² , R ^{3 and} R ⁴ are as defined above. R ^{2 7} and R ^{2 8} represents independently alkyl. Z ⁴ represents a fluorine atom, a chlorine atom, or trifluoromethane sulphoninoleoxy. ]

Compound (35) is obtained by reacting a dialkyl malonate with a nitrobenzene derivative (34) in the presence of a base. Examples of the reaction solvent include ether solvents such as THF, and alcohol solvents such as methanol. Examples of the base include hydrogen hydride such as sodium hydride or hydrogen hydride, alkali amide such as sodium amide or lithium amide, and metal alkoxide such as sodium methoxide or sodium ethoxide. No. The reaction temperature ranges from -20 ° C to the boiling point of the solvent.

Compound (36) is obtained by decarboxylation of compound (35). The reaction conditions for decarboxylation include, for example, a method of reacting lithium bromide in dimethyl sulfoxide or a method of reacting an acid such as hydrochloric acid or a base such as carbonated lime. The reaction temperature ranges from room temperature to the boiling point of the solvent.

The conversion of compound (36) to compound (11) can be performed according to the above-mentioned method F. In the formula (1), a derivative in which X is a nitrogen atom can be produced, for example, according to the following method.

Method I

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , L and Z are as defined above. R ^{2 9} represents alkyl. A rf represents a benzene ring substituted with one or more alkoxy. ]

Compound (38) is obtained by reacting compound (37) with an alkyl chloroformate in the presence of a base in the absence or presence of an inert solvent. Examples of the base include organic bases such as pyridine and 4-N, N-dimethylaminopyridine. Examples of the inert solvent include halogen-based solvents such as dichloromethane and 1,2-dichloroethane, ether-based solvents such as THF, and DMF. The reaction temperature ranges from about _1 o ° c to room temperature.

Compound (39) is obtained by reacting compound (38) with nitric acid in the presence of a hornworm medium. Examples of the catalyst include an acid such as concentrated sulfuric acid. Examples of the reaction solvent include acetic anhydride and the like. The reaction temperature ranges from about 110 ° C. to room temperature.

Compound (40) can be produced by reacting compound (39) with alkoxy-substituted benzyl alcohol according to the method of Mitsunobu (Synthesis, 1 (1981)). Examples of the substituted benzyl alcohol include 4-methoxybenzyl alcohol and 2,4-dimethoxybenzyl alcohol. Compound (40) can also be obtained by reacting compound (39) with an alkoxy-substituted benzyl halide in an inert solvent in the presence of a base. Alkoxy-substituted benzyl halide For example, 4-methoxybenzyl / rechloride and the like can be mentioned. Examples of the base include hydrogen hydride such as sodium hydride or hydrogen hydride, alkali metal carbonate such as lithium carbonate or sodium carbonate, or pyridine or 41 N, N-dimethylaminopyridine. Organic bases can be mentioned. Examples of the inert solvent include ether solvents such as THF, and DMF. The reaction temperature ranges from room temperature to around the boiling point of the solvent.

Compound (41) is obtained by reducing the nitro group of compound (40) with iron acetic acid, aqueous solution of titanium trichloride or tin (II) chloride. Examples of the solvent include acetic acid or an alcoholic solvent such as methanol or ethanol. The reaction temperature ranges from about 11 ° C. to around the boiling point of the solvent.

Compound (42) is obtained by reacting compound (41) in the presence of a base or acid. Examples of the base include alkali metal hydrides such as sodium hydride. Examples of the acid include hydrochloric acid and the like. As the reaction solvent, for example, an alcohol-based solvent such as methanol or ethanol and the like can be mentioned. The reaction temperature ranges from room temperature to around the boiling point of the solvent.

Compound (43) is obtained by reacting compound (42) with compound (12) in the same manner as in the conversion of compound (13) from compound (11) in Method A.

Compound (44) is obtained by reacting compound (43) with diammonium cerium nitrate (IV). Examples of the reaction solvent include water, acetonitrile, and the like, or a mixed solvent thereof. Reaction temperatures range from about 0 ° C. to room temperature.

Compound (45) is compound (44) and Z ⁵ —R ⁵ (R ⁵ is the same as defined above. Z ⁵ is a chlorine atom, bromine atom, iodine atom, or elimination of trifluoromethanesulfonyloxy or the like. ) Is reacted with a base and a catalytic amount of a transition metal in the presence of a ligand. Examples of the base include alkali metal carbonates such as potassium carbonate and cesium carbonate, phosphates such as potassium phosphate, and rod-shaped bases such as triethylamine. Examples of the transition metal include bisdibenzylideneacetone palladium and palladium acetate. Examples of the ligand include phosphine ligands such as BINAP. Examples of the reaction solvent include 1,4-dioxane and toluene. As reaction temperature Ranges from room temperature to around the boiling point of the solvent.

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ²⁹ and Z are as defined above. ]

Compound (46) can be produced from compound (39) in the same manner as in the conversion of compound (45) from compound (44) in Method I.

Compound (47) can be synthesized from compound (46) in the same manner as in the conversion of compound (41) from compound (40) in Method I. It can also be produced by catalytic hydrogenation using a catalyst and a hydrogen source. Examples of the catalyst include a palladium compound such as palladium carbon or palladium hydroxide, platinum oxide, Raney nickel, and the like. Examples of the hydrogen source include hydrogen gas, formate such as formic acid and ammonium formate, or hydrazine. Examples of the solvent include an alcoholic solvent such as ethanol or methanol, and ethyl acetate.

Compound (48) can be synthesized from compound (47) in the same manner as in the conversion of compound (42) from compound (41) in Method I. Compound (45) is obtained by reacting compound (12) with compound (48) in the same manner as in the conversion of compound (11) from compound (11) in Method A.

Method

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ²⁹ and L are as defined above. Z ⁶ represents a leaving group such as a chlorine atom, a fluorine atom or trifluoromethanesulfonyloxy. ]

Compound (46) is obtained by reacting compound (49) with compound (50) in the presence of a base. Examples of the reaction solvent include ether solvents such as THF. Examples of the base include alkali hydrides such as sodium hydride and hydrogen hydride. The reaction temperature includes a range from -20 ° C to the boiling point of the solvent. The compound (46) can be obtained by reacting the compound (49) with the conjugate (50) with a base and a catalytic amount of a transition metal in the presence of a ligand. Examples of the base include alkali metal carbonates such as potassium carbonate and cesium carbonate, phosphates such as potassium phosphate, and organic bases such as triethylamine. Examples of the transition metal include bisdibenzylideneacetone palladium and palladium acetate. Examples of the ligand include phosphine ligands such as f, tri-t-butylphosphine and the like. Examples of the reaction solvent include dioxane and toluene. The reaction temperature ranges from room temperature to around the boiling point of the solvent.

Conversion of compound (46) to compound (45) can be carried out according to the above-mentioned method J.

Method

[Wherein, R ¹ R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ and L are as defined above. Z ⁷ is iodine atom, bromine atom, chlorine atom or trifluoromethanesulfonyl Represents a leaving group such as oxy. ]

Compound (52) can also be obtained by reacting compound (51) with R ⁵ —NH ₂ with a base and a catalytic amount of a transition metal in the presence of a ligand. Examples of the base include alkali metal carbonates such as potassium carbonate and cesium carbonate, phosphates such as potassium phosphate, and organic bases such as triethylamine. Examples of the transition metal include bisdibenzylideneacetone palladium and palladium acetate. Examples of the ligand include phosphine ligands such as f, BINAP and the like. Examples of the reaction solvent include 1,4-dioxane and toluene. The reaction temperature ranges from room temperature to around the boiling point of the solvent. Compound (53) can be synthesized from compound (52) in the same manner as in the conversion of compound (47) from compound (46) in Method J.

Compound (48) can be produced by reacting compound (53) with a carbon monoxide source. Examples of the carbon monoxide source include carbonyldiimidazole, triphosgene and phosgene. Examples of the reaction solvent include DMF and the like. The reaction temperature ranges from room temperature to around the boiling point of the solvent. Conversion of compound (48) to compound (45) can be carried out according to the above-mentioned method J.

In the above reaction, the functional group of each compound can be protected as necessary. As the protecting group, known protecting groups (Protective Groups in Organic Synthesis, T.W. Greene, A Wiley-Interscience Publication (1981), etc.) and the like can be used.

Unless otherwise specified, the raw materials and reagents used above are commercially available compounds or can be produced from known compounds using known methods.

Compound (1) in which X is represented by C—R ⁶ produced according to the above production method may be obtained as a mixture of isomers. In that case, in the final step or the intermediate step, each isomer can be purified by an appropriate purification method such as silica gel gel chromatography.

The optical isomer of the compound (1) in which X is represented by C—R ⁶ can be obtained by a known optical resolution method such as fractional recrystallization of an addition salt with an optically active acid such as tartaric acid.

The prodrug of the compound (1) can be obtained by a conventional method (Chemistry and Industry, 1980, 435; A advanced Drug Discovery Reviews 3, 39 (1989)).

A pharmaceutically acceptable salt of compound (1) or a prodrug thereof is prepared by converting compound (1) or a prodrug thereof to a compound such as hydrochloric acid, citrate or methanesulfonic acid in a solvent such as water, methanol, ethanol or acetone. It can be obtained by mixing with a pharmaceutically acceptable acid. Particularly preferred examples of the compound (1) include those described below.

3- (2-Chlorophenyl) -1-[2- (Jethylamino) ethyl] -4 -Fluoro mouth -3-hydroxy

-2-oxindrin-6-carboxamide

4-bromo-3- (2-chlorophenol)-1-[2- (Jetinoleamino) ethyl] -3-hydroxy-

2-oxoindolin-6-carboxamide

4- -Mouth mouth 3- 3- (2-Houth mouth phenyl)-1- [2- (Jetinoleamino) ethyl] _3-Hydroxy-

2-oxodindoline-6-carboxamide

3-Amino-1- [2- (Jethylamino) ethyl] -3- (2-naphthyl) -2-oxo-4- (trifluoromethylinole) indoline-6-forcenoreboxamide

3- (2-Chlorophenyl) -1- [2- (Jethylamino) ethyl] -3-fluo-2-oxo-4- (trifnoreomethinole) indoline-6-carboxamide

1- [2- (Jethylamino) ethyl-]-3-hydroxy-3- (2-methoxyphenyl) -2-oxo-4- (trimethylomethyl) indoline-6-carbosamide

4--Mouth mouth-1-[2- (Jetylamino) ethyl] -3- -Hydroxy_3- (2-methoxyphenyl) -2-oxoindolin-6-Canoleboxamide

4-c-mouth- 1- [2- (Jetylamino) ethyl] -3- (2-fluorophenyl) -3-hydroxy-2-oxindrin-6-carboxamide

1- [2- (Jethylamino) ethyl] -3- (2-fluorophenyl) -3-hydroxy-2-oxo-4- (trifluoromethyl) indoline-6-caprolucamide

3-(4-Chloro-2-methoxyphenyl)-1- [2- (Jethylamino) ethyl] -3-hydroxy-2-oxo-4-(trifluoromethyl) indoline-6_carboxamide

1- [2- (Jethylamino) ethyl] -3-hydroxy-3_ [2- (hydroxymethyl) phenyl] -2_oxo-4- (trifluoromethyl) indoline-6-carboxamide

4--Mouth mouth-1-[2- (Jetylamino) ethyl] -3 -Hydroxy-3- (2-methoxypheninolate) -2-Oxindrin-6-Lipoxamide

4-chloro-1_ [2- (Jethylamino) ethyl]-3-hydroxy-3- [2- (hydroxymethyl) phenyl] _2-oxoindoline-6-carboxamide

4-Chloro-1- [2- (Jethylamino) ethyl] -3-Hydroxy-3- [2- (Methoxymethyl) phenyl] -2-Oxoindoline-6-carboxamide

4- ク口口 -1-[2- (Jethylamino) ethyl] -3-Hydroxy-3- (1-naphthinole) -2-oxooxoindoline-6-carboxamide

4 -Kokuro-1_ [2- (Jethylamino) ethyl]-3-Hydroxy-3- (2-naphthinole)-2-oxoindolin-6 -carboxamide

3-biphenyl-2-yl—4-chloro—11- [2- (Jetinoleamino) ethyl] -3-hydroxy-2_ oxoindolin-6-carboxamide

4 -Kokuro-3- (2,6-Dichroic feninole)-1- [2- (Jetylamino) ethyl]-3-Hydroxy-2-oxoindrin-6-carboxamide

3- (1-benzofuran-7-inole) -4-cyclobutane [2- (Jetinoleamino) ethynole] -3-hydroxy-2-oxoindrin-6-carboxamide

3--Benzochen-7-yl) -4-chloro- 1- [2- (Jethylamino) ethyl]-3-Hydroxy-2-oxoindrin-6-carboxamide

3_ [2- (Benzyloxy) phenyl] -4- -Kokuguchi -1--[2- (Jethylamino) ethyl] _3_ Hydroxy-2-oxoindrin-6-carboxamide

4_ Cyclo-3-[2- (cyclopropylmethoxy) phenyl]-1-[2- (Jetylamino) ethyl]-3-Hydroxy-2-oxoindrin-6-force / Repoxamide

4-chloro-2--1- [2- (ethylamino) ethyl] -3-hydroxy-3- [2- (2-methoxyethoxy) phenyl] -2-oxoindoline-6_carboxamide

4 '_Black mouth -1'-[2- (Jethylamino) ethynole] -2 '-oxo-, 2' -Dihydro-3H -spi [2-benzofuran-1,3'-indole]-6,- Force / Repoxamide

1- [2- (Jethylamino) ethyl] -2-oxo-4— (trifluoromethyl) -1,2,3 ', 4, -tetrahydrospiro [indono-3,1'-isochromene] -6-force Poxamide

3_ (2-chlorophenyl) -1- [2- (Jethylamino) ethyl] -3-hydroxy-6- [3- (2-oxoimidazolidin-1-yl) prop-1-y 1-yl] -4- (Trifluoromethyl) -1, 3-dihydro-2H-indole-2-one 1- {2- [Bis (cyclopropylmethyl) amino] ethyl} -4--Kuguchi _3-(2-Chloropheninole) -3-hydroxy-2-oxoindoline-6-canolepoxamide

4 -Chloro- 3-(2-Chlorohexyl)-1-[(1-Ethylpyrrolidine-2-inole) methyl] -3-Hydroxy-2-oxoindrin-6-carpoxamide

4_Chloro-3- (2-chloropheninole) -1-[(1-ethylpiperidin-2-yl) methyl] -3-hydroxy-2-oxindrin-6-carpoquinamide

4-—Mouth—3— (2-Chloropheninole) 1-1— (1-Ethinoleazepine—3-inole) methinole] —3-Hydroxy-2-oxoindrin-6-force ^ / Repoxamide

4-Kuguchiguchi -3- (2-guchiguchi feninole) -3- -Hydroxy-1- [2_ (1-methinolepyrrolidine-2-ynole) ethyl] -2-oxoindolin-6-carboxamide

3- (2-chlorophenyl) -3-hydroxy-2-oxo-1- (2-piperidine-1-inoleethyl) -41- (trifluoromethylinole) indoline-6-forcenorboxamide

4-Chloro-3- (2-chlorophenyl)-1- {2- [ethyl (2-methoxethyl) amino] ethyl 3-hydroxy-2- oxoindolin _6-phenolic amide

4_Black mouth-3— (2-Black mouth fue-nore) -1-1 {2- [Echinore (2-fluorene) amino] echinore}-3-Hydroxy-2-oxoindolin-6- Do

4-chloro mouth-3_ (2-chloropheninole)-1-[3- (ethylamino) propyl] _3-hydroxy-2-oxoindolin-6-carboxamide

4 -Kokuro-3- (2-kuguchiguchi)-1- [4- (Jethylamino) but-2-ene_1-inole] -3-Hydroxy-2-oxoindoline-6-carboxamide

4-Methoxy-3- (2-chlorophenyl) -tri- [4- (Jethylamino) butynole] -3-Hydroxy-2-oxoindolin-6-carboxamide

4- (2-Chlorophenyl) -1- [2- (1-Ethylpiperidine-4-yl) ethyl] -3-Hydroxy-2-oxoindolin-6-caproloxamide

1_ (4-Chlorophenyl) -3_ (2-Getylaminoethyl) -2-oxo-7-trifluoromethyl-2,3-dihydro-1H-benzimidazole-5-carboxamide

1- (2,4-Dichloro mouth phenyl) -3- 3- (2-Jetinoleaminoethynole) _2-oxo-7-Trifluoro mouth methyl-2,3-dihydro-1H-Benzimidazono- 5-carboxamide

7-Kokuguchi -1- (2,4-dichlorophenol) -3- (2-Getylaminoethyl) -2-oxo-2,3-dihydro-1H-benzimidazonole-5- Power Revoxamide 7-Couguchi -1- (2,4-dichlorophenyl) -3-[(1-ethylpiperidin-2-inole) methyl] -2-oxo-2,3-dihydro-1H-benzimidazole -5—Ripoxamide

7-Cupro-1-(2,4-dichlorophenyl) -3-[(1-methylpiperidine-2-inole) methyl]-

2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide

7-Chloro-1- (2,4-dichlorophenol) -3-[(1-Ethylpyrrolidine-2-yl) methyl] -2_oxo-2,3-dihydro-1H- Benzimidazole-5-carboxamide

Akuroro -丄- _(2, 6-dichlorophenyl) -3 - (2-oxygenate chill § Mino E chill) -2 - Okiso 2,

3-dihydro-1H-benzimidazole-5-pot olevoxamide

1- (2-Chloropheninole)-3- (2-Jetylaminoechinole) -7-Fluoro-2-oxo-2,3-Dihydro-1H-benzimidazole-5-Caproloxamide

1- (2,4-dichlorophenyl) -3- (2-getylaminoethyl) -7-fluoro-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide

1- (2,4-Dic-mouth phenyl) -3- (2-Gethylaminotinole) -7-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5- Carboxamide

1- (2,4-dichlorophenyl) -3- (2-getinoleaminoethynole)-7-methoxy-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide

4- ク口口 -1-[2- (Jetylamino) ethyl]-3- (2-ethylthiophene)-3-hydroxy-

2-oxoindolin-6-carboxamide

1- [2- (Jethylamino) ethynole] -3- (2-Ethylpheny / re) -3-Hydroxy-2-oxoindrin-4-Trifluoromethyl-6-carboxamide

4--Mouth mouth-1-[2- (Jetylamino) ethynole] _3--(2-butoxypheninole)-3-hydroxy-2-oxodindrin-6-carboxamide

4, 6-dic-mouth-3- [3- (Jethylamino) propoxy] -1-methyl-3- (2-naphthyl) -1,

3-dihydro-2H-indoleno 2-one

4,6-dichloro-3- [3- (Jethylamino) propoxy] -3- (2-naphthyl) -1,3-dihydro-2H-indole-2-one

4-Chloro-1- [2- (decylamino) ethyl] -3-hydroxy-2-oxo-3-[2- (pyridin-3-ylmethoxy) phenyl] indoline-6-carboxamide

5- [3- (2-chlorophenyl) -1- [2- (ethylamino) ethyl] -3-hydroxy-2-oxo41- (trifluoromethyl) —2,3-dihydro-1H— INDONOLE-6-INOLE] —N— (2-HYDROXY (Shetyl) pent-4-inamide

1 '-[2- (Jethylamino) ethyl] -2'-oxo_4' _ (trifluoromethyl) -1 ', 2'-dihydro-3H-spiro [2-benzofuran-1,3'-indole ]-6, -Carboxamide

4-—Mouth mouth—3 -— (2-Mouth mouth feninole) -1-11 [4- (Jetinoleamino) cyclohexyl] —3-Hyd Mouth xy-2-oxoindoline-6-carpoxamide

4-chloro-3- (2-chlorophenole) -1- [3- (Jethylamino) cyclobutyl] -3-hydroxy-2-oxoindoline-6-caproloxamide

4-Cupro-3- (2-chloropheninole) -1 _ {[3_ (Jethylamino) cyclobutyl] methyl} -3-hydroxy-2-oxoindoline-6-carboxamide The compound of the present invention has an anti-feeding effect. Therefore, it can be used as a prophylactic / therapeutic agent for the following diseases, for example. Diabetes, diabetic nephropathy-diabetic complications such as diabetic retinopathy, obesity, hyperlipidemia, arteriosclerosis, high blood pressure, eating disorders (overeating), affective disorders, memory disorders, dementia, hormonal disorders, sex Dysfunction, knee arthritis, metabolic syndrome. The compound of the present invention can be administered orally or parenterally (intramuscular, intravenous, subcutaneous, transdermal, intranasal, suppository, ophthalmic, intracerebral administration). Examples of the dosage form include generally accepted dosage forms, for example, powders, granules, fine granules, tablets, capsules, pills, syrups, suspensions, injections such as liquids, and emulsions. Preparations, rectal suppositories, transdermal agents (ointments, creams, lotions and the like) and the like.

At the time of formulation, it can be produced by an ordinary method using a usual carrier or diluent. For solid preparations such as tablets, the active compound and a pharmaceutically acceptable carrier or excipient (eg, lactose, sucrose, corn starch), a binder (eg, hydroxypropylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose) are used. ), Kazuyo Kagura IJ (sodium carboxymethylcellulose, sodium starch glycolate), a lubricant (such as stearic acid, magnesium stearate, etc.) or a preservative. When preparing parenteral preparations such as solutions and suspensions, the active compound should be dissolved or suspended in a physiologically acceptable carrier or diluent such as water, saline, oil, dextrose solution, etc. And can be prepared as required Auxiliaries such as pH adjusters, buffers, stabilizers, solubilizers, emulsifiers, and osmotic pressure adjusters can also be added.

The dose and frequency of administration of the compound of the present invention generally vary depending on the route of administration, the severity of symptoms, body weight, and the like. The compound of the present invention is generally administered to an adult (body weight of 6 O kg) at a dose of about 1 mg to about 1 g, preferably about 1 mg to about 200 mg, more preferably about 5 mg to about 5 Omg once a day or It is administered more often. It can also be administered once every two days to one week. Toxicity has not been observed at therapeutic doses. Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto. The HPLC conditions used in the purification of the example compounds are as follows.

Condition 1

Column: YMC-ODS A-211 (particle size 5 μm, inner diameter 4.6 mm, total length 25 cm: YMCS Corporation)

Solution A: Water / 0.1% trifluoroacetic acid

Solution B: acetonitrile / 0.1% trifluoroacetic acid

B%: 0 min: 30% 〜30 min: 90%

Detection wavelength: 254 nm

Flow rate: 1.0 mL / min Reference example 1

Mixture of 4-promo-1H-indole-2,3-dione and 6-bromo-1H-indole-2,3-dione To an aqueous solution (200 Ra) of kualaral hydrate (15.8 g, 95.5 mmol), Subsequently, a solution (75 mL, about 80 ° C) of sodium sulfate (21.8 g, 153 mmol), 3_promoaniline (8.0 mL, 73.5 mmol) and hydrochloric acid (6.5 mL, 36 ° / o) was added to the solution. An aqueous solution (85 mL) of droxylamine hydrochloride; ^ (19.0 g, 273 mmol) was added with vigorous stirring. The reaction solution was heated under reflux for 10 minutes and cooled to room temperature. The resulting white solid was collected by filtration, washed with water, and dried to give crude isonitrosoacetamide. Keep the temperature between 50 ° C and 70 ° C in concentrated sulfuric acid (250 mL). Added several times. Thereafter, the reaction solution was stirred at 80 ° C for 10 minutes, and then cooled to room temperature. The reaction solution was poured into crushed ice (about 500 g) and left for 20 minutes. The resulting solid was collected by filtration, washed with water, and dried to synthesize the title mixture (2.5: 1) (10.6 g, 64%). 4-Promo-1H-indole-2,3-

_{^ -NMR (CDC1 3, 270 MHz} ) δ 11.17 (brs, 1H), 7.46 (dd, 1H, J = 8.0, 8.0 Hz), 7 .22 (dd, 1H, J = 0.7, 8.0 Hz), 6.89 ( (dd, 1H, J = 0.7, 8.0 Hz).

6-Bromo-1H-indono- 2,3-dione:

'HNR (CDCI3, 270 MHz) δ 11.10 (brs, 1H), 7.47 (d, 1H, J = 7.9 Hz), 7.26 (dd, 1H, J = l.7, 7.9 Hz), 7.08 (d, 1H , J = l.7 Hz). Reference example 2

4-promo-6-node-1H-indole-2,3 dion

(1) 2-Promo-4-Ed-6-Nitoguchi Tonolen

Under a nitrogen atmosphere, 1-iodosuccinimide (39.1 g, 182 mmol) was added to concentrated sulfuric acid (170 raL) under ice cooling, and the mixture was stirred for 40 minutes. Under ice-cooling, a concentrated sulfuric acid solution (170 mL) of 2-bromo-6-nitrotoluene (25.0 g, 116 mmol) was added dropwise, and the reaction solution was stirred for 6 hours while maintaining the temperature at 5 ° ((10 ° C.). The reaction solution was transferred to ice water, extracted four times with ethyl acetate, and the organic layer was washed successively with aqueous sodium sulfite, water, and saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. Purification by column chromatography (hexane) gave the title compound (38.1 g, 96%).

^ -NMR (CDCI3, 270 MHz) δ ■ 8.12 (d, 1H, J = 1.7 Hz), 8.02 (d, 1H, J = 1.7 Hz), 2.48 (s, 3H).

(2) (E) -2-(2-Buguchi-4--4--6-nitropheninole)-1-dimethylaminothene 2-Promo-4-odo-6- under nitrogen atmosphere Tris (dimethylamino) methane (23.0 g, 158 mmol) was added to a solution of nitrotonolene (36.0 g, 105 ト ol) in N, N-dimethylformamide (200 mL), and the mixture was stirred at 60 ° C for 11 hours. . The reaction solution was concentrated under reduced pressure to obtain a crude product of the title compound.

^X H-NMR (CDCI3, 270 MHz) δ ■ 7.95 (d, 1H, J = 2.0 Hz), 7.70 (d, 1H, J = 2.0 Hz), 6.56 (d, 1H, J = 13.5 Hz), 4.99 ( d, 1H, J = 13.5 Hz), 2.85 (s, 6H).

(3) 4-pud Mo-6-Edo Indole Under a nitrogen atmosphere, an acetone (250 mL) solution of (E) -2- (2-promo-4-iod-6-ditrophenyl) -1-dimethylaminoamine was added to a 20% aqueous solution of titanium trichloride (503 g, 652 mmol). ) And a 4 N aqueous solution of ammonium acetate (1007 g, 1.31 mol) were added, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was added with hydrogen sulfate ridium so as to have a pH of ^ 2, extracted five times with ethyl acetate, the organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was dissolved in ethyl acetate / toluene (1: 1), washed twice with a saturated aqueous solution of sodium bicarbonate, sequentially with water, dried over magnesium sulfate, filtered, and concentrated to obtain a crude product of the title compound.

_{^ -NMR (CDC1 3, 270 MHz} ) δ ■ 8. 26 (brs, 1H), 7. 69 (ra, 1H), 7. 58 (ra, 1H), 7. 1 9 (dd, 1H, J = 3.0, 3.0 Hz), 6.57 (m, 1H).

(4) 4-Bromo-3,3-dibromo-6-odoindrin-2-one

Under a nitrogen atmosphere, pyridinium perbromide hydrobromide (112 g, 351 mmol) was added to a solution of 4-bromo-6-amide / d-butyl alcohol (1000 mL) over 30 minutes. It was added little by little. After stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate / 7 (1: 1), and the aqueous layer was removed. The organic layer was washed successively with water and saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was concentrated under reduced pressure to obtain a crude product of the title compound.

-丽_{R (DMSO- d 6, 270 MHz} ) S - 11. 57 (s, 1H), 7. 75 (. D, 1H, J = l 0 Hz), 7. 26 (d, 1H, J = l (0 Hz).

(5) 4-Bromo-6-ode-1Hindole-2,3-dione

Under a nitrogen atmosphere, 4-promo-3,3-dibromo-6-odoindrin_2_one was dissolved in methanol / water (1: 1, 700 mL) and stirred at 90 ° C for 2 hours. The reaction solution was returned to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1 to 4/1) to give the title compound (4.52 g, 12%, 4ste _PS ).

^J H-NMR (DMSO- d ₆ , 270 MHz) δ11.22 (brs, 1H), 7.66 (d, 1H, J = l.3 Hz), 7.22 (d, 1H, J = l. 3 Hz). Reference Example 3

Methyl 4-octanol-2,3-dioxoindrin-6-canolepoxylate

(1) Methyl 3-chloro-4-hydroxybenzoate

3-nitro-4--4-hydroxybenzoic acid (10.0 g, 55.1 mm) cooled to 0 ° C under nitrogen atmosphere ol) in methanol (100 mL) was slowly dripped with thionyl chloride (6.0 mL, 82.6 mmol) and stirred at 50 ° C for 3 hours. The solvent was distilled off, the residue was dissolved in ethyl acetate, washed successively with water twice and saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the title compound (10.2 g, 99% ).

_{^ -NMR (CDC1 3, 400 MHz} ) δ 8. 05 (d, 1H, J = 2. 0 Hz), 7. 89 (dd, 1H, J = 2. 0, 8. 6 Hz), 7. 06 (d, 1H, J = 8.6 Hz), 5.99 (s, 1H), 3.90 (s, 3H).

(2) Methyl 3-chloro-4-hydroxy-5-nitrobenzoate

Under a nitrogen atmosphere, 0 ° methyl 3 was cooled to C - click port B - 4-hydroxycarboxylic benzoate ^{(. 6 00 g, 32. 2} mmol) in concentrated sulfuric acid (50 mL) solution of 70% nitric acid (3. 5 mL, 40.4 mmol) was slowly added dropwise, and the mixture was stirred at 0 ° C for 2.5 hours. The reaction solution was transferred to ice, extracted twice with ethyl acetate, and the organic layer was washed successively with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate and Nesium, filtered, and the filtrate was concentrated. The residue was purified by silica gel gel chromatography (hexane / ethyl acetate = 2/1) to obtain the title compound (6.01 g, 81%).

^ -NMR (CDCI3, 400 MHz) δ 11.36 (s, 1H), 8.75 (d, 1H, J = 2.1 Hz), 8.35 (d, 1H, J = 2.1 Hz) , 3.96 (s, 3H).

(3) Methyl 3-co-mouth-5-nitro--4- (trifluoromethylsulfonyloxy) benzoate

In a nitrogen atmosphere, to a solution of methyl 3-chloro-4-hydroxy-5-nitrobenzene (2.50 g, 10.8 mmol) in dichloromethane (60 mL) cooled to 0 ° C. , Triethylamine (1.70 mL, 12.2 mraol) and trifluoromethanesulfonic anhydride (2.00 mL, 11.9 mmol) were sequentially added dropwise, and the mixture was stirred at 0 ° C for 1 hour. Water was added, the mixture was extracted with black hole form, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain the title compound (3.27 g, 83%). ^ -NMR (CDCI3, 400 MHz) δ 8.62 (d, 1H, J = 2.1 Hz), 8.45 (d, 1H, J = 2.1 Hz), 4.01 (s, 3H) .

(4) Dimethinole [2-cu-Mouth—4— (Methoxycarbinole) —6-Ethoxy-phenyl] malonate Dimethylmalonic acid (4.83 mL, 42.3) cooled to 0 ° C under nitrogen atmosphere 60 mmol) (1.69 g, 42.3 mmol) was slowly added to a tetrahydrofuran solution (100 mL) of the resulting solution, followed by stirring for 10 minutes. Subsequently, a solution of methyl 3-chloro-5-toro-4-(trifluoromethyls-norefonyoxy) benzoate (11.8 g, 32.5 mmol) in tetrahydrofuran (60 mL) was added dropwise, and the mixture was stirred at room temperature for 12 hours. 1N hydrochloric acid was added, extracted twice with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. After filtration, the solvent was evaporated and the title compound (9.23 g, 82%) was purified by silica gel gel column chromatography (hexane / ethyl acetate = 5/1 to 2/1). Obtained.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8. 61 (d, 1H, J = l. 7 Hz), 8. 37 (d, 1H, J = l. 7 Hz), 5. 58 (s, 1H) , 3.99 (s, 3H), 3.79 (s, 6H).

(5) Methyl 3-chloro-4- (2-methoxy-2-oxetinole) -5-nitrobenzoate Dimethyl [2-cyclohex-4- (methoxycarbonyl) -6- under nitrogen atmosphere Ditrophenyl] To a mixture of malonate (78.1 g, 226 mmol) and lithium chloride (19.2 g, 453 mmol), dimethyl sulfoxide (600 mL) and water (4.10 mL, 228 mol) were added. The mixture was stirred at 100 ° C for 5 hours. A 1N aqueous hydrochloric acid solution was added, and the mixture was extracted four times with ethyl acetate / toluene (1: 1). The organic layers were combined, washed three times with a 1N aqueous hydrochloric acid solution, and dried over magnesium sulfate. After filtration, the solvent was distilled off. To the residue (72.4 g), methanol (200 mL) and 4N hydrochloric acid / 1,4-dioxane solution (55 mL, 220 mmol) were added. The mixture was stirred with C for 2.5 hours. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1 to 3/1) to give the title compound (60.0 g, 92%).

Thigh _{(CDC1 3, 400 MHz) δ} 8. 54 (d, 1H, J = l. 7 Hz), 8. 34 (d, 1H, J = l. 7 Hz), 4. 22 (s, 2H), 3.98 (s, 3H), 3.74 (s, 3H).

(6) Methyl 4-co-mouth- 2-oxoindrin-6-forcenorboxylate

Under a nitrogen atmosphere, a solution of methyl 3-chloro-4- (2-methoxy-2-oxoethyl) -5_nitrobenzoate (60.0 g, 209 mmol) in methanol (800 mL) was added at 0 ° C for 20 minutes. ° /. An aqueous solution of titanium trichloride (1000 g, 1.30 mol) was added dropwise, and the mixture was stirred at room temperature for 14 hours. The reaction solution was transferred to water (ca. 2 L), extracted four times with ethyl acetate, the organic layers were combined, washed with saturated saline, and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the precipitated solid was suspended in hexane / ethyl acetate (2: 1, 700 mL) and collected by filtration to give the title compound (42.5 g, 90%). . ^{_{X H NMR (CDC1 3, 400}} MHz) 8 8. 62 (brs, 1H), 7. 73 (d, 1H, J = 0. 8 Hz), 7. 46 (d, 1H, J = 0. 8 Hz ), 3.93 (s, 3H), 3.60 (s, 2H).

(7) Methynole 3,3-dibromo-4-oxoindolin-6-carboxylate Under a nitrogen atmosphere, methyl 4-oct-2-oxoindolin-6-carboxylate (6.00 g, 26 6 mmol) in t-butyl alcohol (110 mL), pyridine hydrobromide dipromide (21.3 g, 66.6 mmol) was added and the mixture was stirred at 50 ° C. On the way, 14.0 g (43.8 mmol) of pyridine hydrobromide dibromide was added, and the mixture was stirred for a total of 10 hours. After cooling to 0 ° C, water (300 raL) was added, and the mixture was stirred for 30 minutes. The precipitated solid was washed twice with water (50 mL) and dried to give the title compound (9.68 g, 95%).

¾丽_{R (CDC1 3, 400 MHz)} δ 8.88 (brs, 1H), 7.84 (d, 1H, J = l.2 Hz), 7.55 (d, 1H, J = 1.2 Hz), 3.96 (s, 3H) .

(8) Methyl 4-octanol-2,3-dioxoindrin-6-carboxylate

Under a nitrogen atmosphere, methyl 3,3-dibromo-4-chloro-2-oxoindoline-6-caproloxylate (9.68 g, 25.2 mmol), t-butyl alcohol (50 mL), water (100 mL), sulfuric acid Silver (6.00 g, 18.1 mmol) was added and the mixture was stirred at 90 ° C. On the way, silver sulfate (1.90 g, 5.73 mmol) was added, and the mixture was stirred for a total of 4 hours. The reaction solution was cooled to 60 ° C, and ethyl sulphate (250 mL) was added. The reaction solution was filtered, the organic layer of the filtrate was taken, washed with 1N aqueous hydrochloric acid and saturated brine in that order, and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the obtained residue was suspended in hexane / ethyl acetate (5: 1, 200 ml) and collected by filtration to give the title compound (5.91 g, 98%).

Employment _{R (DMS0 - d 6, 400} MHz) δ 11.43 (brs, 1H), 7.58 (d, 1H, J = l.2 Hz), 7.32 (d, 1H, J = l.2 Hz), 3.96 (s , 3H). Reference Example 4

6-Edo-4- (trifluoromethyl) 1H-indole-2,3-dione

(1) 5-Aodo-2-methyl-3-nitrobenzotrifluoride

It was synthesized in the same manner as in Reference Example 2- (1) using 3_etrobenzo and trifluoride instead of 2-bromo-6-nitrotoluene.

_{'H-NMR (CDC1 3,} 270 MHz) δ · 8.19 (d, 1H, J = l.6 Hz), 8.14 (d, 1H, J = l.6 Hz), 2.49 (s, 3H).

(2) (E) -2_ (4-Ed-2--2-nitro-6-trifluoromethylenyl)-1-dimethylaminoamine

2-Bromo one 4-Yodo-6 two Torotonoreen Instead 5- ® ¹ de one 2- Mechinore using one 3-two Torobe emission zone trifluoride Rai de of Reference Example 2 - (2) and in the same manner Synthesized.

XH-NMR (CDCI3, 270 MHz) δ-7.95 (d, 1H, J = 2.0 Hz), 7.85 (d, 1H, J = 2.0 Hz), 6.39 (d, 1H, J = 13.0 Hz), 5.04 (d, 1H, J = 13.0 Hz), 2.83 (s, 6H).

(3) 6-Edo-4 -Trifluoromethylindonele

(E)-2- (2-bromo-4-iod-6-nitrophenyl) -1-dimethinoleaminoethene replaces (E) -2- (4-iodo-2-nitro-6 -Trifluoromethizlespheninole) —Synthesized in the same manner as in Reference Example 2-(3) using 1-dimethylaminoethene.

_{^ - MR (CDC1 3, 270} MHz) δ · 8.38 (brs, 1H), 7.92 (s, 1H), 7.68 (s, 1H), 7.2 7 (m, 1H), 6.71 (m, 1H).

(4) 3,3-Dibromo-6-yl-4-triphnoleo-methinoleindoline-2-one

This compound was synthesized in the same manner as in Reference Example 2- (4), using 6-odo-4-trifthleo-methinoleindol instead of 4_promo-6-odoindole.

_{^ -NMR (DMSO- d 6, 270} MHz) δ - 11.73 (brs, 1H), 7.78 (s, 1H), 7.56 (s, 1H).

(5) 6-Ed—4— (Methyl trifnoreo) —1H—indole-2,3-dione

Use 4-promo-3,3-dibumo-6-propidolin-2-3-butane instead of 3,3_dibromo-6-3-1-do-4-trifluoromethylindoline-2-one The compound was synthesized in the same manner as in Reference Example 2- (5).

- thigh _{R (DMSO- d 6, 270 MHz} ) δ -. 11.31 (brs, 1H), 7.68 (s, 1H), 7.55 (s, 1H) Reference Example 5

4—Funoleo mouth— 6—Ed -1H—Indole-2,3-Dione

(1) 1-Fluoro-5-odo-2-methyl-3-nitrobenzene

The synthesis was carried out in the same manner as in Reference Example 2- (1), except that 2-bromo-6-ditrotonolene was used instead of 2-bromo-6-nitrotrotoluene.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.67-7.73 (m, 2H), 2.19 (d, 3H, J = 2.0 Hz).

(2) Methinole 3- (2-Fluoro-4-odo-6-ditrophenyl) -2-oxopropanoate In a nitrogen atmosphere, 28% sodium methoxide methanol solution (51.7 g, 268 ramol) was added to sulfuric acid. Dimethyl acid (31.6 g, 268 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Subsequently, a methanol solution (50 raL) of 1-fluoro-5-iodo-2-methyl-3-nitrobenzene (15.1 g, 53.6 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The solvent was distilled off, and the mixture was acidified with 3N hydrochloric acid, extracted with ethyl acetate, and dried over magnesium sulfate. After filtration, the solvent is distilled off and purified by silica gel column chromatography (hexane / ethyl acetate == 10/1 to 5/1). This gave the title compound (3.36 g, 19% 2steps).

^X H employment _{R (CDC1 3, 400 MHz)} δ 8. 28 (dd, 1H, J = l. 5, 1. 5 Hz), 7. 78 (dd, 1H, J = l. 5, 8. 1 Hz ), 4.54 (d, 2H, J = l. 0 Hz).

(3) Methyl (2-fluoro-4-odo-6-nitrophenyl) acetate

Under a nitrogen atmosphere, add methyl 3- (2-fluoro-4--4-odo-6-ditropheninole) -2-oxopropanoate (3.00 g, 8.17 mtiiol) to acetic acid (50 mL), 70% Perchloric acid (5.0 mL, 58.0 mraol) and 30% hydrogen peroxide (18.2 mL, 180 ramol) were added, and the mixture was stirred at 50 ° C for 8 hours. The temperature was returned to room temperature, sodium sulfite (ca. 10 g) was added, and the mixture was stirred. Hydrochloric acid was added, extracted with ethyl acetate, and dried over magnesium sulfate. After filtration, the solvent was distilled off to obtain a crude carboxylic acid (6.6 g). To this crude carboxylic acid was added methanol (50 mL), 4N hydrochloric acid / 1,4-dioxane solution (10 mL, 40 mmol), and the mixture was heated under reflux for 6 hours. The solvent was distilled off, 1N aqueous hydrochloric acid was added, extracted with ethyl acetate, and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to give the title compound (2.23 g, 81%).

¾丽_{R (CDC1 3, 400 MHz)} δ 8. 23 (dd, 1H, J = l. 6, 1. 6 Hz), 7. 75 (dd, 1H, J = l. 6, 8. 2 Hz) , 4.00 (d, 2H, J = l. 2 Hz), 3.73 (s, 3H).

(4) 4-Fluoro-6-odo-1,3-dihydro-2H-indono- 2-one

Methinole 3-chloro-4-(2-Methoxy-2-oxetinole) -5 -Nitrobenzoate instead of methyl (2-fluoro-4--4-odo-6--2-trofeninole) acetate And synthesized in the same manner as in Reference Example 3- (6).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7. 74 (brs, 1H), 7. 13 (dd, 1H, J = l. 2, 7. 9 Hz), 7. 0 3 (d, 1H, J = l. 2 Hz), 3.49 (s, 2H).

(5) 3,3-dibromo-4-fluoro-6-odo-1,3-dihydro-2H-indole-2-one methinole 4-c-mouth-2 oxoindrin-6 6-force Mouth-6-Eodo-1,3-dihydro-2H-indole-2-one was synthesized in the same manner as in Reference Example 3- (7).

(6) 4-Fluoro-6-odo-1H-indole-2,3-dione

Under a nitrogen atmosphere, 3,3-dibromo-4-fluoro-6-ode-1,3-dihydro-2H-indole-2-one (2.35 g, 5.40 mmol) in methanol (100 mL) , Water (25 mL), 48 ° /. Hydrobromic acid (10 mL) was added, and the mixture was heated under reflux for 16 hours. Evaporate the solvent, add water, and add ethyl acetate. Extracted twice and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to obtain the title compound (1.13 g, 72%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8. 20 (brs, 1H), 7. 24 (dd, 1H, J = 0. 9, 7. 6 Hz), 7. 1 6 (d, 1H, J = 0.9 Hz) .Reference example 6

l- (4-c-h-phenyl) -2-oxo-7-trifnoreo-methinole 2,3-dihydro-1H-benzimidazole-5-canolebonitrinole

(1) Etinole N- (4-chlorophenyl) carbamate

4-Chloroaniline (2.3531 g) was dissolved in pyridine (20 raL), and ethyl ethyl chloroformate (2.116 mL) was added dropwise under ice cooling. After stirring for 1.5 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with 1N hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (3.6875 g, quantitative).

_{i-NMR (CDC1 3, 300} MHz) δ · 7. 22-7. 34 (m, 4H), 6. 79 (brs, 1H), 4. 22 (q, 2H, J = 7. 1 Hz), 1.30 (t, 3H, J = 7.1 Hz).

(2) Ethyl N- (4-chlorophenol) -N- (2,4-jutro-6-trifluoromethylphenyl) car / meth

Dissolve 4-ethyl phenylcarbamate (1.2281 g) in tetrahydrofuran (30 m3) and add sodium hydride (246.1 mg) with 2-hydroxy-3,5-dibutyl. Nzotrifluoride (1.3870 g) was added, and the mixture was stirred at room temperature for 2 hours. 1N hydrochloric acid was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to give the title compound (1.7323 g, 78%). Was obtained.

_{'H- MR (CDC1 3, 300} MHz) δ. 9. 02 (d, 1Η, J = 2. 5 Hz), 8. 84 (d, 1H, J = 2. 5 Hz), 7. 27 (d , 2H, J = 8.7 Hz), 7.12 (d, 2H, J = 8.7 Hz), 4.23 (brs, 2H), 1.20 (brs, 3H).

(3) Ethyl-(2,4-diamino-6-trifluoromethylphenyl) -N- (4-chlorophenyl) carbamate Ethyl N- (4-chloro phenol) —N- (2,4-dinitro-6-triphenololemethyl phenyl) Carbamate (1.7323 g) is dissolved in methanol (100 mL). Then, a 20% aqueous solution of titanium trichloride (36.967 g) was added under ice cooling, and the mixture was stirred for 2 hours. After adding 1: 1 aqueous sodium bicarbonate solution (800 mL) to the reaction solution, the mixture was extracted twice with ethyl acetate, and the organic layer was washed with saturated saline. It was dried with anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (form: form / methanol = 10/1) to give the title compound (

1. 2292 g, 82%).

^{_{X H-NMR (CDC1 3,}} 300 MHz) δ ■ 7. 33 (d, 2Η, J = 9. 0 Hz), 7. 21 (d, 2H, J = 9. 0 Hz), 6. 39 (d , 1H, J = 2.4 Hz), 6.22 (d, 1H, J = 2.4 Hz), 4.12 (q, 2H, J = 7.1 Hz), 3.83 (brs, 4H ), 1.19 (t, 3H, J = 7.1 Hz).

(4) 5-Amino_1- (4-co mouth phenyl) -7-Trifluoromethinole-1,3-dihydro-2H-benzimidazol-2-one

Ethyl N- (2,4-diamino-6-trifnoreomethylpheninole) -N- (4-chloropheninole) Carbamate (1.2053 g) is dissolved in ethanol (20 mL) and hydrogenated Sodium (129.0 rag) was added, and the mixture was heated under reflux for 9 hours. After cooling, saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol = 10/1 to 5/1) to give the title compound (0.7431 g, 70%).

_{^ -NMR (CDC1 3, 300 MHz} ) δ ■ 11. 17 (s, 1H), 7. 52 (d, 2H, J = 8. 7 Hz), 7. 33 (d, 2H, J = 8. 7 Hz), 6.57 (d, 1H, J = 2.0 Hz), 6.51 (d, 1H, J = 2.0 Hz), 5.26 (s, 2H).

(5) 1- (4-Chloropheninole) -2-oxo-7_trifnoreo mouth / methyl 2,3-dihydro-1H-benzimidazole-5-carbonitrile

5-Amino-1- (4-chlorophenyl) -7-trifluoromethyl / le-1,3-dihydro-2H-benzimidazonole-2-one 40 mg, 2.17 mmol) was dissolved in dimethinoresulfoxide (35 raL). Then, copper cyanide (607 rag, 6.78 mmol) was added, and the mixture was heated to 55 ° C. At the same temperature, t-butyl nitrite (792 zL, 6.66 mmol) was added dropwise over 1.5 hours. After completion of the dropwise addition, stirring was continued at 60 ° C. for further 4 hours. After allowing to cool, a saturated saline solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and filtrated. Was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol = 258) and silica gel column chromatography (hexane / ethyl acetate = 1/1) to give the title compound (177 mg, 23 %).

_{iH-NMR (CDC1 3, 300} MHz) δ · 10.20 (s, 1H), 7.14-7.67 (m, 6H). Reference Example 7

1- (2,4-dichlorophenyl) -2-oxo-7-trifluoromethinolate 2,3-dihydro-1H-benzimidazonole-5-canoleponitrile

(1) Etil N- (2,4-zig mouth mouth feninole) carbamate

2,4-Dichloroaniline was used instead of 4-chloroaniline, and synthesized in the same manner as in Reference Example 6- (1).

^ -NMR (CDCI3, 300 MHz) δ8.13 (d, 1H, J = 9.0 Hz), 7.35 (d, 1H, J = 2.4 Hz), 7.23 (dd, 1H, J = 2.4, 9.0 Hz), 7.07 (brs, 1H), 4.25 (q, 2H, J = 7.1 Hz), 1.33 (t, 3H, J = 7.1 Hz).

(2) Ethyl N- (2,4-dichloromouth feninole) _N- (2,4-dinitro-6-trifluoromethylpheninole) carbamate

The synthesis was carried out in the same manner as in Reference Example 6- (2), using ethinole N- (2,4-dichlorofur) carbamate instead of ethyl N- (4-chloropheninole) carbamate.

_{^ -NMR (CDC1 3, 300 MHz} ) δ - 8.97-9.00 (m, 1H), 8.80 (d, 1H, J = 2.7 Hz), 7.43 -7.48 (m, 1H), 6.97-7.26 (m, 2H) , 4.20-4.31 (m, 2H), 1.15-1.38 (m, 3H).

(3) Echiru N-(2, 4-Jiamino - 6-triflate Ruo Russia methyl phenylene Honoré) - ^N-(2, ⁴ - Jikurorofu Eninore) Cano main Ichito

Etinole N- (4-chloropheninole) -N- (2,4-dinitro-6-trianoleomethinolefenole) Ethyl N- (2,4-dichlorophenyl) one in place of force N- (2,4-Dinitro-6-trifluoromethylphenyl) carbamate was used in the same manner as in Reference Example 6- (3).

'H-NMR (CDCI3, 300 MHz) δ-7.42 (d, 1H, J = 2.3 Hz), 7.12 (d, 1H, J = 2.3 Hz), 7.08 (s, 1H), 6.37 (d, 1H, J = 2.4 Hz), 6.12 (d, 1H, J = 2.4 Hz), 4.20 (q, 2H, J = 7.1 Hz), 3.97 (brs, 4H), 1.25 (t, 3H, J = 7.1 Hz).

(4) 5_amino-1- (2,4-dichlorophenyl) -7-trifluoromethyl-1,3-dihydro-2H -Benzimidazonore-2-one

Echiru N- (2, 4- Jiamino - 6-triflate Ruo b methylphenanthrenes two Honoré)-N-(4 - Kurorofue two Honoré) Echiru instead of carbamate N - ^(2, 4-Jiamino - ⁶ - triflate Ruo B methyl It was synthesized in the same manner as in Reference Example 6- (4) using phenyl) -N- (2,4-dichlorophenyl) carbamate.

^L H-NMR (DMSO- d ₆ , 300 MHz) 5-11.26 (brs, 1H), 7.82-7.83 (m, 1H), 7.55-7.56 (m, 2H), 6.59 (d, 1H, J = l. 9 Hz), 6.51 (d, 1H, J = 1.9 Hz), 5.28 (s, 2H).

(5) 1- (2,4-Dichloromouth phenyl) -2-oxo-7-trifluoromethyl-2,3-dihydro-1H-benzimidazole-5-carbonitrile

5-Amino-1- (4-chloropheninole) -7-Trifluoromethinole-1,3-dihydro-2H-benzimidazonole-2-one The compound was synthesized in the same manner as in Reference Example 6- (5) using 1,4-dichloromethyl-1,7-trifluoromethyl-1,3-dihydro-2H-benzimidazolone-2-one.

^{_{X H-NMR (CDC1 3,}} 300 MHz) δ · 11.16 (s, 1H), 7.67 (d, 1H, J = l.3 Hz), 7.62 (d, 1H, J = 2.0 Hz), 7.51 (d, 1H, J = l.3 Hz), 7.45 (d, 1H, J = 2.0 Hz), 7.42 (brs, 1H). Reference Example 8

Methyl 7-co-mouth- 1- (2-co-mouth-fernyl)-2-oxo-2,3-dihydro-1H-benzimida sonole-5-force / repoxylate

(1) Methyl 3-tert--4-[(2_chlorophenyl) (ethoxycarbinole) amino] -5-di-pi-benzoate

Methyl mouth in the case of benzotrifluoride, 2-methyl-2-octane-5,3-nitro-4- (trifluoromethylsulfonyloxy) benzoate (Reference Example 3- (3 )) And synthesized in the same manner as in Reference Example 6- (2).

¾ Ran _{R (CDC1 3, 400 MHz)} δ 8.50-8.54 (m, 1H), 8.28-8.30 (m, 1H), 7.47-7.49 (m, 1H), 7.15-7.25 (in, 3H), 4.18-4.29 (m, 2H), 3.94-4.03 (m, 3H), 1.24-1.28 (ra, 3H).

(2) Methyl 3-amino-5-chloro-4-([ethoxy-2-amino) (ethoxycarbinole) amino] benzoate Methanol solution of methyl 3-cyclo-4-[(2-cyclohexenyl) (ethoxycarboe) amino] -5-nitrobenzoate (850 mg, 2.06 mmol) cooled to 0 ° C under nitrogen atmosphere (20 mL) at 20 ° /. An aqueous solution of titanium trichloride (15.8 g, 20.5 raraol) was prepared and stirred at 0 ° C. for 30 minutes. The solution was neutralized with baking soda, extracted twice with ethyl acetate, and dried over magnesium sulfate. After filtration, the solvent was distilled off to obtain a crude product of the title compound (7G, 7 mg).

¾丽_{R (CDC1 3, 400 MHz)} δ 7.46-7.54 (m, 2H), 7.19-7.29 (m, 4H), 4.26-4.33 (m, 4H), 3.89 (s, 3H), 1.26 (t, 3H , J = 7.2 Hz).

(3) Methyl 7-chloro-1- (2-chlorophenyl) -2-oxo-1,2,3-dihydro-1H-benzimidazonole-5-butaneboxylate

Under nitrogen atmosphere, methyl 3-amino-5-chloro-4-([2-chlorophenyl) (ethoxycarbonyl) amino] benzoate (700 mg, 1.83 mmol) in methanol (15 mL), 60% sodium hydride (80.2 mg, 2.01 mmol) was added and the mixture was heated under reflux. On the way, 60% sodium hydride (20.2 mg, 0.505 mmol) was added, and the mixture was heated under reflux for a total of 23 hours. 1N hydrochloric acid was added, extracted with ethyl acetate, and dried over magnesium sulfate. After filtration, the solvent was distilled off, and methanol (15 mL) and a 4N hydrochloric acid / 1,4-dioxane solution (0.5 mL, 2.00 mmol) were added, and the mixture was heated under reflux for 6 hours. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1 to 1/1) to give the title compound (537 mg, 85%, 2 steps). .

_{¾ NMR (CDC1 3, 400 MHz} ) δ 10.24 (brs, 1H), 7.77 (d, 1H, J = l.4 Hz), 7.75 (d, 1H, J = 1.4 Hz), 7.59 (dd, 1H, J = l.5, 8.0 Hz), 7.44-7.55 (ra, 3H), 3.91 (s, 3H).

Methyl 7-co-uro-1- (2,4-di-cou-phenyl) -2-oxo-2,3-dihydro-1H-benzimidazol-5-canoleboxylate

(1) Methyl 3-chloro-4 _ [(2,4-dichloromethyl) amino] _5-dinitrobenzoate In a nitrogen atmosphere, methyl 3-chloro-5-nitro-4--4- (methyl trihnoleo Sulfonyloxy) benzoate (Reference Example 3- (3)) (10.0 g, 27.5 mmol) .2,4-dichloroaniline (

To a mixture of 4.84 g, 29.9 mmol) and cesium carbonate (19.8 g, 60.8 mol), dioxane (150 m), bis (dibenzylideneaceton) palladium (503 mg, 0.875 raraol), 4, 5- Bis (diphenylphosphino) -9,9-dimethylxanthene (780 rag, 1.35 mmol) was added, and the mixture was stirred at 50 ° C for 11 hours. About half of the solvent was distilled off, water was added, extracted with ethyl acetate, washed with water and saturated saline, and dried over magnesium sulfate. After filtration, the solvent was distilled off and purified by silica gel column chromatography (hexane / ethyl acetate = 5/1 to 2/1) to give the title compound as a mixture with 2,4-dichloroaniline ( 8.70 g) was obtained.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.71 (d, 1H, J = 2.0 Hz), 8.54 (brs, 1H), 8.27 (d, 1H, J = 2.0 Hz), 7.45 (d, 1H, J = 2.3 Hz), 7.14 (dd, 1H, J = 2.3, 8.6 Hz), 6.69 (d, 1H, J = 8.6 Hz), 3.97 (s, 3H).

(2) Methyl 3-amino-5-octopen-4-[(2,4-dichloropheninole) amino] benzoate Under a nitrogen atmosphere, methyl 3-octamino-4-([2,4-dichlorophenic) Nore) amino] -5-nitrobenzoate (8.60 g, max 27.4 olol) in ethyl acetate (170 mL) was added 10% palladium on carbon (50% wet product) (3.52 g), and hydrogen atmosphere was added. The mixture was stirred at room temperature for 2 hours. The title compound (5.34 g, 56%, 2steps) was filtered off through celite, and the solvent was distilled off. The residue was purified by silica gel gel chromatography (hexane / ethyl acetate = 5/1 to 1/1). Obtained.

¾丽_{R (CDC1 3, 400 MHz)} δ 7.53 (d, 1H, J = l.8 Hz), 7.37-7.39 (m, 2H), 7.04 (dd, 1H, 1 = 2.3, 8.7 Hz), 6.28 ( d, 1H, J = 8.7 Hz), 5.89 (brs, 1H), 4.04 (brs, 2H), 3.91 (s, 3H).

(3) Methyl 7-chloro- 1- (2,4-dichlorophenyl) -2-oxo-2,3-dihydro-1H-benzimidazonole-5-caproloxylate

Under a nitrogen atmosphere, methyl 3-amino-5-chloro-4-[(2,4-dichloropheninole) amino] benzoate (4.98 g, 14.4 mmol) of Ν, Ν-dimethylformamide (50 To the solution, was added porponyldiimidazole (5.88 g, 36.3 mmol), and the mixture was stirred at 90 ° C for 3.5 hours. Water was added, and the mixture was extracted twice with ethyl acetate / toluene (1: 1), washed twice with water and then with saturated saline, and dried over magnesium sulfate. After filtration, the solvent was distilled off to obtain the title compound (5.41 g, quant.).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 10.25 (brs, 1H), 7.79 (d, 1H, J = l.4 Hz), 7.75 (d, 1H, J = 1.4 Hz), 7.61 (d, 1H, J = 2.0 Hz), 7.43-7.49 (ra, 2H), 3.92 (s, 3H). Reference Example 10 Methyl 7-co-mouth- 1- (2,6-dic-mouth)-2-oxo-2,3-dihydro-1H-benzimidazonole-5-canolepoxylate

(1) Methyl 3-chloro-4-[(2,6-dichlorophenyl) amino] -5-dibenzobenzoate Methyl 2,6-dichloroaline is used in place of 2,4-dichloroaline The compound was synthesized in the same manner as in Reference Example 9- (1).

¾丽_{R (CDC1 3, 400 MHz)} 5 9.05 (brs, 1H), 8.76 (d, 1H, J = 2.0 Hz), 8.16 (d, 1H, J = 2.0 Hz), 7.35 (d, 2H, J = 8.1 Hz), 7.15 (t, 1H, J = 8.1 Hz), 3.94 (s, 3H).

(2) Methyl 3-amino-5-chloro-4-([2,6-dichloropheninole) amino] benzoate Methyl 3-chloro-4--4-[(2,4-dichloropheninole) amino] -5— Synthetic method was performed in the same manner as in Reference Example 9- (2), using methinole 3-chloro-4--4-[(2,6-dichloropheninole) amino] -15--2-torate benzoate instead of nitrobenzoate. .

_{¾ NMR (CDC1 3, 400 MHz} ) S 7.44 (d, 1H, J = l.9 Hz), 7.33 (d, 1H, J = l.9 Hz), 7

.25 (d, 2H, J = 8.0 Hz), 6.86 (t, 1H, J = 8.0 Hz), 5.65 (brs, 1H), 4.07 (brs, 2H), 3.89 (s, 3H).

(3) Methinole 7-co mouth— 1- (2,6-dic mouth mouth) —2-oxo—2,3-dihydro-1H-benzimidazono-5-butyreboxylate

Methyl 3-amino-5-chloro-4-4-[(2,4-dichloropheninole) amino] benzoate is replaced by methyl 3-amino-5-chloro-4-4- [(2,6-dichlorophenol The compound was synthesized in the same manner as in Reference Example 9- (3), using (nore) amino] benzoate.

_{¾ NMR (CDC1 3, 400 MHz} ) 6 9.85 (brs, 1H), 7.79 (d, 1H, J = l.3 Hz), 7.76 (d,

1H, J = l.3 Hz), 7.52 (d, 2H, J = 7.7 Hz), 7.44 (t, 1H, J = 7.7 Hz), 3.92 (s, 3H

). Reference Example 1 1

Methyl 1_ (2,4-dichlorophenyl) -7_methyl-2-oxo-2,3-dihydro-1H-benzimidazonole-5_canolepoxylate

(1) Methyl 4-hydroxy-3-methylbenzoate

The synthesis was carried out in the same manner as in Reference Example 3- (1), using 4-hydroxy-3-methylbenzoic acid instead of 3-chloro-4-hydroxybenzoic acid. Awakening: _{R (CDC1 3, 400 MHz)} δ 7.84 (d, 1H, J = 2.0 Hz), 7.79 (dd, 1H, J = 2.0, 8.3 Hz), 6.80 (d, 1H, J = 8.3 Hz), 5.39 ( brs, 1H), 3.88 (s, 3H), 2.28 (s, 3H). (2) Methyl 4-hydroxy-3-methyl _5

Under a nitrogen atmosphere, 70% nitric acid (2.59 mL, 29.9 瞧 ol) was added dropwise to an acetic acid solution (65 mL) of methyl 4-hydroxy-3-methylbenzoate (4.52 g, 27.2 mraol) cooled to 0 ° C. The mixture was stirred at room temperature for 1 hour. Water was added, and the precipitated solid was collected by filtration to give the title compound (5.25 g, 91%).

_{¾ NMR (CDC1 3, 400 MHz} ) 5 11.21 (s, 1H), 8.67 (d, 1H, J = l.9 Hz), 8.11 (d, 1 H, J = 1.9 Hz), 3.93 (s, 3H) , 2.37 (s, 3H).

(3) Methyl 3-methyl-5-nitro-4-[{((trifluoromethyl) sulfoninole] oxy} benzoate

Instead of methyl 3-chloro-4-hydroxy-5-nitrobenzoate, methinole 4-hidoxy-3-methyl-5-nitrobenzozoate is squared, as in Reference Example 3- (3). And synthesized.

_{¾ NMR (CDC1 3, 400 MHz} ) 5 8.52 (d, 1H, J = l.8 Hz), 8.26 (d, 1H, J = l.8 Hz), 3 .97 (s, 3H), 2.56 (s , 3H).

(4) Methyl 4-[(2,4-dichlorophenyl) amino] -3-methyl-5-nitrobenzoate methyl 3-chloro-5-dito-4- (trisulfonolemethylsulfoninolexy) The synthesis was carried out in the same manner as in Reference Example 9_ (1), except that methyl 3-methyl-5-nitro-2--4-[[(triphneololomethinole) sulfonyl] oxy} benzoate was used instead of benzoate.

_{¾ NMR (CDC1 3, 400 MHz} ) 5 8.67 (d, 1H, J = l.9 Hz), 8.53 (brs, 1H), 8.09 (d, 1H, J = l.9 Hz), 7.44 (d, 1H , 1 = 2.3 Hz), 7.10 (dd, 1H, J = 2.3, 8.6 Hz), 6.46 (d, 1H, J = 8.6 Hz), 3.96 (s, 3H), 2.07 (s, 3H)

(5) Methyl 3-amino-4 _ [(2,4-dichrophenyl) amino] -5-methynolebenzoate Methyl 3-chloro-4-[[(2,4-dichrophthyl) amino] Reference Example 9 _ (2) using methyl 4-[(2,4-dichloromouth phenol) amino] -3-methyl-5-butenzoate instead of 5_-trobenzoate Was synthesized in the same manner as described above.

¾ Li _{R (CDC1 3, 400 MHz)} δ 7.34-7.35 (m, 3H), 6.99 (dd, 1H, J = l.3, 8.7 Hz), 6.22 (d, 1H, J = 8.7 Hz), 5.56 ( brs, 1H), 3.94 (brs, 2H), 3.90 (s, 3H), 2.16 (s, 3H). (6) Methyl l- (2,4-dioctanol) -7-methyl-2-oxo-2,3-dihydro-1H-benzimidazonole-5-canolepoxylate

Methyl 3-amino-5-cyclobutene-4-[(2,4-dichloropheninole) amino] Instead of benzoate, methyl 3-amino-4-[(2,4-dichloropheninole) amino] It was synthesized in the same manner as in Reference Example 9- (3) using —5-methylbenzoate.

¾丽_{R (CDC1 3, 400 MHz)} δ 9.90 (brs, 1H), 7.69 (s, 1H), 7.63 (d, 1H, J = l.8 Hz), 7.59 (s, 1H), 7.44-7.50 ( m, 2H), 3.90 (s, 3H), 1.90 (s, 3H). Reference Example 12

Methyl 1- (2,4-dichloromethyl) -7-methoxy-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate

(1) Methinole 4-hydroxy-3-methoxybenzoate

The compound was synthesized in the same manner as in Reference Example 3- (1) using 4-hydroxy-3-methoxybenzoic acid instead of 3-hydroxy-4-hydroxybenzoic acid.

_{¾ NMR (CDC1 3, 400 MHz} ) 5 7.64 (dd, 1H, J = l.8, 8.3 Hz), 7.55 (d, 1H, J = l.8 Hz), 6.94 (d, 1H, J = 8.3 Hz ), 5.99 (s, 1H), 3.95 (s, 3H), 3.89 (s, 3H).

(2) Methyl 4-hydroxy-3-methoxy-5-dibenzoate

It was synthesized in the same manner as in Reference Example 11- (2), using methyl 4-hydroxy-3-methoxybenzoate instead of methyl 4-hydroxy-3-methylbenzoate.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 11.08 (s, 1H), 8.44 (d, 1H, J = l.8 Hz), 7.76 (d, 1 H, J = 1.8 Hz), 4.01 (s, 3H) , 3.95 (s, 3H).

(3) Methyl 3-methoxy-5-nitro-2--4-{[(trifluoromethyl) sulfonyl] oxy} benzoate

It was synthesized in the same manner as in Reference Example 3- (3), using methinole 4-hydroxy-3-_methoxy-5-nitrobenzoate instead of methinole 3-chloro-4-hydroxy-5-nitrobenzoate. .

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.29 (d, 1H, J = l.9 Hz), 7.96 (d, 1H, J = l.9 Hz), 4 .06 (s, 3H), 4.00 (s , 3H).

(4) Methyl 4-[(2,4-dichlorophenyl) amino] -1-3-methoxy-5-nitrobenzoate methinole 3-chloro-5-nitro-4- (triphnoleolomethinolesulfonole Oxy) Benzoe Methyl 3-methoxy-5-nitro-4-{[(trifluoromethylinole) sulfonyl] oxy} benzoate was used in place of the salt, and was synthesized in the same manner as in Reference Example 9- (1).

(5) Methyl 3-amino-4-[[(2,4-dichloropheninole) amino] -1-methoxybenzoate methyl 3-chloro-4-[[2,4-dichloropheninole) amino]- Methyl 4-[(2,4-dichlorophenyl) amino] -3-methoxy-5-etrobenzozoate was used instead of 5-nitrobenzoate, as in Reference Example 9- (2). Synthesized.

(6) Methyl 1- (2,4-dichlorophenyl) -7-methoxy-2-oxo-2,3-dihydro-1H-benzimidazonole-5-canoleboxylate

Methyl 3-amino-5-chloro-4-[(2,4-dioctanolphenyl) amino] Instead of benzoate, methinole 3-amino-4- [(2,4-dichlorophenyl) amino] -5 -It was synthesized in the same manner as in Reference Example 9_ (3) using methoxybenzoate.

_{¾ MR (CDC1 3, 400 MHz} ) δ 10.33 (brs, 1H), 7.54-7.57 (m, 2H), 7.37-7.46 (m, 3H), 3.91 (s, 3H), 3.68 (s, 3H). Reference Example 13

Methyl 1- (2,4-dichloropheninole) -7-fluoro-2-oxo-2,3-dihydro-II-tobenzimidazole-5-carboxylate

(1) Methyl 3-fluoro-4-hydroxybenzoate

It was synthesized in the same manner as in Reference Example 3- (1) using 3-fluoro-4-hydroxybenzoic acid instead of 3-chloro-4-hydroxybenzoic acid.

¾觀_{R (CDC1 3, 400 MHz)} δ 7.76-7.79 (m, 2H), 7.04 (dd, 1H, J = 8.5, 8.5 Hz), 5.70 (brs, 1H), 3.90 (s, 3H).

(2) Methinole 3-Fluoro-4-hydroxy-5-nitrobenzoate

It was synthesized in the same manner as in Reference Example 11- (2) using methyl 3-fluoro-4-hydroxybenzoate instead of methyl 4-hydroxy-3-methyl / rebenzoate.

¾ Li _{R (CDC1 3, 400 MHz)} δ 10.82 (s, 1H), 8.64 (dd, 1H, J = l.9, 1.9 Hz), 8.07 (dd, 1H, J = l.9, 10.1 Hz), 3.96 (s, 3H).

(3) Methyl 3-fluoro-5-nitro-4-{[(trifluoromethyl) sulfonyl] oxy} benzoate

Methyl 3-Chloro-4-hydroxy-5-dibenzobenzoate The compound was synthesized in the same manner as in Reference Example 3- (3) using o-4-hydroxy-5-nitrobenzoate.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.62 (dd, 1H, J = l.9, 1.9 Hz), 8.24 (dd, 1H, J = l.9, 9.1 Hz), 4.02 (s, 3H).

(4) Methyl 4-[(2,4-dichrophthyl) amino] -3-fluoro-5-nitrobenzoate methinole 3-cook-mouth—5-nitro-4- (trifnorelolomethylsulfo Synthesized in the same manner as in Reference Example 9- (1), using methinole 3-benzolone instead of methinole 3-butanoleo-5-dinitro-4-4-{[(triphlenole methinole) snorrehoninole] oxy} benzoate instead of benzolate. did.

(5) Methyl 3-amino-4-[(2,4-dichlorophenyl) amino] -5-furrobenzoate methinole 3-octanol—4-1 [(2,4-dichloropheninole) amino] — Same as in Reference Example 9- (2), using methyl 4-[(2,4-dichloropheninole) amino] -3-fluoro-5-5-nitrobenzoate instead of 5-tronitrozoate And synthesized.

¾ employment _{R (CDC1 3, 400 MHz)} δ 7.36 (d, 1H, J = 2.3 Hz), 7.30 (dd, 1H, J = l.0, 1.7 Hz), 7.20 (dd, 1H, J = l.7 , 9.8 Hz), 7.05 (dd, 1H, J = 2.3, 8.7 Hz), 6.36 (d, 1H, J = 8.7 Hz), 5.68 (brs, 1H), 4.05 (brs, 2H), 3.91 (s, 3H ).

(6) Methyl 1- (2,4-dichlorophenyl) _7-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-5-carboxylate

Methyl 3-amino-5-coguchi-4--4-[(2,4-dichlorophenyl) amino] Instead of benzoate, methyl 3-amino-4-[(2,4-dichlorophenyl) amino] -5 The compound was synthesized in the same manner as in Reference Example 9- (3) using -benzoyl benzoate.

¾ image _{R (CDC1 3, 400 MHz)} S 9.35 (brs, 1H), 7.66 (d, 1H, J = l.3 Hz), 7.62 (d, 1H, J = 2.1 Hz), 7.57 (dd, 1H, J = l.3, 1.3 Hz), 7.48 (d, 1H, J = 8.4 Hz), 7.44 (dd, 1H, J = 2.1, 8.4 Hz), 3.92 (s, 3H).

Methyl 1- (2-chlorophenyl) -7-fluoro-2-oxo-2,3-dihydro-1H-benzimidazole-5-butanolboxylate

(1) Methyl 4-[(2-chlorophenyl) (ethoxycarponyl) amino] -3-fluoro-5-benzobenzoate

2-Chloro-3,5-Zinito Benzotrifluoride instead of Methinole 3-Fluoro-5 It was synthesized in the same manner as in Reference Example 6- (2) using -Nitro-4-{[(trifluoromethyl) sulfonyl] oxy} benzoate (Reference Example 13- (3)).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.45 (s, 1H), 7.93-7.97 (m, 1H), 7.51 (d, 1H, J = 7 .7 Hz), 7.22-7.38 (m, 3H), 4.19 -4.29 (m, 2H), 3.96 (s, 3H), 1.22 (t, 3H, J = 7.1 Hz).

(2) Methyl 3-amino-4-[(2-chloropheninole) (ethoxycarponyl) amino] -5-fur

Methyl 3-chloro-4--4-[(2,4-dichlorophenyl) amino] -methinole 4-5-[(2-chlorophenyl) (ethoxycarbol) amino] -3-fluoro instead of 5-nitrobenzoate It was synthesized in the same manner as in Reference Example 9_ (2) using -5-nitrobenzoate.

(3) Methinole 1- (2-chlorophenyl) -7_fluoro-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate

Under a nitrogen atmosphere, methyl 3-amino-4-[(2-chlorophenyl) (ethoxycarbonyl) amino] -5-fluorobenzoate (873 mg, 2.38 mmol) in methanol (20 raL), 4N hydrochloric acid A 1,1,4-dioxane solution (700 μΐ, 2.80 mmol) was added, and the mixture was heated under reflux for 5 hours. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1 to 0/1) to give the title compound (522 mg, 68%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 11.79 (brs, 1H), 7.70-7.73 (m, 2H), 7.51-7.60 (m, 2H), 7.48 (d, 1H, J = l.3 Hz), 7.45 (dd, 1H, J = l.3, 11.6 Hz), 3.85 (s, 3H).

2- (chloromethyl) -1-ethylpiperidine hydrochloride

(1) Ethyl piperidine-2-carboxylate hydrochloride

Under a nitrogen atmosphere, ethanol (100 mL) was added to pipecolic acid (7.00 g, 54.2 mmol), and thionyl chloride (5.00 mL, 68.5 mmol) was added dropwise under ice cooling, followed by stirring at 70 ° C for 4 hours. The solvent was distilled off, toluene was added, and the solvent was distilled off again to obtain the title compound (10.5 g, quant.).

¾ Keio _{R (DMS0- d 6, 400 MHz} ) δ 10.07 (br, 1H), 9.75 (br, 1H), 4.29 (q, 2H, J = 7 .1 Hz), 3.92-3.96 (m, 1H), 3.62-3.67 (ra, 1H), 3.09-3.15 (m, 1H), 2.24-2.31 (ra, 1H), 1.96-2.14 (m, 2H), 1.80-1.91 (m, 2H), 1.55-1.66 (m , 1H), 1.32 (t , 3H, J = 7.1 Hz).

(2) Ethyl 1-ethylbiperidine-2-carboxylate

Under a nitrogen atmosphere, ethyl piperidine-2-carboxylate hydrochloride (1.50 g, 7.74 mmol), acetonitrile (25 mL), sodium bicarbonate (1.96 g, 23.3 ramol), bromide (750 μΐ, 10.0 mmol) ) And black form (10 raL) were added, and the mixture was stirred at room temperature for 2 hours. To the mixture were added fodor ethyl (500 μΐ, 6.70 ramol) and triethylamine (2.0 mL, 14.3 mmol), and the mixture was further stirred at room temperature for 17 hours. Further, bromide chill (500 μΐ, 6.70 mmol) was added, and the mixture was stirred at 50 ° C. for 5 hours. Saturated aqueous sodium bicarbonate was added, extracted with ethyl acetate, and dried over magnesium sulfate. After filtration, the solvent was distilled off and the residue was purified by silica gel column chromatography (form: form / methanol = 20/1) to give the title compound (1.54 g, quant.).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 4.20 (q, 2H, J = 7.1 Hz), 3.06-3.11 (m, 1H), 2.99-3 .02 (m, 1H), 2.59-2.68 (m, 1H) , 2.28-2.37 (ra, 1H), 2.06-2.12 (m, 1H), 1.80 -1.87 (m, 1H), 1.63-1.78 (m, 4H), 1.24-1.38 (m, 1H), 1.26 (t, 3H, J = 7.1 Hz), 1.07 (t, 3H, J = 7.2 Hz).

(3) -Ethylbiperidine-2-yl) methanol

Under a nitrogen atmosphere, a solution of methyl 1-ethylpiperidine-2-forcenoreboxylate (1.00 g, 5.39 mmol) in tetrahydrofuran (10 mL) was mixed with lithium aluminum hydride (207 rag, 5.45 mmol) in tetrahydrofuran (10 mL). The suspension was added dropwise and stirred at room temperature for 2.5 hours. Water (200 tL), 4N aqueous sodium hydroxide solution (200 mL) and water (600 iL) were sequentially added, and the mixture was stirred at room temperature for 30 minutes. The mixture was filtered, the residue was washed with ethyl acetate, and the filtrate was evaporated. The title compound (664 rag, 86%) was obtained by repeating three times the addition of toluene and the evaporation of the solvent.

¾ NMR (CDC1 _3, 400 negation z) δ 3.75-3.79 (m, 1H ), 3.41-3.45 (m, 1H), 2.93-2.98 (m, 1H), 2.78-2.87 (m, 1H), 2.62 (brs , 1H), 2.42-2.51 (m, 1H), 2.33-2.38 (m, 1H), 2.21-2.27 (m, 1H), 1.52-1.73 (m, 4H), 1.29-1.46 (ra, 2H), 1 . 04 (t, 3 H, J = 7.2 Hz).

(4) 2- (chloromethyl) -1-ethylbiperidine hydrochloride

Under a nitrogen atmosphere, thionyl chloride (0.45 mL, 15.1 mmol) was added to a solution of -ethylbiperidine-2-yl) methanol (450 mg, 3.14 mmol) in chloroform (7.0 mL), and the mixture was heated under reflux for 2 hours. . Evaporate the solvent, add toluene and evaporate the solvent three times Thereby, the title compound (635 mg, quant.) Was obtained.

_{¾ NMR (DMSO- d 6, 400} MHz) δ 9.87 (brs, 1H), 4.03-4.09 (m, 2H), 3.51-3.58 (m, 1H), 3.25-3.31 (m, 1H), 3.10-3.18 ( m, 2H), 2.99-3.06 (m, 1H), 1.94-1.98 (m, 1H), 1.69-1.80 (m, 4H), 1.47-1.54 (m, 1H), 1.22 (t, 3H, J = 7.3 Hz). Reference Example 16

2- (chloromethyl) -1-methylbiperidine hydrochloride

It was synthesized in the same manner as in Reference Example 15- (4), except that 1-methyl-2-pyridinmethanol was used instead of (1-ethylpyridin-2-yl) methanol.

¾ Keio _{R (DMS0 - d 6, 400} MHz) δ 10.75 (brs, 1H), 4.06-4.10 (tn, 1H), 4.00-4.03 (ra, 1H), 3.45-3.52 (ra, 1H), 3.34-3.37 (in, 1H), 3.00-3.09 (m, 1H), 2.79 (d, 3H, J = 4.9 Hz), 1.93-1.97 (m, 1H), 1.64-1.78 (ra, 4H), 1.41-1.53 (m , 4H). Reference Example 17

2_ (Chloromethylethylpyrrolidine hydrochloride

(1) Ethyl prolinate hydrochloride

Synthesized in the same manner as in Reference Example 15- (1) using proline instead of pipecolic acid.

¾ 丽 R (DMS0-d6, 400 MHz) δ 11.19 (brs, 1H), 8.75 (brs, 1H), 4.42-4.49 (ra, 1H), 4.30 (q, 2H, J = 7.1 Hz), 3.52-3.58 (m, 2H), 2.40-2.49 (m, 1H), 2.01-2.21 (m, 3H), 1.33 (t, 3H, J = 7.1 Hz).

(2) Echinore 1-Echinore Proline

It was synthesized in the same manner as in Reference Example 15_ (2) using ethyl prolinate hydrochloride instead of ethyl piperidine-2-carboxylate hydrochloride.

_{¾ NMR (CDC1 3, 400 MHz} ) 8 4.19 (q, 2H, J = 7.1 Hz), 3.19-3.24 (m, 1H), 3.08-3 .12 (m, 1H), 2.71-2.79 (m, 1H) , 2.40-2.48 (m, 1H), 2.27-2.34 (m, 111), 2.08-2.15 (m, 1H), 1.88-1.97 (m, 2H), 1.77-1.85 (m, 1H), 1.28 (t, 3H, J = 7.1 Hz), 1.11 (t, 3H, J = 7.3 Hz).

(3) (1-ethylpyrrolidine-2-yl) methanol

Methyl 1-ethylpiperidine-2-ethylcarboxylate It was synthesized in the same manner as Reference Example 15- (3) using lolinate.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 3.60-3.64 (m, 1H), 3.37-3.40 (m, 1H), 3.15-3.20 (m, 1H), 2.85 (br, 1H), 2.76-2.84 (ra, 1H), 2.54-2.59 (ra, 1H), 2.18-2.31 (m, 2H), 1.81-1.93 (ra, 1H), 1.67-1.81 (m, 3H), 1.10 (t, 3H, J = 7.2 Hz) .

(4) 2- (chloromethyl) -toethylpyrrolidine hydrochloride

It was synthesized in the same manner as in Reference Example 15- (4), except that (1-ethylpyrrolidine-1-yl) methanol was used instead of (1-ethylpyrperidin-2-inole) methanol.

_{¾ NMR (DMS0- d 6, 400} MHz) δ 10.69 (brs, 1H), 4.13-4.17 (m, 1H), 3.94-4.00 (m, 1H), 3.69-3.78 (m, 1H), 3.52-3.59 ( m, 1H), 3.41-3.49 (m, 1H), 3.02-3.15 (m, 2H), 2.21-2.29 (m, 1H), 1.88-2.01 (m, 2H), 1.75-1.86 (m, 1H), 1.26 (t, 3H, J = 7.3 Hz). Reference example 18

2- [bis (cyclopropylmethyl) amino] ethanol

(1) Ethyl N, N-bis (cyclomethyl propylmethyl) glycinate

Under a nitrogen atmosphere, glycineethyl ester hydrochloride (2.00 g, 14.3 ramol) and carbonated lime (5.93 g, 42.9 mmol) were added to N, N-dimethylformamide (30 mL) and cyclopropinolemethyl bromide ( 2.91 mL, 30.0 mmol) were sequentially added, and the mixture was stirred at 50 ° C for 7 hours. Cycle methyl propylmethyl bromide (0.50 mL, 5.16 mmol) was added, and the mixture was stirred at 80 ° C for 6 hours. After adding ice, the mixture was extracted with ethyl acetate / toluene (1: 1), washed three times with a saturated sodium bicarbonate solution, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (form / methanol = 40/1) to give the title compound (2.18 g, 72%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 4.17 (q, 2H, J = 7.1 Hz), 3.59 (s, 2H), 2.58 (d, 4H, J = 6.6 Hz), 1.27 (t, 3H, J = 7.1 Hz), 0.85-0.90 (m, 2H), 0.48-0.53 (ra, 4H), 0.09-0.13 (m, 4H).

(2) 2- [bis (cyclopropylmethyl) amino] ethanol

Methyl 1 - Echirubiperijin - 2 - carboxylate instead Echiru N, using N- bis (consequent opening propyl methyl) glycinate, Reference Example 1 5- (3) and ¾ picture was synthesized in the same manner (CDC1 _3, 400 MHz ) δ 3.56 (t, 2H, J = 5.4 Hz), 2.76 (t, 2H, J = 5.4 Hz), 2 .46 (d, 4H, J = 6.6 Hz), 0.84-0.91 (m, 2H), 0.49-0.53 (m, 4H), 0.10-0.13 (tn, 4H). Reference Example 19

2- (Dicyclopropylamino) ethanol

(1) Prop-form formamide

Under a nitrogen atmosphere, ethanol (28-5 mL) and ethyl formate (28.4 mL, 353 mmol) were sequentially added to sodium carbonate (16.9 g, 159 mmol), and the mixture was cooled to -5 ° C. Subsequently, cyclopropylamine (6.50 g, 114 mmol) was added, and the mixture was stirred at room temperature for 25 hours. After filtration, the solvent was distilled off, and the residue was dissolved in ethyl acetate and filtered. The solvent was distilled off to obtain the title compound (8.09 g, 83 ° /.).

_{¾ NMR (CDC1 3, 400 MHz} ) δ (8.25 (d, J = 11.9 Hz), 8.14 (s)) (1H), (5.92 (br), 5.74 (br)) (1H), (2.70-2.77 ( m), 2.62-2.67 (m)) (1H), 0.75-0.84 (m, 2H),

(0.61-0.66 (m), 0.54-0.58 (m)) (2H).

(2) Benginore (Shiguchi propinole) Honoremamide

Under a nitrogen atmosphere, 60% sodium hydride (4.23 g, 1

To toluene (80 mL) was added, and the mixture was heated to 70 ° C. A solution of cyclopropylformamide (7.50 g, 88.1 mmol) in toluene (15 mL) was slowly added dropwise, and the mixture was stirred at 90 ° C for 10 minutes, and then heated to 40 ° C. Subsequently, a solution of penzinolebromide (13.6 mL, 115 mmol) in tonolene (15 mL) was added dropwise, and the mixture was stirred at 50 ° C for 13 hours. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1 to 1/1) to obtain the title compound (12.9 g, 84%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.38 (s, 1H), 7.23-7.39 (m, 5H), 4.53 (s, 2H), 2. 48-2.53 (m, 1H), 0.67-0.79 (m, 4H).

(3) N-benzyl-N-cyclopropylpropanamine

Under a nitrogen atmosphere, a tetrahydrofuran (200 raL) solution of a 0.89 N ethyl methacrylamide solution of tetrahydrofuran (78.0 mL, 69.4 mmol) was cooled to ⁻⁷⁸ ° C., and tetrisopropoxytitanium (11.1 _g , 39.0 mmol) was added. ) In tetrahydrofuran (20 mL) was added dropwise over 2 minutes and stirred for 2 minutes. Subsequently, a solution of benzyl (cyclopropyl) formamide (5.28 g, 30.2 ol) in tetrahydrofuran (10 mL) was added dropwise over 1 minute, and the mixture was added at -78 ° C for 30 minutes. After stirring, the temperature was gradually raised to room temperature, and the mixture was stirred at room temperature for 36 hours. A saturated aqueous ammonium chloride solution (150 mL) and water (50 mL) were sequentially added, and the mixture was stirred for 4 hours. After filtration and washing of the filtrate with ether, the filtrate was made alkaline with a 15% aqueous sodium hydroxide solution, and the edenole layer was removed. The aqueous layer was extracted three times with ether, and the combined ether layers were washed with saturated saline and dried over potassium carbonate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1) to obtain the title compound (2.97 g, 53%).

删_{R (CDC1 3, 400 MHz)} δ 7. 25-7. 33 (m, 5H), 3. 83 (s, 2H), 1. 80-1. 85 (m, 2H), 0. 37-0 .46 (m, 8H).

(4) N-cyclopropyl propaneamine hydrochloride

Under a nitrogen atmosphere, a 4 N hydrochloric acid / 1,4-dioxane solution (2.7 g) was added to a solution of N-benzyl-N-cyclopropylcyclopropanamine (1.73 g, 9.24 mmol) in methanol (12 mL). 5 mL) and 10% palladium on carbon (173 mg, 50 ° / .wet) were sequentially added, and the mixture was stirred under a hydrogen atmosphere at 0.3 MPa for 16 hours. After filtration, the solvent was distilled off to obtain the title compound (1.37 g, quant.).

_{¾ NMR (DMS0- d 6, 400} MHz) δ 9. 49 (brs, 2H), 2. 73 (ra, 2H), 0. 90-0. 91 (m, 4H), 0. 73-0. 75 (m, 4H).

(5) Etinole N, N_ disuccinic mouth propynoleglycinate

Under a nitrogen atmosphere, a solution of N-cyclopropylcyclopropanamine hydrochloride (500 mg, 3.74 ra raol) in Ν, Ν-dimethylformamide (10 mL) was added to potassium carbonate (1.10 g). , 7.96 mrao 1) and ethyl bromoacetate (415 μΐ, 3.74 ramol) were added sequentially, and the mixture was incubated at room temperature for 4 hours. Water was added, extracted with ethyl acetate / toluene (1: 1), washed three times with saturated aqueous sodium hydrogen carbonate, and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to give the title compound (528 mg, 77%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 4. 19 (q, 2H, J = 7. 1 Hz), 3. 48 (s, 2H), 2. 43-2. 49 (m, 2H), 1. 29 (t, 3H, J = 7.1 Hz), 0.41-0.47 (m, 4H), 0.35-0.39 (m, 4H).

(6) 2- (dicyclopropylamino) ethanol

It was synthesized in the same manner as in Reference Example 15- (3) using ethyl N, N-dicyclopropyl propyl glycinate instead of methyl 1-ethylpiperidine-2-carboxylate. _{¾ NR (CDC1 3, 400 MHz} ) δ 3.66 (dt, 2H, J = 5.4, 5.6 Hz), 2.91 (t, 2H, J = 5.6 H z), 2.22 (t, 1H, J = 5.4 Hz), 1.89 —1.95 (m, 2H), 0.44—0.50 (m, 4H), 0.38— O.42 (m, 4H). Reference Example 20

N-Ethyl-2-methoxyethaneamine hydrochloride

(1) t-Petinoleethyl carbamate

Under a nitrogen atmosphere, chloroform / form (150 mL) and triethylamine (23.0 mL, 165 mmol) were added to ethyl / reamine hydrochloride (11.8 g, 145 mmol), and di-t-butyl dicarbonate (30. 0 g, 137 mmol) was added little by little, and the mixture was stirred at room temperature for 7 hours. Water was added, extracted with chlorophonolem, washed with saturated saline, and dried over magnesium sulfate. After filtration, the solvent was distilled off and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to give the title compound (20.9 g, quant.).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 4.47 (br, 1H), 3.14-3.18 (m, 2H), 1.45 (s, 9H), 1 .11 (t, 3H, J = 7.2 Hz).

(2) t-Puchinoletyl (2-methoxetinole) carbamate

Under a nitrogen atmosphere, 55% sodium hydride (500 mg, 11.5 mmol) was added to a solution of t-butylethylcarbamate (1.45 g, 11.0 mmol) in N, N-diethylformamide (30 mL). 2-Bromoethyl) methyl ether (1.20 mL, 13.1 liters) was added sequentially, and the mixture was stirred at 50 ° C for 3 hours. Water was added, extracted with ethyl acetate / toluene (1: 1), washed twice with water, and dried over magnesium sulfate. After filtration, the solvent was distilled off and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to give the title compound (1.34 g, 60%).

_{¾ NMR (CDC1 3, 400 MHz} ) 6 3.48 (m, 2H), 3.35 (s, 9H), 3.28-3.35 (m, 4H), 1. 46 (s, 9H), 1.09 (t, 3H, J = 7.2 Hz).

(3) N-ethyl-2-methoxyethaneamine hydrochloride

Under a nitrogen atmosphere, a 4N dioxane hydrochloride solution (10 mL) was added to a solution of t-butylethyl (2-methoxethyl) carbamate (1.14 g, 5.61 mmol) in dioxane (10 mL), and the mixture was added at 50 ° C for 8 hours. Stirred. The solvent was distilled off, toluene was added thereto, and the solvent was distilled off. The residue was suspended in getyl ether and collected by filtration to obtain the title compound (662 mg, 85%). ¾ Keio _{R (DMSO - d 6, 400} MHz) δ 8.94 (br, 2H), 3.60 (t, 2H, J = 5.2 Hz), 3.30 (s, 3H), 3.05 (m, 2H), 2.91-2.93 ( m, 2H), 1.19 (t, 3H, J = 7.3 Hz). Reference Example 21

N-ethyl-2-fluoroethaneamine hydrochloride

(1) t-Puccinoletyl (2-fluoroethyl)

Under a nitrogen atmosphere, triethylamine (1.84 mL, 13.2 mmol) was added to a solution of 2-fluoroethanol (769 rag, 12.0 mmol) in dichloromethane (50 mL), and the mixture was cooled to 0 ° C. Subsequently, methanesulfonyl chloride (1.02 mL, 13.2 mmol) was sequentially added, and the mixture was stirred at 0 ° C for 1.5 hours. Water was added, and the mixture was extracted with black form and dried over magnesium sulfate. After filtration, the solvent was distilled off to obtain a crude mesyl compound (1.88 g). Thereafter, synthesis was carried out in the same manner as in Reference Example 21- (2), using a crude mesyl compound instead of (2-promoetinole) methyl ether.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 4.46-4.58 (m, 2H), 3.45-3.51 (m, 2H), 3.31 (m, 2H), 1.46 (s, 9H), 1.12 (t, 3H, J = 7.1 Hz).

(2) N-ethyl-2-fluoroethaneamine hydrochloride

t_butyl ethynole (2- methoxyl) instead of carbamate

The compound was synthesized in the same manner as in Reference Example 20- (3) using 2-fluoroethyl carbamate. _{¾ NMR (DMSO- d 6, 400} MHz) δ 9.25 (brs, 2H), 4.75 (dt, 2H, J = 47.2, 4.6 Hz), 3.25 (dt, 2H, J = 28.1, 4.6 Hz), 2.97 (q , 2H, J = 7.2 Hz), 1.22 (t, 3H, J = 7.2 Hz). Reference Example 22

3-Phenylone mouth pyrrolidine hydrochloride

(1) Benzinole 3-hydroxypyrrolidine-1-force boxylate

Under a nitrogen atmosphere, 3-hydroxypyrrolidine (1.00 g, 11.5 mmol) Tetorahi Dorofura emissions ⁽⁵ 0 mL) was added Toryechi ^ / Amin ⁽² .0 mL, 14.3 mmol) of the mixture was cooled to 0 ° C. Benzyloxycarboyl chloride (6.8 m, 11.5 mmol) was slowly added dropwise, and the mixture was stirred at 0 ° C for 3 hours. Water was added, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. After filtration, the solvent is distilled off and silica gel column chromatography ( The title compound (1.8 g, 58%) was obtained by purification with hexane / ethyl acetate = 1/1 to 0/1).

^{_{L H MR (CDC1 3, 400}} MHz) δ 7.29-7.37 (m, 5H), 5.14 (s, 2H), 4.48 (m, 1H), 3. 41-3.60 (m, 4H), 1.95-2.03 (m , 2H), 1.66-1.69 (m, 1H).

(2) Benzyl 3-fluoropyrrolidine-1-carboxylate

Under a nitrogen atmosphere, a solution of benzyl 3-hydroxypyrrolidine-1-carboxylate (1.00 g, 4.52 mmol) in dichloromethane (15 mL) was cooled to -78 ° C, and dimethylaminosulfuric artfluoride (0.66 raL , 4.97 mmol) was added dropwise. The mixture was slowly heated to room temperature and stirred at room temperature for 3 hours. On the way, dimethylaminosulfur trifluoride (0.40 mL, 3.01 mmol) was added. Water and saturated aqueous sodium bicarbonate were added, extracted with ethyl acetate, and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1 to 1/1) to obtain the title compound (668 mg, 66%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.31-7.38 (m, 5H), 5.16 (s, 2H), 5.12-5.31 (m, 1H), 3.47-3.84 (m, 4H), 2.20-2.30 (m, 1H), 1.91-2.07 (m, 1H).

(3) 3-Fluoropyrrolidine hydrochloride

Under a nitrogen atmosphere, a solution of benzyl 3-fluoropyrrolidin-1-carboxylate (638 rag, 2.86 mmol) in methanol (10 mL) and acetic acid (1.0 mL) were added to 10% palladium hydroxide (200 mg). For hydrogenation. The mixture was filtered through celite, 4N dioxane hydrochloride solution (1 mL) was added, and the solvent was distilled off to obtain the title compound (389 mg, quant.).

¾丽R (DMS0-d _6, 400丽z) 5 9.72 (br, 2H ), 5.43 (ddd, 1H, J = 3.7, 3.7, 52.8

Hz), 3.16—3.48 (m, 4H), 1.97-2.26 (m, 2H).

t-butyl 4- (2-hydroxyshethylidene) piperidine-1-carboxylate

(1) t_butyl 4- (2-ethoxy-2-oxoethylidene) piperidine-1-carboxylate

Under a nitrogen atmosphere, tetrahydrofuran (20 mL) was added to 55% sodium hydride (720 mg, 16.5 mmol), and the mixture was cooled to 0 ° C. After dropping a solution of triethylphosphonoacetate (3.25 mL, 16.4 ramol) in tetrahydrofuran (20 raL), add 1- (t-butoxycarbol) -4 A solution of -piperidone (3.00 g, 15.1 mmol) in tetrahydrofuran (20 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hours. Water was added, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. After filtration, the solvent was distilled off and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to give the title compound (2.82 g, 69%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 5. 71 (s, 1H), 4. 15 (q, 2H, J = 7. 1 Hz), 3. 46-3. 52 (m, 411), 2. 92-2. 95 (tn, 2H), 2.27-2. 29 (m, 2H), 1.47 (s, 9H), 1.28 (t, 3 to I, J = 7.1 Hz) .

(2) t-Butyl 4- (2-hydroxyethylidene) piperidine-1-carboxylate Under a nitrogen atmosphere, t-butyl 4- (2-ethoxy-2-oxoethylidene) piperidine-1 -force ropoxylate (2.50 g, 9.28 mmol) in toluene (50 mL) was cooled to _78 ° C, and 1.01 N diisobutylaluminum hydride toluene solution (18.4 mL, 18.6 mmol) was added. The mixture was added dropwise and stirred at -78 ° C for 3 hours. After adding water and a 5% aqueous solution of potassium hydrogen sulfate, the mixture was filtered, extracted with ethyl acetate, washed with saturated saline and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give the title compound (1.99 g, 94%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 5. 50 (t, 1H, J = 7. 0 Hz), 4. 18 (d, 2H, J = 7. 0 Hz), 3. 40-3. 45 ( ra, 4H), 2.25—2.28 (m, 2H), 2.17-2.20 (m, 211), 1.47 (s, 9H). Reference Example 2 4

Di-t-butinole “(2E) -4-Chloropto-2-en-1-ynole] imidodicarbonate

Under a nitrogen atmosphere, 55% sodium hydride (360 mg, 8.25) was added to a solution of di-1-butyliminodicarboxylate (1.50 g, 6.90 mmol) in N, N-dimethylformamide (30 mL). mmol) and stirred at room temperature for 1 hour. After cooling to 0 ° C, trans-1,4-dichloro-2-butene (5.40 mL, 51.1 mmol) was added, and the mixture was stirred at 60 ° C for 3 hours. After adding zK, the mixture was extracted with ethyl acetate / tonolene (1: 1), washed with a 5% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, and then dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to obtain the title compound (1.67 g, 79%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 5. 74-5. 82 (ra, 2H), 4. 18 (d, 2H, J = 4. 3 Hz), 4. 05 ( d, 2H, J = 5.8 Hz), 1.51 (s, 18H). Reference Example 25

1-Promo-2-[(ethoxymethoxy) methinole] benzene

Under a nitrogen atmosphere, a solution of 2-bromobenzyl alcohol (3.00 g, 16.0 mmol) in tetrahydrofuran (50 mL) was added at 0 ° C to diisopropylethylamine (3.50 mL, 20.1 mmol). Chloromethylethyl Ether (1.35 mL, 14.6 tmol) was sequentially added, and the mixture was stirred at room temperature for 19 hours and heated under reflux for 8 hours. Water was added, extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 7/1) to obtain the title compound (2.75 g, 77%).

丽_{R (CDC1 3, 400 MHz)} δ 7.55 (d, 1H, J = 7.7 Hz), 7.48 (d, 1H, J = 7.7 Hz), 7 • 32 (dd, 1H, J = 7.7, 7.7 Hz), 7.16 (dd, 1H, J = 7.7, 7.7 Hz), 4.82 (s, 2H), 4.68 (s, 2H), 3.68 (q, 2H, J = 7.0 Hz), 1.24 (t, 3H, J = 7.0 Hz) .Reference Example 26

1-promo-2-((methoxymethoxy) ethyl) benzene

(1) 2- (2-bromopheninole) ethanol

Under a nitrogen atmosphere, a solution of 2-bromophenylacetic acid (5.00 g, 23.3 mmol) in tetrahydrofuran (50 mL) was heated to 60 ° C and a suspension of lithium aluminum hydride (880 mg, 23.2 mmol) in tetrahydrofuran (50 mL) was added. And stirred at 60 for 2.5 hours. After cooling to 0 ° C, water (0.9 raL), 4N aqueous sodium hydroxide solution (0.9 mL) and water (2.7 mL) were sequentially added, and the mixture was stirred at room temperature for 1 hour. The solid was removed by filtration, ethyl acetate was added to the filtrate, washed with saturated saline, and dried over magnesium sulfate. After filtration, the solvent was distilled off to obtain the title compound (4.15 g, 89%).

删_{R (CDC1 3, 400 MHz)} δ 7.56 (d, 1H, J = 7.6 Hz), 7.22-7.34 (tn, 2 H), 7.11 (dd, 1H, J = 7.6, 7.6 Hz), 3.89 (dt, 2H, J = 6.6, 6.6 Hz), 3.04 (t, 2H, J = 6.6 Hz), 2.88 (t, 1H, J = 6.6 Hz).

(2) 1-Bromo-2-[(methoxymethoxy) ethyl] benzene

Replace 2-bromobenzino alcohol with 2- (2-bromophene) ethanol The synthesis was carried out in the same manner as in Reference Example 25 using chloromethyl methyl ether instead of mouth methyl ethyl ether.

¾丽R (CDC1 _3, 400丽z) δ 7.54 (dd, 1H , J = l.0, 7.7 Hz), 7.21-7.32 (m, 2H), 7.08 (ddd, 1H, J = l.7, 7.7 , 7.7 Hz), 4.63 (s, 2H), 3.78 (t, 2H, J = 7.1 Hz), 3.31 (s, 3H), 3.06 (t, 2H, J = 7.1 Hz).

1-Promo-2- (methoxymethoxy) benzene

Under a nitrogen atmosphere, a solution of 2-bromobenzyl alcohol (3.0 g, 16 mraol) in tetrahydrofuran (70 mL) was added with sodium hydride (55%, 770 mg, 17.6 ramol) and iodomethane (1.25 ml, 20 mraol). Was added and stirred at room temperature for 2 hours. Water was added, extracted with ethyl acetate, and dried over magnesium sulfate. After filtration, the solvent was distilled off and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 15/1) to obtain the title compound (2.88 g, 89%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.54 (dd, 1 H, J = 7.5, 1 Hz), 7. 6 (dd, 1 H, J = 7.5, 1 Hz), 7.32 (ddd, 1 H, J = 7.5, 7.5, 1 Hz), 7.15 (ddd, 1 H, J = 7.5, 7.5, 1 Hz), 4.53 (s, 2 H), 3.47 (s, 3 H).

7-bromo-1-benzofuran

(1) 1-bromo-2- (2,2-jetoxetoxy) benzene

Under a nitrogen atmosphere, a solution of 2-bromophenol (3.48 mL, 30 mmol) in N, N-dimethylformamide (20 mL) was added to sodium hydride (55%, 1.40 g, 33 mmol), and bromoacetoaldehyde. Getyl acetal (6.8 mL, 45 mmol) was added, and the mixture was stirred at 120 ° C for 2 hours. Water was added, extracted with ethyl acetate, and the organic layer was washed three times with water and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 9/1) to obtain the title compound (11 g).

Negation R (CDC1 _3, 400丽z) δ 7.53 (dd, 1 H, J = 8, 1 Hz), 7.23 (ddd, 1 H, J = 8, 8, 1 Hz), 6.90 (dd, 1 H, J = 8, 1 Hz), 6.84 (ddd, 1 H, J = 8, 8, 1 Hz), 4.88 (d, 1 H, J = 5 Hz), 4.05 (d, 2 H, J = 5 Hz) ), 3.81 (m, 2 H), 3.70 (ra, 2 H), 1.25 (t, 6 H, J = 7 Hz).

(2) 7_promo-1-benzofuran

Under a nitrogen atmosphere, polyphosphoric acid (12 g) was added to a solution of 1-bromo-2- (2,2-ethoxyethoxy) benzene (5.4 g, 18.7 mmol) in benzene (50 mL) with monochrome mouth, and 130. The mixture was stirred at C for 2 hours. Aqueous sodium bicarbonate was added, extracted with getyl ether, and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane) to give the title compound (1.73 g, 2steps 60%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.69 (d, 1 H, J = 2 Hz), 7.54 (dd, 1 H, J = 8, 1 Hz), 7.46 (dd, 1 H, J = 8, 1 Hz), 7.12 (dd, 1 H, J = 8, 8 Hz), 6.85 (d, 1 H, J = 2 Hz).

7-bromo-1-benzothiophene

(1) 1-promo-2-[(2,2-jetoxetinole) thio] benzene

The compound was synthesized in the same manner as in Reference Example 28_ (1) using 2-bromothiophenol instead of 2-bromophenol.

(2) 7-Promo-1-benzothienefen

In the same manner as in Reference Example 28- (2), it was synthesized from 1-bromo-2 _ [(2,2-diethoxyshetyl) thio] benzene.

Hiring R (CDC1 ₃ , 400 MHz) δ 7.78 (dd, 1 H, J = 8, 1 Hz), 7.51 (d, 1 H, J = 5 Hz), 7.49 (d, 1 H, J = 7.5 Hz) ), 7.43 (d, 1 H, J = 5 Hz), 7.25 (dd, 1 H, J = 8, 7.5 Hz).

1- (benzyloxy) -2-bromobenzene

Under a nitrogen atmosphere, a solution of 2-bromophenol (1.16 mL, 10 mmol) in N, N-dimethylformamide (15 mL) was added with benzylbutamide (1.19 mL, 10 mmol) and potassium carbonate (4.1 g). , 30 mmol) and stirred at room temperature for 5 hours. Water was added, extracted with ethyl acetate / toluene (1: 1), and the organic layer was washed three times with water and dried over magnesium sulfate. After filtration, the solvent was distilled off and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/3). The title compound (2.81 g, quant.) Was obtained. Reference example 3 1

1-Bromo-2- (cyclopropyl / remethoxy) benzene

Synthesized from 2-bromophenol and cyclopropylmethyl bromide in the same manner as in Reference Example 30.

¾ Ran _{R (CDC1 3, 400 MHz)} δ 7. 53 (dd, 1 H, J = 7. 5, 1 Hz), 7. 23 (ddd, 1 H, J = 7. 5, 1 Hz), 6 88 (dd, 1 H, J = 7.5, 1 Hz), 6.82 (ddd, 1 H, J = 7.5, 7.5, 1 Hz), 3.89 (d, 2 H, J = 6.5 Hz), 1.30 (m, 1H), 0.65 (m, 2H), 0.40 (ra, 2H) .Reference example 3 2

1-Bromo_2_ (2-methoxyethoxy) benzene

In the same manner as in Reference Example 30, it was synthesized from 2-promophenol and 2-bromoethyl methyl ether.

¾删_{R (CDC1 3, 400 MHz)} δ 7. 53 (dd, 1 H, J = 7. 5, 1 Hz), 7. 25 (ddd, 1 H, J = 7. 5, 1 Hz), 6 92 (dd, 1 H, J = 7.5, 1 Hz), 6.84 (ddd, 1 H, J = 7.5, 7.5, 1 Hz), 4.18 (d, 2 H, J = 5 Hz), 3.82 (d, 2 H, J = 5 Hz), 3.49 (s, 3 H) .Reference example 3 3

1-prop-2-in-1-inoleymidazolidine-2-one

Under a nitrogen atmosphere, a 1.47 N butyllithium hexane solution (15.8 mL, 23.2 mmol) was added dropwise to a suspension of ethylene urea (2.00 g, 23.2 mmol) in tetrahydrofuran (80 raL). did . Further, 3-bromopropyne (2.00 mL, 22.4 mmol) was added, and the mixture was stirred at room temperature for 30 minutes and at 50 ° C for 2 hours. A 5% aqueous solution of potassium hydrogen sulfate was added, extracted with ethyl acetate, and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 → 0/1) to obtain the title compound (641 mg, 22%).

_{MR (CDC1 3, 270 MHz)} δ 4. 74 (brs, 1H), 4. 02 (d, 2H, J = 2. 4 Hz), 3. 41-3. 57 (m, 4H), 2. 24 (t, 1H, J = 2.4 Hz). Reference example 3 4

1 _Promo _2- (2_Methoxyethynole) benzene

The synthesis was carried out in the same manner as in Reference Example 27, using 2-bromophenethylanolecone instead of 2-bromobenzyl alcohol.

¾丽_{R (CDC1 3, 400 MHz)} δ 7. 54 (dd, 1 H, J = 7. 5, 1 Hz), 7. 25 (m, 2 H), 7. 07 (ddd, 1 H, J = 7. 5, 7.5 '1 Hz), 3.61 (t, 2 H, J = 7 Hz), 3.37 (s, 3 H), 3.03 (t, 2 H, J = 7 Hz). Reference Example 3 5

7_PROMO-1-Methyl-1H-indole

(1) 7-Promo-1H-indole

Under a nitrogen atmosphere, a solution of vinylmagnesium bromide in tetrahydrofuran (1.0 mL / L, 51 mL, 51 mmol) was added to a solution of 2-bromoditrobenzene (3.43 g, 17 mmol) in tetrahydrofuran (100 mL). And stirred at -40 ° C for 40 minutes. Water was added, extracted with getyl ether, and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/10) to obtain 7-bromoindole (625 mg, 19%).

(2) 7-Promo-1-methyl-1H-indole

It was synthesized in the same manner as in Reference Example 27 using 7-bromo-1H-indole instead of 2_bromobenzyl alcohol.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7. 52 (dd, 1 H, J = 8, 1 Hz), 7. 33 (dd, 1 H, J = 8, 1 Hz), 6. 98 (d, 1 H, J = 3 Hz), 6.90 (dd, 1 H, J = 8, 8 Hz), 6.45 (d, 1 H, J = 3 Hz), 4.15 (s, 3 H) Reference example 3 6

1-Bromo-2-ethoxybenzene

In the same manner as in Reference Example 30, the compound was synthesized from 2-promophenol and benzoyl chloride. Reference Example 3 7 4-Cross-2--1-odo-2-methoxybenzene

(1) (4-chloro-2-methoxyphenyl) amine

Under a nitrogen atmosphere, to 80 ° C heated tin (II) chloride dihydrate (18. 6 g, 82. 4 mmol ) in ethanol (50 mL) solution of ⁵ - black port - ² - Two trois A suspension of dissol in ethanol (50 mL) was added dropwise, and the mixture was heated under reflux for 3 hours. The solution was transferred to overlay water, adjusted to pH about 8, extracted three times with ethyl acetate, washed sequentially with saturated overlay water and saturated saline, and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to give the title compound (2.83 g, 67%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 6. 75-6. 77 (m, 2H), 6. 62 (d, 1H, J = 8. 8 Hz), 3. 84 (s, 3H), 3. 76 (brs, 2H).

(2) 4-Chloro-1-ode-2-methoxybenzene

Under a nitrogen atmosphere, a solution of sodium nitrite (963 rag, 14.0 mraol) in concentrated sulfuric acid (10 mL) was cooled to 0 ° C, and (4-chloro-2-methoxyphenyl) amine (2.00 g, 12. A solution of 7 (mol) in acetic acid (20 mL) was added dropwise, and the mixture was stirred at 45 ° C for 2 hours. After returning to room temperature, a solution of potassium iodide (3.10 g, 18.7 ramol) in water (10 mL) was added dropwise, and the mixture was stirred at room temperature for 18 hours. Water was added, the mixture was extracted with ethyl acetate, washed sequentially with an aqueous sodium thiosulfate solution, water, and saturated saline, and then dried over magnesium sulfate. After filtration, the solvent was distilled off and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1) to give the title compound (2.76 g, 81%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7. 67 (d, 1H, J = 8. 3 Hz), 6. 83 (d, 1H, J = 2. 2 Hz), 6. 70 (dd, 1H, 1 = 2.2, 8.3 Hz), 3.88 (s, 3H). Reference example 3 8

N_ (2-Hydroxyshechinole)-4-pentinamide

Under a nitrogen atmosphere, thionyl chloride (2.0 mL) was added to 4-pentynic acid (200 mg, 2.03 mmol), and the mixture was heated under reflux for 1 hour. After concentration under reduced pressure, dissolving in tetrahydrofuran (3.0 mL), the solution was added dropwise to an ice-cooled solution of 2-ethanolamine (0.45 mL) in tetrahydrofuran (3.0 mL), and the mixture was added at room temperature for 1.5 hours. Stirred. The reaction solution was acidified by adding aqueous hydrochloric acid, extracted with ethyl acetate, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the title compound (128 mg, 45%). Example 1

3- (2-chlorophenyl) -1- (2- (ethylpyramino) ethyl) -4-fluoro-3-hydroxy-2-oxoindolin-6-canolepoxamide hydrochloride

(1) 1- [2- (Jethylamino) ethynole]-4-Fluoro-6-odo-1H-indole-2,3-dione

In a nitrogen atmosphere, a solution of 4-fluoro-6-odo-1H-indole-2,3-dione (Reference Example 5) (1.00 g, 3.44 mmol) in N, N-dimethylformamide ( 20%), add 60% sodium hydride (351 rag, 8.78 mmol) and 2-ethylethylethyl chloride hydrochloride (715 mg, 4.15 瞧 o 1), and add Stir for 5 hours. The reaction solution was transferred to ice water, extracted twice with ethyl acetate / toluene (1: 1), washed twice with saturated aqueous sodium hydrogen carbonate, and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 to 1/2) to obtain the title compound (252 mg, 19%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7. 18-7. 20 (ra, 2H), 3. 77 (t, 2H, J = 6. 4 Hz), 2. 67 (t, 2H, J = 6 4 Hz), 2.55 (q, 4H, J = 7.1 Hz), 0.97 (t, 6H, J = 7.1 Hz).

(2) 3- (2-Chloropheninole)-1-[2- (Jetylamino) ethyl] -4 -Fluoro-3-Hydroxy-6-ode-1,3-Dihydro-2H-indole- 2-on

In a nitrogen atmosphere, 1- [2- (Jetylamino) ethyl] -4-fluoro-6-thio-1H-Indone mono-2,3-dione (227 mg, 0.582 mmol) in getyl ether (4.5 mL) and toluene (1.5 mL) were added, and a 0.707 N 2-chloromouth phenylmagnesium bromide diethyl ether solution (0.92 mL, 0.650 mmol) prepared at the time of use was added dropwise. The mixture was stirred at room temperature for 5 hours. Saturated aqueous sodium hydrogen carbonate was added, extracted with ethyl acetate, and dried over magnesium sulfate. After filtration, solvent Is distilled off and silica gel column chromatography (chloroform / methanol = 80/1

6060/1) to give the title compound (194 mg, 66%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.11 (dd, 1H, J = l.3, 7.6 Hz), 7.41 (ddd, 1H, J = l.

One

3, 7.6, 7.6 Hz), 7.27-7.32 (m, 2H), 7.13 (d, 1H, J = l.1 Hz), 7.07 (dd, 1H, J = l.3, 7.6 Hz), 3.89-3.97 (m, 1H), 3.69-3.75 (m, 1H), 2.70-2.81 (ra, 2H), 2.56-2.67 (m, 4H), 1.03 (t, 6H, J = 7.1 Hz).

(3) 3- (2-Chlorophenyl) -l- [2- (Jethylamino) ethyl] -4-Fluoro-3-Hydroxy-2-oxoindrin_6_Carbonitrile

Under a nitrogen atmosphere, 3- (2-chlorophenyl) -1--1- [2- (ethylamino) ethyl] -4-fluoro mouth-3-hydroxy-6-odo-1,3-dihydro-2H-indole- To a solution of 2-one (150 mg, 0.298 mraol) in N, N-dimethylformamide (3 mL) was added 60% zinc cyanide (52.5 mg, 0.268 mmol) and tetrakistriphenylphosphine palladium (70 · 2 mg, 0.0607 mmol) and stirred at 70 ° C for 10 hours. The mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added, extracted with ethyl acetate / toluene (1: 1), washed with saturated aqueous sodium hydrogen carbonate, and dried over magnesium sulfate. After filtration, the solvent was distilled off and the residue was purified by silica gel column chromatography (form: methanol / methanol = 80/1 to 50/1) to give the title compound (65.8 mg, 55%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.13 (dd, 1H, J = l.5, 7.8 Hz), 7.44 (ddd, 1H, J = l. 5, 7.8, 7.8 Hz), 7.33 (ddd, 1H, J = l.5, 7.8, 7.8 Hz), 7.29 (d, 1H, J = l.2 Hz), 7.04 (d, 1H, J = l.2 Hz), 7.00 (dd, 1H, J = 1.5, 7.8 Hz), 4.00-4.07 (m, 1H), 3.68-3.75 (m, 1H), 2.70—2.81 (m, 2H), 2.53-2.69 (m, 4H), 1.02 (t, 6H, J = 7.1) Hz).

(4) 3- (2-Mouth mouth feninole) -1-[2- (Jetylamino) ethyl] -4-fluoro-3-hydroxy-2-oxoindrin-6-carboxamide hydrochloride

Under a nitrogen atmosphere, 3- (2-chlorophenyl) -1- [2- (ethylpyramino) ethyl] -4-fluoro-t- of 3-hydroxy-2-oxoindolin-6-carboditrinole (50.0 mg, 0.124 mmol) -Butyl alcohol solution (3 mL) was heated at 50 ° C., and powdered hydroxylic powder (ca. 50 mg) was added, followed by stirring for 1 hour. After cooling to room temperature, water was added, extracted with ethyl acetate, and dried over magnesium sulfate. After filtration, the solvent was distilled off, and 1,4-dioxane (2 mL) and a 4N hydrochloric acid / 1,4-dioxane solution (1 mL) were added, and the solvent was distilled off. The operation of suspending in getyl ether and evaporating the solvent was repeated three times to obtain the title compound (53.0 mg, 94%). _{¾ MR (DMSO- d 6, 400} MHz) δ 10.11 (brs, 1H), 8.10-8.12 (ra, 2H), 7.68 (brs, 1H), 7.65 (s, 1H), 7.50 (dd, 1H, J = 6.9, 6.9 Hz), 7.43 (s, 1H), 7.30-7.40 (m, 2H), 4.09-4.27 (m, 2H), 3.25-3.50 (m, 6H), 1.25 (t, 6H, J = 7.1 Hz ).

Example number R ⁵

Example 2

1- [2- (Jethylamino) ethyl] -3-hydroxy-3- (2-methoxyphenyl) -2-oxo-4- (trifluoromethyl) indoline-6-carboxamide hydrochloride

(1) 1_ [2_ (Jethylamino) ethyl] -6-Ed -4-(Trifluoromethyl)-1H-Indian mono-2,3-dione

Example using 6-odo-4- (trifluoromethyl) -1H-indole-2,3-dione (Reference Example 4) in place of 4_fluoro-6-odo- _1H -indole-2,3-dione 1 Synthesized in the same manner as (1).

_{^ -NMR (CDC1 3, 270 MHz} ) δ · 7.71 (s, 1H), 7.68 (s, 1H), 3.80 (t, 2H, J = 6.1 Hz), 2.69 (t, 2H, J = 6.1 Hz), 2.55 (q, 4H, J = 7.1 Hz), 0.97 (t, 6H, J = 7.1 Hz)

(2) 1- [2- (Jethylamino) ethyl] -3-hydroxy-6-odo-3- (2-methoxyphenyl) -4- (trifluoromethyl) -1,3-dihydro-2H- Indore-2-on In the same manner as in Example 1- (2), 1- [2- (Getylamino) ethyl] -6-odo-4-(trifluomethinole) -1H-indole-2,3-dione and 2-methone It was synthesized from Toxic Magnesium Bromide.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.63 (br, 1H), 7.57 (s, 1H), 7.50 (s, 1H), 7.30 (ddd, 1 H, J = l.4, 7.8, 7.8 Hz), 7.03 (d, 1H, J = 7.8 Hz), 6.79 (d, 1H, J = 7.8 Hz), 3.75-3.88 (m, 2H), 3.53 (brs, 3H), 2.71 (t, 2H, J = 6.8 Hz) ), 2.55-2.65 (m, 4H), 1.04 (t, 6H, J = 7.1 Hz).

(3) 1- [2- (Jethylamino) ethyl] -3-hydroxy-3- (2-methoxyphenyl) -2-oxo-4- (trifluoromethyl) indoline-6-caprolitolinole

Example 1 In the same manner as in ___ (3), 1_ [2- (ethylamino) ethyl] -3-hydroxy-6-ode-3- (2-methoxypheninole) -4- (trifluoromethyl) Synthesized from -1,3-dihydro-2H-indole-2-one.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.70 (br, 1H), 7.54 (s, 1H), 7.39 (s, 1H), 7.33 (dd, 1 H, J = 7.8, 7.8 Hz), 7.07 (dd, 1H, J = 7.8, 7.8 Hz), 6.78 (d, 1H, J = 7.8 Hz), 3.89-3.97 (m, 1H), 3.77-3.86 (m, III), 3.49 (s, 3H), 2.69—2.77 (m, 2H), 2.54-2.68 (m, 4H), 1.02 (t, 6H, J = 7.1 Hz).

(4) 1- [2- (Jethylamino) ethyl] -3-hydroxy-3- (2-methoxyphenyl) -2-oxo-4_ (trifluoromethyl) indoline-6-carboxamide hydrochloride

Example 1 In the same manner as in _ (4), 1- [2- (Getylamino) ethyl] -3-hydroxy-3- (2-methoxyphenyl) -2-oxo-4- (trifluoromethyl) Synthesized from indoline-6-carbonitrile.

¾ NMR (DMSO-d ₆ , 400 MHz) δ 10.33 (brs, 1H), 8.30 (brs, 1H), 8.07 (s, 1H), 7.83 (d, 1H, J = 7.7 Hz), 7.77 (s, 1H ), 7.74 (brs, 1H), 7.29 (dd, 1H, J = 7.7, 7.7 Hz), 7.04 (dd, 1H, J = 7.7, 7.7 Hz), 6.95 (s, 1H), 6.86 (d, 1H, J = 7.7 Hz, 4.18 to 4.30 (m, 2H), 3.29-3.39 (m, 6H), 3.33 (s, 3H), 1.26 (t, 6H, J = 6.2 Hz).

3- (4-chlorophenyl) -l-"_ 2- (getylamino) ethyl 1-3-hydroxy-2-oxo-4- (trifluoromethyl) indoline-6-carboxamide hydrochloride (1) 3— (4-Chlorophenyl) —1_ [2- (Jethylamino) ethyl] -1-hydroxy-6-odo-4- (Trifnoreomethinole) -1,3-dihydro-2H-indole -2-on

In the same manner as in Example 1- (2), 1- [2- (Jetylamino) ethyl] -6-iodo-4- (trifluoromethyl) -1H-indole-2,3-dione (Example 2) -(1)) and 4-phenyl phenylmagnesium bromide.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7. 66 (s, 1H), 7. 54 (s, 1H), 7. 27 (d, 2H, J = 8. 7 Hz), 7. 20 (d, 2H, J = 8.7 Hz), 3.90 (brs, 1H), 3.78 (t, 2H, J = 6.2 Hz), 2.62-2.75 (m, 2H), 2. 48-2. 61 (m, 4H), 0.95 (t, 6H, J = 7.1 Hz).

(2) 3-(4-Chlorophenyl) -1- [2- (ethylamino) ethyl] -3-hydroxy-2-oxo-4- (trifluoromethylinole) indoline 6-caprolitolitrile

In the same manner as in Example 1- (3), 3- (4-chlorophenyl) -1- [2- (getinoleamino) ethyl] -3-hydroxy-6-yl-4- (trifluoromethyl) — Synthesized from 1,3-dihydro-2H-indole-2-one.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7. 63 (s, 1H), 7. 43 (s, 1H), 7. 29 (d, 2H, J = 8. 7 Hz), 7. 19 (d, 2H, J = 8.7 Hz), 4.31 (brs, 1H), 3.78—3.92 (m, 2H), 2.65—2.80 (m, 2H), 2.50-2 64 (m, 4H), 0.93 (t, 6H, J = 7.1 Hz).

(3) 3-(4-chlorophenyl)-1-[2- (ethylamino) ethyl] -3-hydroxy-2-oxo-4- (trifluoromethyl) indoline _6_carboxamide hydrochloride

In the same manner as in Example 1- (4), 3- (4-chlorophene)-[1- (2- (ethylamino) ethyl] -3-hydroxy-2-oxo-4- (trifluo-mouth) (Methinole) synthesized from indoline-6-carbonitrile.

¾ NMR (DMS0-d ₆ , 400 MHz) δ 10.28 (brs, 1H), 8.37 (brs, 1H), 8.17 (s, 1H), 7.91 (s, 1H), 7. 81 (brs, 1H), 7.34 (d, 2H, J = 8.7 Hz), 7.21 (d, 2H, J = 8.7 Hz), 7.06 (s, 1H), 4 12-4. 22 (m, 2H), 3.17-3.44 (m, 6H), 1.21 (t, 6H, J = 6.3 Hz).

3- (2,6-dichlorophenyl) -1_ [2- (ethylpyramino) ethyl 3-hydroxy-2-oxo-4_ (trifluoromethyl) indoline-6-carboxamide hydrochloride

(1) 3-(2,6-dichlorophenyl)-1-[2- (Jethylamino) ethyl] -3-hydroxy-6- 4- (Methyl triphnoleo)-1,3-dihydro-2H-indole-2-one

Under a nitrogen atmosphere, 1 - Promo - 2, 6-dichlorobenzene (350 mg, 0.746瞧ol) of as tetrahydrofuran solution (4.0 mL) - 78 and cooled to ° C, 1. ⁵ 7 defined heptyl lithium (0.53 mL, 0.8 32 mmol) was added dropwise and stirred for 30 minutes. Then, 1- [2- (Jethylamino) ethyl] -6-odo-4- (trifluoromethyl) -1H-indole-2,3-dione (Reference Example 2-(1)) (350 rag, 0 .746 mmol) in tetrahydrofuran (4.0 mL) was added dropwise, and the mixture was stirred at the same temperature for 3 hours. Saturated aqueous sodium bicarbonate was added, extracted with ethyl acetate, and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / methanol = 50/1) to obtain the title compound (311 mg, 71%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.60 (s, 1H), 7.54 (s, 1H), 7.42 (dd, 1H, J = 3.3, 6.3 Hz), 7.17-7.22 (m, 2H), 3.74-3.91 (m, 2H), 2.67-2.78 (m, 2H), 2.60 (q, 4H, J = 7.1 Hz), 1.04 (t, 6H, J = 7.1 Hz).

(2) 3- (2,6-Dichrophenyl) -1--1- [2- (Jethylamino) ethyl] -3-hydroxy-2-oxo-4- (triphnoreolomethyl) indoline Nitori Nore

Example 1 3- (2,6-dichlorophenyl) -1- [2- (ethylamino) ethyl] -3-hydroxy-6-odo-4 (trifluoromethyl) in the same manner as in _ (3). )-Synthesized from 1,3-dihydro-2H-indol-2-one.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.57 (s, 1H), 7.42-7.47 (m, 2H), 7.20-7.25 (m, 2H), 4.36 (brs, 1H), 3.90-3.97 (m, 1H) , 3.78-3.84 (m, 1H), 2.72-2.76 (m, 2H), 2.57-2.62 (m, 411), 1.02 (t, 6H, J = 7.1 Hz).

(3) 3- (2,6-dichlorophenyl) -1- [2- (getinoleamino) ethynole] -3-hydroxy-2-oxo-4- (trifluoromethyl) indoline-6-carboxamide hydrochloride

In the same manner as in Example 1- (4), 3- (2,6-dicyclohexyl) -1- [2-((ethylamino) ethyl] -3-hydroxy-2-oxo-4- (trifluoro) (Lometinole) Indoline-6-potassium was synthesized from liponitrile.

_{¾ NMR (DMS0 - d 6,} 400 MHz) δ 10.39 (brs, 1H), 8.35 (brs, 1H), 8.15 (s, 1H), 7.84 (s, 1H), 7.80 (brs, 1H), 7.51 (dd , 1H, J = 4.1, 5.3 Hz), 7.33-7.37 (m, 2H), 7.30 (s, 1H), 4.14-4.35 (m, 2H), 3.27-3.50 (m, 6H), 1.25 (t, 6H , J = 7.1 Hz). Example 5

3- (2,3-dioctanol) -1- [2- (Jethylamino) ethyl 1-3-hydroxy-2-oxo-4- (trifluoromethyl) indoline-6-carboxamide hydrochloride

(1) 3- (2,3-dichlorophenyl) -1- [2- (ethylamino) ethyl] -3-hydroxy-6-chloride-4_ (trifluoromethyl) -2,3-dihydro-2H -Indore-2 -On

The synthesis was carried out in the same manner as in Example 4- (1) except that 1-bromo-2,3-dichlorobenzene was used instead of 1-bromo-2,6-dichlorobenzene.

¾ Keio _{R (CDC1 3, 400 MHz)} δ 8.03 (d, 1H, J = 8.0 Hz), 7.61 (s, 1H), 7.55 (s, 1H), 7.48 (d, 1H, J = 8.0 Hz), 7.36 (dd, 1H, J = 8.0, 8.0 Hz), 3.97-4.05 (m, 1H), 3.73-3.78 (m, 1H), 2.52-2.83 (m, 6H), 1.02 (t, 6H, J = 7.1 Hz).

(2) 3_ (2,3-dichloropheninole) -1_ [2- (Jethylamino) ethyl] -3-hydroxy-2-oxo--4- (trifluoromethylinole) indoline-6-carbonitrile

In the same manner as in Example 1- (3), 3- (2,3-dicyclohexaphenyl) -1- [2-((ethylamino) ethyl) -3-hydroxy-6-odo-4- (trifluoromethyl) Methyl) -1,3-dihydro-2H-indol-2-one.

_{¾ NMR (CDC1 3, 400 MHz} ) 8 8.04 (d, 1H, J = 8.0 Hz), 7.58 (s, 1H), 7.51 (d, 1H, J = 8.0 Hz), 7.45 (s, 1H), 7.38 ( dd, 1H, J = 8.0, 8.0 Hz), 4.47 (brs, 1H), 4.09-4.16 (m, 1H), 3.72-3.80 (m, 1H), 2.50-2.76 (m, 6H), 1.00 ( t, 6H, J = 7.1 Hz).

(3) 3- (2,3-dichlorophenyl) -1- [2- (getinoleamino) ethynole] -3-hydroxy-2--4-oxo-4- (trifluoromethyl) indoline_6_carboxamide hydrochloride

In the same manner as in Example 1- (4), 3- (2,3-dicyclopentaphenyl) -1- [2- (getylamino) ethyl] -3-hydroxy-2-oxo-4- (trifluo) It was synthesized from (rmethyl) indoline-6-carbonitrile.

_{¾ NMR (DMS0- d 6, 400} MHz) δ 10.38 (brs, 1H), 8.36 (brs, 1H), 8.17 (s, 1H), 8.07 (d, 1H, J = 8.0 Hz), 7.85, (s, 1H), 7.81 (brs, 1H), 7.67 (d, 1H, J = 8.0 Hz), 7.57 (s, 1H), 7.52 (dd, 1H, J = 8.0, 8.0 Hz), 4.17-4.37 (m, 2H), 3.23-3.46 (m, 6H), 1.26 (t, 6H, J = 6.7 Hz). 4 -Kokuguchi 3-(2-Kokuguchi feninole) -1- [2- (Jethylamino) ethynole] -3-Hydroxy-2-

(1) Methyl 4-chloro- 1- [2- (Jethylamino) ethyl] _2,3-dioxoindoline-6-forcenorboxylate

4-Methyl 4-octanol-2,3-dioxindrin _6_carboxylate (Reference Example 3) in place of 4-funoleo mouth 6-ode 1H-indole-2,3-dione, It was synthesized in the same manner as in Example 1- (1).

¾丽_{R (CDC1 3, 400 MHz)} δ 7.71 (d, 1 H, J = 0.9 Hz), 7.52 (d, 1 H, J = 0.9 Hz), 3.98 (s, 3 H), 3.84 (t, 2 H, J = 6.4 Hz), 2.71 (t, 2 H, J = 6.4 Hz), 2.55 (q, 4 H, J = 7.1 Hz), 0.96 (t, 6 H, J = 7.1 Hz).

(2) Methyl 4-cyclobut-3- (2-chlorophenyl) -1- [2- (getylamino) ethyl] -3-hydroxy-2-oxoindolin-6-carboxylate

In a nitrogen atmosphere, cooled to -78 ° C in methyl 4-cloro-1- [2- (ethylamino) ethyl] -2,3-dioxoindrin-6-carboxylate (546 mg, 1.61 mmol ) Was added dropwise to a solution of (0.8 mL) in Tonolene (8.0 mL), and stirred at -78 ° C for 1 hour at -78 ° C for 1 hour. Saturated aqueous sodium bicarbonate was added, extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (form: methanol / methanol = 80/1 to 50/1) to give the title compound (404 mg, 56%). _{¾ NMR (CDC1 3, 400 MHz} ) δ 8.17 (dd, 1 H, J = 1.4, 7.6 Hz), 7.65 (d, 1 H, J = 1.2 Hz), 7.53 (d, 1 H, J = 1.2 Hz) , 7.42 (ddd, 1 H, J = 1.4, 7.6, 7.6 Hz), 7.31 (ddd, 1 H, J = 1.4, 7.6, 7.6 Hz), 7.26 (dd, 1 H, J = 1.4, 7.6 Hz) 8

, 3.92 to 4.03 (ra, 1 H), 3.94 (s, 3 H), 3.77 to 3.84 (m, 1 H), 3.74 (br, 1 H), 2.70 to 2.84 (ra, 2 H), 2.54 to 2.69 (m, 4 H), 1.02 (t, 6 H, J = 7.1 H z).

(3) 4-Cross mouth-3- (2-Cross mouth feninole)-1- [2- (Jetinoleamino) ethyl] -3-hydroxy-2-oxoindolin-6-carboxylate hydrochloride

In a nitrogen atmosphere, methyl 4-chloro-3- (2-chlorophenyl) -1- [2- (ethylamino) ethyl] _3-hydroxy-2-oxoindoline-6-carboxylate (283 rag, 0.627 awake ol) To a solution of the above in tetrahydrofuran (1.5 mL) -methanol (1.5 mL) was added a 1N aqueous sodium hydroxide solution (700 μΐ, 0.700 mmol), and the mixture was stirred at 50 ° C. for 2 hours. The solvent was distilled off, 4N hydrochloric acid / 1,4-dioxane solution (2.0 mL) was added, and the solvent was distilled off. The procedure of adding toluene and distilling off the solvent was repeated four times to obtain a crude product of the title compound (386 mg).

^X H NMR (DMSO-d ₆ , 400 MHz) δ 13.51 (brs, 1 H), 10.83 (brs, 1 H), 8.15 (dd, 1 H, J = 1.6, 7.8 Hz), 7.71 (d, 1 H , J = 1.1 Hz), 7.50 (d, 1 H, J = 1.1 Hz), 7.48 (ddd, 1 H, J = 1.3, 7.8, 7.8 Hz), 7.42 (s, 1 H), 7.38 (ddd, 1 H, J = 1.6, 7.8, 7.8 Hz), 7.32 (dd, 1 H, J = 1.3, 7.8 Hz), 4.31 to 4.38 (m, 1 H), 4.13 to 4.19 (m, 1 H), 3.24 to 3.38 (ra, 6 H), 1.25 (t, 6 H, J = 7.2 Hz).

(4) 4-co- mouth-3- (2-co-mouth phenyl)-1- [2- (ethylpyramino) ethyl] -3-hydroxy-2-oxoindrin-6-carpoxamide hydrochloride

Under a nitrogen atmosphere, 4-chloro-3- (2-chlorophenyl) -1- [2- (ethylamino) ethyl] -3-hydroxy-2-oxoindoline-6-carboxylate hydrochloride (250 mg, max 0.406 瞧) 1), ammonium chloride (44.5 mg, 0.832 mmol), trihydroxybenzotriazole (72.4 mg, 0.536 mmol), N, N-dimethylformamide (2.0 raL), 1-ethyl-3- (dimethylamino) (Propyl) carposimid hydrochloride (101 mg, 0.527 mmol) and triethylamine (260 μΐ, 1.87 mmol) were added, and the mixture was stirred at room temperature for 48 hours. Saturated aqueous sodium bicarbonate was added, extracted with ethyl acetate / toluene (1: 1), washed with saturated aqueous sodium bicarbonate, and dried over magnesium sulfate. After filtration, obtain a pretended integral shed ³ 8 mg) of the title compound purified by the solvent was distilled off by silica gel column chromatography (black port Holm / methanol = 15/1). Subsequently, it is dissolved in 1,4-dioxane (2 mL), and 4N hydrochloric acid / 1,4-dioxane solution (1 mL) is added. The solvent was distilled off. The title compound (134 mg, 70%, 2steps) was obtained by suspending in Getinole ether and collecting by filtration.

¾ NMR (DMS0-d ₆ , 400 MHz) 8 10.38 (brs, 1 H), 8.17 (brs, 1 H), 8.14 (dd, 1 H, J = 1.4, 7.8 Hz), 7.79 (s, 1 H) , 7.69 (brs, 1 H), 7.50 (s, 1 H), 7.8 (ddd, 1 H, J = 1.4, 7.8, 7.8 Hz), 7.38 (ddd, 1 H, J = 1.4, 7.8, 7.8 Hz), 7.33 (s, 1 H), 7.32 (dd, 1 H, J = 1.4, 7.8 Hz), 4.24 to 4.32 (m, 1 H), 4.08 to 4.15 (m, 1 H), 3.24 to 3.42 (m, 6 H), 1.25 (t, 6 H, J = 7.2 Hz).

Example 7

1- {2- [bis (cyclopropylmethyl) amino] ethyl} -4-chloro-3- (2-chlorophenyl) -3-hydroxy-2-oxoindoline-6-carboxamide hydrochloride

(1) Methyl 1- {2- [bis (propylmethyl) amino] ethyl 4-octanol-2,3-dioxoindolin-6-hexylboxylate Under a nitrogen atmosphere, a solution of 2- [bis (cyclopropylmethyl) amino] ethanol (Reference Example 18) (262 mg, 1.55 mmol) in chloroform (4.0 mL) was added to a solution of thionyl chloride (200; uL, 2.74 mmol). ) Was added dropwise, and the mixture was heated under reflux for 1 hour. The solvent was distilled off, and toluene was added and the solvent was distilled off three times to obtain a chloride. Then, in the same manner as in Example 1- (1), the title compound was obtained from methyl 4-hydroxy-2,3-dioxoindrin-6-carboxylate (Reference Example 3) and the above-mentioned chloride (Reference Example 3). 286 mg, 54%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.70 (d, 1 H, J = 1.0 Hz), 7.57 (d, 1 H, J = 1.0 Hz), 3.97 (s, 3 H), 3.90 (t, 2 H , J = 6.4 Hz), 2.91 (t, 2 H, J = 6.4 Hz), 2.45 (d, 4 H, J = 6.5 Hz), 0.71 to 0.78 (m, 2 H), 0.41 to 0.46 (m, 4 H), 0.05-0.09 (ra, 4 H).

(2) Methyl l- {2- [bis (cyclopropylmethyl) amino] ethyl} -4--4-tert- (2-chloropheninole) -3-hydroxy-2-oxoindrin-6-carboxylate

In the same manner as in Example 6- (2), methyl 1- {2- [bis (cyclopropylmethyl) amino] ethyl} -4-coguchi-2,3-dioxindrin-6 -Synthesized from carboxylate. _{¾ NMR (CDC1 3, 400 MHz} ) δ 8.19 (dd, 1 H, J = 1.4, 7.8 Hz), 7.65 (d, 1 H, J = 1.2 Hz), 7.56 (d, 1 H, J = 1.2 Hz) , 7.42 (ddd, 1 H, J = 1.4, 7.8, 7.8 Hz), 7.31 (ddd, 1 H, J = 1.4, 7.8, 7.8 Hz), 7.25 (dd, 1 H, J = 1.4, 7.8 Hz) , 4.10 to 4.15 (tn, 1 H), 3.93 (s, 3 H), 3.77 to 3.84 (m, 1 H), 3.11 to 3.14 (m, 1 H), 2.87 to 2.92 (ra, 1 H), 2.61 (dd, 2 H, J = 6., 13.1 Hz), 2.44 (dd, 2 H, J = 6.7, 13.1 Hz), 0.80 to 0.85 (m, 2 H), 0.48 to 0.52 (m, 4 H) , 0.11 to 0.14 (m, 4 H).

(3) 1- {2 [bis (cyclopropylmethyl) amino] ethyl} -4-chloro-3- (2-chlorophenyl) -3-hydroxy-2-oxoindolin-6-carboxylate hydrochloride

Example 6-In a similar manner to (3), methyl 1- {2- [bis (cyclopropylmethyl) amino] ethyl} -4-chloro-3- (2-chlorophenyl ')-3-hydroxy Synthesized from 2-oxoindolin-6-carboxyle 1.

丽_{R (DMS0 - d 6, 400} MHz) δ 13.54 (br, 1 H), 10.46 (br, 1 H), 8.15 (dd, 1 H, J = 1.6, 7.7 Hz), 7.72 (d, 1 H, J = 1.1 Hz), 7.51 (d, 1 H, J = 1.1 Hz), 7.49 (ddd, 1 H, J = 1.3, 7.7, 7.7 Hz), 7.41 (s, 1 H), 7.39 (ddd, 1 H , J = 1.6, 7.7, 7.7 Hz), 7.33 (dd, 1 H, J = 1.3, 7.7 Hz), 4.21 to 4.33 (ra, 2 H) , 3.22 to 3.50 (m, 6H), 1.17 to L35 (ra, 2H), 0.63 to 0.65 (m, 4H), 0.45 (ra, 4H).

(4) 1- {2- [bis (cyclopropylmethyl) amino] ethyl} -4--4-cyclo-3- (2-chlorophenyl) -3-hydroxy-2-oxoindoline_6-carboxamide hydrochloride

Example 6 In the same manner as in-(4), 1- {2_ [bis (cyclopropylmethyl) amino] ethyl} -4-cyclo mouth_3- (2-cyclophenyl) -3-hydroxy-2- It was synthesized from oxoindoline-6-canolepon hydrochloride.

¾ employment _{R (DMS0 - d 6, 400} MHz) 8 10.20 (brs, 1 H), 8.16 (s, 1 H), 8.14 (s, 1 H), 7.83 (s, 1 H), 7.68 (s, 1 H), 7.47 to 7.52 (m, 2 H), 7.32 to 7.41 (ra, 3 H), 4.16 to 4.32 (m, 2 H), 3.41 to 3.51 (ra, 2 H), 3.20 to 3.34 (m, 4 H), 1.16 (m, 2 H), 0.65 (m, 4 H), 0.45 to 0.47 (m, 4 H).

4-c-mouth-3- (2-chloro-phenyl) -1-[(1-ethynolepi-lysine-2-yl) methyl] -3--h-doxy-2-oxoindrin-6-carboxamide hydrochloride salt

(1) Methyl 4-chloro-1-[(1-ethylpyrrolidine-2-inole) methyl] _2,3-dioxoindrin-6-carboxylate

Example 1-In the same manner as in (1), methyl 4-coguchi-2,3-dioxoindrin- ^6- carboxylate (Reference Example 3) and 2- (chloromethyl) -1- Synthesized from etilubi-mouth lysine hydrochloride (Reference Example 17).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.71 (d, 1 H, J = 1.1 Hz), 7.63 (d, 1 H, J = 1.1 Hz), 3.98 (s, 3 H), 3.76 ~ 3.78 (m, 2H), 3.12 to 3.16 (m, 1H), 2.86 to 2.91 (ra, 2H), 2.38 to 2.42 (m, 1H), 2.18 to 2.24 (ra, 1H), 1.84 to 1.91 (m, 1 H), 1.62 to 1.77 (m, 3 H), 1.11 (t, 3 H, J = 7.2 Hz).

(2) Methyl 4_chloro mouth_3- (2_chloro mouth phenyl) -1-[(1-ethylpyrrolidine-2-ynole) methyl] -3-hydroxy-2-oxodindrin_6_carboxylate

In the same manner as in Example 6- (2), methyl 4-chloro-1-ethylpyrrolidine-2-yl) methyl] _2,3-dioxoindoline-6-carboxylate was used.

¾丽_{R (CDC1 3, 400 MHz)} δ 8.14 - 8.18 (ra, 1 H), 7.65 (m, 1 H), 7.56 ~ 7. 60 (m, 1 H), 7.40 ~ 7.44 (ra, 1 H) , 7.25 to 7.34 (m, 2 H), 3.94 (s, 3 H), 3.84 to 3.90 (m, 1 H), 3.72 to 3.77 (m, 1 H), 2.88 to 3.22 (m, 3 H), 2.37 to 2.53 (m, 1 H), 2.20 to 2.26 (m, 1 H), 1.68 to 1.91 (m, 4H), 1.10 to 1.19 (m, 3H).

(3) 4-Chloro-3-((2-phenyl) phenyl) -1 _ [(1-ethylpyrrolidine-2-yl) methyl] -3-hydroxy-2-oxoindoline-6-caprolponate

In the same manner as in Example 6- (3), methyl 4-chloro-3- (2-chlorophenyl)-ethylpyrrolidine-2-yl) methyl] -3-hydroxy-2-oxoindoline It was synthesized from -6-carboxylate.

_{¾ NMR (DMS0- d 6, 400} MHz) δ 13.57 (br, 1 H), 10.69~ 10.98 (m, 1 H), 8.14 ~ 8.17 (m, 1 H), 7.62~ 7.63 (m, 1 H), 7.32 to 7.53 (m, 5 H), 4.29 — 4.31 (m, 2 H), 3.39 to 3.75 (ra, 3 H), 3.12 (m, 2 H), 2.19 to 2.21 (m, 1 H), 1.87 to 1.99 (ra, 3H), 1.26 to 1.34 (m, 3H).

(4) 4-Mouth mouth-3- (2-Chloropheninole) _1-[(1-Ethylpyrrolidine-2-yl) methinole] -3-Hydroxy-2-oxoindoline-6-carboxamide hydrochloride

In the same manner as in Example 6- (4), 4-chloro-3- (2-chlorophenyl) -1-[(1-tylbi-lysine-2-ynole) methyl] -3-hydroxy-2 -Oxindrin-6_carboxylate hydrochloride.

_{¾ NMR (DMS0- d 6, 400} MHz) δ 10.31 (br, 1 H), 8.14~ 8.17 (m, 2 H), 7.63 ~ 7.68 (m, 2 H), 7.47~ 7.53 (m, 2 H), 7.32 to 7.41 (m, 3 H), 4.18 to 4.28 (m, 2 H), 3.13 to 3.82 (m, 5 H), 1.83 to 2.24 (ra, 4 H), 1.31 (t, 3 H, J = 6.4 Hz). 'Example 9

4-Chloro-3- (2-chlorophenyl) -3-hydroxy-1-"-methylbiperidin-2-yl) methyl] -2-oxoindoline-6-carboxamide hydrochloride

(1) Methyl 4-cyclo-1-((1-methylpiperidin-2-yl) methyl]-2,3-dioxodindrin-6-force benzoylate, methinole 4-methyl-1--1- (1- Methynoleazepan-3-inole) _2,3-dioxoindrin-6-ca ^ / boxylate

Example 1 In the same manner as in-(1), methyl 4-cyclo-2,3-dioxoindolin-6-carboxylate (Reference Example 3) and 2_ (chloromethyl) -1-methylpi Perysine hydrochloride (Reference Example 1 The reaction is carried out from 6), and the reaction is carried out with methyl 4-hydroxy-1--1-((1-methylbiperidin-2-yl) methyl] -2,3-dioxoindrin-6-carboxylate and methyl 4-methoxy. Mouth-1- (1-methylazepan-3-yl) -2,3-dioxoindrin-6-carboxylate was obtained.

Methyl 4-click every mouth - 1- [(1 - methylpiperidine - 2-I) methyl] -2, 3 - Jiokisoindori emissions - 6 Karupokishireto: ¾丽_{R (CDC1 3, 400 MHz)} δ 7.73 ( d, 1 H, J = 1.1 Hz), 7.49 (d, 1 H, J = 1.1 Hz), 4.05 (dd, 1 H, J = 4.5, 14.0 Hz), 3.99 (s, 3 H), 3.71 (dd , 1 H, J = 9.3, 14.0 Hz), 2.87 to 2.91 (ra, 1 H), 2.47 (s, 3 H), 2.40 to 2.46 (m, 1 H), 2.17 to 2.24 (m, 1 H), 1.70 to 1.75 (m, 1 H), 1.55 to 1.61 (m, 3 H), 1.21 to 1.37 (m, 2 H).

Methyl 4 Black hole - 1 - (1-Mechiruazepan - 3 - I le) -2, 3 - di O Kiso indoline - 6 - carbonitrile _{Kishireto: ¾ NMR (CDC1 3, 400} MHz) δ 8.26 (brs, 1 H), 7.71 (s, 1 H), 4.54 to 4.57 (m, 1 H), 3.98 (s, 3 H), 2.80 to 2.86 (m, 2 H), 2.47 to 2.54 (m, 1 H), 2.39 (s, 3 H), 2.11 to 2.22 (m, 1 H), 1.26 to 1.89 (m, 6 H).

(2) Methyl 4-chloro-3- (2-chlorophenol) -3-hydroxy-1-[(1-methylpiperidin-2-yl) methyl] -2-oxoindrin-6-carboxylate

Example 6-Synthesized from methyl 4-chloro-1-([1-methylbiperidin-2-yl) methyl] -2,3-dioxoindoline-6-carboxylate in the same manner as in (2). did.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.17 (dd, 1 H, J = 1.4, 7.6 Hz), 7.65 (d, 1 H, J = 1.2 Hz), 7.50 (d, 1 H, J = 1.2 Hz) , 7.2 (ddd, 1 H, J = 1.4, 7.6, 7.6 Hz), 7.31 (ddd, 1 H, J = 1.4, 7.6, 7.6 Hz), 7.25 (dd, 1 H, J = 1.4, 7.6 Hz), 3.94 (s, 3H), 3.90 to 4.00 (m, 2H), 2.86 to 2.89 (m, 1H), 2.49 (s, 3H), 2.44 to 2.47 (ra, 1H), 2.16 ~ 2.23 (m, 1 H), 1.68 to 1.76 (m, 2 H), 1.56 to 1.61 (m, 2 H), 1.36 to 1.45 (ra, 1 H), 1.20 to 1.26 (m, 1 H) .

(3) 4-Mono-3--3- (2-chlorophen-2-ole) -3-hydroxy-1-[(1-methylpiperidine-2-ynole) methyl] -2-oxoindrin-6_carboxylic acid Hydrochloride

Example 6 In the same manner as in-(3), methyl 4-chloro-3- (2-chlorophenol) -3-hydroxy-1-[(1-methylpiperidine-2-yl) methyl ]-Synthesized from 2-oxoindrin-6-carboxylate.

_{¾ NMR (DMS0- d 6, 400} MHz) δ 13.59 (br, 1 H), 10.72~ 11.14 (m, 1 H), 8.15 (dd, 1 H, J = 1.6, 8.0 Hz), 7.32~ 7.82 (m , 6 H), 4.04 to 4.32 (m, 2 H), 3.14 to 3.71 (m, 4 H), 2.87 to 2.99 (m, 3 H), 1.35 to 2.00 (ra, 5 H).

(4) 4-Chloro-3- (2-Chlorophenyl) -3-hydroxy-1-[(1-methylbiperidin-2-yl) methyl] -2-oxoindrin-6-carboxamide hydrochloride

Example 6 In the same manner as in-(4), 4-chloro-3- (2-chlorophenyl) -3-hydroxy-1-[(1-methylpiperidine-2-ynole) methyl] -2-oxoindrin- It was synthesized from 6-carboxylate hydrochloride.

_{¾ NMR (DMS0 - d 6,} 400 MHz) δ 10.24~ 10.99 (m, 1 H), 8.01 ~ 8.23 (m, 2 H), 7.29~ 7.73 (m, 7 H), 4.09~ 4.22 (m, 2 H ), 2.90 to 3.74 (m, 6 H), 1.23 to 2.02 (m, 6 H).

4-Mouth-3- (2-Chlorophenyl) -3-hydroxy-1- (1-methylazepan-3-yl) -2-oxoindoline-6-carboxamide hydrochloride

(1) Methyl 4-chloro-3- (2-chlorophenol) -3-hydroxy-1- (1-methinoleazepan-3-inole) -2-oxoindoline-6-carboxylate

Example 6 In a manner similar to that of-(2), methyl 4-kuguchiguchi-1- (1-methylazepan-3-inole) -2,3-dioxoindrin-6-carboxylate was synthesized. .

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.16 (d, 1 H, J = 7.7 Hz), 8.03 (br, 1 H), 7.64 (d, 1 H, J = 0.8 Hz), 7.41 (dd, 1 H , J = 7.7, 7.7 Hz), 7.31 (dd, 1 H, J = 7.7, 7.7 Hz), 7.25 (d, 1 H, J = 7.7 Hz), 4.52 (br, 1 H), 3.94 (s, 3 H), 3.64 (br, 1 H), 3.08 to 3.13 (m, 1 H), 2.73 to 2.82 (m, 2 H), 2.58 to 2.63 (ra, 1 H), 2.39 (s, 3 H) , 2.26 to 2.35 (m, 1 H), 1.59 to 1.95 (ra, 6 H).

(2) 4-Mouth Rho 3— (2-Mouth phenyl))-3-Hydroxy-1- (1-methylazepan-3-yl) _2-oxoindrin-6-carboxylate hydrochloride

· In the same manner as in Example 6- (3), methyl 4-chloro-3- (2-chlorophenol) -3-hydroxy-1- (1-methylazepan-3-yl) -2 -Oxindrin-6-carboxylate.

¾删_{R (DMS0- d 6, 400 MHz} ) δ 13.55 (br, 1 H), 9.9~ 11.1 (m, 1 H), 8.13 (d, 1 H, J = 7.1 Hz), 7.31 ~ 7.73 (m, 6H), 4.79 (m, 1H), 3.21 to 3.73 (m, 4H), 2.83 (brs, 3H), 1.78 to 2.21 (m, 6H). (3) 4-chloro-3- (2-chlorophenyl) -3-hydroxy-1- (1-methylazepan-3-yl) -2-oxoindolin-6-carboxamide hydrochloride

In the same manner as in Example 6- (4), 4-chloro-3- (2-chlorophenyl) -3-hydroxy-1- (1-methylazepan-3-yl) -2-oxoindoline- Synthesized from 6-potassium hydrochloride.

¾ NMR (DMS0_d ₆ , 400 MHz) 8 9.47 to 10.37 (m, 1 H), 8.12 to 8.15 (m, 2 H), 7.25 to 7.83 (ra, 7 H), 4.12 to 4.70 (ra, 1 H), Example 11: 3.18 to 3.78 (m, 4 H), 2.87 to 2.90 (m, 3 H), 1.50 to 2.18 (m, 6 H).

4-Chloro-3- (2-chlorophenyl) -1- [(treetylpiperidin-2-yl) methyl] -3-hydr oxy-2-oxoindrin-6-carboxamide hydrochloride

(1) Methyl 4-chloro_1-[(1-Ethylbiperidine-2-inole) methyl] -2,3-dioxoindrin-6-carboxylate, methinole 4-octa-1- (1-ethylethylazepan-3 -Yl) -2,3 -Dioxoindoline-6-potassolevoxylate

In the same manner as in Example 1 _ (1), methyl 4-octanol-2,3-dioxoindrin-6-carboxylate (Reference Example 3) and 2_ (chloromethyl) -1 The reaction was carried out from -ethyl-biperidine hydrochloride (Reference Example 15) to give methyl 4-chloro-1-([1-ethylethylperiperin-2-inole) methyl] -2,3-dioxindrin-6-force Noreboxylate and methinole 4-co-mouth: L- (1-ethinoleazepan-3-yl) -2,3-dioxoindrin-6-carboxylate were obtained.

Methyl 4 - click every mouth Echirupi Bae lysine - 2 - Inore) methyl] -2, 3 - Jiokisoindori down-6-carboxylate: Luo _{R (CDC1 3, 400 MHz)} δ 7.72 (d, 1 H, J = 0.7 Hz ), 7.49 (d, 1 H, J = 0.7 Hz), 4.06 (dd, 1 H, J = 5.1, 14.0 Hz), 3.98 (s, 3 H), 3.76 (dd, 1 H, J = 9.1, 14.0) Hz), 2.82 to 2.93 (ra, 3 H), 2.63 to 2.72 (m, 1 H), 2.37 to 2.43 (rn, 1 H), 1.52 to 1.73 (m, 4 H), 1.32 to 1.39 (m, 2 H), 1.10 (t, 3 H, J = 7.1 Hz).

Methyl 4 - click every mouth - 1 - - Echiruazepan - 3-I le) _2, 3 - di O Kiso I command phosphate - 6 Kanorebo Kishireto: employment _{R (CDC1 3, 400 MHz)} 8 8.18 (brs, 1 H) , 7.70 (s, 1 H), 4.55 to 4.56 (ra, 1 H), 3.98 (s, 3 H), 3.03 (dd, 1 H, J = 5.0, 14.3 Hz), 2.84 to 2.92 (m, 2 H ), 2.55 to 2.64 (m, 2 H), 2.44 to 2.49 (m, 1 H), 1.52 to 1. 89 (m, 6 H), 1.04 (t, 3 H, J = 7.1 Hz).

(2) Methyl 4-chloro-3- (2-chlorophenol) -1-[(1-Ethylbiperidin-2-yl) methyl] -3-hydroxy-2-oxoindoline-6-force Noreboxile

Example 6-Synthesized from methyl 4-chloro-1-([1-ethylpyperidin-2-yl) methyl] _2,3-dioxoindoline- ⁶ -carboxylate in the same manner as in (2). .

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.15 (dd, 1 H, J = 1.5, 7.7 Hz), 7.65 (d, 1 H, J = 1.2 Hz), 7.52 (d, 1 H, J = 1.2 Hz) , 7.42 (ddd, 1 H, J = 1.5, 7.7, 7.7 Hz), 7.31 (dd, 1 H, J = 1.5, 7.7, 7.7 Hz), 7.26 (dd, 1 H, J = 1.5, 7.7 Hz) , 3.94 (s, 3 H), 3.91 to 3.96 (m, 2 H), 2.85 to 2.97 (m, 3 H), 2.71 to 2.76 (m, 1 H), 2.36 to 2.43 (m, 1 H), 1.28 ~ 1.88 (m, 6 H), 1.15 (t, 3 H, J = 7.1 Hz).

(3) 4-chloro-3- (2-phenylphenyl) -1-[-ethylpyridin-2-ynole) methinole] -3-hydroxy-2-oxoindrin-6-caproluvate

Example 6-In the same manner as in (3), methyl 4-coguchi-3- (2-chlorofuininole) -1- [l-ethylbiperidin-2-yl) methyl] -3-hydroxy-2 _Oxoindoline-6-carboxylate was synthesized.

¾ NMR (DMS0_d ₆ , 400 MHz) 8 13.58 (br, 1 H), 10.68 to 10.86 (ra, 1 H), 8.15

(d, 1 H, J = 8.0 Hz), 7.31 to 7.80 (m, 6 H), 4.05 to 4.36 (m, 2 H), 3.10

~ 3.73 (tn, 6 H), 1.23 ~ 1.96 (m, 8 H).

(4) 4-Mouth raw 3-(2-Mouth mouth feninole) -1-[(1-Ethylbiperidine-2-yl) methinole] -3-Hydroxy- ₂ -oxoindrin carboxamide Hydrochloride

Example 6 In the same manner as in (4), 4-kuguchi-3- (2-chlorophenyl) -1-[(1-ethylpyperidin-2-yl) methyl] -3-hydroxy-2- Oxindrin-6-potassium ribonate hydrochloride.

_{¾ NMR (DMS0 - d 6,} 400 MHz) δ 9.96~ 10.49 (m, 1 H), 8.14~ 8.19 (tn, 2 H), 7.57~ 7.93 (m, 2 H), 7.47~ 7.53 (m, 2 H ), 7.32 to 7.41 (m, 3 H), 3.94 to 4.36 (ra, 2 H), 3.10 to 3.73 (m, 5 H), 1.40 to 1.99 (m, 6 H), 1.33 (t, 3 H, J = 7.0 Hz) .Example 12 4-cyclo-3- (2-chlorophenyl) -1--ethylethylazepan-3-inole) -3-hydroxy-2-oxoindolin-6-carboxamide hydrochloride

(1) Methyl 4-cyclo-3- (2-chloropheninole) -1- (1-ethylazepane-3-yl) -3-hydroxy-2-oxoindrin-6-carboxylate

Synthesized from methyl 4-clo-1- (1-ethylethylazepan-3-yl) -2,3-dioxoindrin-6-carboxylate in the same manner as in Example 6- (2). did.

¾删_{R (CDC1 3, 400 MHz)} δ 8.16 (dd, 1 H, J = 1.3, 7.7 Hz), 8.04 (br, 1 H), 7.64 (d, 1 H, J = 1.1 Hz), 7.41 (ddd , 1 H, J = 1.3, 7.7, 7.7 Hz), 7.31 (d dd, 1 H, J = 1.3, 7.7, 7.7 Hz), 7.25 (dd, 1 H, J = 1.3, 7.7 Hz), 4.55 (br , 1 H), 3.94 (s, 3 H), 3.09 to 3.14 (m, 1 H), 2.84 to 2.91 (m, 2 H), 2.55 to 2.63 (m, 2 H), 2.27-2.35 (m, 1 H), 1.57 to 1.93 (m, 6 H), 1.05 (t, 3 H, J = 7.1 Hz).

(2) 4-Cross mouth 3- (2-Cross mouth phenyl) -1- (1-Ethylazepane_3-inole) -3-Hydroxy-2-oxoindrin-6-carboxylate hydrochloride

Example 6 In the same manner as in-(3), methyl 4-octanol-3- (2-chloropheninole) -1- (1-ethylpyrazepan-3-inole) -3-hydroxy-2- Oxindrin-6-carboxylate.

_{¾ NMR (DMSO- d 6, 400} MHz) δ 13.55 (brs, 1 H), 10.11 ~ 10.98 (m, 1 H), 8.1 1 ~ 8.16 (m, 1 H), 7.31 ~ 7.90 (m, 6 H) , 4.71 to 4.93 (m, 1H), 3.18 to 4.06 (m, 6H), 1.61 to 2.21 (m, 6H), 1.24 to 1.35 (m, 3H).

(3) 4- ク口口 — 3— (2-chlorophenyl) -1- (1-ethylethylazepan-3-yl) -3-hydroxy-2-oxindrin-6-carpoxamide hydrochloride

Example 6-In the same manner as in (4), 4-cyclo-3-(2-chlorophenyl) -1- (1-ethylthipan-3-yl) -3-hydroxy-2- Synthesized from oxoindoline-6-carboxylate hydrochloride.

_{¾ NMR (DMSO- d 6, 400} MHz) β 9.60 ~ 10.60 (m, 1 H), 8.12 ~ 8.25 (m, 2 H), 7.69 ~ 8.00 (ra, 2 H), 7.46 ~ 7.61 (m, 2 H ), 7.24 to 7.40 (m, 3 H), 4.78 (m, 1 H), 3.20 to 4.22 (m, 6 H), 1.63 to 2.33 (m, 6 H), 1.26 (t, 3 H, J = 7.1 Hz). Example 13

4- (2-chloropheninole) -1- [2- (dicyclopropylamino) ethyl] -3-hydroxy-2-oxoindoline-6-carboxamide hydrochloride

(1) Methyl 4-chloro- 1- [2- (dicyclopropylamino) ethyl]-2,3-dioxoindoline-6-carboxylate

To a solution of 2- (dicyclopropylamino) ethanol (Reference Example 19) (100 rag, 0.708 mraol) in dichloromethane (2.0 mL) cooled to 0 ° C in a nitrogen atmosphere, triethylamine (100 ^ L, 0.717 ramol) The prepared 1.292 N methanesulfonyl chloride solution in dichloromethane (550 μΐ, 0.711 mmol) was added. Subsequently, lithium chloride (45.0 mg, 1.06 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Water was added, extracted with toluene, and dried with magnesium sulfate. After filtration, the solvent was distilled off to about 1/3 position, and toluene was added to distill off to 1/3 position twice more. 4N hydrochloric acid / 1,4-dioxane solution (50

0 L) was added, and the solvent was distilled off to obtain a crude chloride. Bow I Continuing In the same manner as in Example ι- (ι), use methyl 4-coguchi-2,3-dioxoindrin-6-carboxylate (Reference Example 3) and the above-mentioned chloride. The title compound (99.8 mg, 44%) was obtained.

_{¾ MR (CDC1 3, 400 MHz} ) δ 7.73 (d, 1 H, J = 1.0 Hz), 7.51 (d, 1 H, J = 1.0 Hz), 3.99 (s, 3 H), 3.96~ 4.01 (m, 2 H), 3.01 (t, 2 H, J = 7.3 Hz), 2.0 3 to 2.08 (m, 2 H), 0.38 to 0.54 (m, 8 H).

(2) Methyl 4-cyclobut-3- (2-chloropheninole) -1- [2- (dicyclopropylamino) ethyl] -3-hydroxy-2-oxoindrin-6-carboxylate

In the same manner as in Example 6_ (2), it was synthesized from methyl 4-kuguchi-1- [2- (dicyclopropylamino) ethyl] -2,3-dioxoindrin-6-carboxylate. .

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.15 (d, 1 H, J = 7.5 Hz), 7.66 (d, 1 H, J = 1.2 Hz), 7.55 (d, 1 H, J = 1.2 Hz), 7.42 (dd, 1 H, J = 7.5, 7.5 Hz), 7.32 (dd, 1 H, J = 7.5, 7.5 Hz), 7.28 (d, 1 H, J = 7.5 Hz), 4.02 to 4.07 (m, 2 H ), 3.95 (s, 3 H), 3.03 to 3.08 (ra, 2 H), 2.06 to 2.10 (m, 2 H), 0.41 to 0.54 (m, 8 H).

(3) 4-Cupro-3- (2-Cupactuyl) -1- [2- (Dicyclopropinoleamino) ethyl] -3-hydroxy-2-oxoindoline-6-carboxylate salt

Example 6-In the same manner as in (3), methyl 4-chloro-3- (2-chloropheninole) -1- [2- ( Synthesized from dicyclopropylamino) ethyl] -3-hydroxy-2-oxoindolin-6-propoxylate.

丽_{R (DMSO- d 6, 400 MHz} ) δ 13.53 (brs, 1 H), 11.02 (brs, 1 H), 8.15 (d, 1 H, J = 7.8 Hz), 7.70 (s, 1 H), 7.47 7.51 (m, 2 H), 7.32 to 7,39 (m, 3 H), 4.36 to 4.40 (m, 2 H), 3.70 to 3.85 (m, 2 H), 3.19 (m, 2 H), 0.36 ~ 1.23 (m, 8H).

(4) 4- (3- (2-chlorophenyl) -1- [2- (dicyclopropylamino) ethyl] -3_hydroxy-2-oxoindoline-6-carboxamide hydrochloride

Example 6 In the same manner as in _ (4), 4-kuguchi-3- (2-chlorophenyl) -1- [2- (dicyclopropylamino) ethyl] -3-hydroxy-2-oxodindrin- It was synthesized from 6-carboxylate.

Thigh (DMS0-d ₆₎ 400 MHz) δ 10.64 (brs, 1 H), 8.12 to 8.16 (m, 2 H), 7.80 (brs, 1 H), 7.68 (s, 1 H), 7.45 to 7.51 ( m, 2 H), 7.29 to 7.41 (m, 3 H), 4.28 to 4.35 (m, 2 H), 3.46 to 3.68 (m, 2 H), 3.18 (m, 2 H), 0.84 to 1.23 ( m, 8 H). Example 14

4-Chloro-3- (2-chlorophenyl) -3-hydroxy-1_ [2- (1-methylpyrrolidine-2-inole) ethyl 2-oxoindrin-6-carboxamide hydrochloride

(1) Methyl 4-chloro-1_ [2_ (1_methylpyrrolidine-2-inole) ethyl] -2,3-dioxindrin-6-carboxylate

Example 1 In the same manner as in-(1), methyl 4-kuguchi-2,3-dioxoindrin-6-carboxylate (Reference Example 3) and 2- (2-cloguchiethyl) It was synthesized from -1_methylpyrrolidine hydrochloride.

¾ NMR (CDC1 ₃₎ 400 MHz) δ 7.73 (d, 1 H, J = 1.0 Hz), 7.46 (d, 1 H, J = 1.0 Hz), 3.99 (s, 3 H), 3.74 to 3.97 (m, 2H), 3.06 to 3.10 (m, 1H), 2.30 (s, 3H), 1.57 to 2.20 (m, 8H).

(2) Methyl 4-chloro-3- (2-chlorophenyl) -3-hydroxy-1- [2- (1-methylpyrrolidin-2-yl) ethyl] -2-oxoindrin-6-carboxylate

In the same manner as in Example 6- (2), methyl 4-hydroxy--1- [2_ (1-methylpyrrolidine-2- Yl) ethyl] -2,3-dioxindrin-6-carboxylate.

¾ Awakening: _{R (CDC1 3, 400 MHz)} δ 8. 18 (d, 1 H, J = 7. 9 Hz), 7. 65 (s, 1 H), 7. 40 ~ 7. 46 (m, 2 H ), 7.24 to 7.33 (m, 2H), 3.94 (s, 3H), 3.74 to 4.02 (m, 2H), 3.04 to 3.07 (m, 2H) 1 H), 1.60 to 2.28 (m, 10 H).

(3) 4-Mouth mouth-3- (2-chlorophenyl) -3-hydroxy-1- [2- (1-methylpyrrolidine-2-ynole) ethyl] -2_oxoindoline-6-carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4-chloro-3- (2-chlorophenyl) -3-hydroxy-1- [2- [1- (1- Methylpyrrolidine-2-ynole) ethynole] was synthesized from 2-oxoindolin-6-carboxylate.

_{¾ NMR (DMSO- d 6, 400} MHz) 8 10. 18 (brs, 1 H), 8. 13~ 8. 18 (m, 2 H), 7. 65 ~ 7. 68 (m, 2 H), 7.46 to 7.50 (m, 2 H), 7.38 (dd, 1 H, J = 7.7, 7.7 Hz), 7.32 (d, 1 H, J = 7.7 Hz) ), 7.27 (s, 1 H), 3.83 to 3.91 (m, 2 H), 3.04 to 3.53 (m, 3 H), 2.80 to 2.82 (m, 3 H), 2.30 to 2.46 (m, 2 H), 1.76 to 2.01 (m, 4 H) .Example 15

4-Chloro-3- (2-chloropheninole) -1- [3- (dimethylamino) propyl] -3-hydroxy-2-oxindrin-6-carboxamide hydrochloride

(1) Methyl 4-co-mouth 1- [3- (dimethylamino) propyl] -2,3-dioxoindrin-6-carboxylate

Example 1 In the same manner as in (1), methyl 4-co- mouth-2,3-dioxoindrin-6-carboxylate (Reference Example 3) and 3-dimethylaminoprovirk Synthesized from do hydrochloride

¾ negation _{R (CDC1 3, 400 MHz)} δ 7. 72 (d, 1 H, J = 1. 0 Hz), 7. 57 (d, 1 H, J = 1. 0 Hz), 3. 98 (s , 3H), 3.87 (t, 2H, J = 6.8 Hz), 2.34 (t, 2H, J = 6.6 Hz), 2.17 (s, 6H), 1 85 (tt, 2 H, J = 6.6, 6.8 Hz).

(2) Methyl 4-oct-3- (2-chlorophenyl) -1- [3- (dimethylamino) propyl] -3-hydroxy-2-oxoindolin-6-carboxylate

In a manner similar to that of Example 6- (2), it was synthesized from methyl 4-hydroxy-1- [3- (dimethylamino) propyl] -2,3-dioxoindrin-6-carboxylate. _{¾ MR (CDC1 3, 400 MHz} ) δ 8.19 (dd, 1 H, J = 1.6, 7.8 Hz), 7.64 (d, 1 H, J = 1.2 Hz), 7.49 (d, 1 H, J = 1.2 Hz) , 7.42 (ddd, 1 H, J = 1.3, 7.8, 7.8 Hz), 7.30 (ddd, 1 H, J = 1.6, 7.8, 7.8 Hz), 7.24 (dd, 1 H, J = 1.3, 7.8 Hz) , 3.98 to 4.06 (m, 1 H), 3.94 (s, 3 H), 3.73 to 3.79 (m, 1 H), 2.49 to 2.56 (m, 1 H), 2.28 to 2.35 (ra, 1 H), 2.13 (s, 6 1.1), 1.82 to 1.95 (m, 2H). (3) 4-Kokuroku 3- (2-chloropheninole) — 1- [3- (dimethylamino) propyl] -3-hydroxy 2-oxodindine-6-carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4-chloro-3- (2-chlorophenyl) -1- [3- (dimethylamino) propyl] -3-h Synthesized from droxy-2-oxoindoline-6-carboxylate.

¾ 丽 R (DMS0-d ₆ , 400 MHz) δ 9.94 (brs, 1 H), 8.14 to 8.17 (m, 2 H), 7.64 to 7.65 (m, 2 H), 7.46 to 7.50 (m, 2 H) , 7.38 (ddd, 1 H, J = 1.7, 7.7, 7.7 Hz), 7.32 (dd, 1 H, J = 1.3, 7.7 Hz), 7.27 (s, 1 H), 3.83 to 3.87 (m, 2 II) , 3.14 to 3.21 (m, 2 H), 2.77 (s, 3 H), 2.76 (s, 3 H), 2.03 to 2.08 (m, 2 H).

4-chloro-3- (2-chlorophenyl) -3-hydroxy-1_ (2-morpholine-4-yletinole) -2-oxodindin-6-carboxamide hydrochloride

(1) Methyl 4-coguchi-1_ (2-morpholine-4-ylethyl) -2,3-dioxoindrin-6-butanolboxylate

Example 1-In a similar manner as in (1), methyl 4-cyclo-2,3-dioxoindrin-6-carboxylate (Reference Example 3) and 4- (2-chloroethyl) morpholine hydrochloride Synthesized from salt. ¾ Keio _{R (CDC1 3, 400 MHz)} δ 7.73 (d, 1 H, J = 1.0 Hz), 7.49 (d, 1 H, J = 1.0 Hz), 3.99 (s, 3 H), 3.90 (t, 2 H, J = 5.8 Hz), 3.61 to 3.66 (m, 4H), 2.65 (t, 2H, J = 5.8 Hz), 2.52 to 2.54 (m, 4H).

(2) Methinole 4-Monochrome -3- (2-Chloropheninole) -3- -Hydroxy- 1_ (2-Monolefolin-4 -leletyl) -2-oxoindrin-6-carboxylate

(2) the same way, methyl 4-click port B - - Example 6 1 - (2-morpholin - 4-Iruechiru) - ^2, 3 - was synthesized from 6-carboxylate - di O Kiso indoline. ¾ negation _{R (CDC1 3, 400 MHz)} δ 8.17 (d, 1 H, J = 7.5 Hz), 7.66 (d, 1 H, J = 1.1 Hz)? 7.51 (d, 1 H, J = 1.1 Hz), 7.43 (dd, 1 H, J = 7.5, 7.5 Hz), 7.32 (dd, 1 H, J = 7.5, 7.5 Hz), 7.26 (d, 1 H, J = 7.5 Hz), 3.95 (s, 3 H) , 3.81 to 4.05 (m, 2 H), 3.67 to 3.70 (m, 4 H), 2.75 to 2.82 (m, 1 H), 2.60 to 2.67 (m, 3 H), 2.44 to 2.51 (ra, 2 H) .

(3) 4_Black mouth—3- (2-Black mouth fenole) —3-Hydroxy— 1- (2-Morpholine _4_Inoleethinole) -2-Oxoindoline_6-Carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4-chloro-3- (2-chlorophenyl) -3-hydroxy-1- (2-morpholine-4- (Irethyl) Synthesized from 2-oxoindolin-6-carboxylate.

¾ MR (DMS0-d ₆₎ 400 MHz) δ 10.79 (brs, 1 H), 8.14 to 8.16 (m, 2 H), 7.75 (s, 1 H), 7.69 (s, 1 H), 7.46 to 7.51 ( m, 2 H), 7.38 (ddd, 1 H, J = 1.7, 7.6, 7.6 Hz), 7.30 to 7.33 (ra, 2 H), 4.27 to 4.31 (m, 1 H), 4.13 to 4.15 (m , 1 H), 3.98 to 04 (m, 2 H), 3.23 to 3.83 (m, 8 H).

4— mouth—3_ (2-chloropheninole) —3-hydroxy-2-oxo-11- (2-pyrrolidine-1-inoleethyl) indoline-6-carboxamide hydrochloride

(1) Methyl 4-oct-2'-dioxo-1- (2-pyrrolidine-1-ylethyl) indoline-6-carboxylate

In the same manner as in Example 1- (1), methyl 4-coguchi-2,3-dioxoindrin-6-carboxylate (Reference Example 3) and 1- (2-chloroethyl) pyrrolidine hydrochloride were used. Synthesized from salt. ¾ Keio _{R (CDC1 3, 400 MHz)} δ 7.72 (d, 1 H, J = 0.9 Hz), 7.50 (d, 1 H, J = 0.9 Hz), 3.98 (s, 3 H), 3.92 (t, 2 H, J = 6.7 Hz), 2.78 (t, 2 H, J = 6.7 Hz), 2.58 to 2.60 (m, 4 H), 1.73 to 1.79 (m, 4 H).

(2) Methyl 4-chloro-3- (2-chlorophen-2-ole) -3-hydroxy-2-oxo-1- (2-pyrrolidin-1-ylethyl) indoline-6-carboxylate

In a manner similar to that of Example 6- (2), the compound was synthesized from methyl 4-cyclo-2,3-dioxo-1- (2-pyrrolidine-1-ylethyl) indoline-6-carboxylate.

¾ thigh _{R (CDC1 3, 400 MHz)} δ 8.21 (dd, 1 H, J = 1.4, 7.8 Hz), 7.65 (d, 1 H, J = 1.2 Hz), 7.48 (d, 1 H, J = 1.2 Hz), 7.41 (ddd, 1 H, J = 1.4, 7.8, 7.8 Hz), 7.30 (ddd, 1 H, J = 1.4, 7.8, 7.8 Hz) ), 7.24 (dd, 1 H, J = 1.4, 7.8 Hz), 4.11 to 4.20 (m, 1 H), 3.94 (s, 3 H), 3.75 to 3.82 (ra, 1 H), 3.02 to 3.09 (m , 1 H), 2.61 to 2.77 (m, 3 H), 2.55 to 2.57 (m, 2 H), 1.79 to 1.82 (m, 4 H).

(3) 4-chloro-3- (2-chlorophenol) -3-hydroxy-2-oxo-1- (2-pyrrolidine-1-ylethyl) indoline-6-carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4-chloro-3- (2-chlorophenol) -3-hydroxy-2-oxo-1- ( It was synthesized from 2-pyrrolidine-1-ylethyl) indoline-6-carboxylate.

_{¾ NMR (DMS0- d 6, 400} MHz) δ 10.53 (brs, 1 H), 8.14~ 8.16 (m, 2 H), 7.71 (s, 1 H), 7.67 (s, 1 H), 7.46 ~ 7.50 ( m, 2 H), 7.38 (ddd, 1 H, J = 1.5, 7.

6, 7.6 Hz), 7.31 to 7.33 (m, 2 H), 4.24 to 4.31 (m, 1 H), 4.02 to 4.07 (m, 1 H), 3.36 to 3.73 (tn, 4 H), 3.09 to 3.18 ( m, 2 H), 2.02 to 2.04 (m, 2 H), 1.88 to 1.93 (m, 2 H).

_4-click port row 3 i ₍₂ - chlorophenyl) Single _"2 - (Jimechiruamino) Echiru] _ _3-hydroxy _ ₂ - Okisoindorin - 6-carboxamide hydrochloride

(1) Methyl 4-chloro-2,3-dioxo-1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] indoline-6-carboxylate

In a nitrogen atmosphere, a solution of 60% sodium hydride (1.019 g, 25.5 mmol) in N, N-dimethylformamide (100 mL) was added at 0 ° C with methyl 4-chloro-1- (2- (Jetylamino) ethyl). -2,3-Dioxoindolin-6-carboxylate (Example 6- (1)) (5.55 g, 23.2 mmol) in N, N-dimethylformamide (10 mL) and 2- (2- A solution of (chloroethoxy) tetrahydropyran (4.20 g, 25.5 mmol) in N, N-dimethylformamide (6 mL) was added, and the mixture was stirred at 80 ° C for 1 hour and at 100 ° C for 2 hours. Ethyl acetate / toluene (1: 1) was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate. After drying over magnesium sulfate and filtration, the solvent was distilled off. Silica gel column 'skeleton Matogurafi one (hexane / acetate Echiru = ² / 1-1 / 1 to, black hole Holm / methanol = 1 / 0-100 / 1) twice to give, solvent was evaporated to give the title compound ( ^{^{3 .16 g, '37 ° /}} .) was obtained. _{¾ NMR (CDC1 3, 400 MHz} ) 5 7.73 (s, 1H), 7.71 (s, 1H), 4.58 (brs, 1H), 3.98 (s, 3H), 3.90 ~ 4.12 (m, 3H), 3.67 ~ 3.79 (ra, 2H), 3.45 to 3.51 (m, 1H), 1.40 to 1.78 (m, 6H).

(2) Methinole 4-—3- (2-chloro-2-phenyl) -3-hydroxy-2-oxo-1-[2- (tetrahydro-2H-pyran-2-yloxy) ethyl] indolin- 6-carboxylate

Example 6 In a similar manner to that of-(2), methyl 4-chloro-2,3-dioxo-1_ [2- (tetrahydrido-2H-bilan-2-yloxy) ethyl] indoline-6-carboxylate 1 Synthesized from

¾丽_{R (CDC1 3, 400 MHz)} δ 8.14 ~ 8.18 (m, 1H), 7.63 ~ 7.74 (ra, 2H), 7.40 (ddd, 1H, J = 1.3, 6.9, 6.9 Hz), 7.28 ~ 7.33 (m , 1H), 7.25 (dd, 1H, J = 1.3, 7.9 Hz), 4.57 to 4.60 (m, 1H), 3.86 to 4.18 (m, 3H), 3.93 (s, 3H), 3.70 to 3.85 (m, 2H ), 3.42 to 3.51 (m, 1H), 1.40 to 1.84 (ra, 6H).

(3) Methyl 4-chloro-3- (2_chlorophenyl) -3-hydroxy-1- (2-hydroxyethyl) -2-oxoindolin-6-carboxylate

In a nitrogen atmosphere, methyl 4-chloro-3- (2-chlorophenyl) -3-hydroxy-2-oxo-1-[2- (tetrahydro-2H-pyran-2-yloxy) ethyl] indoline-6- Pyridinium p-toluenesulfonate (134 mg, 0.53 mraol) was added to a methanol (53 mL) solution of carboxylate (2.56 g, 5.33 mmol), and the mixture was stirred at 50 ° C for 6 hours. The solvent was distilled off, and the residue was purified by silica gel gel column chromatography (form: methanol / methanol = 20/1) to give the title compound (2.03 g, 96%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.09 (dd, 1H, J = 1.6, 7.9 Hz), 7.62 (d, 1H, J = 0.9 Hz), 7.47 (d, 1H, J = 0.9 Hz), 7.38 ( ddd, 1H, J = 1.3, 7.4, 7.9 Hz), 7.29 (ddd, 1H, J = 1.6, 7.4, 7.9 Hz), 7.23 (dd, 1H, J = 1.3, 7.9 Hz), 5.03 (brs, 1H), 4.01 to 4.08 (ra, 1H), 3.92 (s, 3H), 3.85 (brs, 2H), 3.65 — 3.76 (m, 1H), 3.34 (brs, 1H).

(4) Methynole 4- -2- (2- (dimethylamino) ethyl) -3--3-hydroxy-2-oxoindrin-6-carboxylate

In a nitrogen atmosphere, methinole 4-chloro-3- (2-chloro-mouth feninole) -3-hydroxy-1_ (2-hide-mouth quichetyl) -2-oxoindrin-6-carboxylate 1, (99 mg, 0.25 mmol) of axis Rorometan solution (2.5 mL) in pyridine at _{0 ° C (40 u l 0.5} mmol), triflate Ruo b methane Sulfonic anhydride (46 // L, 0.28 mmol) was added and stirred for 1 hour. A 50% aqueous dimethylamine solution (113 mg, 1.1 mmol) was added, and the mixture was stirred at 0 ° C for 4 hours. Saturated aqueous sodium bicarbonate was added, extracted with ethyl acetate, and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / methanol = 50/1 to 30/1) to give the title compound (80 mg 76%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.18 (d, 1H, J = 7.6 Hz), 7.64 (d, 1H, J = 1.2 H z), 7.44 (d, 1H, J = 1.2 Hz), 7.40 (ddd , 1H, J = 1.3, 7.6, 7.9 Hz), 7.29 (ddd, 1H, 1.7, 7.9, 7.9 Hz), 7.23 (dd, 1H, J = 1.3, 7.9 Hz), 4.18 (ddd, 1H, J = 6.0 , 9.2, 14.4 Hz), 3.94 (s, 3H), 3.68 (ddd, 1H, J = 4.2, 6.3, 14.4 Hz), 2.89 (ddd, 1H, J = 6.3, 9.2, 12.8 Hz), 2.51 (ddd, 1H, J = 4.2, 6.0, 1 2.8 Hz), 2.31 (s, 6H).

(5) 4- (3- (2-dimethylamino) ethyl) -3-hydroxy-2-oxindrin-6_carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4-chloro-3- (2-chlorophenyl) -1-[2- (dimethylamino) ethyl] -3 It was synthesized from -hydroxy-2-oxoindoline-6_carboxylate.

¾丽_{R (CDC1 3, 400 MHz)} ( free form) δ 8.23 (dd, 1H, J = 1.2, 7.8 Hz), 7.45 (s, 1H), 7.41 (dd, 1H, J = 7.8, 7.8 Hz), 7.39 (s, 1H), 7.30 (dd, 1H, J = 7.8, 7.8 Hz), 7.23 (d, 1H, J = 7.8 Hz), 6.82 (brs, 1H), 5.95 (brs, 1H), 3.53 to 3.99 (m, 2H), 2.72 to 2.84 (ra, 1H), 2.45 to 2.55 (m, 1H), 2.19 (s, 6H).

1- {2- [Benzyl (ethyl) amino] ethynole '} -4-cyclo-2--3- (2-hydroxyphenyl) -3-hydroxy-2-oxoindrin-6-carboxamide hydrochloride

(1) Methyl 1- {2- [benzyl (ethyl) amino] ethyl 4-oct-3- (2-chlorophenyl) -3-hydroxy-2-oxoindoline _6_carboxylate

In the same manner as in Example 18- (4), methyl 4-chloro-3- (2-chlorophenol) -3-hydroxy-1- (2-hydroxyethyl) -2-oxoindrin-6 -Carboxylate (Example

18- (3)) and N-ethylbenzylamine.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.15 (dd, 1H, J = 1.2, 7.8 Hz), 7.62 (d, 1H, J = 1.2 Hz), 7.39 (ddd, 1H, J = 1.2, 7.8, 7.8 Hz), 7.33 (d, 1H, J = 1.2 Hz), 7.13 to 7.32 (m, 6H), 3.92 to 4.03 (m, 1H), 3.92 (s, 3H), 3.50 to 3.75 (m, 4H), 2.55 to 2.87 (m, 4H), 1.88 (brs, 1H), 1.10 (t, 3H, J = 7.1 Hz).

(2) 1- {2- [Benzyl (ethynole) amino] ethyl} -4-culo-3- (2-chlorophenyl) -3-hydroxy-2-oxoindrin-6-carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 1_ {2- [benzyl (ethyl) amino] ethynole} -4-4 Synthetic from 3-hydroxy-2-oxoindolin-6-carboxylate.

_{¾ NMR (CDC1 3, 400 MHz} ) ( free form) δ 8.16 (dd, 1H, J = 1.3, 7.8 Hz), 7.40 (d dd, 1H, J = 1.4, 7.8, 7.8 Hz), 7.16~ 7.33 (m , 8H), 7.08 (d, 1H, J = 1.0 Hz), 5.80 to 5.92 (brs, 1H), 5.68 to 5.80 (brs, 1H), 3.93 to 4.02 (m, 1H), 3.68 to 3.76 (m, 1H ), 3.71 (d, 1H, J = 13.5 Hz), 3.57 (d, 1H, J = 13.5 Hz), 2.59-2.87 (m, 4H), 1.09 (t, 3H, J = 7.1 Hz).

4- ク口口 -3- (2-chlorophenyl) -3-hydroxy-2-oxo-1- (2-piperidine-1-inoleethyl) indoline-6-carboxamide hydrochloride

(1) Methyl 4-chloro-3- (2-chloro-2-phenol) -3-hydroxy-2-oxo-1- (2-piperidine-1-yletinole) indoline-6-carboxylate

Example 18 In a similar manner to 8- (4), methyl 4-chloro-3- (2-chlorophenyl) -3-hydroxy-1- (2-hydroxyethyl) -2-oxoindrin-6- Synthesized from carboxylate (Example 18- (3)) and piperidine.

¾删_{R (CDC1 3, 400 MHz)} δ 8.21 (dd, 1H, J = 1.5, 7.9 Hz), 7.65 (d, 1H, J = 1.2 Hz), 7.50 (d, 1H, J = 1.21 Hz), 7.41 (ddd, 1H, J = 1.4, 4.7, 7.9 Hz), 7.30 (ddd, 1H, J = 1.5, 7.4, 7.9 Hz), 7.24 (dd, 1H, J = 1.4, 7.9 Hz), 4.15 (ddd, 1H, J = 6.0, 8.8, 14.5 Hz), 3.94 (s, 3H), 3.75 (ddd, 1H, J = 4.6, 6.1, 14.5 Hz), 2.82 (ddd, 1H, J = 6.1, 8.8 '13.0 Hz) , 2.63 (brs, 2H), 2.55 (ddd, 1H, J = 4.6, 6.0, 13.0 Hz), 2.38 (brs, 2H), 1.40 to 1.60 (m, 6H).

(2) 4-Mono-3--3- (2-chlorophenyl) -3-hydroxy-2-oxo-1- (2-piperidine_1-ylethyl) indoline-6-carboxamide hydrochloride In the same manner as in Example 6- (3) and Example 6_ (4), methyl 4-chloro-3- (2-chlorophenyl) -3-hydroxy-2-oxo-1- (2-piperidine (1-Ilethyl) was synthesized from indoline-6-carboxylate.

_{¾ NMR (DMS0 - d 6,} 400 MHz) δ 9.84 (brs, 1H), 8.14 (dd, 1H, J = 1.5, 7.9 Hz), 8.13 (s, 1H), 7.71 (s, 1H), 7.68 (s , 1H), 7.51 (s, 1H), 7.48 (ddd, 1H, J = 1.3, 7.9, 7.9 Hz), 7.39 (ddd, 1H, J = 1.5, 7.9, 7.9 Hz), 7.32 (dd, 1H, J = 1.3, 7.9 Hz), 7.31 (s, 1H), 4.05 to 4.31 (m, 2H), 3.50 to 3.75 (m, 2H), 3.25 to 3.45 (m, 2H), 2.94 to 3.09 (m, 2H), 1.27 to 1.90 (m, 6H). Example 21

4- ク口口 -3- (2-chlorophenole) -3-hydroxy-1- [2_ (4-methylpyrazine-1-inole) ethyl] -2-oxoindolin-6-caproloxamide hydrochloride

(1) Methyl 4-oral mouth—3- (2-oral feninole) —3-hydroxy-1- [2- (4-methylpiperazine-1-yl) ethyl] -2-oxindrin -6-carboxylate

Example 18 In a similar manner as in 8- (4), methyl 4-kuguchi-3- (2-chloropheninole) -3-hydroxy-1- (2-hydroxyethyl) -2-oxo-indrin- It was synthesized from 6-carboxylate (Example 18- (3)) and 1-methylbiperazine.

¾ negation _{R (CDC1 3, 400 MHz)} δ 8.21 (dd, 1H, J = 1.5, 7.9 Hz), 7.64 (d, 1H, J = 1.2 Hz), 7.48 (d, 1H, J = 1.2 Hz), 7.41 (ddd, 1H, J = 1.3, 7.3, 7.9 Hz), 7.30 (ddd, 1H, J = 1.5, 7.3, 7.9 Hz), 7.24 (dd, 1H, J = 1.3, 7.9 Hz), 4.00

~ 4.08 (m, 1H), 3.93 (s, 3H), 3.80 (ddd, 1H, J = 5.2, 6.5, 14.5 Hz), 2.73 to 2.85 (m, 1H), 2.59 to 2.71 (m, III), 2.27 ~ 2.58 (m, 8H), 2.22 (s, 3H)

(2) 4-Chloro-3- (2-chlorophenyl) -3-hydroxy-1- [2- (4-methylbiperazine-1-yl) ethyl] -2-oxoindolin-6-carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4-chloro-3- (2-chlorophenyl) -3-hydroxy-1- [2- (4 -Methinolepiperazine-1-inole) ethinole] -2-oxoindolin- ⁶ -carboxylate.

¾ NMR (CD ₃ 0D, 400 MHz) δ 8.27 (dd, 1H, J = 1.7, 8.0 Hz), 7.66 (d, 1H, J = 1.2 Hz), 7.57 (d, 1H, J = 1.2 Hz), 7.48 (ddd, 1H, J = 1.2, 7.4, 8.0 Hz), 0

7.38 (ddd, 1H, J = 1.7, 7.4, 7.9 Hz), 7.31 (dd, 1H, J = 1.2, 7.9 Hz), 4.38 to 4.46 (m, 1H), 4.09 to 4.17 (m, 1H), 3.11 to 3.90 (m, 10H), 3.01 (s, 3H).

Example 22

4-Chloro-3- (2-chloro mouth feninole)-1-{2- [Echinole (2-methoxethyl) amino] ethene / re} _3-Hydroxy-2-oxoindrin-6-carboxamide hydrochloride

(1) Methyl 4-chloro-3- (2-chloro-2-phenyl) -1_ {2- [ethyl (2-methoxethyl) amino] ethyl} -3-hydroxy-2-oxoindolin-6-carboxy Rate

Example 18 In a similar manner to that of Example 4- (4), methyl 4-hydroxy-3- (2-chlorophenyl) -3-hydroxy-1- (2-hydroxyethyl) -2-oxoindrin-6-carboxy (Example 18- (3)) and N-ethyl-2-methoxyethaneamine (free form of Reference Example 20). ¾ employment _{R (CDC1 3, 400 MHz)} 8 8.27 (dd, 1H, J = 1.6, 7.9 Hz), 7.62 (d, 1H, J =

1.2 Hz), 7.45 (d, 1H, J = 1.2 Hz), 7.41 (ddd, 1H, J = 1.4, 7.7, 7.9 Hz), 7.30 (ddd, 1H, J = 1.6, 7.7, 7.9 Hz), 7.23 ( dd, 1H, J = 1.4, 7.9 Hz), 5.36 (brs, 1H), 4.25 (ddd, 1H, J = 5.0, 9.0, 14.4 Hz), 3.94 (s, 3H), 3.56 (ddd, 1H, J = 4.8, 4.8, 14.4 Hz), 3.05 to 3.34 (m, 2H), 2.98 (s, 3H), 2.39 to 2.89 (m, 6H), 1.96 (brs, 1H), 1.02 (t, 3H, J = 7.1 Hz ).

(2) 4-Black mouth _3- (2-Black mouth fu-nore) -1-{2- [Ethyl (2-methoxethyl) amino] ethyl 3-Hydroxy-2-oxoindoline-6-Caproloxam Do hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4-chloro-3- (2-chlorophenol) -1- {2- [ethyl (2-methyl Toxityl) amino] ethyl} -3-Hydroxy-2-oxoindrin-6-carboxylate.

¾ 丽 R (DMS0-d ₆ , 400 MHz) δ 10.19 (brs, 1H), 8.15 (s, 1H), 8.14 (dd, 1H, J = 1.6, 8.0 Hz), 7.74 (s, 1H), 7.67 ( s, 1H), 7.52 (s, 1H), 7.49 (ddd, 1H, J = 1.3, 7.3, 8.0 Hz), 7.39 (ddd, 1H, J = 1.6, 7.3, 8.0 Hz), 7.32 (dd, 1H, J = 1.3, 8.0 Hz), 7.31 (s, 1H), 4.07 to 4.32 (m, 2H), 3.63 to 3.80 (m, 2H), 3.22 to 3.55 (m, 9H), 1.26 (t, 3H, J = 7.1 Hz) .Example 23

4-Kuguchi-3- (2-chlorophenyl)-1-{2- [ethyl (2fluoroethyl) amino] ethyl]-3-hydroxy-2-oxoindolin-6-carpoxamide hydrochloride

(1) Methyl 4-tert-butyl-3- (2-chlorophenyl) -1- {2- [ethyl (2-fluoroethyl) amino] ethynole} -3-hydroxy-2-oxoindoline-6-butanolboxylate

Example 18-In the same manner as in (4), methyl 4_chloro-3- (2-chlorophenyl) -3-hydroxy-1- (2-hydroxyethyl) -2-oxo-indrin-6- It was synthesized from carboxylate (Example 18- (3)) and N-ethyl-2-fluoroethaneamine (free form of Reference Example 21).

Keio _{R (CDC1 3, 400 MHz)} δ 8.19 (dd, 1H, 1.3, 7.9 Hz), 7.65 (d, 1H, J = 1.2 Hz), 7.51 (d, 1H, J = 1.2 Hz), 7.41 (ddd, 1H, J = 1.4, 7.9, 7.9 Hz), 7.30 (ddd, 1H, J = 1.3, 7.9, 7.9 Hz), 7.25 (dd, 1H, J = 1.4, 7.9 Hz), 4.40 to 4.57 (ra, 2H) , 4.01 to 4.20 (m, 1H), 3.94 (s, 3H), 3.61 to 3.80 (m, 1H), 2. 62 to 2.96 (m, 6H), 1.04 (t, 3H, J = 7.1 Hz).

(2) 4-Cupro-3- (2-chloropheninole) -1- {2- [Ethyl (2-ethylacetyl) amino] ethyl 3-hydroxy-2-oxoindoline-6- Carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4-chloro-3- (2-chlorophenyl) -1- {2- [ethyl (2-fluoroethyl) ) Amino] ethyl} -3-Hydroxy-2-oxoindrin-6-carboxylate.

_{¾ NMR (CDC1 3, 400 MHz} ) ( free form) δ 8.20 (dd, 1H, J = 1.4, 7.8 Hz), 7. 2 (d, 1H, J = 1.3 Hz), 7.41 (ddd, 1H, J = 1.5, 7.8, 7.8 Hz), 7.36 (d, 1H, J =

1.3 Hz), 7.31 (ddd, 1H, J = 1.4, 7.8, 7.8 Hz), 7.25 (dd, 1H, J = 1.4, 7.8 Hz), 6.33 (brs, 1H), 5.87 (brs, 1H), 4.45 ~ 4.61 (m, 2H), 4.02 (ddd, 1H,

J = 7.1, 7.1, 14.2 Hz), 3.79 (ddd, 1H J = 6.8, 6.8, 14.2 Hz), 2.65 — 2.94 (m, 6H), 1.03 (t, 3H, J = 7.1 Hz).

4-Chloro-3- (2-chlorophenyl) _1- [2- (disopropynoleamino) ethyl] -3-hydroxy-2-oxoindolin-6-carboxamide hydrochloride

(1) Methyl 4-chloro-3- (2-chlorophenol) -1- [2- (diisopropylamino) ethyl] -3-hydroxy-2_oxoindoline-6-carboxylate

Example 18 In a similar manner to that of-(4), methyl 4-chloro-3- (2-hydroxyphenyl) -3-hydroxy-1_ (2-hydroxyethyl) -2-oxoindrin_6_carboxylate The compound was synthesized from (Example 18- (3)) and disopropylamine.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.15 (dd, 1H, J = 1.6, 8.0 Hz), 7.64 (d, 1H, J =

(1.2 Hz), 7.53 (d, 1H, J = 1.2 Hz), 7.41 (ddd, 1H, J = 1.3, 7.2, 8.0 Hz), 7.31 (ddd, 1H, J = 1.6, 7.2, 7.9 Hz), 7.26 ( dd, 1H, J = 1.3, 7.9 Hz), 3.94 (s, 3H), 3.67 to 3.89 (m, 2H), 3.02 to 3.14 (m, 2H), 2.65 to 2.85 (m, 2H), 1.78 (brs, 1H), 1.05 (d, 6H, J = 6.5 Hz), 1.04 (d, 6H, J = 6.5 Hz).

(2) 4-Methoxy-3- (2-chlorophenyl) -1- [2- (diisopropylamino) ethyl] -3-hydroxy-2-oxoindoline-6-carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4-chloro-3- (2-chlorophenyl) -1- [2- (diisopropylamino) ethyl] -3-Hydroxy-2-oxoindoline-6 -Synthesized from lipoxylate.

_{¾ NMR (CD 3 0D, 400} MHz) δ 8.14 (dd, 1H, J = 1.7, 7.9 Hz), 7.48 (d, 1H, J =

1.26), 7.46 (d, 1H, J = 1.2 Hz), 7.38 (ddd, 1H, J = 1.3, 7.4, 7.9 Hz), 7.28 (ddd, 1H, J = 1.7, 7.4, 7.9 Hz), 7.20 ( dd, 1H, J = 1.3, 7.9 Hz), 4.05 to 4.27 (m, 2H), 3.72 to 3.85 (m, 2H), 3.32 to 3.42 (ra, 2H), 1.32 to 1.44 (m, 12H). twenty five

1- [2- (tert-Butylamino) ethyl] -4 -coguchi-3_ (2-chlorophenyl) -3-hydroxy-2-oxoindoline-6-carboxamide hydrochloride

(1) Methyl 1- [2- (tert-butynoleamino) ethynole]-4-octopen-3_ (2-chlorophenyl) -3-hydroxy-2-oxoindolin-6-carboxylate

Example 18 In a similar manner to that of Example 4- (4), methyl 4- (3-hydroxy-2-phenyl) -3-hydroxy-2- (2-hydroxyethynole) -2- It was synthesized from oxindrin-6-carboxylate (Example 18- (3)) and t-butylamine.

¾删_{R (CDC1 3, 400 MHz)} δ 8.23 (dd, 1H, J = 1.5, 7.9 Hz), 7.65 (s, 1H), 7. 48 (s, 1H), 7.41 (dd, 1H, J = 7.4 , 7.9 Hz), 7.30 (ddd, 1H, J = 1.5, 7.4, 8.0 Hz), 7.23 (d, 1H, J = 8.0 Hz), 4.01 to 4.09 (s, 1H), 3.94 (s, 3H) , 3.79 (ddd, 1H, J = 5.2, 5.2, 14.4 Hz), 3.05 to 3.42 (brs, 2H), 2.94 to 2.98 (m, 2H), 1.09 (s, 9H).

(2) 1- [2- (tert-butylamino) ethyl] -4-clo-3--3- (2-chlorophenyl) -3-hydroxy-2-oxoindrin-6-carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 1_ [2- (tert-butylamino) ethynole] -1- 4-guchi-3 -) 3-Hydroxy-2-oxindrin-6-force synthesized from lipoxylate.

_{¾ NMR (DMS0 - d 6,} 400 MHz) δ 8.95 (brs, 2H), 8.16 (s, 1H), 8.15 (dd, 1H, J = 1.6, 8.0 Hz), 7.75 (s, 1H), 7.68 (s , 1H), 7.52 (s, 1H), 7.49 (ddd, 1H, J = 1.3, 7.2, 8.0 Hz), 7.39 (ddd, 1H, J = 1.6, 7.2, 7.9 Hz), 7.33 (dd, 1H, J = 1.3, 7.9 Hz), 7.31 (s, 1H), 3.98 to 4.22 (m, 2H), 3.05 to 3.20 (ra, 2H), 1.34 (s, 9H). Example 26

4-Methoxy-3- (2-chlorophenyl)-1- [2- (ethylamino) ethyl Ί-3-hydroxy-2-year-old xoindoline-6-carboxamide hydrochloride

In a nitrogen atmosphere, methyl 4-chloro mouth _3- (2-chloro mouth feninole) -3-hydroxy-1- (2-hide mouth kisshethyl) -2-oxoindrin-6-carboxylate (Example 18- ( 3)) To a dichloromethane solution (2 mL) of (82 rag, 0.21 mmol) was added pyridine (34 L, 0.42 mmol) and trifluoromethanesulfonic anhydride (42 μΙ, 0.25 mmol) at 0 ° C. Stirred for 1 hour. A 70% aqueous solution of ethylamine (135 mg, 2.1 mol) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off, and tetrahydrofuran (2.1 mL), di-1-butyldicarbonate (92 mg, 4.2 mmol) and 4-dimethylaminopyridine (13 mg, 0.11 mmol) were added, and the mixture was stirred at room temperature in a nitrogen atmosphere. Stirred for 2 days. Saturated aqueous sodium bicarbonate was added, extracted with ethyl acetate, and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9/1 to 4/1) to obtain a Boc form (81 mg, 75%). Then, an amide (49 mg, 0.096 mmol) was obtained in the same manner as in Example 6- (3) and Example 6- (4). After adding 1,4-dioxane (2 mL) and 4N hydrochloric acid / 1,4-dioxane solution (2 mL), the mixture is stirred at 50 ° C for 2 hours, the solvent is distilled off, and the residue is diluted with getyl ether. After washing, the title compound (14 mg, 20%) was obtained. '¾ NMR (DMS0-d ₆ , 400 MHz) δ 9.02 (brs, 1H), 8.89 (brs, 1H), 8.17 (s, 1H), 8.15 (dd, 1H, J = 1.7, 7.9, 7.9 Hz), 7.75 (d, 1H, J = 1.0 Hz), 7.67 (s, 1H), 7.51 (d, 1H, J = 1.0 Hz), 7.49 (ddd, 1H, J = 1.3, 7.9, 7.9 Hz), 7.39 (d dd, 1H, J = 1.7, 7.9, 7.9 Hz), 7.32 (dd, 1H, J = 1.3, 7.9 Hz), 7.30 (s, 1H), 3.93 to 4.22 (m, 2H), 3.13 to 3.30 (m, 2H), 2.95 to 3.13 (m, 2H), 1.10 (t, 3H, J = 7.0 Hz).

4- (3-chloro-2-phenyl) -1- [2- (3-fluoropyrrolidine-1-yl) ethyl 3-hydroxy-2-oxoindoline-6-carboxamide hydrochloride

(1) Methyl 4-cyclo-3- (2-chlorophenyl) -1- [2- (3-fluoropyrrolidine-1-ynole) ethyl] -3-hydroxy-2-oxoindoline_6_carboxylate Example 18 In a similar manner to 8- (4), methyl 4-chloro_3- (2-cyclohexaphenyl) -3-hydroxy-1- (2-hydroxyethyl) -2-oxoindrin-6 The compound was synthesized from -carboxylate (Example 18- (3)) and 3-fluoropyrrolidine (free from Reference Example 22).

¾ Ran _{R (CDC1 3, 400 MHz)} δ 8.24 (dd, 1H x 1/2, J = 1.3, 7.9 Hz), 8.21 (dd, 1 H x 1/2, J = 1.3, 7.9 Hz), 7.66 ( d, 1H 1/2, J = 1.2 Hz), 7.65 (d, 1H x 1 I, J = 1.2 Hz), 7.46 (d, 111 x 1/2, J = 1.2 Hz), 7.44 (d, 1H 1 / 2, J = 1.2 Hz), 7.42 (ddd, 1H, J = 1.1, 7.4, 7.9 Hz), 7.30 (ddd, 1H, J = 1.3, 7.4, 7.9 Hz), 7.24 (dd, 1H, J = 1.1, 7.9 Hz), 5.47 (brs, 1H x 1/2), 5.22 to 5.25 (m, 1H x 1/2), 5.08 to 5.11 (m, 1H x 1/2), 5.05 (brs, 1H x 1/2), 4.25 (ddd, 1H 1/2, J = 5.7, 9.8, 14.6 Hz), 4.14 (ddd, 1H x 1/2, J = 6.4, 8.4, 14.6 Hz), 3.94 (s, 3H 1/2), 3.93 (s, 3H x 1/2), 3.67 to 3.82 (m, 1H), 1.95 to 3.30 (m, 8H).

(2) 4-cyclo-3- (2-chlorophenyl) -1- [2- (3-fluoropyrrolidine-1-yl) ethyl] -3-hydroxy-2-oxooxoindoline-6 -Carboxamide hydrochloride

Same as Example 6- (3) and Example 6- (4); methyl 4-chloro-3- (2-chlorophenylinole) -1- [2- (3-fluoropyrrolidine -1-yl) ethyl] -3-Hydroxy-2-oxoindoline-6-carboxylate.

Response R (DMS0-d ₆ , 400 MHz) δ 11.04 (brs, 1H), 8.36 (s, 1H), 8.15 (d, 1H, J = 8.0 Hz), 7.77 (s, 1H), 7.68 (s, 1H), 7.51 (s, 1H), 7.49 (t, 1H, J = 8.0 Hz), 7.39 (t, 1H, J = 8.0 Hz), 7.33 (d, 1H, J = 8.0 Hz), 7.27 (s, 1H), 5.35 to 5.62 (m, 1H), 3.25 to 4.45 (m, 8H), 2.00 to 2.40 (m, 2H).

4-Cu-mouth _3_ (2-chlorophenole) -3-hydroxy-1- [2- (4-methylbiperidine-1-ynole) ethyl] -2-oxoindoline-6-caproloxamide hydrochloride

(1) Methyl 4-methyl-3- (2-chlorophenyl) -3-hydroxy-1- [2- (4-methylbiperidin-1-inole) ethynole] -2-oxoindolin-6-carboxylate

In the same manner as in Example 18- (4), methyl 4-chloro-3- (2-chloropheninole) -3-hydroxy-1- (2-hydroxyethyl) -2-oxoindrin-6 -Carboxylate (Example 18- (3)) and 4-methylbiperidine. ¾ NMR (CDCI3, 400 MHz) δ 8.21 (dd, 1H, J = 1.3, 8.0 Hz), 7.65 (d, 1H, 1H, J = 1.2 Hz), 7.50 (d, 1H, J = 1.2 Hz), 7.42 (ddd, 1H, J = 1.4, 7.3, 8.0 Hz), 7.30 (ddd, 1H, J = 1.5, 7.3, 7.9 Hz), 7.24 (ddd, 1H, J = 1.4, 7.9 Hz), 4.16 (ddd, 1H, J = 6.1, 8.9, 14.5 Hz), 3.94 (s, 3H), 3.75 (ddd, 1H, J = 4.6, 6.1, 14.5 Hz), 3.18-3.26 (m, 1H), 2.78 to 2.91 ( m, 2H), 2.52 to 2.66 (m, 1H), 2.05 to 2.16 (m, 1H), 1.90 to 2.00 (m, 1H), 1.57 to 1.69 (ra, 2H)

, 1.30 to 1.45 (m, 1H), 1.10 to 1.29 (m, 2H), 0.91 (d, 3H, J = 6.5 Hz).

(2) 4-Chloro-3- (2-octanol) -3-hydroxy-1- [2- (4-methylbiperidine-1-yl) ethyl] _2-oxoindoline-6-carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6_ (4), methyl 4-chloro-3- (2-chloromethyl) -3-hydroxy-1--1- [2- (4- Methylpiperidine-11-yl) ethyl] -2-oxoindolin-6-carboxylate.

¾ Li _{R (DMS0 - d 6, 400} MHz) δ 9.98 (brs, 1H), 8.16 (s, 1H), 8.15 (dd, 1H, J = 1.6, 8.0 Hz), 7.76 (s, 1H), 7.69 ( s, 1H), 7.51 (s, 1H), 7.48 (ddd, 1H, J = 1.2, 8.0, 8.0 Hz), 7.39 (ddd, 1H, J = 1.6, 8.0, 8.0 Hz), 7.33 (dd, 1H, J = 1.2, 8.0 Hz), 7.32 (s, 1H), 4.04 to 4.34 (ra, 2H), 3.52 to 3.78 (ra, 2H), 3.28 to 3.47 (m, 2H), 2.95 to 3.12 (ra, 2H) , 1.78 to 3.12 (ra, 2H), 1.35 to 1.69 (m, 3H), 0.94 (t, 3H, J = 6.3 Hz).

4- (2-chloropheninole) -3-hydroxy-2-oxo-1- [2 (4-phenylpiperazin-1-yl) ethyl] indoline-6-carboxamide dihydrochloride

(1) Methyl 4-tert-butyl-3- (2-chloropheninole) -3-hydroxy-2-oxo-1- [2- (4-phenylpyperidin-1-ynole) ethyl] indoline-6- Carboxylate

Example 18 In the same manner as in-(4), methyl 4-cyclohex-3- (2-cyclohexenyl) -3-hydroxy-1- (2-hydroxyethyl) -2-oxoindrin -Synthesized from 6-carboxylate (Example 18- (3)) and 4-phenylpiperidine.

¾ Keio _{R (CDC1 3, 400 MHz)} δ 8.18 (dd, 1H, J = 1.4, 8.1 Hz), 7.66 (d, 1H, J = 1.2 Hz), 7.52 (d, 1H, J = 1.2 Hz), 7.41 (ddd, 1H, J = 1.4, 7.3, 8.1 Hz), 7.31 (ddd, 1H, J = 1.4, 7.3, 7.9 Hz), 6.95 to 7.28 (ra, 3H), 6.91 (d, 2H, J = 8.7 Hz), 6.85 (t, 1H, J = 7.3 Hz), 4.13 (ddd, 1H, J = 6.0, 8.4, 14.7 Hz), 3.93 (s, 3H), 3.85 (ddd, 1H, J = 5.3, 5.3, 14.7 Hz), 3.14 to 3.22 (m, 4H), 2.61 to 2.95 (m, 6H).

(2) 4-chloro-3- (2-chlorophenyl) -3-hydroxy-2-oxo-1--1- [2- (4-phenylpiperazine-1-yl) ethyl] indoline-6-carboxami Do dihydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4-chloro-3- (2-chlorophenyl) -3-hydroxy-2-oxo-1-1 [2- ( Synthesized from 4-phenylpiperidine-1-inole) ethyl] indoline-6-carboxylate.

^{_{X H NMR (DMSO- d 6,}} 400 MHz) δ 10.85 (brs, 1Η), 8.17 (s, 1H), 8.16 (d, 1H, J = 7.8 Hz), 7.82 (s, 1H), 7.70 (s, 1H), 7.51 (s, 1H), 7.49 (dd, 1H, J = 7.8, 7.8 Hz), 7.39 (dd, 1H, J = 7.8, 7.8 Hz), 7.34 (s, 1H), 7.33 (d, 1H , J = 7.8 Hz), 7.28 (dd, 2H, J = 7.4, 8.1 Hz), 7.04 (d, 2H, J = 8.1 H), 6.88 (t, 1H, J = 7.4 Hz), 4.10 to 4.45 (m , 2H), 2.92 to 4.10 (m, 10H).

4- ク口口 -3- (2-Chloropheninole) -1- [2- (3,5-dimethylpiperazine-1-inole) ethyl] -1-hydroxy-2-oxoindoline-6-carboxamide dihydrochloride

(1) Methyl 4-cyclo-3- (2-chlorophenyl) -1_ [2- (3,5-dimethylpiperazine-1-yl) ethyl] -3-hydroxy-2-oxoindrin-6-carboxyle One

Example 1 In a similar manner to 8- (4), methyl 4-chloro-3- (2-chlorobutyryl) -3-hydroxoxy-1- (2-hydroxyethyl) -2-oxoindolin It was synthesized from -6-carboxylate (Example 18- (3)) and 2,6-dimethylbiperazine.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.17 (dd, 1H, J = 1.5, 7.9 Hz), 7.66 (d, 1H, J = 1.2 Hz), 7.43 (d, 1H, J = 1.2 Hz), 7.41 ( ddd, 1H, J = 1.4, 7.5, 7.9 Hz), 7.31 (ddd, 1H, J = 1.5, 7.5, 7.9 Hz), 7.25 (dd, 1H, J = 1.4, 7.9 Hz), 4.05 to 4.14 (m, 1H), 3.94 (s, 3H), 3.72 to 3.93 (ra, 1H), 2.80 (brs, 2H), 2.63 to 3.20 (ra, 6H), 1.94 to 2.11 (m, 2H), 1.20 (d, 3H, J = 6.3 Hz), 1.17 (d, 3H, J = 6.5 Hz).

(2) 4- (3-chloro-2-phenyl) -1- [2- (3,5-dimethylpiperazine-1-isole) ethyl] -3-hydroxy-2-oxoindrin-6 -Holpoxamide dihydrochloride In a similar manner to Example 6- (3) and Example 6- (4), methyl 4-chloro-3- (2-chlorophenyl) -1- [2- (3,5-dimethyl Piperazine-1-yl) ethyl] -3-Hydroxy-2-oxindrin-6-carboxylate.

_{¾ NMR (CDC1 3, 400 MHz} ) ( free form) δ 8.27 (dd, 1H, J = 1.5, 8.0 Hz), 7.40 (ddd, 1H, J = 1.3, 7.4, 8.0 Hz), 7.39 (s, 1H) , 7.32 (s, 1H), 7.29 (ddd, 1H, J = 1.5, 7.4, 8.0 Hz), 7.23 (dd, 1H, J = 1.3, 8.0 Hz), 6.85 (brs, 1H), 5.99 (brs , 1H), 3.70 to 4.12 (m, 2H), 2.30 to 3.28 (m, 7H), 1.50 to 1.72 (m, 2H), 0.98 (d, 3H, J = 6.2 Hz), 0.96 (d, 3H, J = 6.4 Hz). Example 3 1

4- (2-chloropheninole) -3- 3-hydroxy-2- (2- [methyl (propyl) amino] ethyl} -2-oxoindoline-6-carboxamide hydrochloride

(1) Methyl 4-cyclo-3-(2-cyclophenyl) -3-hydroxy-1_ {2- [methyl (propyl) amino] ethyl}-2-oxoindrin-6-carboxylate

Example 1 In a similar manner to 8- (4), methyl 4-chloro-3- (2-chlorophenyl) -3-hydroxy-1- (2-hydroxyethyl) -2-oxoindrin -Synthesized from 6-carboxylate (Example 18- (3)) and N-methyl-N-propylamine.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.21 (dd, 1H, J = 1.4, 8.2 Hz), 7.65 (s, 1H), 7. 46 (s, 1H), 7.27~ 7.43 (m, 2H), 7.24 (d, 1H, J = 7.9 Hz), 3.95 to 4.20 (m, 1H), 3.94 (s, 3H), 3.68 to 3.75 (m, 1H), 2.33 to 2.92 (ra, 4H), 2.32 (s, 3H ), 1.46 (dd, 2H, J = 7.5, 15.3 Hz), 0.87 (t, 3H, J = 7.5 Hz).

(2) 4-Chloro-3- (2-chlorophenyl) -3-hydroxy-1- {2- [methyl (propynole) amino] ethyl} _2-oxoindoline-6-carboxamide hydrochloride

In the same manner as in Example 6_ (3) and Example 6_ (4), methyl 4-chloro-3- (2-chlorophenyl) -3-hydroxy-1- {2- {methyl [ Propinole) amino] ethyl Synthesized from 2-oxoindoline-6-carboxylate.

Response R (DMS0-d ₆ , 400 MHz) δ 10.52 (s, 1H), 8.20 (s, 1H), 8.15 (dd, 1H, J =

1.5, 8.0 Hz), 7.83 (s, 1H), 7.67 (s, 1H), 7.50 (s, 1H), 7.48 (ddd, 1H, J = 1.2, 8.0, 8.0 Hz), 7.39 (ddd, 1H, J = 1.5, 8.0, 8.0 Hz), 7.31 to 7.34 (m, 2H), 4.05 to 4.40 (m, 2H), 3.00 to 3.60 (m, 4H), 2.88 (s, 3H), 1.70 to 1 .78 (m, 2H), 0.89 to 0.95 (m, 3H). Example 32

Sodium 4-chloro-3- (2-chlorophenol) -1- "3- (Jetylamino) propyl] -3-hydroxy-2-oxindrin-6-force repoxylate

(1) Methyl 4-chloro- 1- [3- (Jethylamino) propyl] -2,3-dioxoindoline-6-forcenorboxylate

In the same manner as in Example 7- (1), it was synthesized from methyl 4-chloro-2,3-dioxoindoline-6-carboxylate (Reference Example 3) and 3- (getylamino) propanol.

¾丽_{R (CDC1 3, 400 MHz)} δ 7.72 (d, 1 H, J = 1.0 Hz), 7.51 (d, 1 H, J = 1.0 Hz), 3.98 (s, 3 H), 3.85 (t, 2 H, J = 7.2 Hz), 2.49 to 2.54 (ra, 6 H), 1.84 to 1.89 (m, 2 H), 1.00 (t, 6 H, J = 7.1 Hz).

(2) Methyl 4-cyclo-3- (2-chlorophenyl) -1- [3- (getylamino) propyl] -3-hydroxy-2-oxoindoline-6-carboxylate

In the same manner as in Example 6- (2), the compound was synthesized from methyl 4-co- mouth_1- [3- (getylamino) propyl] -2,3-dioxoindoline-6-carboxylate.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.17 (d, 1 H, J = 7.8 Hz), 7.64 (s, 1 H), 7.47 (s, 1 H), 7.41 (dd, 1 H, J = 7.8, 7.8 Hz), 7.30 (dd, 1 H, J = 7.8, 7.8 Hz), 7.24 (d, 1 H, J = 7.8 Hz), 3.94 (s, 3 H), 3.89 to 3.99 (m, 1 H), 3.77 to 3.83 (ra, 1 H), 2.44 to 2.63 (m, 6 H), 1.86 to 1.93 (m, 2 H), 1.00 (t, 6 H, J = 7.1 Hz). (3) 4-chloro-3- (2-chlorophenol) -tri [3- (ethylamino) propyl] -3-hydroxy-2-oxoindrin-6-carboxylate sodium salt

In a nitrogen atmosphere, methyl 4-chloro-3- (2-chlorophenyl) -1_ [3-((ethylamino) propyl] -3-hydroxy-2-oxoindoline-6-carboxylate (33.1 mg, 0.0 711 mmol) )) In tetrahydrofuran (0.2 mL) and methanol (0.2 mL), 1N aqueous sodium hydroxide solution (70 μΐ, 0.070 mmol) was added, and the mixture was stirred at 50 ° C. On the way, 1N aqueous sodium hydroxide solution (20 μΐ, 0.020 mmol) was added, and the mixture was stirred at 50 ° C. for a total of 5 hours. The solvent was distilled off, toluene was added, the solvent was distilled off, and the residue was suspended in getyl ether and collected by filtration to obtain the title compound (30.3 mg, 90%).

Hiring R (DMSO-d ₆ , 400 MHz) δ 8.13 (dd, 1 H, J = 1.5, 7.9 Hz), 7.44 (ddd, 1 H, J = 1.5, 7.9, 7.9 Hz), 7.41 (d, 1 H, J = 0.7 Hz), 7.35 (dd, 1 H, J = 1.5, 7.9 Hz), 7.34 (d, 1 H, J = 0.7 Hz), 7.30 (ddd, 1 H, J = 1.5, 7.9, 7.9) Hz), 7.00 (s, 1 H), 3.67 to 3.76 (m, 2 H), 2.39 to 2.49 (m, 6 H), 1.69 to 1.76 (m, 2 H), 0.95 (t, 6 H, J = 7.1 Hz).

Example 33

4- ク口口 -3- (2-Chlorophenyl) -tri [3- (Jethylamino) propyl Ί-3-hydroxy-2-oxoindrin-6-carboxamide hydrochloride

Example 6 In the same manner as in (3), methyl 4-hydroxy-3- (2-chlorophenyl) 10- [3- (getinoleamino) propinole] -3-hydroxy-2-oxooxoindine-6-carboxylate ( Example 32- (2)) (34.6 mg, 0.0743 ramol) to give a crude carboxylic acid compound. Under a nitrogen atmosphere, the crude carboxylic acid was cooled to 0 ° C, and tetrahydrofuran (1.0 mL), 0.143 N triethylamine tetrahydrofuran solution (1.2 mL, 0.172 mraol), and 0.176 N isopropyl chloroformate solution (500 μΐ, 0.088 mmol), and the mixture was stirred at 0 ° C for 1 hour. Subsequently, concentrated ammonia water (2.0 mL) was added, and the mixture was stirred at 0 ° C for 1 hour. The mixture was extracted with ethyl acetate and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / methanol = 20/1 to 10/1) to obtain a free form of the title compound. It was dissolved in 1,4-dioxane (1.0 mL), 4N hydrochloric acid / 1,4-dioxane solution (1.0 mL) was added, and the solvent was distilled off. The title compound (5.7 mg, 16%) was obtained by repeating three times adding toluene and distilling off the solvent.

_{¾ NMR (DMS0- d 6, 400} MHz) δ 9.70 (brs, 1 H), 8.18 (brs, 1 H), 8.15 (dd, 1 H, J = 1.5, 7.8 Hz), 7.69 (d, 1 H, J = 1.0 Hz), 7.65 (brs, 1 H), 7.47 to 7.51 (m, 2 H), 7.39 (ddd, 1 H, J = 1.5, 7.8, 7.8 Hz), 7.33 (dd, 1 H, J = 1.5, 7.8 Hz), 7.28 (s, 1 H), 3.88 (t, 2 H, J = 6.9 Hz), 3.09 to 3.20 (m, 6 H), 2.03 to 2.05 (m, 2 H) , 1.21 (t, 6 H, J = 7.2 Hz).

1- (4-Aminobuto-2-en-1-yl) -4 -Kokuro-3- (2-Chlorophenyl) -3-Hydroxy-

2-oxoindrin-6-carboxamide hydrochloride

(1) Methyl 1- {4- [bis (tert-butoxycarbonyl) amino] but-2-ene-1-inole} _4

2,3-Dioxindrin-6-carboxylate

Example 1 In the same manner as in (1), methyl 4-cloro-2,3-dioxoindolin-6-carboxylate (Reference Example 3) and di-t-butynole [(2E) -4-clobut-2-butene-1-inole] imidodicarbonate (Reference Example 24).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.73 (d, 1 H, J = 1.1 Hz), 7.38 (d, 1 H, J = 1.1 Hz), 5.85 (dt, 1 H, J = 15.5, 5.8 Hz), 5.64 (dt, 1 H, J = 15.5, 5.8 Hz), 4.39 (d, 2 H, J = 5.8 Hz), 4.17 (d, 2 H, J = 5.8 Hz), 3.97 (s, 3 H), 1.45 (s, 18 H).

(2) Methyl 1- {4- [bis (tert-butoxycarbonyl) amino] but-2-ene-1-yl} -4-4-chloro-3- (2-chlorophenyl) -3-hydroxy-2 -Oxoindoline-6-canolepoxilate

In the same manner as in Example 6- (2), methyl 1_ {4- [bis (tert-butoxycarbonyl) amino] pt-2-ene-1-inole} _4-culo-2,3- Synthesized from dioxindrin-6-hydroxylboxylate.

¾丽_{R (CDC1 3, 400 MHz)} δ 8.16 (dd, 1 H, J = 1.5, 7.8 Hz), 7.66 (d, 1 H, J = 1.2 Hz), 7.41 - 7.45 (m, 2 H), 7.32 (ddd, 1 H, J = 1.5, 7.8, 7.8 Hz), 7.25 to 7.27 (m, 1 H), 5.91 (dt, 1 H, J = 15.5, 5.4 Hz), 5.70 (dt, 1 H, J = 15.5, 5.4 Hz), 4.42 (d, 2 H, J = 5.4 Hz), 4.18 (d, 2 H, J = 5.4 Hz), 3.93 (s, 3 H), 1.46 (s, 18 H).

(3) Methyl 1- {4-[(tert-butoxycarbo-nore) amino] but-2-ene-1-yl}-4-chloro- 3_ (2_clo-funenole) -3 -Hydroxy-2-oxoindoline-6-carboxylate Under a nitrogen atmosphere, methyl 1- {4- [bis (tert-butoxycarbo-nore) amino] but_2-en-1-yl}-4-c -To a solution of 3- (2-c-mouth mouth feninole) -3-hydroxy-2-oxoxindrin-6-forcenorboxylate (944 mg, 1.52 mmol) in dichloromethane (10 mL) was added a 1.32 standard trifluoroacetic acid dichloromethane solution ( 1.50 mL, 1.98 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1 to 1/1) to obtain the title compound (704 mg, 89%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.16 (d, 1 H, J = 7.7 Hz), 7.67 (d, 1 H, J = 1.2 Hz), 7.41~ 7.45 (m, 2 H), 7.32 (ddd, 1 H, J = 1.6, 7.7, 7.7 Hz), 7.26 to 7.27 (m, 1 H), 5.83 to 5.90 (m, 1 H), 5.65 to 5.72 (m, 1 H), 4.59 (br, 1 H) , 4.35-4.48 (m, 2 H), 3.94 (s, 3 H), 3.76 (ra, 2 H), 1.43 (s, 18 H). (4) 1-{4- [(tert-butoxycarbo- L) Amino] pt-2-ene_1-yl}-4-chloro-3- (2-chloropheninole) —3-hydroxy-2-oxoindoline-6-capillonic acid

Under a nitrogen atmosphere, methyl 1- {4-[(tert-butoxycarbonyl) amino] but-2--2-en-1-yl}-4-chloro-3- (2-chlorophenol) -3 -Hydroxy-2-oxoindolin-6-cal To a solution of boxylate (94.6 mg, 0.181 mmol) in tetrahydrofuran (1.0 raL) and methanol (1.0 mL) was added a 1N aqueous sodium hydroxide solution (400 μL, 0.400 mmol), and the mixture was stirred at 50 ° C for 1 hour. A 5% aqueous solution of potassium hydrogen sulfate was added, extracted with ethyl acetate, and dried over magnesium sulfate. After filtration, the solvent was distilled off to obtain the title compound (83.7 mg, 91%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.18 (m, 1 H), 7.61 (m, 1 H), 7.42~ 7.43 (m, 2

H), 7.31 (dd, 1 H, J = 7.8, 7.8 Hz), 7.25 to 7.27 (m, 1 H), 5.86 to 5.90

(m, 1 H), 5.70 (dt, 1 H, J = 15.5, 5.8 Hz), 4.73 (brs, 1 H), 4.35 to 4.46

(m, 2 H), 3.76 (m, 2 H), 1.46 (s, 9 H).

(5) tert-butyl {4- [6- (aminopropyl) -4-chloro-3- (2-chlorophenyl) -3-hydroxy-2-oxo-2,3-dihydro- 1H-Indonele 1-innole] but- 2-en- 1-yl} Carbamate

Under a nitrogen atmosphere, 1- {4-[(tert-butoxycarbonyl) amino] but-2-ene-1-yl} -4-1-chloro-3- (2-butanol) -3-hydroxy — 2-oxoindolin— 6-canoleponic acid (75.0 mg, 0.148 mmol), ammonium chloride (15.8 mg, 0.295 mmol), 1-hydroxybenzotriazole (26.0 mg, 0.192 mmol), Ν, Ν-dimethylformami (1.5 mL), 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride (36.9 mg, 0.192 mmol), and triethylamine (60 μL, 0.430 mmol), and the mixture was stirred at room temperature for 10 hours. Water was added, extracted with ethyl acetate / toluene (1: 1), washed with water, and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate: = 1/2 to 0/1) to obtain the title compound (72.2 mg, 96%). _{¾ NMR (CDC1 3, 400 MHz} ) δ 8.20 (dd, 1 H, J = 1.4, 7.7 Hz), 7. 0 ~ 7.46 (m, 2 H), 7.32 (ddd, 1 H, J = 1.4, 7.7 ' 7.7 Hz), 7.25 to 7.27 (m, 2 H), 7.00 (brs, 1 H), 5.87 to 5.91 (m, 1 H), 5.76 (br, 1 H), 5.59 to 5.64 (m, 1 H), 4.46 (m, 2 H), 3.67 to 3.72 (m, 2 H), 1.35 (s, 9 H).

(6) 1- (4-Aminobut-2-en-1-yl) -4-chloro-3- (2-chlorophenyl) _3-hydroxy-2-oxoindoline-6-carboxamide hydrochloride

In a nitrogen atmosphere, tert-butyl {4- [6- (aminocarbonyl) -4- (3-chloropheninole) -1-hydroxy-2-oxo-2,3-dihydro-1H-indole — 1-inole] but-2-en-1-yl} carbamate (68.8 mg, 0.136 mmol) in 1,4-dioxane (1.5 mL) Five

A 4N hydrochloric acid / 1,4-dioxane solution (1.0 mL) was added, and the mixture was stirred at 50 ° C. for 1 hour. The solvent was distilled off, toluene was added and the solvent was distilled off to obtain the title compound (67.0 rag, quant.).

¾ 丽 R (DMS0-d ₆ , 400 MHz) δ 8.13 to 8.16 (m, 2 H), 7.99 (brs, 3 H), 7.61 (s, 1 H), 7.46 to 7.50 (m, 3 H), 7.38 (ddd, 1 H, J = 1.5, 7.7, 7.7 Hz), 7.32 (dd, 1 H, J = 1.5, 7.7 Hz), 5.86 to 5.95 (m, 2 H), 4.43 to 4.44 (ra, 2 H) , 3.46-3.48 (m, 2 H) .Example 35

1- (4-Aminoptinole) -4-chloro mouth -3- (2-chloropheninole) -3-hydroxy-2 oxoindrin-6-carboxamide hydrochloride

Under a nitrogen atmosphere, 1- (4-aminobut-2-en-1-yl) _4-coclo-3- (2-chlorophenyl) _3-hydroxy-2-oxoindoline-6-carboxamide hydrochloride (implementation Example 34) To a solution of (30.0 mg, 0.0667 mmol) in methanol (2.0 mL) and acetic acid (0.5 mL), 5% rhodium carbon (20.0 mg) was added and hydrogenated. The mixture was filtered through celite, the solvent was distilled off, and the addition of toluene and the solvent was repeated three times to give the title compound (22.9 rag, 76%). ¾ NMR (DMS0-d ₆ , 400 MHz) δ 8.20 (brs, 1 H), 8.14 (dd, 1 H, J = 1.4, 7.7 Hz), 7.88 (brs, 3 H), 7.63 (brs, 1 H) , 7.58 (s, 1 H), 7.45 to 7.49 (m, 2 H), 7.37 (ddd, 1 H, J = 1.4, 7.7, 7.7 Hz), 7.31 (d, 1 H, J = 7.7 Hz), 3.77 (m, 2H), 2.84 to 2.85 (m, 2H), 1.69 to 1.74 (m, 4H).

4—Kokuro-3_ (2Kuguchi Feninole) — “4- (Jetinoleamino) pt-2-ene-1-ynole] -13-Hydroxy-2-oxoindoline-6-carboxamide hydrochloride

(1) Methyl 1 - (4 - Aminobuto 2-E down - 1 - I) -4- click every mouth - 3- (2-chlorophenyl) -3 - hydroxy - ₂ - Okisoindorin - 6 - carboxylate hydrochloride

Example 34-In a similar manner to (6), methyl 1- {4-[(tert-butoxycarboninole) amino] pt-2-en-1-yl}-4-c It was synthesized from 3- (2-chloropheninole) -3-hydroxy-2-oxoindoline-6-carboxylate (Example 34- (3)).

¾ NMR (DMSO- d ₆ , 400 MHz) δ 8.15 (dd, 1 H, J = 1.4, 7.8 Hz), 7.98 (brs, 3 6

H), 7.51 (d, 1 H, J = 1.2 Hz), 7.48 (d, 1 H, J = 1.2 Hz), 7.47 (ddd, 1 H, J = 1.4, 7.8, 7.8 Hz), 7.41 (s, 1H), 7.39 (ddd, 1 H, J = 1.4, 7.8, 7.8 Hz), 7.32 (dd, 1 H, J = 1.4, 7.8 Hz), 5.89 to 5.90 (ra, 2 H), 4.49 to 4.50 ( m, 2H), 3.88 (s, 3H), 3.47 (m, 2H).

(2) Methyl 4-tert-but-3- (2-chlorophenyl)-1- [4- (ethylpyramino) but-2-en-toyl]-3-hydroxy-2-oxoindoline-6-butanolboxylate

Under a nitrogen atmosphere, methyl 1- (4-aminobut-2-ene-1-yl) -4_chloro-3- (2-chlorophenol) -3-hydroxy-2-oxoindoline-6-carboxylate Dichloromethane (3.0 mL) and acetoaldehyde (150 μΐ, 2.66 mmol) were added to the hydrochloride (100 mg, 0.218 mmol), and the mixture was stirred at room temperature for 1 hour. Subsequently, sodium triacetoxyborohydride (139 rag, 0.656 ramol) was added, and the mixture was stirred at room temperature for 15 hours. Saturated aqueous sodium hydrogen carbonate was added, extracted with ethyl acetate, and dried over magnesium sulfate. After filtration, the solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform / methanol = 20/1 to 10/1) to give the title compound (68.4 rag, 66%).

_{¾ NMR (CDC1 3, 400 MHz} ) 6 8.24 (dd, 1 H, J = 1.4, 7.8 Hz), 7.65 (d, 1 H, J = 1.2 Hz), 7.42 (ddd, 1 H, J = 1.4, 7.8 , 7.8 Hz), 7.39 (d, 1 H, J = 1.2 Hz), 7.31 (ddd, 1 H, J = 1.4, 7.8, 7.8 Hz), 7.25 (dd, 1 H, J = 1.4, 7.8 Hz) , 6.02 (dt, 1 H, J = 15.7, 6.6 Hz), 5.75 (dt, 1 H, J = 15.7, 5.1 Hz), 4.57 (dd, 1 H, J = 5.1, 15.8 Hz), 4.30 (dd, 1 H, J = 5.1, 15.8 Hz), 3.93 (s, 3 H), 3.20 (d, 2 H, J = 6.6 Hz), 2.61 (q, 4 H, J = 7.2 Hz), 1.05 (t, 6 (H, J = 7.2 Hz).

(3) 4-Couguchi-3- (2-chlorophenyl) -1-[4- (Jethylamino) but-2-en-1-inole] -3-hydroxoxy-2-oxoindrin-6-carboxamide Hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4-chloro-3- (2-chlorophenol) -1- [4- (getinoleamino) but-2- [En-1-yl] -3-hydroxy-2-oxoindoline-6-carboxylate.

¾ NMR (DMS0-d ₆ , 400 MHz) δ 9.90 (brs, 1 H), 8.15 (dd, 1 H, J = 1.5, 7.8 Hz), 8.14 (brs, 1 H), 7.61 (brs, 1 H ), 7.47 to 7.52 (m, 3 H), 7.39 (ddd, 1 H, J = 1.5, 7.8, 7.8 Hz), 7.32 (dd, 1 H, J = 1.5, 7.8 Hz), 5.95 to 6.10 (ra, 2H), 4.48 to 4.49 (m, 2H), 3.75 to 3.77 (m, 2H), 2.96 to 3.07 (m, 4H ), 1.17 (t, 3 H, J = 7.2 Hz), 1.17 (t, 3 H, J = 7.2 Hz).

4-chloro-3-(2-cyclohexyl) -1-[4- (Jethylamino) butyl] -3-hydroxy-2- 2-oxoindolin-6-carboxamide hydrochloride

In the same manner as in Example 35, 4-chloro-3- (2-chlorophenol) -1- [4- (ethylamino) but-2-en-1-yl] -3-hydroxy It was synthesized from -2-oxoindoline-6-caproloxamide hydrochloride (Example 36).

_{¾ NMR (DMS0 - d 6,} 400 MHz) δ 10.02 (brs, 1 H), 8.15 (dd, 1 H, J = 1.3, 7.7 Hz), 8.22 (brs, 1 H), 7.62 (m, 2 H) , 7.46 to 7.49 (ra, 2 H), 7.37 (ddd, 1 H, J = 1.3, 7.7, 7.7 Hz), 7.31 (dd, 1 H, J = 1.3, 7.7 Hz), 3.79 to 3.81 (m, 2 H), 3.06 to 3.09 (m, 6H), 1.71 to 1.76 (m, 4H), 1.20 (t, 6H, J = 7.2 Hz).

4_Black mouth -3--(2-Black mouth fuel)-1-[4- (Dimethylamino) but-2-ene-1-yl] -3- 3-Hydroxy-2-oxoindoline-6-carboxamide hydrochloride salt

(1) Methyl 4-chloro-3- (2-chlorophenol) -1- [4- (dimethylamino) but-2-ene-1-yl] -3-hydroxy-2-oxindrin -6-carboxylate

Using formaldehyde in place of acetaldehyde, and in the same manner as in Example 36- (2), methyl 1- (4-aminobut-2-en-1-yl) -4--4-butanol-3- (2-Chloroquinone) 3-Hydroxy-2-oxoindoline-6-carboxylate hydrochloride (Example 36- (1)).

^{_{L H NMR (CDC1 3, 400}} MHz) δ 8.21 (dd, 1 Η, J = 1.4, 7.8 Hz), 7.64 (d, 1 H, J = 1.2 Hz), 7.41 (ddd, 1 H, J = 1.4, 7.8, 7.8 Hz), 7.40 (d, 1 H, J = 1.2 Hz), 7.30 (ddd, 1 H, J = 1.4, 7.8, 7.8 Hz), 7.23 (dd, 1 H, J = 1.4, 7.8 Hz) ), 5.93 (dt, 1 H, J = 15.6, 6.6 Hz), 5.71 (dt, 1 H, J = 15.6, 5.0 Hz), 4.54 (dd, 1 H, J = 5.0, 16.3 Hz), 4.28 (dd , 1 H, J = 5.0, 16.3 Hz), 3.92 (s, 3 H), 2.99 (d, 2 H, J = 6.6 Hz), 2.21 (s, 6 H).

(3) 4-Cross mouth-3- (2-Cross mouth feninole) -1- [4- (Dimethylamino) but-2-ene-1-inole] -3-Hydroxy-2-oxoindoline-6-carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4-tert-butyl-3- (2-chlorophenyl) -1- [4- (dimethylamino) but-2- [En-1-yl] -3-hydroxy-2-oxoindoline-6-carboxylate.

_{¾ NMR (DMSO- d 6, 400} MHz) δ 10.13 (brs, 1 H), 8.15 (dd, 1 H, J = 1.5, 7.8 Hz), 8.14 (brs, 1 H), 7.60 (brs, 1 H) , 7.46 to 7.55 (m, 3 H), 7.39 (ddd, 1 H, J = 1.5, 7.8, 7.8 Hz), 7.32 (dd, 1 H, J = 1.5, 7.8 Hz), 5.90 ― 6.06 (ra, 2 H), 4.49 (d, 2 H, J = 4.9 Hz), 3.71-3.73 (m, 2 H), 2.68 (s, 3 H), 2.67 (s, 31.1).

4-chloro-3 (2-phenylmethyl) -tri [4- (dimethylamino) ptinole] 3-hydroxy-2_oxindrin-6-carboxamide hydrochloride

In the same manner as in Example 35, 4- (4- (2-chloropheninole) -1- [4- (dimethylamino) but-2-en-1-yl] -3-hydroxy It was synthesized from 2-oxoindoline-6-carboxamide hydrochloride (Example 38). Example 40

4- (3-Chloropheninole) -3-hydroxy-2-oxo-1 (2-piperidine-4-yrideneethyl) indoline-6-carboxamide hydrochloride

(1) Methyl 1- {2- [1- (tert-butoxycarbonyl) piperidine-4-ylidene] ethyl}-4-octa-2,3-dioxoindrin-6-carboxylate

Under a nitrogen atmosphere, a solution of t-butyl 4- (2-hydroxyethylidene) piperidine-1-carboxylate (Reference Example 23) (500 rag, 2.20 mraol) in dichloromethane (5.0 mL) was added with N-promosuccinimide. (392 mg, 2.20 mraol) _s triphenylphosphine (576 mg, 2.20 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to obtain a bromo compound. In a nitrogen atmosphere, methyl 4-cyclo-2,3-dioxoindrin-6-carboxylate (Reference Example 3) (420 rag, 1.75 mmol) was added to N, N-dimethylformamide ( 3.0 m), 60% sodium hydride (6.4 tng, 1.75 mmol), and bromo, Ν, 溶液 -dimethylformamide (7.0 mL) solution. Next, the mixture was stirred at 50 ° C for 3.5 hours. Water was added, extracted with ethyl acetate / toluene (1: 1), washed twice with water, and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1 to 1/1) to obtain the title compound (625 mg, 80%).

¾ Keio _{R (CDC1 3, 400 MHz)} δ 7.73 (d, 1 H, J = 1.0 Hz), 7.39 (d, 1 H, J = 1.0 Hz), 5.27 (t; 1 H, J = 7.1 Hz), 4.42 (d, 2 H, J = 7.1 Hz), 3.98 (s, 3 H), 3.52 to 3.53 (m, 2 H), 3.41 to 3.44 (m, 2 H), 2.45 to 2.48 (m, 2 H) , 2.17 to 2.21 (m, 2 H), 1.48 (s, 9 H).

(2) Methyl 1- {2- [1- (tert-butoxycarbonyl) piperidine-4-ylidene] ethyl 4-oct-3- (2-oct-2-phenyl) -3-hydroxy -2-oxoindolin-6-canolepoxylate

In the same manner as in Example 6- (2), methyl 1- {2- [1- (tert-butoxycarbonyl) pyridine-4-ylidene] ethyl} -4-cyclo-2,3-dimethyl Oxindrin-6-carboxylate.

_{¾ NMR (CDC1 3, 400 MHz} ) 6 8.16 (dd, 1 H, J = 1.4, 7.9 Hz), 7.66 (d, 1 H, J = 1.1 Hz), 7.44 (d, 1 H, J = 1.1 Hz) , 7.43 (ddd, 1 H, J = 1.4, 7.9, 7.9 Hz), 7.32 (ddd, 1 H, J = 1.4, 7.9, 7.9 Hz), 7.26 (dd, 1 H, J = 1.4, 7.9 Hz) , 5.37 (t, 1 H, J = 6.7 Hz), 4.36 to 4.55 (m, 2 H), 3.94 (s, 3 H), 3.36 to 3.54 (m, 4 H), 2.43 to 2.50 (m, 2 H ), 2.18 (m, 2 H), 1.47 (s, 9 H).

(3) 1- {2- [1- (tert-Butoxycanolebonyl) piperidine-4-ylidene] ethyl}-4-c-mouth -3-(2-chloro-phenenole) -3-hydroxy_2 -Oxoindoline-6_carboxylic acid

Example 34-In the same manner as in (4), methyl 1- {2- [1- (tert-butoxycarbonyl) piveridine—4-ylidene] ethynole} —4-chloro-2--3- (2-chlorophenol (Ninore) Synthesized from 3-hydroxy-2-oxoindoline-6-carboxylate.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.17 (dd, 1 H, J = 1.4, 7.8 Hz), 7.72 (d, 1 H, J = 1.2 Hz), 7.47 (d, 1 H, J = 1.2 Hz) , 7.42 (ddd, 1 H, J = 1.4, 7.8, 7.8 Hz), 7.26 to 7.25 (m, 2 H), 5.37 (t, 1 H, J = 6.7 Hz), 4.38 to 4.56 (m, 2 H ), 3.36 to 3.57 (m, 4H), 2.48 to 2.50 (m, 2H), 2.18 to 2.21 (m, 2H), 1.47 (s, 9H).

(4) tert-Butyl 4- {2- [6- (aminocarbonyl)-4- (3-amino-2-phenyl) -3 -Hydroxy-2-oxo-2,3-dihydro-1H-indole-1-ynole] ethylidene} piperidin-1-olenoboxylate

In the same manner as in Example 34- (5), 1_ {2- [1- (tert-butoxycarbonyl) piperidine-4-ylidene] ethyl} -4-chloro-3- (2-chlorophenol) ) -3-Hydroxy-2-oxoindrin-6-carboxylic acid.

¾丽_{R (CDC1 3, 400 MHz)} δ 8.16 (dd, 1 H, J = 1.4, 7.7 Hz), 7.43 (ddd, 1 H, J = 1.4, 7.7, 7.7 Hz), 7.26~ 7.35 (ra, 4 H), 6.07 (br, 1 H), 5.66 (br, 1 H), 5.37 (t, 1 H, J = 7.1 Hz), 4.35 to 4.54 (ra, 2 H), 3.34 to 3.55 (m, 4 H ), 2.42 to 2.48 (ra, 2 H), 2.16 to 2.19 (m, 2 H), 1.47 (s, 9 H).

(5) 4-Methoxy-3- (2-chloropheninole) -3-hydroxy-2-oxo-1-(2-piperidine-4-ylideneethyl) indoline-6-carboxamide hydrochloride

In the same manner as in Example 34- (6), tert-butyl 4- {2- [6- (aminocarbinole) -4_chloro-3- (2-chlorophenyl) -3-hydroxy] -2-oxo-2,3-dihydro-1H-indole-1-yl] ethylidene} piperidine-1-carboxylate.

¾ Ran _{R (DMSO- d 6, 400 MHz} ) 5 8.88 (brs, 2 H), 8.15 (s, 1 H), 8.13 (s, 1 H), 7.60 (s, 1 H), 7.45~ 7.50 (ra , 3 H), 7.38 (ddd, 1 H, J = 1.5, 7.8, 7.8 Hz), 7.31 (dd, 1 H, J = 1.5, 7.8 Hz), 5.45 (t, 1 H, J = 6.8 Hz) , 4.35 to 4.50 (m, 2 H), 3.02 to 3.13 (m, 4 H), 2.63 to 2.67 (ra, 2 H), 2.33 to 2.39 (ra, 2 H).

4-Cross mouth _3-(2-Cross feninole) -3-hydroxy-2-oxo-1- (2-piperidine-4-ylethyl) indoline-6-carboxamide hydrochloride

In the same manner as in Example 35, 4-ku-guchi-3- (2-ku-guchi)-3-hydroxy-2-oxo-1- (2-piperidine-4-ylideneethyl) indoline-6 -Synthesized from carboxamide hydrochloride (Example 40).

Orchid R (DMSO-d ₆ , 400 MHz) δ 8.84 (m, 1 H), 8.61 (m, 1 H), 8.18 (brs, 1 H), 8.14 (dd, 1 H, J = 1.4, 7.8 Hz ), 7.63 (brs, 1 H), 7.43 to 7.50 (m, 3 H), 7.37 (ddd, 1 H, J = 1.4, 7.8, 7.8 Hz), 7.31 (dd, 1 H, J = 1.4, 7.8 Hz), 3.7 6 to 3.80 (m, 2 H), 3.24 to 3.28 (m, 2 H), 2.73 to 2.82 (m, 2 H), 1.88 to 1.96 (m, 2 H), 1.53 to 1.65 (m, 3 H), 1.32 to 1.42 (m, 2 H).

Example 42

4_Black mouth_3_ (2-Ku mouth mouth phenyl) -l_ [2- (1-Ethylbiperidine-4-ylidene) ethyl] -3-Hydroxy-2-oxoindoline-6-caproloxamide hydrochloride

(1) Methyl 4-co-mouth 3- (2-chloropheninole) -3-hydroxy-2-oxo-1-(2-piperidin-4-ylideneethyl) indoline-6-carboxylate hydrochloride

Example 34 In a similar manner to that of-(6), methyl 1- {2_ [1- (tert-butoxycarbonyl) piperidine-4-ylidene] ethyl} -4- ク口口 -3- (2- クMouth mouth Fuel) _3-Hydroxy-2-oxoindoline-6-carboxylate (Example 40- (2)).

Reaction R (DMSO— d ₆ , 400 MHz) δ 8.91 (brs, 2 H), 8.14 (dd, 1 H, J = 1.6, 7.9 Hz), 7.50 (d, 1 H, J = 1.3 Hz), 7.47 (d, 1 H, J = 1.3 Hz), 7.47 to 7.50 (m, 1 H), 7.37 to 7.41 (m, 2 H), 7.32 (dd, 1 H, J = 1.3, 7.9 Hz), 5.39 (t , 1 H, J = 7.0 Hz), 4.40 to 4.53 (m, 2 H), 3.89 (s, 3 H), 3.03 to 3.14 (m, 4 H), 2.68 to 2.71 (m, 2 H), 2.37 to 2.40 (m, 2 H).

(2) Methyl 4-cyclo-3- (2-chlorophenyl) -1- [2--ethylbiperidine-4-ylidene) ethyl] -3-hydroxy-2-oxoindrin-6-carboxylate

Example 36 In a similar manner to that of-(2), methyl 4-chloro-3- (2-chlorophenyl) -3-hydroxy-2-oxo-1- (2-piperidine-4-ylideneethyl) indoline Synthesized from -6-force / repoxylate hydrochloride.

¾ NMR (CDC1 _3, 400 thigh ζ) δ 8.17 (dd, 1 H, J = 1.4, 7.7 Hz), 7.66 (d, 1 H, J = 1.2 Hz), 7.44 (d, 1 H, J = 1.2 Hz ), 7.42 (ddd, 1 H, J = 1.4, 7.7, 7.7 Hz), 7.32 (ddd, 1 H, J = 1.4, 7.7, 7.7 Hz), 7.26 (dd, 1 H, J = 1.4, 7.7 Hz) ) , 5.28 (t, 1 H, J = 7.0 Hz), 4.49 (dd, 1 H, J = 7.0, 15.3 Hz), 4.38 (dd, 1 H, J = 7.0, 15.3 Hz), 3.94 (s, 3 H ), 2.46 to 2.57 (m, 8 H), 2.29 (m, 2 H), 1.12 (t, 3 H, J = 7.2 Hz).

(3) 4-Mouth mouth-3-(2-Chlorophenyl)-1- [2- (1-Ethylbiperidine_4-ylidene) ethyl] -3-Hydroxy_2-oxoindrin-6-Caproloxamide Hydrochloride salt

In the same manner as in Example 6_ (3) and Example 6- (4), methyl 4-chloro-3- (2-chlorophen-2-ole) -1- [2- (1-ethylpyperidine-4 -Ylidene) ethyl] -3-Hydroxy-2-oxoindrin-6-carboxylate.

Orchid R (DMS0-d ₆ , 400 MHz) 8 10.12 to 10.22 (m, 1 H), 8.13 to 8.15 (m, 2 H), 7.64 (brs, 1 H), 7.45 to 7.50 (m, 3 H) , 7.38 (ddd, 1 H, J = 1.4, 7.7, 7.7

Hz), 7.31 (dd, 1 H, J = 1.4, 7.7 Hz), 5.45 (t, 1 H, J = 6.8 Hz), 4.40 to 4.48 (m, 2 II), 2.73 to 3.13 (m, 6 H) , 2.40 to 2.55 (m, 4 H), 1.25 (t, 3 H,

J = 7.2 Hz).

4 口口 — 3— (2— 口口ふフ / レ) — 1 [2— (1 -Echinolepiperidine-4—inole) ethinole] -3-hydroxy-2 oxoindrin-6-carboxamide Hydrochloride

In the same manner as in Example 35, 4-kuguchi-3- (2-chlorophenyl) -1- [2- (1-ethylbiperidine-4-ylidene) ethyl] -3-hydroxy-2-oxoindoline -Synthesized from 6-carboxamide hydrochloride (Example 42).

Hiring R (DMS0-d ₆ , 400 MHz) δ 9.82 (brs, 1 H), 8.14 (dd, 1 H, J = 1.6, 7.8 Hz), 8.17 (brs, 1 H), 7.63 (brs, 1 H ), 7.45 to 7.52 (m, 3 H), 7.38 (ddd, 1 H, J = 1.5, 7.8, 7.8 Hz), 7.32 (dd, 1 H, J = 1.5, 7.8 Hz), 7.23 (s, 1 H) ), 3.77 to 3.81 (m, 2H), 3.44 to 3.51 (m, 2H), 3.02 to 3.07 (m, 2H), 2.73 to 2.78 (m, 2H), 1.95 to 2.02 (m, 2H), 1.46 to 1.63 (m, 5H), 1.23 (t, 3H, J = 7.2 Hz).

Example 44

4-Black mouth _: [-[2- (Jetylamino) ethyl 1 -3-hydroxy-3- (2-methylpheninole) -2-oxoindrin-6-carboxamide hydrochloride

(1) Methyl 4-chloro-1- (2- (ethylamino) ethyl) -3-hydroxy-3- (2-methylphenyl) -2-oxoindolin-6-carboxylate

It was synthesized in the same manner as in Example 6- (2), except that 2-methylphenylmagnesium bromide prepared at the time of use was used instead of 2-chlorophenylmagnesium bromide.

¾ negation _{R (CDC1 3, 400 MHz)} δ 7.95 (d, 1H, J = 7.4 Hz), 7.67 (d, 1H, J = 1.2 H z), 7.54 (d, 1H, J = 1.2 Hz), 7.30 ( dd, 1H, J = 7.4, 7.4 Hz), 7.25 (ddd, 1

H, J = 1.4, 7.4, 7.4 Hz), 7.06 (d, 1H, J = 7.4 Hz), 3.95 (s, 3H), 3.80 to 4.00 (m, 2H), .3.66 (brs, 1H), 2.68 to 2.83 (ra, 2H), 2.52 to 2.67 (m, 4H),

I.85 (s, 3H), 1.00 (t, 6H, J = 7.1 Hz).

(3) 4-Cupro-1- [2- (ethylpyramino) ethyl] -3-hydroxy-3- (2-methylphenyl) _2-oxoindoline-6-carboxamide hydrochloride In the same manner as in Example 6- (3) and Example 6- (4), methyl 4-chloro-1- (2- (Jetyl Rmino) ethyl) -3-hydroxy-3- (2- Methylphenyl) -2-oxoindolin-6-carboxylate.

Keio _{R (DMS0 - d 6, 400} MHz) δ 10.47 (s, 1H), 8.19 (s, 1H), 7.91 (brs, 1H) 7 .83 (s, 1H), 7.70 (s, 1H), 7.53 ( s, lH), 7.28 (dd, 1H, J = 7.4, 7.4 Hz), 7.22 (ddd, 1H, J = 1.2, 7.4, 7: 4 Hz), 7.06 (d, 1H, J = 7.4 Hz) , 7.01 (s, 1H), 4.28 to 4.35 (m, 1H), 4.08 to 4.17 (m, 1H), 3.18 to 3.35 (m, 6H), 1.71 (brs, 3H), 1.25 (t, 6H, J = 7.2 Hz). Example 45

4-Cupro-1-[2- (Jethylamino) ethyl] -3-Hydroxy-3- [2- (Hydroxymethyl) phenyl] -2-oxoindoline-6-carboxamide hydrochloride

(1) Methyl 4-oct-l- [1- [2- (Jethylamino) ethyl]]-3-[{2-[(ethoxymethoxy) methyl] phenyl} -3-hydroxy-2-oxoindoline-6-carboxy Rate

Instead of 2-chlorophenylmagnesium bromide, a Grignard reagent prepared from 1-bromo-2-[(ethoxymethoxy) methyl] benzene (Reference Example 25) and magnesium was used, and Example 6- (2) Was synthesized in the same manner as described above.

_{lH NMR (CDC1 3, 400 MHz} ) δ 7.72 (d, 1H, J = 1.1 Hz), 7.53 (d, 1H, J = 1.1 Hz), 7.40 (d, 1H, J = 7.6 Hz), 7.26~ 7.31 ( m, 1H), 7.16 (brs, 1H), 6.15 to 7.00 (m, 2H), 4.75 (brs, 2H), 4.75 to 5.60 (m, 2H), 3.97 (s, 3H), 3..50

~ 3.90 (m, 4H), 2.67 ~ 2.72 (m, 2H), 2.54 (q, 4H, J = 7.1 Hz), 1.18 (t,

3H, J = 7.0 Hz), 0.95 (t, 6H, J = 7.1 Hz).

(2) 4-Cross mouth-1_ [2_ (Jethylamino) ethyl] -3_ {2-[(Ethoxymethoxy) methyl] phenol 3-hydroxy-2-oxoindrin-6-cal'boxamide

In the same manner as in Example 6- (3) and Example 34- (5), methyl 4-chloro-1--1- [2- (ethylamino) ethyl] -3_ {2-[(ethoxymethoxy) methyl] Synthesized from fenyl} -3-hydroxy-2-oxoindoline- ⁶ -carboxylate.

¾ Keio R (CDC1 _3, 400顧z) δ 7.44 (d, 1H , J = 1.1 Hz), 7.40~ 7.44 (m, 1H), 7.40 (d, 1H, J = 1.1 Hz), 7.29 (ddd, 1H , J = 0.8, 7.5, 7.5 Hz), 7.17 (brs, 1H), 6.35 to 6.97 (m, 2H), 6.35 (brs, 1H), 6.00 (brs, 1H), 4.85 to 5.60 ( m, 2H), 4.74 (brs, 2H), 3.55 to 3.90 (m, 4H), 2.68 to 2.72 (m, 2H), 2.55 (q, 4H, J = 7.1 Hz), 1.19 (t, 3H, J = (7.0 Hz), 0.95 (t, 6H, J = 7.1 Hz). (3) 4-chloro- [2- (Jethylamino) ethyl] -3-hydroxy-3- [2- (hydroxymethinole) phenyl]- 2_oxoindoline-6-carboxamide hydrochloride

4-chloro-2--1- [2- (Jethylamino) ethyl] -3--3- {2-[(ethoxymethoxy) methyl] pheninole} -3-Hydroxy-2-oxoindoline-6-caprolupoxamide (40.7 mg, Concentrated hydrochloric acid (0.035 tnL, 0.416 mmol) was added to a methanol (1 mL) solution of 0.083 mmol), and the mixture was stirred at 50 ° C for 1 hour. The solvent was distilled off to obtain the title compound (35.4 mg, 91%).

_{¾ NMR (DMS0- d 6, 400} MHz) δ 10.27 (s, 1Η), 8.20 (s, 1H), 7.81 (s, 1H), 7.70 (s, 1H), 7.55 (s, 1H), 7.44 (brs , 1H), 7.30 to 7.38 (ra, 2H), 7.02 (s, 1H), 5.07 (brs, 1H), 4.03 to 4.27 (m, 2H), 3.17 to 3.45 (m, 8H), 1.23 (t, 6H , J = 7.2 Hz). Example 46

3- (1-Benzofuran-2-yl) -4-c-mouth- 1- [2- (Jethylamino) ethyl] _3-hydroxy-2-oxoindoline-6-carboxamide hydrochloride

(1) Methyl 3- (1-benzofuran-2-yl) _4-co-mouth- 1- [2- (Jethylamino) ethyl] -3-hydroxy-2-oxoindoline-6-carboxyle 1,

In a nitrogen atmosphere, a 1.56 N butyllithium hexane solution (0.24 mL, 0.38 mmol) was added to a solution of 2,3-benzofuran (61 tng, 0.52 mraol) in tetrahydrofuran (2 mL) at −40 ° C., and the mixture was stirred for 30 minutes. . Furthermore, tetrahydrofuran of methyl 4-cyclo-1-[2- (decylamino) ethyl] -2,3-dioxoindolin-6-carboxylate (Example 6- (1)) (117 mg, 0.35 mmol) (5 mL) solution and stirred for 2 hours. A saturated aqueous solution of ammonium chloride was added, extracted with ethyl acetate, and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel gel column chromatography (chloroform / methanol = 50/1) to give the title compound (35 mg, 22%).

¾ negation R (CDC1 _3, 400丽z) δ 7.74 (d, 1H , J = 1.2 Hz), 7.57 (d, 1H, J = 1.2 H z), 7.52 ~ 7.55 (m, 1H), 7.35 (d, 1H, J = 7.8 Hz), 7.18 to 7.25 (m, 2H), 6.94 (d, 1H, J = 0.8 Hz), 3.95 (s, 3H), 3.83 to 3.88 (m, 2H), 2.66 to 2.82 (m , 2H), 2.50 to 2.65 (m, 4H), 0.96 (t, 6H, J = 7.1 Hz). (2) 3- (1-Benzofuran-2-yl) -4-chloro-1_ [2- (Jetylamino) ethyl] -3-Hydroxy-2-oxysindrin-6-carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 3- (1-benzofuran-2-yl) -4-cyclobutane_1_ [2- (Jethylamino) ethyl] _3 Synthesized from -hydroxy-2-oxoindolin-6-carboxylate.

删_{R (DMS0-d 6, 400} MHz) δ 10.35 (brs, 1H), 8.22 (s, 1H), 7.83 (s, 1H), 7 .72 (s, 1H), 7.65~ 7.68 (m, 1H) , 7.59 (s, 1H), 7.42 to 7.45 (ra, 1H), 7.33 (s, 1H), 7.22 to 7.28 (m, 2H), 7.08 (s, 1H), 4.10 to 4.34 (ra, 2H), 3.12 to 3.52 (m, 6H), 1.23 (t, 6H, J = 6.8 Hz).

4-chloro- 1- [2- (Jethylamino) ethyl] -3-hydroxy-3- [2- (methoxymethyl) phenyl 1-2-oxoindoline-6-carboxamide hydrochloride

(1) Methyl 4-chloro- 1- [2- (Jethylamino) ethyl] -3-hydroxy-3- [2- (methoxymethineole) pheninole] -2-oxoindoline-6-carboxylate

Example 6 _ (2) Example 2 _ (2) using a Grignard reagent freshly prepared from 1-bromo-2- (methoxymethyl) benzene (Reference Example 27) and magnesium in place of 2-butanol magnesium bromide Was synthesized in the same manner as described above.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.73 (d, 1 H, J = 1 Hz), 7.53 (d, 1 H, J = 1 Hz), 7.34 (dd, 1 H, J = 7.4, 1 Hz) , 7.29 (dd, 1 H, J = 7.4, 1 Hz), 7.17 (m, 2 H), 5.20 (br, 1 H), 4.7 (br, 1 H), 3.96 (s, 3 H), 3.83 ( m, 2H), 3.43 (br, 3H), 2.70 (m, 2H), 2.54 (4H, q, J = 7.1 Hz), 0.96 (6H, t, J = 7.1 Hz).

(2) 4-Chloro-1-[2- (Jethylamino) ethynole] -3-Hydroxy-3- [2- (Methoxymethoxy) phenyl] -2-Oxoindrin-6-carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4-hydroxy-l- [2- (decylamino) ethyl] -3-hydroxy-3_ [2- (methyl It was synthesized from toxicmethyl) phenyl] -2-oxoindolin-6-carboxylate.

_{¾ NMR (DMSO- d 6, 400} MHz) δ 10.48 (br, 1 H), 8.21 (br, 1 H), 7.83 (br, 1 H), 7.70 (br, 1 H), 7.55 (br, 1 H ), 7.33 (br, 2 H), 7.00 (br, 1 H), 4.21 (br, 1 H), 4.05 (br, 1 H), 3.49 (br, 1 H), 2.89 (br, 3 H), 1.09 (br, 6 H). Example 48

4-Black mouth-1-"2- (Jethylamino) ethyl"]-3-hydroxy-3- (1-naphthinole) _2-oxoindoline-6-carboxamide.hydrochloride

(1) Methyl 4-chloro-1_ [2- (ethylpyramino) ethyl] -3-hydroxy-3- (1-naphthyl) -2-oxoindoline-6-carboxylate

The synthesis was carried out in the same manner as in Example 6_ (2), using a Grignard reagent prepared at the time of use from 1-butane, monaphthalene and magnesium in place of 2-chloro-mouth feninole magnesium bromide.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.9-7.26 (m, 9 H), 3.96 (s, 3 H), 3.9 (ra, 2 H), 2.8 (ra, 2 H), 2.6 (4 H, m ), 0.99 (6 H, t, J = 7.5 Hz).

(2) 4-c-mouth- 1- [2- (Jethylamino) ethyl] -3-hydroxy-3_ (1-naphthyl) -2-oxooxoline-6-carpoxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4-chloro-1- (2- (Jetylamino) ethyl) -3-hydroxy-3- (1-naphthyl) Synthesized from 2-oxoindoline-6-carboxylate.

¾丽_{R (CDC1 3, 400 MHz)} ( free form) δ 8.2 (br, 1 H ), 7.88 (brt, J = 7 Hz, 2 H), 7.6-7.5 (br, 3 H), 7.4 (brm, 2 H), 7.3 (br, 1 H), 6.28 (br, 1 H), 5.79 (br, 1 H), 3.95 (br, 2 H), 2.86 (ra, 1 H), 2.77 (m, 1 H ), 2.61 (4 H, m), 0.99 (t, 6 H, J = 7 Hz).

4-Chloro-1- [2- (getylamino) ethyl] -3-hydroxy-2- (2-naphthyl) 2-oxoindoline-6-carboxamide hydrochloride

(1) Methyl 4-chloro- 1- [2- (Jethylamino) ethyl] -3-hydroxy-3- (2-naphthyl ')-2-oxoindoline-6-carboxylate

The synthesis was carried out in the same manner as in Example 6- (2), using a Grignard reagent prepared at the time of use from 2-promonaphthalene and magnesium in place of 2-cu-mouth feninole magnesium bromide.

_{¾ NMR (CDC1 3, 400 MHz} ) 8 7.99 (d, 1H, J = 2 Hz), 7.8 (m, 3 H), 7.73 (d, 1 H, J = 1 Hz), 7.59 (d, 1 H, J = 1 Hz), 7.48 (dd, 2 H, J = 6.5, 3.5 Hz), 7.37 (dd, 1 H, J = 8.5, 2 Hz), 3.97 (s, 3 H), 3.92 (t, 1 H, J = 6.5 Hz), 3.8 (m, 1 H), 2.75 (t, 2 H, J = 6.5 Hz), 2.57 (4 H, q, J = 7 Hz), 0.96 (t, 6

H, J = 7 Hz).

(2) 4-Cupro-1-[2- (Jethylamino) ethyl] -3-Hydroxy-3- (2-naphthyl) -2-oxoindolin-6-carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4_chloro-1- [2- (decylamino) ethyl] _3-hydroxy-3- (2-naphthyl) -2 -Oxoindolin-6-carboxylate.

¾ Keio _{R (CDC1 3, 400 MHz)} ( free form) δ 7.99 (d, 1 H , J = 1 Hz), 7.80 (brm, 3 H), 7.77 (d, 1 H, J = 8 Hz), 7.53 (d, 1 H, J = 1 Hz), 7.47 (d, 1 H, J = 6 Hz), 7.46 (d, 1 H, J = 6 Hz), 7.41 (d, 1 H, J = 1 Hz) , 7.36 (dd, 1 H, J = 8.6, 1 Hz), 6.53 (br, 1 H), 5.92 (br, 1 H), 3.92 (m, 1 H), 3.84 (m, 1 H), 2.78 ( m, 2 H), 2.61 (q, 4 H, J = 7 Hz), 0.97 (t, 6 H, J = 7 Hz).

3-Biphenyl-2-inole-4-chloro-1_ [2_ (Jethylamino) ethyl] -3-hydroxy-2-oxoindolin-6-carboxamide hydrochloride

(1) Methyl 3-biphenyl-2-isle-4-coguchi-1- [2- (Jethylamino) ethyl] -3-hydroxy-2-oxoindoline-6-carboxylate

Example 4-In the same manner as in (1), methyl 4-kuguchi- 1- [2- (getylamino) ethyl] -2,3-dioxoindoline-6-carboxylate (Example 6_ ( It was synthesized from 1)) and 2-bromobiphenyl.

_{¾ MR (CDC1 3, 400 MHz} ) δ 8.22 (br, 1 H), 7.57 (d, 1 H, J = 1 Hz), 7.50 (d dd, 1 H, J = 7.5, 7.5, 1 Hz), 7.34 (ddd, 1 H, J = 7.5, 7.5, 1 Hz), 7.19 (dd, 1 H, J = 7.5, 7.5 Hz), 7.08 (dd, 1 H, J = 7.5, 7.5 Hz), 7.01 (d, 1 H, J = 7.5 Hz), 7.00 (dd, 1 H, J = 7.5, 1.2 Hz), 6.91 (s, 1 H), 6.73 (dd, 1 H, J = 7.5, 7.5 Hz), 6.32 (br , 1 H), 4.3 (br, 1 H), 3.93 (s, 3 H), 3.79 (m, 1 H), 2.82 (brm, 1 H), 2.58 (m, 2H), 2.52 (q, 4 H , J = 7 Hz), 0.95 (t, 6 H, J = 7 Hz). (2) 3-Bifenyl-2-inole-4-clo- 1- [2- (Jethylamino) ethyl] -3-hydroxy-

2-oxoindrin-6-carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 3-bifenyl-2-yl-4-chloro- 1- [2- (Jetylamino) ethyl] -3 It was synthesized from -hydroxy-2-oxoindoline-6-carboxylate.

_{NMR (CDC1 3, 400 MHz)} ( free form) 8 8.23 (br, 1 H ), 7.51 (ddd, 1 H, J = 7.5, 7.5, 1 Hz), 7.36 (ddd, 1 H, J = 7.5, 7.5 , 1 Hz), 7.23 (d, 1 H, J = 1 Hz), 7.18 (dd, 1 H, J = 7.5, 7.5 Hz), 7.08 (dd, 1 H, J = 7.5, 7.5 Hz), 7.00 ( br, 1 H), 6.99 (dd, 1 H, J = 7.5, 1 Hz), 6.81 (s, 1 H), 6.75 (dd, 1 H, J = 7.5, 7.5 Hz), 6.33 (br, 1 H ), 6.15 (br, 1 H), 5.77 (br, 1 H), 4.70 (br, 1 H), 3.78 (m, 1 H), 2.88 (m, 1 H), 2.50 (m, 6 H), 0.95 (t, 6 H, J = 7 Hz).

4_Chloro-3- (2,6-dichlorophenyl) -1- [2_ (Jethylamino) ethyl] -3-hydroxy-2-oxodindrin-6-carboxamide hydrochloride

(1) Methyl 4-chloro-3- (2,6-dichlorophenyl) -1-[2- (Jethylamino) ethyl]-

3-Hydroxy_2-oxoindoline-6-carboxylate

1- [2- (Jethylamino) ethyl] -6-Ed-4- (trifluoromethyl) -1H-Indole-2,3-dione Instead of Methinole 4-Chloro-1-[2- (Jethylamino) Ethinole] -2,3-doxoindoline-6-carboxylate (Example 6- (1)), and synthesized in the same manner as in Example 4- (1).

¾丽_{R (CDC1 3, 400 MHz)} δ 7.68 (d, 1 H, J = 1 Hz), 7.53 (d, 1 H, J = 1 Hz), 7.43 (dd, 1 H, J = 7, 2.3 Hz ), 7.23 (m, 2 H), 4.2 (br, 1 H), 3.94 (s, 3 H), 3.94 (m, 1 H), 3.81 (m, 1 H), 2.77 (t, 2 H, J = 7 Hz), 2.62 (qd, 4 H, J = 7, 1.5 Hz), 1.04 (t, 6 H, J = 7 Hz).

(2) 4-Chloro-3- (2,6-dichroic feninole) -1- [2- (Jetylamino) ethyl] -3-hydroxy-2-oxoindoline-6-carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4-co-mouth _3-(2,6-dic-mouth feninole) -1- [2- (Jetylamino) Ethyl] -3-hydroxy-2-oxoindolin-6-carboxylate. 30

¾ NMR (CDC1 _3, 400丽z) (free form) δ 7.50 (s, 1 Η ), 7.43 (dd, 1 Η, J = 7, 2 Hz), 7.39 (s, 1 H), 7.21 (m, 2H), 6.35 (br, 1H), 5.66 (br, 1H), 3.99 (m, 1H), 3.85 (m, 1H), 2.81 (t, 2H, J = 7 Hz), 2.67 (m, 4 H), 1.06 (6 H, t, J = 7 Hz).

3- (1-benzofuran-7-inole) -4-chloro-1- [2- (getylamino) ethyl] _3-hydroxy-2-oxoindrin-6-carboxamide hydrochloride

(1) Methyl 3- (1-benzofuran-7-yl) -4-cguchi-1- [2- (Jethylamino) ethynole] -3-hydroxy-2_oxoindoline-6-carboxylate

Synthesized in the same manner as in Example 6- (2), except that 7-bromo-1-benzofuran (Ref. did.

¾丽_{R (CDC1 3, 400 MHz)} δ 7.65 (d, 1 H, J = 1 Hz), 7.60 (d, 1 H, J = 6 Hz), 7.59 (d, 1 H, J = 1 Hz), 7.57 (dd, 1 H, J = 8, 1 Hz), 7.39 (d, 1 H, J = 2 Hz), 7.29 (dd, 1 H, J = 8, 8 Hz), 6.71 (d, 1 H, J = 2 Hz), 4.27 (br, 1 H), 3.95 (s, 3 H), 3.91 (m, 2 H), 2.83 (ra, 1 H), 2.77 (m, 1 H), 2.61 (ra, 4 H), 1.02 (t, 6 H, J = 7 Hz).

(2) 3- (1-Benzofuran-7-yl)-4-chloro- 1- [2- (Jetylamino) ethyl] -3-Hydroxy-2-oxysindrin-6-carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 3- (1-benzobenzo-7-yl) -4-chloro-1--1- [2- (ethylamino) ethyl ] -3-Hydroxy-2-oxoindoline-6-carboxylate.

¾丽R (CDC1 _3, 400 negation z) (free form) δ 7.69 (dd, 1 H , J = 7.5, 1 Hz), 7.57 (dd, 1 H, J = 8, 1 Hz), 7.50 (d, 1 H, J = 1 Hz), 7.37 (d, 1 H, J = 2 Hz), 7.30 (dd, 1 H, J = 8, 8 Hz), 6.71 (d, 1 H, J = 3.5 Hz) ), 6.34 (br, 1 H), 5.77 (br, 1 H), 3.91 (t, 2 H, J = 7 Hz), 2.84 (m, 1 H), 2.75 (m, 1 H), 2.61 (m , 4 H), 1.01 (6 H, t, J = 7 Hz). Three

3- (1-benzocen-7-yl) _4-cloth_1- [2- (getylamino) ethyl] -3-hydroxy-2-oxoindoline-6-carboxamide hydrochloride

(1) Methyl 3- (1-benzocen-7-yl) -4-oct- 1- [2- (Jethylamino) ethyl] -3-hydroxy-2-oxoindoline-6-carboxylate

In place of 2-chloro phenylmagnesium bromide, a Grignard reagent prepared at the time of use from 7-bromo-1-benzothiophene (Reference Example 29) and magnesium was used.

Synthesized in the same manner as in (2).

¾ employment _{R (CDC1 3, 400 MHz)} δ 7.80 (dd, 1 H, J = 8, 1 Hz), 7.70 (d, 1 H, J = 1 Hz), 7.61 (d, 1 H, J = 1 Hz ), 7.40 (dd, 1 H, J = 8, 8 Hz), 7.31 (d, 1 H, J = 8 Hz), 7.31 (s, 1 H), 4.40 (br, 1 H), 3.99 (m, 1H), 3.96 (s, 3H), 3.80 (ra, 1H), 2.85 (m, 1H), 2.70 (m, 1H), 2.60 (m, 4H), 0.99 (t, 6 H, J = 7 Hz).

(2) 3_ (1 -Venzochen-7-yl) -4-chloro-1-[2- (Jetylamino) ethyl] -3-hydr xy-2-oxysadrin-6-carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 3- (1-benzozo-7-yl) _4-coguchi-1- [2- (Jetylamino) ethyl ] It was synthesized from 3-hydroxy-2-oxosindrin-6-carboxylate.

¾丽_{R (CDC1 3, 400 MHz)} ( free form) δ 7.79 (dd, 1 H , J = 8, 1 Hz), 7.57 (br, 1H), 7.52 (d, 1 H, J = 1 Hz), 7.37 (m, 2 H), 7.30 (m, 2 H), 6.62 (br, 1 H), 6.02 (br, 1 H), 3.87 (m, 2 H), 2.82 (m, 1 H), 2.68 ( m, 1 H), 2.55 (m, 4 H), 0.95 (6 H, t, J = 7 Hz).

32

Example 54

3-[2- (benzyloxy) phenyl] -4-chloro-1-[2- (Jethylamino) ethynole] -3-hydr oxy-2-oxoindolin-6-carpoxamide hydrochloride

(1) Methyl 3- [2- (benzyloxy) phenyl] -4- 4-chloro-1- [2- (ethylpyramino) ethyl] -3-hydroxy-2-oxoindoline-6-carboxylate

Example 6-(2) Example 6- (2) using a Grignard reagent prepared at the time of use from 1- (pendinoreoxy) -2-bromobenzene (Reference Example 30) and magnesium in place of 2-bromobutane magnesium bromide. Was synthesized in the same manner as described above.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.01 (d, 1 H, J = 7.5 Hz), 7.61 (d, 1 H, J = 1 H z), 7.25-7.35 (ra, 4 H), 7.11 (ddd , 1 H, J = 7.5, 7.5, 1 Hz), 7.02 (d, 1 H, J = 1 Hz), 6.91 (brd, 1 H, J = 7 Hz), 6.85 (d, 1 H, J = 8 Hz), 4.70 (s, 2 H), 4.25 (br, 1 H), 3.97 (s, 3 H), 3.68 (m, 1 H), 2.41-2.57 (m, 7 H), 0.74 (t, 6 H, J = 7 Hz).

(2) 3- [2- (Benzyloxy) phenyl] -4-culo-1- [2- (Jethylamino) ethyl] -3-hydroxy-2-oxoindoline-6-caproloxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 3- [2- (benzyl / reoxy) phenyl] -4-coctan-1-[2- ( [Ethylamino) ethyl] -3-hydroxy-2-oxoindolin-6-carboxylate.

_{¾ NMR (CDC1 3, 400 MHz} ) ( free form) δ 8.02 (d, 1 H , J = 7.5 Hz), 7.32 (m, 5 H), 7.10 (ddd, 1 H, J = 7.5, 7.5, 1 Hz ), 6.94 (d, 1 H, J = 1 Hz), 6.91 ( brd, 1 H, J = 7.5 Hz), 6.85 (d, 1 H, J = 7.5 Hz), 6.24 (br, 1 H), 5.77 (br, 1 H), 4.76 (br, 1 H), 4.68 ( s, 2 H), 3.62 (ra, 1 H), 2.65 (m, 1 H), 2.49 (m, 4 H), 0.93 (t, 6 H, J = 7 Hz).

4 口口 -3_ [2- (Cyclopropylmethoxy) phenyl] -1- [2- (Jethylamino) ethynole] _3-Hydroxy-2-oxoindolin-6-carboxamide hydrochloride

(1) Methinole 4-c-mouth-3- [2- (Cyc-propylmethoxy) phenyl] _1- [2- (Jetylamino) ethyl] -3-hydroxy-2-oxodindrin-6-forcenorboxylate

Example 6-(2) using a Grignard reagent prepared at the time of use from 1-bromo-2- (cyclopropylmethoxy) benzene (Reference Example 31) and magnesium in place of 2-chloropheno-magnesium bromide. ).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.86 (br, 1 H), 7.62 (d, 1 H, J = 1 Hz), 7.45 (d, 1 H, J = 1 Hz), 7.26 (m, 1 H ), 7.04 (dd, 1 H, J-7.5, 7.5 Hz), 6.70 (d, 1 H, J = 8 Hz), 4.19 (m, 1 H), 3.94 (s, 3 H), 2.81 (m, 1 H), 2.73 (m, 1 H), 2.63 (m, 4 H), 1.01 (t, 6 H, J = 7 Hz), 0.85 (br, 1 H), 0.46 (m, 1 H), 0. 36 (m, 1 H), 0.11 (m, 1 H),-0.07 (m, 1 H).

(2) 4-Couguchi-3- [2- (Cyclopropylmethoxy) phenyl] -1- [2- (Jethylamino) ethyl] -3-hydroxy-2-oxoindoline-6-carboxamide hydrochloride

Example 6-(3), Example 6 In the same manner as in _ (4), methyl 4-co-guchi-3- [2- (sic-co-pyrmethoxy) pheninole]-1-[2 -(Getylamino) ethyl] -3-Hydroxy-2-oxoindoline-6-carboxylate.

¾删_{R (CDC1 3, 400 MHz)} ( free form) δ 7.88 (br, 1 H ), 7.39 (d, 1 H, J = 1 Hz), 7.27 (m, 2 H), 7.04 (d, 1 H , J = 7, 7 Hz), 6.70 (d, 1 H, J = 8 Hz), 6.22 (br, 1 H), 5.75 (br, 1 H), 4.8 (br, 1 H), 4.18 ( tn, 1 H), 3.60 (m, 2 H), 3.44 (ra, 1 H), 2.83 (m, 1 H), 2.71 (m, 1 H), 2.62 (tn, 4 H), 1.01 (t, 6 H, J = 7 Hz), 0.8 (br, 1 H), 0.44 (m, 1 H), 0.39 (m, 1 H), 0.10 (m, 1 H),-0.07 (m, 1 H). Example 56 4-Chloro-1-[2- (Jetylamino) ethyl] -3-hydroxy-3- [2- (2-methoxyethoxy:) phenyl] -2-oxoindoline-6-caproloxamide hydrochloride

(1) Methyl 4-co-mouth- 1- [2_ (Jethylamino) ethyl] -3-hydroxy-3- [2- (2-methoxhetoxy) phenyl] -2-oxoindrin-6_carboxylate

Example 1 was replaced with 2-bromo-2-magnesium bromide using a glyuanole reagent prepared on a daily basis from 1-promo-2- (2-methoxyethoxy) benzene (Reference Example 32) and magnesium. 6-Synthesized in the same manner as (2).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.80 (br, 1 H), 7.62 (d, 1 H, J = 1 Hz), 7.46 (d, 1 H, J = 1 Hz), 7.29 (ddd, 1 H , J = 8, 7.5, 1 Hz), 7.05 (d, 1 H, J = 7.5 Hz), 6.79 (d, 1 H, J = 8 Hz), 4.13 (m, 1 H), 3.95 (m, 1 H), 3.94 (s, 3 H), 3.84 (ra, 1 H), 3.61 (m, 1 H), 3.33 (m, 2 H), 2.82 (m, 1 H), 2.71 (m, 1 H) , 2.62 (m, 4 H), 1.01 (t, 6 H, J = 7 Hz).

(2) 4-c-mouth- 1- [2- (Jetylamino) ethyl] -3-hydroxy-3- [2- (2-methoxyethoxy) phenyl] -2-oxoindoline-6-carboxamide hydrochloride salt

In the same manner as in Example 6- (3) and Example 6_ (4), methyl 4-chloro-1--1- [2- (getylamino) ethynole] -3-hydroxy-3- [2-(2 -Methoxyethoxy) pheninole] -2-oxoindrin-6-carboxylate.

¾丽_{R (CDC1 3, 400 MHz)} ( free form) δ 7.84 (br, 1 H ), 7.38 (d, 1 H, J = 1 Hz), 7.29 (ra, 2 H), 7.05 (dd, 1 H , J = 7.5 Hz), 6.78 (d, 1 H, J = 8 Hz), 6.37 (br, 1 H), 5.87 (br, 1 H), 5.2 (br, 1 H), 4.08 (m, 1H), 3.95 (m, 1H), 3.82 (brm, 1H), 3.64 (ra, 1H), 3.32 (m, 2H), 3.22 (s, 3H), 2.80 (ra, 1H) ), 2.70 (m, 1 H), 2.61 (m, 4 H), 1.01 (t, 6 H, J = 7 Hz).

4, -Black mouth-1 '-[2- (Jethylamino) ethyl] -2'-oxo-1', 2'-dihydro-3Η-spiro [2-benzofuran-1._3'-indole] -6, _ Carboxamide hydrochloride.

(1) Methyl 4-tert-butyl 1- [2- (Jethylamino) ethyl] -3-hydroxy-3- [2- (hydroxymethyl) pheninole] -2-oxoindolin-6-carboxylate

Example 45- In a similar manner to (3), methyl 4-chloro-1- [2- (ethylpyramino) ethyl] -3_ {2-[(ethoxymethoxy) methyl] phenyl} -3-hydroxy- It was synthesized from 2-oxoindoline-6-carboxylate (Example 45- (1)).

¾丽_{R (CDC1 3, 400 MHz)} ( free form) δ 7.76 (d, 1H, J = 1.0 Hz), 7.54 (d, 1H, J = 1.0 Hz), 7.35 (d, 1H, J = 7.4 Hz) , 7.30 (ddd, 1H, J = 1.2, 7.4, 7.4 Hz), 7.17 (dd, 1H, J = 7,, 7.4 Hz), 6.93 (brs, 1H), 5.04 (brs, 1H), 4.94 (b rs , 1H), 3.96 (s, 3H), 3.85 to 3.96 (m, 1H), 3.63 to 3.79 (m, 1H), 2.65 to 2.83 (ra, 2H), 2.50 to 2.62 (m, 4H), 0.95 (t , 6H, J = 6.9 Hz).

(2) Methyl 4, -cloth--[2- (Jethylamino) ethyl] -2, -oxo-, 2'-dihydro-3Η-spiro [2-benzofuran-1,3, indole] -6'- Carboxylate

In a nitrogen atmosphere, methyl 4-clo-2--1- [2- (ethylamino) ethyl] -3-hydroxy-3- [2- (hydroxymethinole) phenyl] -2-oxoindoline-6-carboxylate To a solution of (419 mg, 0.87 mmol) in dichloromethane (10 mL) at 0 ° C triethylamine (0.48 mL, 3.46 mmol) and methanesolephoninolechloride (67 and 0.87 mmol) in dichloromethane (7 mL). The solution was added and stirred for 2 hours. Saturated aqueous sodium bicarbonate was added, extracted with ethyl acetate, and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (form: methanol / methanol = 20/1) to give the title compound (342 mg, 92%).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.66 (d, 1H, J = 1.2 Hz), 7.53 (d, 1H, J = 1.2 H z), 7.33~ 7.40 (m, 2H), 7.20~ 7.25 (m, 1H), 6.82 (d, 1H, J = 7.7 Hz), 36

5.64 (d, 1H, J = 11.9 Hz), 5.52 (d, 1H, J = 11.9 Hz), 3.96 (s, 3H), 3.88 to 4.00 (m, 1H), 3.71 to 3.77 (m, 1H), 2.66 ~ 2.81 (tn, 2H), 2.53 to 2.63 (m, 4H), 0.99 (t, 6H, J = 7.1 Hz).

(3) 4, -Kuguchi-1 '-[2- (Jetylamino) ethyl] -2'-oxo-1,2, -dihydro-3--spiro [2-benzofuran-1,3'-indole ] -6, -Carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4'-chloro--[2- (Jetylamino) ethyl] -2'-oxo-1 ', 2'- Synthesized from dihydro-3Η-spiro [2-benzofuran-1,3, -indole] -6, -potassolevoxylate.

丽_{R (DMSO- d 6, 400 MHz} ) δ 10.25 (brs, 1H), 8.21 (brs, 1H), 7.90 (brs, 1H), 7.73 (s, 1H), 7.59 (s, 1H), 7.48 (d , 1H, J = 7.4 Hz), 7.43 (dd, 1H, J =

7.4, 7.4 Hz), 7.28 (dd, 1H, J = 7.4, 7.4 Hz), 6.99 (d, 1H, J = 7.4 Hz), 5.48 (d, 1H, J = 12.4 Hz), 5.43 (d, 1H, J = 12.4 Hz), 4.10 to 4.23 (m, 2H),

3.15 to 3.52 (m, 6H), 1.09 (t, 6H, J = 7.0 Hz).

1- [2- (Jethylamino) ethyl] -2-oxo-4- (trifluoromethyl) -1,2,3 ', 4, -tetrahydrospiro [indole-3, -isochromene Ί—-6-carboxami Do hydrochloride

(1) 1- [2- (Jethylamino) ethyl] -3-hydroxy-6-odo-3--3- {2_ [2- (Methoxymethoxy) ethyl] phenyl} -4- (methyl trifluoromethyl) -1 , 3_dihydro-2H-indole-2-one

In the same manner as in Example 1- (2), 1- [2- (Jetinoleamino) ethyl] -6-thio-4- (trifluoromethyl) -1H-indole-2,3-dione (Example 2- (1)) and 1-promo-2-[(met It was synthesized using a Darinal reagent freshly prepared from [Ximethoxy) ethyl] benzene (Reference Example 26) and magnesium.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.69 (s, 1 H), 7.49 (s, 1 H), 7.31 (d, 1 H, J = 7.3 Hz), 7.25 (dd, 1 H, J = 7.3, 7.3 Hz), 6.96 (dd, 1 H, J = 7.3, 7.3 Hz), 6.67 (s, 1 H), 6.45 (d, 1 H, J = 7.3 Hz), 4.63 (d, 1 H, J = 6.8) Hz), 4.54 (d, 1 H, J = 6.8 Hz), 4.45 to 4.57 (ra, 1 H), 4.01 to 4.04 (m, 1 H), 3.71 to 3.82 (m, 2 H), 3.55 to 3.62 ( m, 1 H), 3.11 (s, 3 H), 2.99 to 3.03 (m, 1 H), 2.47 to 2.61 (m, 6 H), 0.97 (t, 3 H, J = 7.1 Hz), 0.94 (t , 3 H, J = 7.1 Hz).

(2) 1- [2- (Jethylamino) ethyl] -3-hydroxy-3_ [2- (2-hydroxyethyl) phenyl] -6-odo-4- (trifluoromethyl) -1,3 -Dihydro-2H-indole-2-one Example 57 In a similar manner to (1), tri [2- (getylamino) ethyl] -3-hydroxy-6-ode-3- {2- [2- ( Methoxymethoxy) ethyl] phenyl} -4- (trifluoromethyl) -1,3-dihydro-21-toindoleno-2-one.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.65 (s, 1 H), 7.51 (s, 1 H), 7.23 (m, 2 H), 7.0 0 ~ 7.02 (m, 1 H), 6.45 ~ 6.47 (m , 1H), 3.99 (m, 2H), 3.78 to 3.82 (m, 1H), 3.61 to 3.66 (m, 3H), 3.20 (brs, 1H), 2.65 (m, 2H), 2.53 ~ 2.55 (m, 4H), 0.97 (t, 6H, J = 7.1 Hz).

(3) 1- [2- (Jethylamino) ethyl] -6-odo-4- (trifluoromethyl) -3,, 4'-dihydrospiro [indole-3,1, -isochromene] -2 (1H) -On

Example 57 In the same manner as in (2), 1- [2- (Jethylamino) ethyl] -3-hydroxy-3 -— [2- (2-hydroxyethynole) phenyl] -6-odo- Synthesized from 4- (trifluoromethyl) -1,3-dihydro-2H-indole-2-one.

_{lU NMR (CDC1 3, 400 MHz} ) δ 7.59 (s, 1 Η), 7.51 (s, 1 Η), 7.19 ~ 7.20 (m, 2 H), 7.00 ~ 7.04 (m, 1 H), 6.53 (d, 1 H, J = 7.8 Hz), 4.92 to 4.99 (m, 1 H), 4.09 to 4.14 (m, 1 H), 3.84 to 3.91 (m, 1 H), 3.63 to 3.68 (ra, 1 H), 3 .18 to 3.27 (m, 1 H), 2.76 to 2.81 (m, 1 H), 2.69 (t, 2 H, J = 6.7 Hz), 2.58 (q, 4 H, J = 7.1 Hz), 1.01 (t, 6 H, J = 7.1 Hz).

(4) 1- [2- (Jethylamino) ethyl] _2-oxo-4- (trifluoromethyl) -1,2,3 ', 4'-tetrahydrospiro [indoneno-3, -isochromene] -6-carbo -Trinore In the same manner as in Example 1- (3), 1- [2- (Jethylamino) ethyl] -6-odo-4-(trifluomethinole) -3 ′, 4′-dihydrospiro [indole-3, 1, -Isochromene] -2 (1H)-

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.56 (s, 1 H), 7.42 (s, 1 H), 7.21~ 7.23 (ra, 2 H), 7.01~ 7.05 (m, 1 H), 6.50 (d, 1 H, J = 7.7 Hz), 4.92 to 4.99 (m, 1 H), 4.12 to 4.16 (m, 1 H), 3.90 to 3.97 (ra, 1 H), 3.64 to 3.70 (m, 1 H), 3 .20 — 3.25 (m, 1 H), 2.79 to 2.83 (m, 1 H), 2.67 to 2.76 (m, 2 H), 2.57 (q, 4 H, J = 7.1 Hz), 0.98 (t, 6 H , J = 7.1 Hz).

(5) 1- [2- (Jethylamino) ethyl] -2-oxo-4-(trifluoromethyl) -1,2,3 ', 4'-tetrahydrospiro [indole-3,1'-isochromene] _6 __________________________________________________________________ ル Lup0xamide hydrochloride In the same manner as in Example 1_ (4), 1- [2- (getylamino) ethyl] -2-oxo-4- (trifluo mouth methinole) -1,2,3 ', 4 - tetrahydrospiro [indole - 3, 1 '_ isochromen] - ⁶ - was synthesized from the force Lupolen nitrile.

¾ 丽 R (DMS0-d ₆ , 400 MHz) δ 10.33 (brs, 1 H), 8.39 (brs, 1 H), 8.26 (s, 1 H), 7.89 (s, 1 H), 7.86 (brs, 1 H), 7.29 (d, 1 H, J = 7.4 Hz), 7.24 (dd, 1 H, J = 7.4, 7.4 Hz), 7.06 (dd, 1 H, J = 7.4, 7.4 Hz), 6.60 (d, 1 H, J = 7.4 Hz), 4.75 to 4.80 (m, 1 H), 4.18 to 4.23 (m, 2 H), 4.07 to 4.11 (m, 1 H), 3.03 to 3.73 (m, 7 H) , 2.81 to 2.85 (m, 1 H), 1.23 (t, 6 H, J = 7.1 Hz)

Example 59 4-chloro mouth _3- (2-chloro mouth phenyl) -1- [2- (Jetylamino) ethyl] -3 -Fluoro mouth-2-oxoindoline-6-carboxamide hydrochloride

Under a nitrogen atmosphere, free of 4-chloro-3- (2-chlorophenyl) -1- [2- (getylamino) ethyl] -3-hydroxy-2-oxoindoline-6-caprolupoxamide hydrochloride (Example 6) A solution of the compound (44.3 mg, 0.102 mmol) in methylene chloride (2.0 mL) was cooled to -78 ° C, and sulfa-trifluoride digylamine complex (30 μΐ, 0.226 mmol) was added, and the temperature was gradually raised to room temperature. Stir for 4 hours while warming. Saturated aqueous sodium hydrogen carbonate was added, extracted with ethyl acetate, and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / methanol = 20/1 to 10/1) to obtain a free form of the title compound. Subsequently, it was dissolved in 1,4-dioxane (2.0 mL), 4N hydrochloric acid / 1,4-dioxane solution (1 mL) was added, and the solvent was distilled off. Getyl ether was added and the solvent was distilled off to give the title compound (20.8 mg, 43%).

Response R (DMS0-d ₆ , 400 MHz) δ 10.22 (brs, 1 H), 8.25 (brs, 1 H), 7.95 (d, 1 H, J = 7.7 Hz), 7.91 (s, 1 H), 7.81 (brs, 1 H), 7.64 (s, 1 H), 7.59 (dd, 1 H, J = 7.7, 7.7 Hz), 7.53 (dd, 1 H, J = 7.7, 7.7 Hz), 7.48 (d, 1H, J = 7.7 Hz), 4.19 to 4.33 (m, 2H), 3.23 to 3.51 (ra, 6H), 1.25 (t, 6H, J = 7.2 Hz).

3-(2- octaphenyl)-1- [2- (ethylamino) ethyl]-3-fluoro-2-oxo-4- (trifluoromethyl) indoline-6-carboxamide hydrochloride

(1) 3- (2-Chlorophenyl) -1- [2- (Jethylamino) ethyl] -3-hydroxy-6-iod-4- (trifluoromethyl) -1,3-dihydro-21 Toindole-2-one

1- [2- (Jetylamino) ethyl] -4 -Fluo-mouth-6-Edo-1H-Indole-2,3-Dione 'instead of 1- [2- (Jetylamino) ethyl] -6-Edo-4- Synthesized in the same manner as in Example 1- (2) using (triphnoreolomethyl) -III-indole-2,3-dione (Example 2- (1))

_{^ -NMR (CDC1 3> 270 MHz} ) δ .8.09 (d, 1H, J = 6.8 Hz), 7.61 (s, 1H), 7.53 (s, 1H), 7.41 (dd, 1H, J = 6.8, 6.8 Hz ), 7.21-7.32 (m, 2H), 3.97-4.11 (m, 1H), 3.68-3.78 (m, 1H), 2.55-2.84 (ra, 6H), 1.03 (t, 6H, J = 7.1 Hz) ) (2) 3- (2-Chlorophenyl) -1- [2- (Jethylamino) ethyl] -3-Hydroxy-2-oxo-4- (trifluoromethyl) indoline-6-caprolitolitrile

Example 1 In the same manner as in (3), 3- (2-chlorophenyl) -1- [2- (ethylamino) ethyl] _3-hydroxy-6-odo-4_ (trifluoromethylinole) )-Synthesized from 1,3-dihydro-2H-indole-2-one.

^{_{1 H-NMR (CDC1 3,}} 270 MHz) 8 · 8.07 (d, 1H, J = 7.6 Hz), 7.57 (s, 1H), 7.40-7.47 (m, 2H), 7.33 (ddd, 1H, J = l .5, 7.6, 7.6 Hz), 7.24 (dd, 1H, J = 1.5, 7.6 Hz), 4.03-4.13 (m, 1H), 3.73-3.83 (m, 1H), 2.59-2.78 (m, 6H ), 1.01 (t, 6H, J = 7.1 Hz).

(3) 3- (2-chlorophen) -1- [2- (Jetylamino) ethyl] -3-hydroxy-2-oxo-4- (4-methyl-methyl) indoline-6-caproloxamide

In the same manner as in Example 1- (4), 3- (2-chlorophenyl) -1- [2- (getylamino) ethyl] -3-hydroxy-2-oxo-4- (methyl trifluo) Synthesized from indoline-6-carbo-tolyl.

_{XH-NMR (CDC1 3, 270} MHz) ( free form) δ · 8.12 (d, 1H , J = 7.4 Hz), 7.76 (s, 1H), 7.66 (s, 1H), 7.41 (dd, 1H, J = 7.4, 7.4 Hz), 7.21 to 7.33 (m, 2H), 6.53 (br, 1H), 6.03 (br, 1H), 3.83 to 4.04 (m, 2H), 2.55 to 2.87 (m, 6H), 1.01 (t , 6H, J = 7.1 Hz).

(4) 3- (2-Chloropheninole) -1- [2-((ethylamino) ethyl) -3-fluo-2-oxo-4_ (trifluoromethyl) indoline-6-carboxamide hydrochloride

In the same manner as in Example 59, 3- (2-chlorophenyl) -1- [2- (ethylpyramino) ethyl] -3-hydroxy-2-oxo-4- (trifluoromethyl) indoline It was synthesized from -6-carboxamide hydrochloride.

^ -NMR (DMSO-d ₆ , 400 MHz) δ · 10.32 (brs, 1Η), 8.43 (brs, 1H), 8.31 (s, 1H), 7.94 (s, 1H), 7.92 (brs, 1H), 7.88 (d, 1H, J = 7.7 Hz), 7.58 (dd, 1H, J = 7.7, 7.7 Hz), 7.51 (dd, 1H, J = 7.7, 7.7 Hz), 7.46 (d, 1H, J = 7.7 Hz) Hz), 4.30-4.35 (m, 2H), 3.23-3.8 (ra, 6H), 1.25 (t, 6H, J = 7.2 Hz).

3_ (2-cloth feninole) -1_ [2- (Jetylamino) ethyl] -3-hydroxy-6- "3- (2-oxo 41 Soymidazolidine-1-yl) prop-trin-1-yl]-4- (trifluoromethyl)-1,3-dihydro-2H-indole-2-

Under a nitrogen atmosphere, 3_ (2-chlorophenyl)-1-[2- (ethylpyramino) ethyl] _3-hydroxy-6_oxide-4- (trifluoromethyl) -1,3- Dihydro-2H-indole-2-one (Example 60- (1)) (72.0 mg, 0.130 mmol) 1-prop-2-in-1-inoleimidazolidin-2-one (Reference Example 33) (28.0 mg, 0.226 mmol), triethylamine (1.0 mL), tetrahydrofuran (0.5 mL), and toluene (0.5 mL) were added, and the mixture was heated to 50 ° C. Further, dichlorobistriphenylphosphine palladium (22.6 mg, 0.0322 mmol) _N copper iodide (12.8 mg, 0.0672 mmol) was added, and the mixture was stirred at 50 ° C for 3 hours. Water and saturated aqueous sodium hydrogen carbonate were added, extracted with ethyl acetate, and dried over magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / methanol = 30/1 to 20/1) to obtain a free compound (62.5 tng). Subsequently, it was dissolved in 1,4-dioxane (4.0 mL), and a 4N hydrochloric acid / 1,4-dioxane solution (1.5 mL) was added. Toluene was added and the solvent was distilled off. The precipitated solid was suspended in getyl ether and collected by filtration to obtain the title compound (58.3 mg, 77%).

1H NMR (DMS0-d ₆ ) δ; 10.30 (brs, 1H), 8.06 (d, 1H, J = 7.3 Hz), 7.71 (s, 1H), 7.16-7.49 (ra, 5H), 6.63 (s, 1H), 4.12-4.33 (m, 4H), 3.26-3.50 (ra, 10H), 1.24 (t, 6H, J = 7.1 Hz)

4-Methoxy-3- (2-chlorophenyl) -3- [3- (getylamino) propoxy] -1-methyl-2-oxoindoline-6-carboxamide hydrochloride

(1) Methyl 4-coguchi-2,3-dioxoindrin-6-carboxylate Methyl 4-coguchi-2,3-dioxindrin in a nitrogen atmosphere To a solution of -6-carboxylate (Reference Example 3) (1.198 g, 5 mraol) in tetrahydrofuran (5 mL) was added ⁶⁰ % sodium hydride (220 mg, 5.5 mmol), and the mixture was stirred for 10 minutes. Methyl iodide (0.34 m, 5.5 mol) was added, and the mixture was stirred at room temperature for 2.5 hours and at 50 ° C for 2 hours. Further, methyl iodide (0.28 mL, 4.5 mmol) was added, and the mixture was stirred at 50 ° C for 2.5 hours. Water was added and extracted with ethyl acetate. After drying over magnesium sulfate and filtration, the solvent was distilled off and the residue was suspended and washed with getyl ether to give the title compound (512 mg). The filtrate is further concentrated, purified by silica gel column chromatography (hexane / ethyl acetate = 3/1 to 2/1), and suspended and washed with getyl ether to give the title compound (76 mg, total 46% ).

¾丽R (CDC1 _3, 400 thigh z) δ 7.75 (d, 1H , J = 1.1 Hz), 7.46 (d, 1H, J = 1.1 H z), 3.99 (s, 3H), 3.32 (s, 311) .

(2) Methyl 4-oct-3--3- (2-chloropheninole)-3-hydroxy-1-methyl-2-oxoindrin-6-butanolboxylate

In the same manner as in Example 6- (2), it was synthesized from methyl 4-chloro-1-methyl-2,3-dioxoindolin-6_carboxylate.

Ran _{R (CDC1 3, 400 MHz)} δ 8.15 (dd, 1H, J = 1.5, 7.9 Hz), 7.65 (d, 1H, J = 1.2 Hz), 7.43 (d, 1H, J = 1.2 Hz), 7.38 ( ddd, 1H, J = 1.4, 7.9, 7.9 Hz), 7.30 (ddd, 1H, J = 1.5, 7.9, 7.9 Hz), 7.24 (dd, 1H, J = 1.4, 7.9 Hz), 4.14 (brs, 1H) , 3.94 (s, 3H), 3.31 (s, 3H).

(3) Methyl 4-chloro-3- (2-chlorophenyl) -3- [3- (ethylpyramino) propoxy] -1-methyl-2-oxoindoline-6-carboxylate In a nitrogen atmosphere, to a solution of 3-dimethylamino-1-propanol (2.65 mL, 20 mmol) in dichloromethane (40 mL) at 0 ° C., was added methanesulfo-yurc-mouth lid (1.70 m, 22 mmol), Stir for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added, the mixture was extracted with ethyl acetate, dried over magnesium sulfate, filtered, and the solvent was distilled off. Purification by silica gel column chromatography (chloroform / methanol / aqueous ammonia = 20/10 / 0-5 / 1 / 0-250 / 50/1) gave the mesyl form (639 mg, 15%). Then, 4, Ν-dimethylformamide of methyl 4- (3-hydroxy-2-phenyl) -3-hydroxy-1-methyl-2-oxoindoline-6-carboxylate (100 mg, 0.27 mmol) (2.7 mL), 60% sodium hydride (12 mg, 0.3 mmol) was added to the solution, and the mixture was stirred at room temperature for 30 minutes. Then, the mesyl form (63 mg, 0.3 瞧 .1) was added, and the mixture was added at 70 ° C for 4 hours. Stirred. Further, 60% sodium hydride (10 mg, 0.25 mmol) was added, and the mixture was stirred at 70 ° C for 1 hour. A saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with ethyl acetate / toluene (1: 1), dried over magnesium sulfate, filtered, and the solvent was distilled off. The title compound (32 mg, 25%) was obtained by purification by silica gel column chromatography (chloroform / methanol = 20/1 to 10/1).

¾顺_{R (CDC1 3, 400 MHz)} δ 8.23 (dd, 1H, J = 1.6, 8.0 Hz), 7.67 (d, 1H, J = 1.2 Hz), 7.42 (d, 1H, J = 1.2 Hz), 7.39 (ddd, 1H, J = 1.4, 7.2, 8.0 Hz), 7.27 (ddd, 1H, J = 1.6, 7.2, 8.0 Hz), 7.21 (dd, 1H, J = 1.4, 8.0 Hz), 3.95

(s, 3H), 3.36 to 3.43 (m, 1H), 3.34 (s, 3H), 3.08 to 3.15 (ra, 1H), 2.52 to 2.68 (ra, 2H), 2.51 (q, 4H, J = 7.2 Hz ), 2.71 to 2.90 (m, 2H), 1.00 (t, 6H, J = 7.2 Hz).

(4) 4-Methoxy-3- (2-chlorophenyl) -3- [3- (ethylamino) propoxy] -1-methyl-2-oxoindrin-6-carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4-hydroxy-3- (2-chlorophenyl) -3- [3- (ethylpyramino) propoxy] -tomethyl Synthesized from 2-oxoindolin-6-hydroxyloxylate.

_{¾ NMR (CDC1 3, 400 MHz} ) ( free form) δ 8.23 (dd, 1H, J = 1.6, 8.1 Hz), 7.39 (d dd, 1H, J = 1.4, 7.2, 8.1), 7.30 (s, 2H) , 7.27 (ddd, 1H, J = 1.6, 7.2, 8.0 Hz), 7.21 (dd, 1H, J = 1.4, 8.0 Hz), 6.13 (brs, 1H), 5.77 (brs, 1H), 3.34 to 3.43 (m , 1H), 3.33 (s, 3H), 3.09 to 3.16 (m, 1H), 2.53 to 2.67 (m, 2H), 2.52 (q, 4H, J = 7.2 Hz), 1.75 to 1.88 (m, 2H), 1.01 (t, 6H, J = 7.2 Hz) Example 63

4-Promo-3_ (2-chlorophenyl) -1--"2- (Jethylamino) ethyl Ί_-3 -Hydroxy-2-oxindrin-6-Carboxamide

(1) 4-Promo- 1- [2- (Jethylamino) ethyl 6-Ed -1H -Indole-2,3-Sion 4-Fnorolero-6-Eod -1H -Indone 2, instead of 3-Dione 4 -Bromo-6-odo-

It was synthesized in the same manner as in Example 1_ (1) using 1H-indole-2,3-dione (Reference Example 2).

_{^ -NMR (CDC1 3, 270 MHz} ) 5 - 7.65 (d, 1H, J = l.3 Hz), 7.35 (d, 1H, J = l.3 Hz), 3.76 (t, 2H, J = 6.3 Hz ), 2.67 (t, 2H, J = 6.3 Hz), 2.55 (q, 4H, J = 7.3 Hz), 0.97 (t, 6H, J = 7.3 Hz).

(2) 4-Bromo-3-(2-chlorophenyl)-1- [2- (Jethylamino) ethyl] -3-Hydroxy-6-odo-1,3-Dihydro-2H-indole- 2-ON

1- [2- (Jetylamino) ethyl]-4 -Fluoro-6 -Edo-1H-indole -2,3-Dione Instead of 4-bromo-1- [2- (Jetyylamino) ethyl] -6_Edo- The compound was synthesized in the same manner as in Example 1- (2) using 1H-indole-2,3-dione.

^L H - Li _{R (CDC1 3, 270 MHz)} δ · 8.18 (dd, 1H, J = l.5, 7.1 Hz), 7.49 (. D, 1H, J = l 3 Hz), 7.40 (ddd, 1H, J = l.5, 7.1, 7.1 Hz), 7.28-7.34 (ra, 2H), 7.25 (d, 1H, J = l.3 Hz), 4.00 (ra, 1H), 3.68 (m, 1H), 2.70 —2.88 (m, 2H), 2.65 (m, 4H), 1.04 (t, 6H, J = 6.9 Hz).

(3) 4-Bromo-3- (2-chlorophenyl) -1- 1- [2- (Jethylamino) ethyl] -3-hydroxy -2-Oxindrin-6-Power Retriever

In the same manner as in Example 1- (3), 4-bromo-3- (2-chlorobutanoyl [2- (getylamino) ethyl] -3-hydroxy-6-thio-1,3- Synthesized from dihydro-2H-indole-2-one.

_{XH-NMR (CDC1 3, 270} MHz) δ · 8.20 (dd, 1Η, J = 7.9, 1.6 Hz), 7.42 (m, 1H), 7.4 1 (d, 1H, J = l.3 Hz), 7.27- 7.36 (m, 2H), 7.14 (d, 1H, J = l.3 Hz), 4.11 (ddd, 1H, J = 14.8, 5.9, 5.9 Hz), 3.68 (ddd, 1H, J = ll.6, 5.9 , 5.9 Hz), 2.76 (m, 1H), 2.67 (m, 5H), 1.03 (t, 6H, J = 7.3 Hz).

(4) 4-Promo-3- (2-chlorophenyl)-1- [2- (Jethylamino) ethyl] _3-hydroxy-2-oxoindolin-6-carboxamide

Example 1 In a manner similar to that of-(4), 4-promo-3- (2-chlorofuyuel) -1- [2- (ditylamino) ethyl] -3-hydroxy-2-oxoindoline-6-carbo Synthesized from nitrile

_{'H-NMR (CDC1 3,} 270 MHz) ( free form) δ · 8.24 (dd, 1H , J = l.3, 7.6 Hz), 7.51 (ra, 2H), 7.41 (ddd, 1H, J = l. 3, 7.6, 7.6 Hz), 7.20-7.34 (m, 2H), 6.49 (brs, 1H), 5.83 (brs, 1H), 3.96 (m, 1H), 3.84 (m, 1H), 2.82 (m, 1H), 2.73 (m, 1H), 2.64 (q, 2H, J = 7.3 Hz), 2.62 (q, 2H, J = 7.3 Hz), 1.03 (t, 6H, J = 7.3 Hz).

Example 64

1- (4-Chlorophenyl) -3- (2-ethylaminoethyl) -2-oxo-7-Trifnoroleolomethyl-2,3-dihydro-1H-benzimidazole-5-carboxamide

1- (4-Chlorophenyl) -2-oxo-7-trifluoromethinole-2,3-dihydro-1H-benz Imidazonole-5-carbonitrile (Reference Example 6-(5)) (0.1767 g) was dissolved in N, N-dimethinoleformamide (5 mL), and sodium hydride (27.2 mg) was added. The mixture was stirred at room temperature for 5 minutes. 2-Cle-mouth triethylamine hydrochloride (117.1 mg) and triethylamine (0.109 raL) were stirred and stirred at 60 ° C to 70 ° C for 1 hour. After cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 2-methyl-2-propanol (15 mL), heated to 50 ° C, added with potassium hydroxide powder (0.7340 g), and stirred for 1 hour. After cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by HPLC using condition 1 to give the title compound (90.4 mg, 30%). i H-NMR (DMS0 - d 6, 300 MHz: Torifuzoreo port acetate) δ - 9. 54 (brs, 1H), 8. 17 (brs, 2H), 7. 96 (brs, 1H), 7. 60 -7.66 (m, 3H), 7.46 (d, 2H, J = 8.6 Hz), 4.34 (br s, 2H), 3.45-3.60 (m, 2H), 3 20-3. 40 (m, 4H), 1.20 (t, 6H, J = 7.0 Hz).

HPLC retention time: 15.8 min (Condition 1) Example 6 5

1- (2,4-dioctanol)-3-(2-Getylaminoethyl) -2-oxo-7-trifluoromethyl-2,3-dihydro-1H-benzimidazole-5- Coleboxamide

1- (4-chlorophene-nore) -2-oxo-7-trifluoromethylinole-2,3-dihydro-1H-benzimidazole-5_carbonitrile instead of 1- (2,4- Example 6 4 using 2- (oxo) -7-trifluoro-7-trihydronomethyl-2,3-dihydro-1H-benzimidazole_5-carboditrinole (Reference Example 7_ (5)). Was synthesized in the same manner as described above.

'H-NMR (DMS0_d ₆ , 300 MHz: trifluoroacetate) δ ■ 9.44 (brs, 1H), 8.20 (brs, 2H), 7.95-7.98 (m, 2H), 7. 63-7.66 (m, 3H), 4.39 (brs, 2H), 3.45-3.60 (ra, 2H), 3.20-3.40 (m, 4H), 1.19 ( brs, 6H).

HPLC retention time: 17.6 min (condition 1)

7-Chloro-1- (2-chlorobutanol) -3- [2- (Jethylamino) ethynole]-2-oxo-2,3-dihydro-1H-benzimidazole-5-caproloxamide Hydrochloride

(1) Methyl 7-chloro-mouth (2-cyclohexanol) -3- [2- (Jethylamino) ethynole] -2-oxo-2,3-dihydro-1H-benzimidazole-5 -Power ruboxylate

4-Fluoro-6-odo-1H-indole -2,3-dione substitute 7-c-mouth-1- (2-c-mouth fernyl)-2-oxo-2,3-dihydro-1H- The compound was synthesized in the same manner as in Example 1- (1) using benzimidazole-5-canolepoxylate (Reference Example 8).

¾丽_{R (CDC1 3, 400 MHz)} δ 7.75 (d, 1H, J = l.4 Hz), 7.72 (d, 1H, J = l.4 Hz), 7 .54 (dd, 1H, J = l .5, 8.0 Hz), 7.38—7.49 (m, 3H), 4.04 (t, 2H, J = 6.7 Hz), 3.93 (s, 3H), 2.82 (t, 2H, J = 6.7 Hz), 2.59 (q, 4H, J = 7.1 Hz), 0.99 (t, 6H, J = 7.1 Hz).

(2) Ί-Cupro-1- (2-chlorophenyl) -3- (2- (Jetinoleamino) ethynole) -2-oxo-2,3-dihydro-1H-benzimidazolone-5-carboxylic acid Hydrochloride

In the same manner as in Example 6- (3), methyl 7-chloro-1- (2-chlorophenyl) -3- [2-((ethylamino) ethyl) -2-oxo-2,3-dihydro-1H- Synthesized from benzimidazolone 5-hexyloxylate.

_{¾ MR (DMS0 - d 6,} 400 MHz) δ 13.2 (br, 1H), 10.6 (br, 1H), 7.95 (s, 1H), 7.7 6 (dd, 1H, J = l.6, 7.7 Hz), 7.71 (dd, 1H, J = l.6, 7, 7 Hz), 7.64 (s, 1H), 7.60 (ddd, 1H, J = l.6, 7.7, 7.7 Hz), 7.54 (ddd, 1H, J = l.6, 7.7, 7.7 Hz), 4.35 (br, 2H), 3.19 (br, 6H), 1.14 (br, 6H).

(3) 7-Chloro-1- (2-chloromethylphenyl) -3- [2- (ethylpyramino) ethyl] -2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide hydrochloride salt

In the same manner as in Example 6- (4), 7-chloro-l- (2-l-phenyl) -3- [2- (Jetyl ') Amino) ethyl] -2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid hydrochloride.

¾ MR (DMS0-d ₆ , 400 MHz) δ 10.41 (brs, 1H), 8.09 (brs, 1H), 8.06 (d, 1H, J = 1.3 Hz), 7.76 (dd, 1H, J = 1.8, 7.7 Hz), 7.70 (dd, 1H, J = l.5, 7.7 Hz), 7.67 (d, 1H, J = l.3 Hz), 7.60 (ddd, 1H, J = l.8, 7.7, 7.7 Hz ), 7.54 (brs, 1H), 7.54 (ddd, 1H, J = l, 5, 7.7, 7.7 Hz), 4.33-4.46 (m, 2H), 3.43-3.55 (ra, 2H), 3.21 -3.32 (ra, 4H), 1.23 (t, 3H, J = 7.2 Hz), 1.23 (t, 3H, J = 7.2 Hz).

7-Ku-guchi-1- (2,4-Jik-guchi fuenore) -3_ (2-Jetinoleaminoethinole) -2-oxo-2,3-dihydro-1H-benzimidazole-5- Carboxamide

(1) Methynole 7-chloro mouth -1- (2,4-dichloropheninole) -3--(2-getylaminoethyl) -2-oxo-2,3-dihydro-1H-benzimidazole -5 -Carboxylate

4-Fluoro-6-odo-1H-indole-2,3-Dione is replaced by methyl 7-chloro-1- (2,4-dichlorophenyl) -2-oxo-2,3-dihydro-1H The compound was synthesized in the same manner as in Example 1- (1) using -benzimidazole-5-hydroxypropylate (Reference Example 9).

^ -NMR (CDClg, 400 MHz) δ 7.76 (d, 1H, J = 1.4 Hz), 7.74 (d, 1H, J = 1.4 Hz), 7.56 (d, 1H, J = 1.9 Hz ), 7.39-7.42 (m, 2H), 4.05 (t, 2H, J = 6.6 Hz), 3.93 (s, 3H), 2.85 (t, 2H, J = 6.6 Hz), 2.62 (q, 4H, J = 7.1 Hz), 0.99 (t, 6H, J = 7.1 Hz). (2) 7_ chloro mouth -1- (2, 4-dichloropheninole) -3- (2-ethylpyraminoethyl) -2-oxo-2,3-dihydro-1H-benzimidazole- 5-carboxylic acid

Example 6-In the same manner as in (3), methyl 7_chloro-1- (2,4-dichloromouth phenyl) -3- (2-methylethylaminoethyl) -2-oxo-2,3 Synthesized from 1-dihydro-1H-benzimidazole-5-carboxylate.

^X H-NMR (DMS0-d ₆ , 400 MHz) δ 13.25 (brs, 1H), 10.75 (brs, 1H), 7.99 (d, 1H, J = 1.8 Hz), 7.94 (d, 1H, J = l.8 Hz), 7.89 (d, 1H, J = 8.5 Hz), 7.65-7.68 (m, 2H), 4.38-4.50 (m, 2H), 3.36-3.56 (ra, 2H), 3.11-3.34 (m , 4H), 1.22 (t, 6H, J = 7.2 Hz), 1.22 (t, 6H, J = 7.2 Hz).

(3) 7-chloro mouth _l- (2,4-dichlorophenyl) -3- (2-dimethylaminoethyl) -2-oxo-2,3-dihydro-1H-benzimidazole-5-potoxolamide

In the same manner as in Example 6- (4), 7-coguchi-1- (2,4-dichlorophenyl) -3- (2-methylaminoaminoethyl) -2-oxo-2,3-dihydro- It was synthesized from 1H-benzimidazole-5-carboxylic acid.

^ -NMR (DMS0-d ₆ , 400 MHz) δ 10.49 (brs, 1Η), 8.10 (brs, 1H), 8.06 (d, 1H, J = 1.8 Hz), 7.94 (d, 1H, J = l .8 Hz), 7.85 (d, 1H, J = 8.5 Hz), 7.65-7.68 (m, 2H), 7.55 (brs, 1H), 4.36-4.44 (m, 2H), 3.44-3.54 (m, 2H ), 3.20-3.31 (m, 4H), 1.23 (t, 6H, J = 7.2 Hz), 1.22 (t, 6H, J = 7.2 Hz).

Example number

Example 6 8

7-Kokuguchi- 1- (2,6-Dichlorophenyl) -3- 3- [2- (Jethylamino) ethyl] -2_oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide Hydrochloride

(1) Methynole 7-Chloro-1- (2,6-dichlorophenyl) -3- [2- (Jethylamino) ethyl] -2-oxo-2,3-dihydro-1H-benzimidazono-5 -Power repoxylate

4-Fluoro-6-odo-1H-indole-2,3-Dione in place of methyl 7-co-bro-1-(2,6-zic-bout feninole) -2-oxo-2,3 It was synthesized in the same manner as in Example 1- (1) using -dihydro-1H-benzimidazol-5-carboxylate (Reference Example 10).

Keio _{R (CDC1 3, 400 MHz)} δ 7. 77 (d, 1H, J = l. 4 Hz), 7. 74 (d, 1H, J = l. 4 Hz), 7. 47 (d, 2H, J = 8.4 Hz), 7.39 (t, 1H, J = 8.4 Hz), 4.05 (t, 2H, J = 6.5 Hz), 3.94 (s, 3H), 2.82 (t, 211, J = 6.5 Hz), 2.57 (q, 4H, J = 7.1 Hz), 0.98 (t, 6H, J = 7.1 Hz).

(2) 7-chloro-1- (2,6-dichlorophenyl) -3- [2- (ethylpyramino) ethyl] -2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid Hydrochloride

Example 6-In the same manner as in (3), methyl 7-chloro-1- (2,6-dichlorophenyl) -3- [2- (ethylamino) ethyl] -2-oxo-2,3- Synthesized from dihydro-1H-benzimidazole-5-potassyl oxylate. 丽 R (DMS0_d ₆ , 400 MHz) S 13.34 (brs, 1H), 10.68 (brs, 1H), 8.06 (d, 1H, J = 1.0 Hz), 7.76 (d, 2H, J = 7.9 Hz), 7.71 ( d, 1H, J = 1.0 Hz, 7.66 (t, 1H, J = 7.9 Hz), 4.49 (m, 2H), 3.47 (m, 2H), 3.24 (m, 4H), 1.22 (t, 6H , J = 7.0 Hz).

(3) 7-Chloro-1-(2,6-dichloropheninole) -3- [2- (ethylpyramino) ethyl] -2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide hydrochloride salt

Example 6 In the same manner as in _ (4), 7-coguchi-1- (2,6-dichlorophenyl) -3- [2- (ethylamino) ethyl] -2-oxo-2,3 -Dihydro-1H-benzimidazonole-5-potassium was synthesized from rubonic acid hydrochloride.

¾ 丽 R (DMS0-d ₆ , 400 MHz) δ 10.44 (brs, 1H), 8.13 (d, 1H, J = l.1 Hz), 8.11 (brs, 1H), 7.76 (d, 2H, J = 7.5 Hz), 7.71 (d, 1H, J = 1.1 Hz), 7.66 (t, 1H, J = 7.5 Hz), 7.59 (brs, 1H), 4.44 (t, 2H, J-6.8 Hz), 3.49—3.54 (m, 2H), 3.24—3.27 (m, 4H), 1.23 (t, 6H, J = 7.2 Hz).

1- (2,4-dichlorophenyl) -3- [2- (ethylpyramino) ethyl] _7-methyl-2-oxo-2,

3-dihydro_m-benzimidazole-5-carboxamide hydrochloride

(1) Methyl 1- (2,4-dichrophthyl) -3- (2- (ethylpyramino) ethyl) -7-methyl-2-oxo-2,3-dihydro-1H-benzimidazomono-5 -Power repoxylate

Methyl 1_ (2,4-dichlorophenol) -7-methinole-2_oxo_2,3-dihydro-1H in place of 4_fluoro-6-odo-1H-indole-2,3-dione The compound was synthesized in the same manner as in Example 1- (1) using -benzimidazono-5-5-carboxylate (Reference Example 11).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7 · 67 (d, 1Η, J = l.2 Hz), 7.58-7.59 (m, 2H), 7.41-7 .42 (m, 2H), 4.02 (t, 2H, J = 6.9 Hz), 3.92 (s, 3H), 2.82 (t, 2H, J = 6.9 Hz), 2.60 (q, 4H, J = 7.1 Hz), 1.90 (s, 3H), 1.00 (t, 6H, J = 7.1 Hz).

(2) 1_ (2,4-dichloropheninole) _3-[2- (Jethylamino) ethyl] -7-methyl-2_oxo-2,3-dihydro-1H-benzimidazole- ⁵ -capillonic acid Hydrochloride

Example 6- (3) the same way, methyl 1 - (2, 4 - dichloro port Hue sulfonyl) - 3- [2 - (Jechi Ruamino) Echiru] - ₇ Mechinore ₂ one Okiso -2, 3 - Dihydro-1H-benzimidazonole-5-force synthesized from lipoxylate.

_{NMR (DMS0 - d 6, 400} MHz) δ 12.87 (brs, 1H), 10.86 (brs, 1H), 7.97 (d, 1H, J = 2.3 Hz), 7.85-7.88 (m, 2H), 7.68 (dd, 1H, J = 2.3, 8.5 Hz), 7.54 (s, 1H), 4.41 (m, 2H), 3.20-3.44 (m, 6H), 1.82 (s, 3H), 1.22 (t, 6H, J = 6.6 Hz).

(3) 1- (2,4-Dichlorophenizole) -3--[2- (Jet / reamino) ethyl] _7-Methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5_carboxami De hydrochloride

Example 6 In the same manner as in-(4), 1- (2,4-dichlorophenyl) -3- [2- (decylamino) ethyl] -7-methinole-2-oxo-2,3-dihydro -Synthesized from 1H-benzimidazono-5-carboxylic acid hydrochloride.

¾ NMR (DMSO—d ₆ , 400 MHz) δ 10.40 (brs, 1H), 7.97 (d, 1H, J = 2.3 Hz), 7.94 (brs, 1H), 7.91 ( d, 1H, J = 0.7 Hz), 7.81 (d, 1H, J = 8.5 Hz), 7.68 (dd, 1H, J = 2.3, 8.5 Hz), 7. 48 (d, 1H, J = 0.7 Hz), 7.37 (brs, 1H), 4.33-4.40 (m, 2H), 3 • 42-3.53 (m, 2H), 3 21—3.3.31 (m, 4H), 1.81 (s, 3H), 1.23 (t, 3H, J = 7.2 Hz), 1.22 (t, 3H, J = 7.2) Hz) .Example 7 0

l- (2,4 dichlorophenyl) -3--[2- (ethylpyramino) ethyl]-7-methoxy-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide hydrochloride

(1) Methyl 1- (2,4-dichrophthyl) -3- [2- (ethylpyramino) ethyl] -7-methoxy-2-oxo-2,3-dihydro-1H-benzimidazole-5 -Carboxylate

4-Fluoro-6-odo-1H-indole-2,3-Dione, instead of methyl, 1- (2,4-dioctaphenyl) -7-methoxy-2-oxo-2,3-dihydro- The compound was synthesized in the same manner as in Example 1_ (1), using 1H-benzimidazono-5-hydroxyphenol (Reference Example 12).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7. 52-7. 53 (m, 2H), 7. 33-7. 40 (m, 3H), 4. 02 (t, 2H, J = 6. 9 Hz ), 3.94 (s, 3H), 3.67 (s, 3H), 2.82 (t, 2H, J = 6.9 Hz), 2.60 (q, 4H, J = 7.1 Hz) ), 1.00 (t, 6H, J = 7.1 Hz).

(2) 1- (2,4-Dichloromouth phenyl)-3-[2- (Getylamino) ethyl] -7 -Methoxy-2-oxo-2,3-dihydro-1H-benzimidazole- 5-carboxylate

(3) In a similar manner, methyl 1 - Example 6 (2, 4 - dichloro port Hue sulfonyl) - ³ - [2- (Jechi Ruamino) Echiru] - 7 - main butoxy - 2 Okiso - 2, Synthesized from 3-dihydro-1H-benzimidazole-5-carboxylate.

Ran _{R (DMS0 - d 6, 400} MHz) δ 13. 02 (brs, 1H), 10. 61 (brs, 1H), 7. 87 (d, 1H, J = 2.3 Hz), 7.72 (d, 1H, J = 8.5 Hz), 7.70 (d, 1H, J = 1.1 Hz), 7.60 (dd, 1H, J = 2.3, 8.5 Hz), 7.37 (d, 1H, J = l.1 Hz), 4.37-4.39 (m, 2H), 3.62 (s, 3H), 3.15-3.50 (m, 6H), 1.17-1.24 (m, 6H).

(3) 1- (2,4-Dichloro-mouth feninole) -3--[2- (Jethylamino) ethyl] -7-methoxy-2-oxo-2,3-dihydro-1H-benzimi Dazol-5-force ^ / poxamide hydrochloride

Example 6 In the same manner as in-(4), 1- (2,4-dimethoxyphenyl) -3- [2- (ethylpyramino) ethyl] _7-methoxy-2-oxo-2,3-dihydro -Synthesized from 1H-benzimidazole-5-carboxylate hydrochloride.

¾ NMR (DMS0-d ₆ , 400 MHz) δ 10.24 (brs, 1H), 8.01 (brs, 1H), 7.87 (d, 1H, J = 2.3 Hz), 7.73 (d, 1H, J = 1.0 Hz ), 7.68 (d, 1H, J = 8.5 Hz), 7.59 (dd, 1H, J = 2.3, 8.5 Hz), 7.44 (brs, 1H), 7.36 (d, 1H, J = 1.0 Hz), 4.28 -4.40 (m, 2H), 3.62 (s, 311), 3.44-3.52 (m, 2H), 3.21-3.39 (m, 4H), 1.22 (t, 3H, J = 7.2 Hz), 1.21 (t , 3H, J = 7.2 Hz). Example 71

1- (2,4-Dichlorophenyl) -3- 3- [2_ (ethylpyramino) ethyl] -7-fluoro-2-oxo-2,3-dihydro 1H-benzimidazole-1-5-carboxamide hydrochloride

(1) Methinole 1_ (2,4-Dichloro mouth) -3_ [2- (Jetylamino) ethyl] -7-Fluoro-2-oxo-2,3-dihydro-1H-benzimidazole-5_ Carboxylate

4-Fluoro-mouth 6-Edodo-1H-indole-2,3-Dione instead of methyl 1_ (2,4-dichloropheninole) -7-fluoro-2-oxo-2,3-dihydro-1H- The compound was synthesized in the same manner as in Example 1_ (1) using benzimidazono-5-hydroxyphenol (Reference Example 13).

¾丽_{R (CDC1 3, 400 MHz)} δ 7.65 (d, 1H, J = l.2 Hz), 7.58 (d, 1H, J = 2.1 Hz), 7 .54 (dd, 1H, J = l.2 , 11.3 Hz), 7.38-7.44 (ra, 2H), 4.03 (t, 2H, J = 6.5 Hz), 3.94 (s, 3H), 2.81 (t, 2H, J = 6.5 Hz), 2.58 (q , 4H, J = 7.0 Hz), 0.98 (t, 6H, J = 7.0 Hz).

(2) 1- (2,4-Dichrophine) -3- [2- (Jethylamino) ethyl]-7-Fluoro-2-oxo-2,3-dihydro-1H-benzi Midazole-5-carboxylate

Example 6-In the same manner as in (3), methyl 1- (2,4-dichlorophenyl) -3- [2- (ethylenamino) ethyl] _7_fluoro-2-oxo-2,3-dihydro -1H-Benzimidazonore-5- Synthesized from carboxylate.

Li _{R (DMS0 - d 6, 400} MHz) 8 13.26 (brs, 1H), 10.41 (brs, 1H), 7.96 (d, 1H, J = 2.3 Hz), 7.91 (d, 1H, J = l.0 Hz ), 7.88 (d, 1H, J = 8.5 Hz), 7.68 (dd, 1H, J = 2.3, 8.5 Hz), 7.53 (dd, 1H, J = l.0, 10.5 Hz), 4.42 (m, 2H) , 3.21-3.49 (m, 6H), 1.22 (t, 6H, J = 6.9 Hz).

(3) 1- (2,4-Dichloropheninole) -3--[2- (Jethylamino) ethyl] -7-Fluoro mouth-2-oxo-2,3-dihydro-1H-benzimidazole-5- Carboxamide hydrochloride

Example 6-1- (2,4-dichlorophenyl) -3- [2- (getinoleamino) ethyl] -7-fluoro-2-oxo-2,3-dihydro- Synthesized from 1H-benzimidazole-5-force norebon hydrochloride.

^X H NMR (DMS0-d ₆ , 400 MHz) δ 10.23 (brs, 1Η), 8.05 (brs, 1H), 7.96 (d, 1H, J = 2.3 Hz), 7.93 (d, 1H, J = l.1 Hz), 7.84 (d, 1H, J = 8.5 Hz), 7.68 (dd, 1H, J = 2.3, 8.5 Hz), 7.55 (dd, 1H, J = l.0, 12.0 Hz), 7.55 (brs, 1H ), 4.33-4.43 (m, 2H), 3.44-3.59 (m, 2H), 3.21-3 · 32 (m, 4H), 1.23 (t, 3H, J = 7.2 Hz), 1.23 (t, 3H, J = 7.2 Hz). Example 72

1- (2-chlorophenyl) -3- 3- [2- (ethylpyramino) ethyl] -7-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-5-carboxamide hydrochloride

(1) Methyl 1- (2-chlorophenyl) -3- [2- (ethylpyramino) ethyl] -7-fluoro-2-oxo-2,3-dihydro-1H-benzimidazonole-5-force repoxylate

4-Hunoleo mouth 6-Ed -1H-indole-2,3-Dione is replaced by methyl 1- (2-neck mouth fenyl) -7-Fluoro-2-oxo-2,3-dihydro-1H The compound was synthesized in the same manner as in Example 1- (1) using -benzimidazole-5-carboxylate (Reference Example 14).

丽_{R (CDC1 3, 400 MHz)} δ 7.65 (d, 1H, J = l.3 Hz), 7.39-7.57 (m, 5H), 4.04 (t, 2H, J = 6.7 Hz), 3.93 (s, 3H ), 2.82 (t, 2H, J = 6.7 Hz), 2.59 (q, 4H, J = 7.0 Hz), 0.99 (t, 6H, J = 7.0 Hz).

(2) 1_ (2-chlorophenyl) -3- [2- (ethylpyramino) ethyl] -7-fluoro-2,2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid hydrochloride

Example 6-In the same manner as in (3), methyl 1_ (2_chlorophenol) -3- [2- ( Mino) ethyl] -7-Fluoro-2-oxo-2,3-dihydro-1H-benzimidazole-5-butane.

_{¾ MR (DMS0- d 6, 400} MHz) δ 13.2 (br, 1H), 10.93 (brs, 1H), 7.90 (d, 1H, J = 1.2 Hz), 7.84 (dd, 1H, J = 2.0, 7.5 Hz ), 7.72 (dd, 1H, J = l.6, 7.9 Hz), 7.53- 7.61 (tn, 2H), 7.51 (dd, 1H, J = l.2, 11.6 Hz), 4.40—4.47 (m, 2H ), 3.38-3.51 (m, 2H), 3.16-3.33 (m, 4H), 1.23 (t, 3H, J = 7.2 Hz), 1.23 (t, 3H, J = 7.2 Hz)

(3) 1_ (2-chlorophenyl) -3- (2- (ethylpyramino) ethyl) -7-fluoro-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide hydrochloride

In the same manner as in Example 6- (4), 1- (2-chlorophenyl) -3- [2- (decylamino) ethyl] -7-fluoro-2-oxo-2,3-dihydro-1H Synthesized from -benzimidazole-5-carboxylic acid hydrochloride.

Marauder R (DMS0-d ₆ , 400 MHz) δ 10.49 (brs, 1H), 8.07 (brs, 1H), 7.98 (s, 1H), 7.79 (dd, 1H, J = 2.0, 7.4 Hz), 7.73 (dd , 1H, J = l.7, 7.8 Hz), 7.51-7.61 (m, 4H), 4.32-4.46 (ra, 2H), 3.44-3.55 (m, 2H), 3.21-3.37 (m, 4H), 1.24 (t, 3H, J = 7.2 Hz), 1.23 (t, 3H, J = 7.2 Hz).

Example 73

Arc mouth- 1_ (2,4-dichlorophenyl)-3-[2- (1-methylpyrrolidine-2-yl) ethyl]-2-oxo-2,3-dihydro-1H-benz Imidazole-5-carboxamide hydrochloride

(1) Methyl 7-octopen-1- (2,4-dichlorophenyl) -3- [2- (1-methylpyrrolidine-2-ynole) ethyl] -2-oxo-2,3-dihydro -1H-benzimidazole-5-carboxylate Example 1 In the same manner as in (1), methyl 7-coguchi-1- (2,4-dichlorophenol) -2-oxo The compound was synthesized from -2,3-dihydro-1H-benzimidazole-5-carboxylate (Reference Example 9) and 2- (2-tert-methylethylpyrrolidine hydrochloride).

¾丽_{R (CDC1 3, 400 MHz)} δ 7.78 (d, 1H, J = l.2 Hz), 7.68 (d, 1H, J = l.2 Hz), 7, 57 (d, 1H, J = 2.0 Hz), 7.39-7.45 (m, 2H), 4.06-4.08 (m, 2H), 3.94 (s, 3H), 3.04-3.09 (m, 1H), (2.28, 2.32) (s, 3H), 1.56-2.22 (m, 8H).

(2) 7-Chloro-1_ (2,4-dichlorophenyl) _3- [2- (1-methynolepyrrolidine-2-ynole) ethyl] -2-oxo-2,3-dihydro-1H-benzimidazole- 5-carboxylate

Example 6-In the same manner as in (3), methyl 7-coguchi-1- (2,4-dichlorophenyl) -3- [2- (tomethylpyrrolidine-2-inole) ethyl] -2 -Oxo-2,3-dihydro-1H-benzimidazonone-5-potassolevoxyle 1

¾丽_{R (DMSO- d 6, 400 MHz} ) δ 13.27 (brs, 1H), 10.73 (brs, 1H), 7.93-7.95 (ra,

2H), 7.80 (dd, 1H, J = 2.3, 8.5 Hz), 7.63-7.68 (m, 2H), 4.10-4.14 (m, 2H), 3.28-3.53 (m, 2H), 2.98-3.03 (ra, 1H), (2.76, 2.75) (s, 3H), 2.27-2.40 (m, 2H), 1.90-2.09 (m, 311), 1.71-1.74 (m, HI).

(3) 7-Couguchi-1- (2,4-dichlorophenyl) -3_ [2- (1-methylpyrrolidine-2-yl) ethynole] -2-oxo-2,3-dihi Dro-1H-benzimidazole-5-pothalopoxamide hydrochloride In the same manner as in Example 6- (4), 7-octopen-1--1- (2,4-dichlorofuran) -3_ [2- ( 1-Methinolepyrrolidine_2-inole) ethynole] -2-oxo-2,3-dihydro-1H-benzimidazole-5_carboxylate hydrochloride.

¾ 丽 R (DMS0-d ₆ , 400 MHz) δ 10.29 (brs, 1H), 8.10 (brs, 1H), 7.94-7.98 (m, 2H), 7.78 (dd, 1H, J = 2.6, 8.5 Hz), 7.64-7.67 (ra, 2H), 7.53 (brs, 1H), 4.08 -4.11 (m, 2H), 3.30-3.56 (m, 2H), 3.00-3.06 (m, 1H), (2.78, 2.80) (s , 3H), 2.28—2.43 (m, 2H), 1.88—2.07 (ra, 3H), 1.69—1.74 (m, 1H).

7—Black mouth— 1— (2,4-Dichloro mouth phenyl) -3 — “(1-Methylse.peridine—3-yl) methinole] -2-Oxo-2,3-dihydro-1H-benzimidazol- 5-carboxamide hydrochloride

(1) Methyl 7-chloro-1-(2, 4-dichloropheninole) -3--[(1-methylpiperidin-3-inole) methinole]-2-oxo-2, 3-dihydro-1H- Benzimidazole-5-carboxylate Example 1 In the same manner as in Example 1- (1), methyl 7-coculo-11- (2,4-dichlorophenyl))-2-year-old oxo-2,3 The compound was synthesized from -dihydro-1H-benzimidazole-5-carboxylate (Reference Example 9) and 3-chloromethyl-1-methylpiperidine hydrochloride.

Keio _{R (CDC1 3, 400 MHz)} δ 7.78 (d, 1H, J = l.3 Hz), 7.67 (d, 1H, J = l.3 Hz), 7 .56 (d, 1H, J = l. 6 Hz), 7.39—7.45 (m, 2H), 3.94 (s, 3H), 3.82-3.89 (m, 2H), 2.69-2.80 (m, 2H), (2.23, 2.26) (s, 3H), 1.54-2.02 (m, 6H), 1.10-1.16 (m, 1H).

(2) 7-Kouter funnel (2,4-dic-opener phenyl) -3-[(1-Methylpiperidin-3-yl) methinole] -2-oxo-2,3-dihydro- 1H-Benzimidazole-5-potassium hydrochloride

Example 6-Methyl 7-chloro-1- (2,4-dichlorophenyl) -3-[(1-methylpiperidin-3-yl) methyl] -2-oxo in the same manner as in (3) The compound was synthesized from -2,3-dihydro-1H-benzimidazole-5-carboxyle-11.

丽 R (DMS0-d ₆ , 400 MHz) δ 13.28 (brs, 1H), (10.56, 10.39) (brs, 1H), 7.86 to 7.96 (m, 2H), 7.81 (d, 1H, J = 8.5 Hz) , 7.65-7.68 (m, 2H), 3.88-4.02 (m, 2H), 3.30-3.65 (m, 2H), 2.71-2.86 (m, 2H), (2.68, 2.68) (s, 3H), 2.44- 2.45 (m, 1H), 1.71-1.84 (m, 3H), 1.21–1.26 (m, 1H).

(3) 7—Kokuguchi—11- (2,4-Dikuguchi fuunil) -3-[(1-Methylpiperidine—3-yl) methinole] -2-oxo-2,3-dihydro- 1H-benzimidazole-5-carboxamide hydrochloride

In the same manner as in Example 6_ (4), 7-coguchi-1_ (2,4-dichlorophenyl) -3-([1-methylpiperidin-3-yl) methinole] -2-oxo -Synthesized from 2,3-dihydro-1H-benzimidazonole-5-carboxylate hydrochloride.

¾ NMR (DMS0-d ₆ , 400 丽 ζ) δ (9.95, 9.79) (brs, 1H), 8.10 (brs, 1H), 7.92-7.98 (ra, 2H), (7.84, 7.79) (d, 1H, J = 8.5 Hz), 7.65-7.69 (m, 2H), 7.53 (brs, 1H), 3.86-3.97 (m, 2H), 3.30-3.46 (ra, 2H), 2.74-2.85 (m, 2H) , (2.72, 2.71) (s, 3H), 2.43 (m, 1H), 1.67—1.84 (m, 3H), 1.20-1.28 (m, 1H).

7-c-mouth- 1- (2,4-dic-mouth) -3 _ [(1-Ethylpiperidin-2-yl) methyl] _2_ oxo-2,3-dihydro-1H-benzi Midazole-5-carboxamide hydrochloride

(1) Methyl 7-chloro-1- (2-, 2-dichlorophenyl) -3-[(1-ethylpyperidin-2-yl) methinole] -2-oxo-2,3-dihydro-1H-beta Nsimidazonole-5-ca / boxylate, methyl 7-coguchi-1: (2,4_cyclohexene) —3- (1-ethylethylazepan-3-inole) -2- Oxo-2,3-dihydro-1H-benzimidazole-5-hexyloxylate

In the same manner as in Example 1- (1), methyl 7-coguchi-1- (2,4-dichlorophenyl) -2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate (reference Example 9) and 2- The reaction was carried out from (chloromethyl) -1-ethylbutylperidine hydrochloride (Reference Example 15) to give methyl 7-chloro-1- (2-, 2-dichlorophenol) -3--3-[(1-ethylbiperidine-2-yl). Le) Methyl] -2-oxo-2,3-dihydro-1H-benzimidazonole-5-propoxylate and methyl 7-octopen-1-((2,4-dioctanol)-) 3- (1-Ethylazepan-3-inole) -2-oxo_2,3-dihydrido 1H-benzimidazole-5-carboxylate was obtained.

Methynole 7-octopene-1- (2,4-dichloropheninole) -3-[(1-ethylpiperidin-2-yl) methyl] -2-oxo-2,3-dihydro-1H- benz I Mi imidazole - 5 - power _{Norebokishireto: ¾ NMR (CDC1 3, 400} MHz) 6 7,78 (d, 1H, J = l.2 Hz), 7.70 (d, 1H, J = l.2 Hz), 7.56 (d, 1H, J = 2.1 Hz), 7.39-7.46 (m, 2H), 4.24-4.33 (m, 1H), 3.86—3.99 (m, 1H), 3.94 (s, 3H), 2.94-3.01 ( ra, 1H), 2.85-2.92 (m, 2H), 2.72 to 2.82 (m, 1H),

2.38 to 2.46 (m, 1H), 1.55 to 1.71 (ra, 4H), 1.27 to 1.44 (m, 2H), L 10 to 1.16 (m,

3H); Rf = 0.30 (black-mouthed form / methanol = 20/1).

Methinole 7-cyclohexyl (2,4-dicyclohexyl) -3- (1-ethylethylazepan-3-inole) -2-oxo-2,3-dihydro-1H-benzimidazole-5- carboxylate:删_{R (CDC1 3, 40 0 MHz} ) δ 8.22 (br, 1H), 7.76 (d, 1H, J = l.3 Hz), 7.55 (d, 1H, J = 2.1 Hz), 7.

43 (d, 1H, J = 8.4 Hz), 7.39 (d, 1H, J = 2.1, 8.4 Hz), 4.64-4.68 (m, 1H), 3.94 (s, 3H), 3.15-3.20 (m, 1H) , 2.88-2.99 (m, 2H), 2.52-2.65 (m, 3H), 2.31-2.

35 (m, 1H), 1.97-2.00 (m, 1H), 1.87-1.91 (m, 2H), 1.58-1.75 (m, 2H), 1.04-

1.09 (m, 3H); Rf = 0.34 (cloth form / methanol = 20/1).

(2) 7-chloro-1-(2,4-dichloromethyl) -3-[(1-ethylbiperidin-2-yl) methyl]

-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate

Example 6-Methyl 7-chloro-1- (2,4-dichlorophenyl) -3- [

(1-Ethylpiperidine-2-inole) methyl] -2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate.

¾ NMR (DMSO- d ₆ , 400 MHz) δ 13.29 (brs, 1H), 10.98 (br, 1H), 7.87-7.99 (ra,

3H), 7.66—7.68 (m, 2H), 4.32-4.57 (m, 2H), 3.29—3.81 (m, 5H), 1.45—2.08 (m

, 6H), 1.27 (t, 3H, J = 6.8 Hz).

(3) 7-co mouth-1-(2,4-dic mouth phenyl) -3--[(1-ethylpyridin-2-yl) methyl] -2-oxo-2,3-dihydro-1H -Benzimidazole-5-carboxamide hydrochloride

Example 6 In the same manner as in-(4), 7-chloro-1- (2,4-dichlorophenyl) -3 _ [(1-ethyl Rubiperidin-2-ynole) methyl] -2-oxo-2,3-dihydro-1H-benzimidazole_5-carboxylic acid salt.

_{¾ MR (DMSO- d 6, 400} MHz) δ 9.81-10.11 (m, 1H), 7.72-8.17 (m, 4H), 7.56-7.7 1 (m, 3H), 4.21-4.55 (ra, 2H), 3.70 Example 76 —3.88 (m, 1H), 3.11—3.57 (m, 4H), 1.42—1.99 (ra, 6H), 1.24-1.31 (m, 3H).

7-Cu mouth mouth (2,4-dichlorophenyl) -3- (1-Ethylazepan-3-inole) -2 -oxo-2,3

-Dihydro-1H-benzimidazole-5-carboxamide hydrochloride

(1) 7-Cout mouth—11- (2,4-Jiku mouth) 2 3- (1-ethyl-azepan-3-yl) -2-oxo-

2,3-dihydro-1H-benzimidazole-5_carboxylate

In the same manner as in Example 6- (3), methyl 7-chloro-1- (2,4-dichlorophenyl) -3- (

1-Ethylazepan-3-yl) -2-oxo-2,3-dihydro-1H-benzimidazo-mono-5-carboxylate.

Kirei R (DMS0_d ₆ , 400 MHz) δ 13.28 (brs, 1H), 10.47-11.89 (br, 1H), 7.74-8.1

7 (m, 3H), 7.64-7.67 (m, 2H), 4.98—5.17 (m, 1H), 3.34—4.41 (m, 6H), 1.65—2.34 (m, 6H), 1.25 (m, 3H ).

(2) 7-Cupro-1- (2-, 4-dichlorophenol) -3- (1-Ethylazepan-3-yl) -2-oxo-2,3-dihydro-1H-benzimidazole- 5-potassium lipoxamide hydrochloride

In the same manner as in Example 6- (4), 7-coguchi-1- (2,4-dichlorophenyl) -3- (1-ethynoleazepan-3-yl) -2-oxo-2 Synthesized from 1,3-dihydro-1H-benzimidazole-5-carboxylic acid hydrochloride.

¾丽_{R (DMSO- d 6, 400 MHz} ) δ 9.97-10.36 (m, 1H), 7.91-8.27 (ra, 3H), 7.57-7.7

8 (m, 4H), 4.97-4.99 (m, 1H), 3.23-4.10 (m, 6H), 1.63-2.41 (m, 6H), 1.24-1.28 (m, 3H).

7-coguchi-1- (2,4-dichlorophenol) -3-((1-methylbiperidine-2-isle) methyl] -2-oxo-2,3-dihydro-1H-benzimidazole-5 -Carboxamide hydrochloride

(1) Methyl 7-chloro-1 _ (2,4-dichlorophenyl) -3-[(1-methylpiperidine-2-inole) Methyl] -2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate, SS J-1120

In the same manner as in Example 1- (1), methyl 7-chloro-1- (2,4-dichlorophenyl) -2-cyclohexyl-2,3-dihydro-1H-benzimidazole-5 -Carboxylate 1, (Reference Example 9) and 2- (chloromethyl) -1-methylbiperidine hydrochloride (Reference Example 16) were reacted to give methyl 7-octanol-1- (2,4-dichlorophenol). Enyl) -3-[(1-Methylpiperidin-2-yl) methyl] -2-oxo-2,3-dihydro -1H-benzimidazole-5-carboxylate and methyl (2,4-Dichlorophenyl) -3_ (1-methylazepan-3-inole) -2-oxo-2,3-dihydrido-1H-benzimidazole-5-carboxylate was obtained.

Methinole 7-cook mouth-1- (2,4-dichroic phenyl) -3-([1-methylbiperidine-2-inole) methinole] -2-oxo-2,3-dihydro-1H-benz Imidazoru - 5-carboxylate: ¾ employment _{R (CDC1 3, 400 MHz)} δ 7.78 (d, 1H, J = l.2 Hz), 7.69 (d, 1H, J = l.2 Hz), 7.56 ( d, 1H, J = 2.1 Hz), 7.45 (d, 1H, J = 8.5 Hz), 7.40 (d, 1H, 1 = 2.1, 8.5 Hz), 4.26 -4.32 (m, 2H), 3.94 (s, 3H ), 3.84-3.94 (in, 1H), 2.88-2.91 (m, 1H), 2.48-2.57 (m, 1H), (2.47, 2.48) (s, 3H), 2.17-2.24 (m, 1H) , 1.54-1.74 (m, 4H), 1.32-1.42 (m, 1H), 1.18-1.28 (m, 1H); Rf = 0.26 (cloth form / methanol = 20/1).

Methyl 7-cloth funnel (2,4-dichloropheninole) —3- (1-methinoleazepane-3-inole) -1-oxo-2,3-dihydro-1H-benzimidazolone / le- 5 - carboxylate:丽_{R (CDC1 3, 40 0 MHz} ) β 8.23 (br, 1H), 7.76 (d, 1H, J = l.4 Hz), 7.56 (d, 1H, J = 2.1 Hz), 7 .

43 (d, 1H, J = 8.4 Hz), 7.39 (d, 1H, J = 2.1, 8.4 Hz), 4.64-4.69 (m, 1H), 3.94 (s, 3H), 3.13-3.18 (m, 1H) , 2.86-2.92 (m, 1H), 2.74-2.79 (ra, 1H), 2.58-2.

64 (ra, 1H), 2.43 (s, 3H), 2.29-2.34 (m, 1H), 1.99-2.03 (m, 1H), 1.57-1.90

(m, 4H); Rf = 0.30 (chlorophonolem / methanole = 20/1).

(2) 7-Chloro-1- (2,4-dichloromouth phenyl) -3 _ [(1-methylbiperidin-2-yl) methyl]

-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid hydrochloride

In the same manner as in Example 6- (3), methyl 7-chloro-1_ (2,4-dichloromouth phenyl) _3_ [

(1-Methinoleviperidin-2-yl) methyl] -2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate.

¾丽_{R (DMS0 - d 6, 400} MHz) δ 13.29 (brs, 1H), 10.88 - 11.12 (br, 1H), 7.84-7.9 9 (m, 3H), 7.66-7.68 (m, 2H), 4.23-4.61 (m, 2H), 2.85-3.78 (m, 6H), 1.35-1.91 (m, 6H).

(3) 7-Chloro-1_ (2,4-dic-open-mouth feninole) -3-[-Methylpiperidine-2-inole) methyl] -2-oxo-2,3-dihydro-1H-benz Imidazole-5-potassium lipoxamide hydrochloride

In the same manner as in Example 6- (4), 7-chloro-1- (2,4-dichloropheninole) -3-[[1-methylinorepiperidine-2-inole) methinole] -2-oxo -Synthesized from 2,3-dihydro-1H-benzimidazole-5-carboxylate hydrochloride.

l \ {NMR (DMS0_d ₆ , 400 MHz) δ 10.21-10.76 (m, 1Η), 7.80-8.21 (m, 4H), 7.56-7.72 (m, 3H), 4.16-4.56 (m, 2H), 2.89—3.71 (m, 6H), 1.38—1.96 (m, 6H).

7-cout mouth-1_ (2,4-dichlorophenyl) -3- (1-methylazepan-3-yl) -2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxami Do hydrochloride

(1) 7-Cupro-1- (2,4-dichlorophenyl) -3- (1-methylazepan-3-yl) -1-2-oxo-2,3-dihydro-1H-benzimidazole-5 -Carpon hydrochloride

Example 6 In the same manner as in _ (3), methyl 7_chloro-1- (2-, 2-dichlorophenyl) -3- (1-methylazepan-3-ynole) -2-oxo-2,3 It was synthesized from 1-dihydro-1H-benzimidazole-5-carboxylate.

_{¾ NMR (DMSO- d 6, 400} MHz) δ 13.29 (brs, 1H), 10.26 - 11.03 (br, 1H), 7.74-8.1 4 (m, 3H), 7.64-7.68 (m, 2H), 5.04 (ra , 1H), 3.21-4.10 (m, 4H), 2.85-2.93 (ra, 3H), 1.65-2.30 (m, 6H).

(2) 7-Kuguchi— 1— (2,4-dichloropheninole) -3- (1-Methylazepane-3-inole) —2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide Hydrochloride

Example 6 In the same manner as in (4), 7-coguchi-1- (2,4-dichlorophenyl) -3- (1-methylazepan-3-yl) -2-oxo-2 Synthesized from 1,3-dihydro-1H-benzimidazole-5-carboxylic acid hydrochloride.

丽 R (DMS0-d ₆₎ 400 MHz) δ 10.04-10.69 (m, 1H), 7.81-8.22 (m, 3H), 7.56-7.78 (ra, 4H), 4.96 (m, 1H), 3.23- 4.14 (m, 4H), 2.86-3.00 (m, 3H), 1.63-2.43 (m, 6H). Example 79

7-c mouth mouth-1- (2,4-dichloro mouth phenyl) -3--[(1-ethylpyrrolidine-2-yl) methinole]-2-oxo-2,3-dihydro-1H-benzimidazole -5-Carboxamide hydrochloride

(1) Methyl 7-chloro-1-(2,4-dichlorophenyl) -3-[[1-ethylpyrrolidine-2-inole) methinole] -2-oxo-2,3-dihydro-1H-benz Imidazonole-5-forceboxylate In the same manner as in Example 1- (1), methyl 7_chloro-1- (2,4-dichloromouth fuel) -2-oxo-2,3-dihydro- It was synthesized from 1H-benzimidazole-5-canoleboxylate (Reference Example 9) and 2- (culomethyl) -1-ethylpyrrolidine hydrochloride (Reference Example 17).

¾ employment _{R (CDC1 3, 400 MHz)} δ 7.76-7.82 (m, 2H), 7.56 (d, 1H, J = 2.1 Hz), 7.44 (d, 1H, J = 8.4 Hz), 7.40 (dd, 1H, J = 2.1, 8.4 Hz), 3.87-4.09 (m, 2H), 3.94 (s, 3H), 3.10-3.20 (m, 1H), 2.86-2.99 (m, 2H), 2.38-2.47 (m, 1H) , 2.17-2.26 (ra, 1H), 1.68-1.87 (m, 4H), (1.11, 1.15) (t, 3H, J = 7.2 Hz).

(2) 7-chloro-1-(2,4-dichlorophenol) -3- [(1-ethylpyrrolidine-2-yl) methyl] -2-oxo-2,3-dihydro -1H-Benzimidazonole-5-Potassium sulfonate

Example 6 In the same manner as in-(3), methyl 7-chloro-1- (2,4-dichlorophenyl) -3-[(1-ethynolepyrrolidine-2-inole) methinole] _2- Synthesized from oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate.

_{¾ NMR (DMS0 - d 6,} 400 MHz) δ 13.30 (brs, 1H), 10.80~11.01 (br, 1H), 7.80-7 .98 (m, 3H), 7.66-7.69 (m, 2H), 4.48- 4.61 (m, 2H), 3.50-3.87 (m, 3H), 3.11 (m, 2H), 1.81-2.22 (m, 4H), 1.25-1.31 (m, 3H).

(3) 7-Kuguchi-1- (2,4-Diguguchi feninole) -3- [(1-Ethylpyrulidin-2-yl) methyl] -2 -oxo-2,3- Dihydro-1H-benzimidazole-5-carboxamide hydrochloride

Example 6-In the same manner as in (4), 7-coguchi-1- (2,4-dichlorophenyl) -3-[(1-ethynolepyrrolidine-2-yl) methyl]- It was synthesized from 2-oxo-2,3-dihydro-1H-benzimidazonole-5-carboxylate hydrochloride.

¾ employment _{R. (DMS0 - d 6,} 400 MHz) δ 10.01-10.38 (m, 1H), 7.74-8.09 (m, 4H), 7.65-7 70 (m, 2H), 7.56 (brs, 1H), 4.34 -4.53 (m, 2H), 3.09-3.93 (m, 5H), 1.80-2.26 (m, 4H), 1.24-1.30 (m, 3H).

Example 80

[[2_ (3-azabisik mouth “3.2.2] non-3-inole) ethyl] -4 -ku-ro-3- (2-ku-guchiphenyl) -3-hydroxy-2-oxooxoindolin -6-force Lupoxamide hydrochloride

(1) Methyl 1- [2- (3-azabicyclo [3.2.2] non-3-yl) ethyl] _4-chloro-3- (2-chlorophenyl) -3-hydroxy-2-oxindrin -6-carboxylate

Example 18 In a manner similar to that of Example 4- (4), methyl 4-cyclobut-3- (2-chlorophenyl) -3-hydroxy-1- (2-hydroxyethyl) -2-oxoindrin-6-carboxy It was synthesized from the rate (Example 18_ (3)) and 3-azabicyclo [3.2.2] nonane.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.17 (d, 1H, J = 7.3 Hz), 7.65 (d, 1H, J = 1.2 H z), 7.51 (d, 1H, J = 1.2 Hz), 7.42 (ddd , 1H, J = 1.4, 7.3, 7.3 Hz), 7.31 (ddd, 1H, J = 1.6, 7.3, 7.9 Hz), 7.26 (dd, 1H, J = 1.4, 7.9 Hz), 3.96 to 4.04 (m , 1H), 3.94 (s, 3H), 3.79 to 3.93 (in, 1H), 3.60 (brs, 1H), 2.79 to 2.87 (m, 1H), 2.77 (dd, 2H, J = 4.3, 11.2 Hz ), 2.65 to 2.70 (m, 1H), 2.61 (dd, 2H, J = 4.4, 11.3 Hz), 1.89 (brs, 2H), 1.51 to 1.72 (m, 8H).

(2) 1- [2- (3-azabisic mouth [3.2.2] non-3-yl) ethyl] _4-chloro-3- (2-chlorophenyl) -3-hydroxy-2-oxoindoline-6- Carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 1- [2- (3-azabicyclo [3.2.2] non-3-yl) ethyl] -4-chloro The compound was synthesized from -3- (2-chloropheninole) -3-hydroxy-2-oxoindoline-6-carboxylate.

¾ 丽 R (DMSO d ₆ , 400 MHz) δ 9.65 (brs, 1H), 8.19 (s, 1H), 8.15 (dd, 1H, J = 1.7, 8.0 Hz), 8.08 (d, 1H, J = 1.0 Hz ), 7.73 (s, 1H), 7.51 (d, 1H, J = 1.0 Hz), 7.48 (ddd, 1H, J = 1.4, 7.3, 7.9 Hz), 7.39 (ddd, 1H, J = 1.7, 7.3) , 7.9 Hz), 7.34 (s, 1H), 7.33 (dd, 1H, J = 1.4, 7.9 Hz), 4.17 to 4.38 (m, 211), 3.77 to 3.87 (m, 1H), 3.67 to 3.77 (m, 1H), 3.32 to 3.42 (ra, 2H), 3.2

0 to 3.30 (ra, 2H), 1.98 to 2.17 (m, 4H), 1.60 —1.80 (m, 6H).

1- [2- (7-azabisic mouth [2.2.1] hept-7-inole) ethyl] _4-chloro-3- (2-chlorophenyl) -3-hydroxy-2-oxoindoline-6-carboxamide Hydrochloride

(1) Methyl 1- [2- (7-azabicyclo [2.2.1] hept-7-yl) ethyl] -4-chloro-3- (2-octaphenyl) _3-hydroxy-2-oxindrin- 6-carboxyle 1,

In a similar manner to that of Example 18_ (4), methyl 4-cyclo-3_ (2-chlorophenyl) -3-hydroxy-1- (2-hydroxyethyl) _2-oxoindrin-6-carboxylate (Example 18- (3)) and 7-azabicyclo [2.2.1] heptane.

¾丽_{R (CDC1 3, 400 MHz)} δ 8.24 (dd, 1H, J = 1.5, 8.0 Hz), 7.65 (d, 1H, J = 1.2 Hz), 7.48 (d, 1H, J = 1.2 Hz), 7.41 (ddd, 1H, J = 1.3, 7.3, 8.0 Hz), 7.29 (ddd, 1H, J = 1.5, 7.3, 7.9 Hz), 7.23 (dd, 1H, J = 1.3, 7.9 Hz), 5.66 (brs, 1H ), 4.19 (ddd, 1H, J = 5.1, 9.9, 14.6 Hz), 3.93 (s, 3H), 3.68 (ddd

, 1H, J = 4.7, 5.1, 14.6 Hz), 3.45 (brs, 2H), 2.90 (ddd, 1H, J = 5.1, 9.9, 12.9 Hz), 2.66 (ddd, 1H, J = 4.7, 5.1, 12.9 Hz) ), 1.63 to 1.82 (ra, 4H), 1.

25-1.37 (m, 4H).

(2) 1- [2- (7-azabicyclo [2.2.1] hept-7-inole) ethyl] -4-chloro-3-3- (2-chlorophenyl) -3-hydroxy-2-oxoindoline-6- Lipoxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 1- [2- (7-azabisik mouth [2.2.1] hept-7-yl) ethyl] -4-chloro Mouth-3- (2-chloropheninole) -3-synthesized from hydroxy-2-indoline-6-carboxylate.

Keio _{R (DMSO- d 6, 400 MHz} ) δ 10.25 (brs, 1H), 8.19 (s, 1H), 8.15 (dd, 1H, J = 1.6, 8.1 Hz), 7.79 (d, 1H, J = 0.9 Hz ), 7.69 (s, 1H), 7.51 (d, 1H, J = 0.9 Hz), 7.49 (ddd, 1H, J = 1.3, 7.4, 8.1 Hz), 7.39 (ddd, 1H, J = 1.6, 7.4, 7.9 Hz), 7.34 (s, 1H), 7.32 (dd, 1H, J = 1.3, 7.9 Hz), 4.39 (brs, 1H), 4.25 to 4.35 (m, 1H), 4.25 (brs, 1H), 4.06 To 4.17 (ra, 1H), 3.39 to 3.49 (m, 1H), 3.18 to 3.28 (m, 1H), 1.93 to 2.15 (m, 4H), 1.65 to 1.82 (m, 4H).

Example 82

4-Ku-1-[2-(Getylamino) ethyl]-3-(2-Ethylphenyl) _ 3-Hydroxy-2-oxoindoline-6-Carboxamide hydrochloride

(1) Methyl 4-chloro- 1- [2- (Jethylamino) ethyl] -3- (2-ethylphenyl) -3-hydroxy-2-oxindoline-6-forcenorboxylate

The synthesis was carried out in the same manner as in Example 6- (2), using a Grignard reagent prepared at the time of use from 1-bromo-2-ethynolebenzene and magnesium in place of 2-chloromouth feninole magnesium bromide.

¾ Li _{R (CDC1 3, 400 MHz)} δ 7.90 (br, 1 H), 7.67 (d, 1 H, J = 1 Hz), 7.56 (d, 1 H, J = 1 Hz), 7.30 (m, 2 H), 7.15 (m, 2 H), 3.98 (br, 1 H), 3.97 (s, 3 H), 3.82 (m, 2 H), 2.74 (m, 2 H), 2.60 (m, 4 H) , 2.27 (br, 1 H), 2.07 (br, 1 H), 1.00 (t, 6 H, J = 7 Hz), 0.88 (t, 3 H, J = 7 Hz).

(2) 4_cloguchi_1- [2- (Jetylamino) ethyl] -3- (2-ethylthiophene) -3-hydroxy-2-oxoindrin-6-carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4-chloro-1--1- [2- (decylamino) ethyl] -3- (2-ethylphenyl) -3-h Synthesized from droxy-2-oxoindoline-6-carboxylate.

_{¾ NMR (CDC1 3, 400 MHz} ) ( free form) δ 7.96 (br, 1 H ), 7.47 (d, 1 H, J = 1 Hz), 7.32 (m, 3 H), 7.18 (m, 1 H) , 6.25 (br, 1 H), 5.75 (br, 1 H), 4.30 (br, 1H), 3.97 (m, 1 H), 3.83 (m, 1 H), 2.81 (m, 1 H), 2.72 (m, 1 H), 2.60 (m, 4 H), 2.25 (br, 1 H) ), 2.05 (br, 1 H), 1.00 (t, 6 H, J = 7 Hz), 0.90 (t, 3 H, J = 7 Hz).

4_Black mouth-1_ [2- (Jethylamino) ethyl] -3-hydroxy-3- [2- (2-methoxethyl) phenyl] -2-oxoindrin-6-carboxamide hydrochloride

(1) Methyl 4-chloro-1- [2- (ethylpyramino) ethyl] -3-hydroxy-3- [2- (2-methoxetinole) phenyl] -2-oxoindoline-6-carboxylate

Example 6-(2) using a Grignard reagent prepared at the time of use from tribromo-2- (2-methoxethyl) benzene (Reference Example 34) and magnesium in place of 2-chloro phenylmagnesium bromide. ).

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.73 (d, 1 H, J = 1 Hz), 7.50 (d, 1 H, J = 1 Hz), 7.26 (brm, 1 H), 7.00 (br, 2 H ), 6.60 (br, 1 H), 3.95 (s, 3 H), 3.83 (m, 2 H), 3.68 (m, 2 H), 3.34 (s, 3 H), 2.67 (t, 2 H, J = 7 Hz), 2.53 (q, J = 7 Hz, 4 H), 0.95 (t, 6 H, J = 7 Hz).

(2) 4-Cloro-1-[2- (Jethylamino) ethyl] -3-Hydroxy-3- [2- (2-methoxethyl) phenyl] -2-oxoindrin-6-carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4-cloguchi-1- [2- (getylamino) ethyl]-3-hydroxy-3--3- [2- ( Synthesized from 2-methoxyethynole) pheninole] -2-oxoindolin-6-carboxylate.

_{¾ NMR (CDC1 3, 400 MHz} ) ( free form) 8 7.40 (d, 2 H , J = 5 Hz), 7.27 (d, 1 H, J = 7.5 Hz), 7.02 (br, 2 H), 6.63 ( br, 1 H), 6.21 (br, 1 H), 5.77 (br, 1 H) '4.15 (br, 1 H), 3.83 (m, 2 H), 3.65 (br, 2 H), 3.33 (s, 3H), 2.67 (t, 2 H, J = 7 Hz), 2.53 (q, J = 7 Hz, 4 H), 0.95 (t, 6 H, J = 7 Hz).

4-Kuguchi-1-"2_ (Jetylamino) ethyl 1-3 -hydroxy-2-oxo-3-" 2- (pyridine-3-ylmethoxy) phenyl] indoline-6-carpoxamide dihydrochloride

(1) Methyl 4-chloro-1- [2- (acetylamino) ethyl] -3-hydroxy-3- (2-hydroxy Shihueninore)-2-oxoindrin-6-force noreboxylate

Under a nitrogen atmosphere, a tetrahydrofuran solution (0.89 mol / L, 1.5 mL, 1.32 mmol) of ethylethyl bromide was added to a solution of phenol (145 mg, 1.54 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off and dichloromethane (15 raL) and methyl 4-chloro-1- (2- (ethylamino) ethyl) -2,3-dioxoindoline-6-carboxylate (Example 6- (1) ) (150 mg, 0.44 mmol) and stirred at room temperature for 8 hours. Water was added, and the mixture was extracted with black form and dried over magnesium sulfate. After filtration, the solvent was distilled off and the residue was purified by silica gel gel column chromatography (chloroform / methanol = 10/1) to obtain the title compound (139 mg, 73%).

¾ Li _{R (CDC1 3, 400 MHz)} 6 7.73 (d, 1 H, / = 1 Hz), 7.43 (d, 1 H, = 1 Hz), 7.21 (ddd, 1 H, zone = 8, 8, 1 Hz), 7.10 (br, 1 H), 6.85 (brd, 1 H, / = 8 Hz), 6.84 (dd, 1 H, / = 8, 8 Hz), 3.90 (s, 3 H), 3.83 ( m, 2 H), 2.72 (m, 2 H), 2.57 (m, 4 H), 0.93 (t, 6 H, J = 7 Hz).

(2) Methyl 4-chloro-1- [2- (ethylpyramino) ethyl] -3-hydroxy-2-oxo-3- [2_ (pyridine-3-ylmethoxy) phenyl] indoline-6-carboxylate

In the same manner as in Reference Example 30, methyl 4-kuguchi- 1- [2- (getylamino) ethyl] -3-hydroxy-3- (2-hydroxypheninole) -2-oxoindoline-6-forcenorboxylate And 3- (chloromethyl) pyridine hydrochloride.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.58 (dd, 1 H, / = 4.5, 2 Hz), 8.33 (s, 1 H), 7. 99 (br, 1 H), 7.60 (d, 1 H, = 1 Hz), 7.34 (ddd, 1 H, 8, 8, 1 Hz), 7.16 (ra, 3 H), 7.04 (s, 1 H), 6.86 (d, 1 H, zo = 8 Hz) , 4.80 (d, 1 H, / = 11 Hz), 4.72 (d, 1 H, J = 11 Hz), 3.96 (s, 3 H), 3.74 (ra, 1 H), 3.85 (m, 1 H) , 2.50 (m, 6 H), 0.94 (t, 6 H, / = 7 Hz).

(3) 4-Chloro-1- [2- (ethylpyramino) ethyl] -3-hydroxy-2-oxo-3- [2- (pyridin-3-ylmethoxy) fur] indoline-6-carboxami De dihydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4-chloro-1_ [2- (decylamino) ethyl] -3-hydroxy-2-oxo-3- [2 -(Pyridine-3-ylmethoxy) phenyl] Indoline-6-carboxylate.

¾ Keio _{R (CDC1 3, 400 MHz)} ( free form) δ 8.55 (dd, 1 H , J = 5, 2 Hz), 8.08 (d, 1 H, J = 7.5 Hz), 7.78 (br, 1 H) , 7.77 (m, 1 H), 7.35 (m, 4 H), 7.04 (dd, 1 H, / = 7.5, 7.5 Hz), 6.85 (d, 1 H, J = 8 Hz), 6.75 (s, 1 H), 5.78 (br, 1 H), 4.71 (s, 2 H), 3.67 (m , 1 H), 2.45 (m, 7 H), 0.94 (t, 6 H, 7 Hz).

4-Kuguchiguchi _1-[2- (Jetinoleamino) ethyl]-3-Hydroxy- -methyl-2_oxo-2,3-dihydro-11'H-3,7, -Vindole-6-carboxamide hydrochloride salt

(1) Methyl 4-chloro- 1- [2- (Jethylamino) ethyl] -3-hydroxy- -methyl-2-oxo-2,3-dihydro-1Η, H-3,7, -bindole-6- Carboxylate

Example 4-In the same manner as in (1), methyl 4-chloro_1_ [2- (ethylpyramino) ethyl] -2,3-dioxoindrin-6-carboxylate (Example 6- (1 )) And 7-promo-1-methyl-1H-indole (Reference Example 35).

¾丽_{R (CDC1 3, 400 MHz)} δ 7.81 (d, 1 H, J = 1 Hz), 7.62 (dd, 1 H, J = 8, 1 Hz), 7.54 (d, 1 H, J = 1 Hz ), 7.15 (d, 1 H, J = 3 Hz), 6.81 (dd, 1 H, J = 8, 8 Hz), 6.57 (d, 1 H, J = 3 Hz), 6.50 (d, 1 H, J = 8 Hz), 4.47 (s, 3 H), 3.98 (s, 3 H), 3.78 (m, 2 H), 2.70 (m, 1 H), 2.63 (m, 1 H), 2.54 (m, 4 H), 0.93 (t, 6 H, J = 7 Hz).

(2) 4-Chloro-1-[2- (Jethylamino) ethyl] -3-Hydroxy-1'-methyl-2-oxo-2,3-dihydro-1H, l'H-3,7'-bi Indole-6-carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4-chloro-1--1- [2- (decylamino) ethyl] -3-hydroxy- -methyl-2-oxo- It was synthesized from 2,3-dihydro-1H, Η-3,7'-bindonolle-6-butyrenoboxylate.

¾ 丽 R (CDC1, 400 MHz) (free) 67.62 (dd, 1 H, J = 8, 1 Hz), 7.48 (d, 1 H, J = 1 Hz), 7.42 (d, 1 H, J = 1 Hz), 7.15 (d, 1 H, J = 3 Hz), 6.81 (dd, 1 H, J = 8, 8 Hz), 6.57 (d, 1 H, J = 3 Hz), 6.49 (d, 1 H, J = 8 Hz), 6.40 (br, 1 H), 5.85 (br, 1 H), 4.71 (br, 1 H), 4.46 (s, 3 H), 3.80 (m, 1 H), 3.72 (m, 1 H), 2.75 (m, 1 H), 2.54 (m, 5 H), 0.94 (t, 6 H, J = 7 Hz) .Example 86

4-Kuguchi-1-[2- (Jetylamino) ethyl] -3_ (2-ethoxyphenyl)-3-hydroxy-2-oxoindrin-6-carpoxamide hydrochloride

(1) Methinole 4-c-mouth- 1- [2- (Jethylamino) ethyl] -3- (2-ethoxyphenyl) -3-hydroxy-2-oxoindoline-6-potoxylate

In the same manner as in Example 6- (2), except that 2-chloropheninolemagnesium bromide was replaced with 1-promo-2-ethoxybenzen (Reference Example 36) and a Darinal reagent prepared at the time of use from magnesium. And synthesized.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.91 (br, 1 H), 7.62 (d, 1 H, J = 1 Hz), 7.44 (d, 1 H, J = 1 Hz), 7.29 (ddd, 1 H , J = 8, 8, 1 Hz), 7.05 (dd, 1 H, J = 8, 8 Hz), 6.74 (d, 1 H, J = 8 Hz), 4.55 (br, 1 H), 3.94 (s , 3 H), 4.19 (m, 1 H), 3.84 (m, 1 1-1), 3.72 (m, 1 H), 3.58 (ra, 1 H), 2.84 (m, 1 H), 2.73 (m , 1 H), 2.62 (m, 4 H), 1.02 (t, 6 H, J = 7 Hz), 0.98 (t, 3 H, J = 7 Hz).

(2) 4-cloth_1- [2- (Jetylamino) ethyl] -3- (2-ethoxyphenyl) -3-hydroxy-2-oxindrin_6_carpoxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4-chloro- 1- [2- (2-ethylethyl) Amino) ethyl] -3- (2-ethoxyphenyl) -3-hydroxy-2-oxindoline-6-force synthesized from lipoxylate.

¾删_{R (CDC1 3, 400 MHz)} ( free form) δ 7.93 (br, 1 H ), 7.39 (d, 1 H, J = 1 Hz), 7.28 (ddd, 1 H, J = 8, 8, 1 Hz), 7.27 (d, 1 H, J = 1 Hz), 7.07 (dd, 1 H,

J = 8, 8 Hz), 6.74 (d, 1 H, J = 8 Hz), 6.38 (br, 1 H), 5.82 (br, 1 H), 5.20 (br, 1 H), 4.17 (m , 1 H) 3.84 (m, 1 H), 3.71 (m, 1 H), 3.60 (m, 1 H), 2.86 (m, 1 H), 2.71 (m, 1 H), 2.63 (m, 4 H ), 1.02 (t, 6 H, J = 7 Hz), 0.98

(t, 3 H, J = 7 Hz).

4-Promo-1- [2- (Jethylamino) ethyl] _3-Hydroxy-3- (2-naphthyl) -1,3-dihydro-2H-indole-1-one

(1) 4-bromo-1- [2- (Jethylamino) ethyl] -1H-indole-2,3-dione

4_Fluoro-6-odo-1H-indole-2,3-dione instead of 4-promo-1H-indole-2,3-dione and a mixture of 6-promo-indole-2,3-dione The compound was synthesized in the same manner as in Example 1- (1) using (Reference Example 1).

^{_{1 H-NMR (CDC1 3,}} 270 MHz) δ 7.44 (d, 1H, J = 7.7 Hz), 7.25 (dd, 1H, J = l.5, 7. 7 Hz), 7.17 (d, 1H, J = l.5 Hz), 3.77 (t, 2H, J = 6.6 Hz), 2.69 (t, 2H, J = 6.6 Hz), 2.55 (q, 4H, J = 7.1 Hz), 0.97 (t, 6H, J = 7.1 Hz).

(2) 4_Promo-1- [2- (Jethylamino) ethyl] -3-Hydroxy-3- (2-naphthyl) -1,3-dihydro-2H-indole-2-one

Example 1 In the same manner as in-(2), 4-promo-1- [2- (Jethylamino) ethyl] -1H-in 72 Doll -2, ³ - dione and 2 - was synthesized from naphthyl magnesium bromide Mi de.

_{LH- MR (CDC1 3, 270 MHz} ) δ 8.00 (d, 1Η, J = l.6 Hz), 7.75-7.85 (m, 3H), 7.44- 7.50 (m, 2H), 7.34 (dd, 1H, J = 2.0, 8.6 Hz), 7.19-7.30 (ra, 2H), 6.97 (dd, 1H, J = l, 0, 7.6 Hz), 3.61-3.93 (ra, 2H), 2.72 (t, 2H, J = 6.9 Hz), 2.57 (q, 4H, J = 7.1 Hz), 0.97 (t, 6H, J = 7.1 Hz).

3-amino- [2- (Jetylamino) ethyl] -3-(2-naphthyl) -2-oxo-4-(trifluo

(1) 1- [2- (Jethylamino) ethyl] _3-hydroxy-6-odo-3-(2-naphthyl) -4- (trinoleo-methinole) —1,3-dihydro-2H-indonole-2-one

In the same manner as in Example 1- (2), 1- [2- (Jethylamino) ethyl] -6-pod-4- (trifluoromethyl) -1H-indole-2,3-dione Example 2-Synthesized from (1)) and 2_naphthylmagnesium bromide.

_{^ -NMR (CDC1 3, 270 MHz} ) δ 7.87 (d, 1H, J = l.8 Hz), 7.73-7.82 (m, 3H), 7.68 (s, 1H), 7.61 (s, 1H), 7.43- 7.48 (m, 2H), 7.20 (dd, 1H, J = l.8, 8.7 Hz), 3.68-3.91 (m, 2H), 2.70 (t, 2H, J = 5.8 Hz), 2.56 (q, 4H, J = 7.0 Hz), 0.96 (t, 6H, J = 7.0 Hz).

(2) 3-amino-1-[2- (Jetylamino) ethyl] -6-odo-3- (2-naphthyl) -4_ (trif-norelomethyl)-1,3-dihydro-2H-indole-2-one

Under a nitrogen atmosphere, 1- [2- (Jethylamino) ethyl] -3-hydroxy-6-odo-3- (2-naphthyl) -4- (methyl triphnoleo) -1,3-dihydro-2H-indole- 2-on (100 rag, 0 .176 mmol) was added with Shiojiri Zhonyl (2.0 tiiL), and the mixture was stirred at room temperature for 1.5 hours. The thiol chloride was distilled off under reduced pressure to obtain a crude chloro form.

Under a nitrogen atmosphere, triethylamine (60 μΐ, 0.430 mmol) and sodium azide (27.0 mg, 0.415 mmol) were added to a solution of the crude chloro form in N, N-dimethylformamide (1.5 mL), and the mixture was heated at 70 ° C. Stirred for 2.5 hours. The reaction solution is returned to room temperature, saturated aqueous sodium bicarbonate is added, extracted with ethyl acetate / toluene: 1), washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and the filtrate is concentrated to give a crude azide form. (100 mg) was obtained.

_{1 H-NMR (CDC1 3,} 270 MHz) 6 7.73-7.83 (m, 5H), 7.66 (s, 1H), 7.45-7.52 (m, 2 H), 7.17 (dd, 1H, J = l.8, 8.7 Hz), 3.73-3.91 (m, 2H), 2.69 (t, 2H, J = 6.3 Hz), 2.54 (q, 4H, J = 7.1 Hz), 0.94 (t, 6H, J = 7.1 Hz).

Under a nitrogen atmosphere, tin (II) dihydrate (58.5 mg, 0.259 mraol) was added to a solution of the crude azide (89.0 mg, 0.150 mmol) in methanol (1.5 mL), and the mixture was stirred at room temperature for 1.5 hours. After the reaction solution was concentrated, a saturated aqueous sodium hydrogen carbonate solution was added thereto, extracted with ethyl acetate, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by gel chromatography on silica gel (form / methanol = 40/1) to give the title compound (70.2 mg, 79%, 3 steps).

^{_{X H-NMR (CDC1 3,}} 270 MHz) δ 7.77-7.85 (m, 3H), 7.72 (d, 1H, J = 8.7 Hz), 7.67 (s, 1H), 7.60 (s, 1H), 7.45-7.50 (m, 2H), 7.12 (dd, 1H, J = l.8, 8.7 Hz), 3.85-3.95 (m, 1H), 3.64-3.74 (m, 1H), 2.68 (t, 2H, J = 6.6 Hz), 2.54 (q, 4H, J = 7.1 Hz), 2.47 (brs, 2H), 0.96 (t, 6H, J = 7.1 Hz).

(3) 3-Amino-1- [2- (Jetylamino) ethyl] -3- (2-naphthyl) -2-oxo-4-(trif-norolomethyl) indoline-6-carbonitrinole

In the same manner as in Example 1- (3), 3-amino-1- [2- (ethylpyramino) ethyl] -6-odo-3- (2-naphthyl) -4--(trifluoromethyl)- It was synthesized from 1,3-dihydro-2H-indole-2-one.

'H-NMR (CDCI3, 270 MHz) δ 8.04 (d, 1H, J = 8.6 Hz), 7.58 (d, 1H, J = 0.7 Hz), 7.42 (d, 1H, J = 0.7 Hz), 7.41 (dd , 1H, J = l.8, 8.6 Hz), 7.26 (d, 1H, J = l.8 Hz), 4.06-4.17 (m, 1H), 3.68-3.78 (m, 1H), 2.53-2.86 ( m, 6H), 1.00 (t, 6H, J = 7.1 Hz).

(4) 3-Amino-1_ [2- (Jetylamino) ethyl]-3_ (2-naphthyl) -2-oxo- 4--(Trif (Rolomethyl) indoline-6-potroloxamide hydrochloride

In the same manner as in Example 1 _ (4), 3-amino-1- [2- (ethylpyramino) ethynole] -3- (2-naphthyl) -2-oxo--4- (trifluoromethyl) indoline- Synthesized from 6-carbonitrile.

_{^ - MR (DMSO- d 6,} 270 MHz) δ 10.37 (brs, 1Η), 8.35 (brs, 1H), 8.15 (s, 1H), 8.08 (d, 1H, J = 8.9 Hz), 7.85 (s, 1H), 7.80 (brs, 1H), 7.50-7.61 (m, 3H), 4.13-4.39 (m, 2H), 3.16-3.47 (m, 6H), 1.26 (t, 6H, J = 7.3 Hz). Example 89

5- [3- (2-chlorophenyl) -1- [2- (Jethylamino) ethynole] -3-Hydroxy-2-oxo41- (triphnoleolomethyl) -2,3-dihydro-1H-indole-6 -Yl] -N- (2-hydroxy

In the same manner as in Example 61, N- (2-hydroxyethyl) -4-pentynamide (Reference Example 38) was used instead of 1-prop-2-yn-1-inoleimidazolidin-2-one. And synthesized. _{^ - MR (DMSO - d 6} , 270 MHz) 5 10.30 (brs, 1H), 8.01-8.09 (m, 2H), 7.64 (s, 1 H), 7.46 (ddd, 1H, 1 = 1.5, 7.4, 7.4 Hz), 7.14-7.40 (m, 4H), 4.70 (brs, 1H), 4.13-4.31 (tn, 2H), 3.10-3.48 (m, 10H), 2.68 (t, 2H, J = 7.3 Hz), 2.40 (t, 2H, J = 7.3 Hz), 1.24 (t, 6H, J = 7.1 Hz).

4--Mouth- 1-[2- (Jetylamino) ethyl] -3_ (2_fluorophenyl) _3-hydroxy-2_oxoindoline-6-carboxamide hydrochloride

(1) Methyl 4-chloro _1- [2- (Jetylamino) ethyl] -3_ (2-fluorophenyl) -3-hydroxy-2-oxoindoline-6-carboxylate

Example 4-In the same manner as in (1), methyl 4-chloro-1_ [2- (ethylpyramino) ethyl] -2,3-dioxoindrin-6-carboxylate (Example 6- ( It was synthesized from 1)) and 2-bromofurobenzene.

¾丽_{R (CDC1 3, 400 MHz)} δ 8.00 (dd, 1 H, J = 7.8, 7.8 Hz), 7.66 (d, 1 H, J

= 1.1 Hz), 7.54 (d, 1 H, J = 1.1 Hz), 7.24 to 7.35 (m, 2 H), 6.92 (dd, 1 H, J = 7.8, 11.2 Hz), 3.94 (s, 3 H) , 3.91 to 3.98 (m, 1 H), 3.80 to 3.88 (m, 1 H), 2.54 to 2.84 (m, 6 H), 1.02 (t, 6 H, J = 7.1 Hz)

(2) 4-Chloro-1-1 [2- (Jethylamino) ethyl] -3- (2-fluoropheninole) -3-hydroxy-2-oxoindrin-6-carboxamide hydrochloride

In the same manner as in Example 6- (3) and Example 6- (4), methyl 4-chloro-1- [2- (getylamino) ethynole] -3- (2-fluorophenyl) -3- It was synthesized from hydroxy-2-oxoindoline-6-force lipoxylate.

¾ 删 R (DMS0-d ₆ , 400 MHz) δ 10.44 (brs, 1 H) '8.16 (brs, 1 H), 8.00 (ddd, 1 H, J = 1.5, 8.0, 8.0 Hz), 7.81 (s, 1H), 7.67 (brs, 1H), 7.50 (s, 1H), 7.30 to 7.40 (m, 2H), 7.23 (brs, 1H), 7.05 (dd, 1H, J = 8.0, 11.3 Hz), 4.11 to 4.31 (m, 2 H), 3.23 to 3.39 (m, 6 H), 1.25 (t, 6 H, J = 6.3 Hz)

3_ (4-chloro-2-methoxypheninole) -1- [2- (Jetinoleamino) ethyl] -3-hydroxy-2-oxo-4- (trifluoromethyl) indoline-6-carboxamide hydrochloride

(1) 3-(4-chloro_2-methoxyphenyl) -1- [2- (ethylamino) ethyl] -3-hydroxy-6-yl-4- (trifluoromethyl)-1,3- Dihydro-2H-indole-2-one

Synthesized in the same manner as in Example 4- (1), except that 4-bromo-2,6-dichlorobenzene was replaced with 4-methoxy-1-methoxy-2-methoxybenzene (Reference Example 37). .

_{¾ MR (CDC1 3, 400 MHz} ) δ 7.66~ 7.71 (br, 1 H), 7.58 (s, 1 H), 7.49 (s, 1 H), 7.04 (dd, 1 H, J = 1.6, 8.4 Hz) , 6.76 (d, 1 H, J = 1.6 Hz), 3.72 to 3.93 (m, 2 H), 3.50 (s, 3 H), 2.50 to 2.76 (m, 6 H), 1.04 (t, 6 H, J = 7.1 Hz)

(2) 3- (4-Chloro-2-methoxyphenyl) -1- [2- (ethylpyramino) ethyl] -3-hydroxy-2-oxo-4- (trimethylomethyl) indoline-6- Force report

Example 1 In the same manner as in _ (3), 3- (4-chloro-2-methoxyphenyl) -1- [2- (getinoleamino) ethynole] -3-hydroxy_6_ 一 -1--4- ( It was synthesized from methyl (trifluoromethyl) -1,3-dihydro-2H-indole-2-one.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.74 (br, 1 H), 7.55 (s, 1 H), 7.38 (s, 1 H), 7. 08 (dd, 1 H, J = 1.8, 8.4 Hz) , 6.76 (d, 1 H, J = 1.8 Hz), 3.98 to 4.05 (m, 1 H), 3.72 to 3.79 (ra, 1 H), 3.46 (s, 3 H), 2.54 to 2.82 (m, 6 H ), 1.02 (t, 6 H, J = 7.1 Hz)

(3) 3- (4-Chloro-2-methoxyphenyl) -1- [2- (ethylamino) ethyl] -3-hydroxy-2-oxo-4-((trifluoromethyl) indoline-6-caproloxamide Hydrochloride

Example 1 In the same manner as in-(4), 3- (4-co- mouth-2-methoxyphenol) -1- (2- (ethylamino) ethyl) -3-hydroxy-2-oxo- It was synthesized from 4- (trifluoromethyl) indoline-6-carbonitrile. ¾ NMR (DMSO—d ₆ , 400 MHz) 5 11.27 (brs, 1 H), 8.31 (brs, 1 H), 8.06 (s, 1 H), 7.76 to 7.82 (ra, 3 H), 7.12 (d, 1 H, J = 8.5 Hz), 7.10 (s, 1 H), 6.97 (s, 1 H), 4.14 to 4.27 (m, 2 H), 3.38 (s, 3 H), 3.34 (m, 6 H) , 1.24 to 1.25 (m, 6 H) Example 92

1 '-[2- (Jethylamino) ethyl] -2, -oxo-4,-(trifluoromethyl)-, 2, -dihydro-3H-spiro [2-benzofuran-3, -indole 1-6' -Carboxamide hydrochloride

(1) 1- [2- (Jethylamino) ethyl] -3_ {2-[(ethoxymethoxy) methyl] phenyl) -3-hydroxy-6-3-1-do-4- (trifluoromethyl) -1,3- Dihydro-2H-indole-2-one

In the same manner as in Example 1_ (2), 1- [2- (Getylamino) ethyl] -6-odo-4-(trifluoromethyl) -1H-indole-2,3-dione (Example 2- (1 )) And 1-bromo-2-[(ethoxymethoxy) methyl] benzene (Reference Example 25) and a Darinal reagent prepared at the time of use from magnesium.

¾丽_{R (CDC1 3, 400 MHz)} δ 7.65 (s, 1 H), 7.52 (s, 1 H), 7.37 (d, 1 H, J = 7.5 Hz), 7.23 (dd, 1 H, J = 7.5 , 7.5 Hz), 7.09 (dd, 1 H, J = 7.5, 7.5 Hz), 6.70 (s, 1 H), 6.51 (d, 1 H, J = 7.5 Hz), 5.38 (d, 1 H, J = 11.8 Hz), 5.0 1 (d, 1 H, J = .11.8 Hz), 4.78 to 4.79 (m, 2 H), 3.76 to 3.81 (m, 1 H), 3.5 7 to 3.68 (ra, 3 H), 2.63 (t, 2 H, J = 6.1 Hz), 2.52 (q, 4 H, J = 7.0 Hz), 1.24 (t, 3 H, J = 7.0 Hz), 0.96 (t, 6 H, J = 7.1 Hz) )

(2) 1- [2- (Jethylamino) ethyl] -3-Hydroxy-3- [2- (hydroxymethyl) phenyl ] -6-Edo-4- (trifluoromethyl) -1,3-dihydro-2H-indole-2-one Example 4 1_ [2- (Jetylamino) in the same manner as in 5_ (3). -Ethyl] -3--{2-[(ethoxymethoxy) methyl] phenyl] -3-hydroxy-6-iodo-4_ (trifluoromethyl) _1,3-dihydro-2H-indole-2-one Synthesized from

_{¾ NMR (CDC1 3, 400 MHz} ) δ 7.69 (s, 1 H), 7.53 (s, 1 H), 7.09~ 7.31 (m, 3 H), 6.47 (br, 1 H), 5.19 (br, 1 H ), 5.06 (br, 1 H), 3.64 to 3.77 (m, 2 H), 2.65 (m, 2 H), 2.54 (q, 4 H, J = 7.1 Hz), 0.96 (t, 6 H, J = 7.1 Hz)

(3) 1 '-[2-((Jetylamino) ethyl)]-6, -odo-4 to (2-V-fluoromethyl) -3H-speech [2-benzofuran-1,3'-ind-no-no-le] -2, (1 , H) -ON

Example 5 1- [2- (Getylamino) ethyl] -3-hydroxy-3- [2- (hydroxymethyl) phenyl] -6-yl-4 in the same manner as in 7- (2). -(Trifluo methinole) -1,3-Dihide mouth -2H-indole-2-one

¾ Li _{R (CDC1 3, 400 MHz)} δ 7.61 (s, 1 H), 7.54 (s, 1 H), 7.34~ 7.35 (m, 2 H), 7.17~ 7.21 (m, 1 H), 6.76 (d , 1 H, J = 7.7 Hz), 5.61 (d, 1 H, J = 11.8 Hz), 5.40 (d, 1 H, J = 11.8 Hz), 3.83 to 3.90 (m, 1 H), 3.61 to 3.69 (ra, 1 H), 2.65 to 2.72 (m, 2 H), 2.57 (q, 4 H, J = 7.1 Hz), 1.00 (t, 6 H, J = 7.1 Hz)

(4)-[2- (Jethylamino) ethyl] _2'-oxo-4 '-(trifluoromethyl) -1,1,2, -dihydro-3H-spiro [2-benzofuran-1,3, -indole] -6, -Capillone trinole Example 1-In the same manner as in (3),-[2- (Jethylamino) ethyl]-6'-Edo-4 '-(Trifluoromethyl) -3H-spiro [ It was synthesized from 2-benzofuran-1,3'-indole] -2, (Η) -one.

¾丽_{R (CDC1 3, 400 MHz)} δ 7.57 (s, 1 H), 7.45 (s, 1 H), 7.37~ 7.40 (m, 2 H), 7.19~ 7.24 (m, 1 H), 6.75 (d , 1 H, J = 7.7 Hz), 5.64 (d, 1 H, J = 11.8 Hz), 5.43 (d, 1 H, J = 11.8 Hz), 3.90 to 3.97 (ra, 1 H), 3.64 to 3.70 (m, 1 H), 2.65 to 2.77 (m, 2 H), 2.56 (q, 4 H, J = 7.1 Hz), 0.98 (t, 6 H, J = 7.1 Hz)

(5) 1, _ [2- (Jethylamino) ethyl] -2, -oxo-4,-(trifluoromethyl) -1 ', 2'-dihydro-3H-spiro [2-benzofuran-1,3' -Indole] -6 carboxamide hydrochloride 1 '-[2- (Jetylamino) tyl] -2'-oxo-4,-(in the same manner as in Example 1- (4)) Trifluoromethinole) -1 ', 2, -Dihydro-3--spiro [2-benzofuran-1,3'-indole] -6'-carbonitrile.

¾ NMR (DMS0_d ₆ , 400 MHz) δ 10.23 (brs, 1 H), 8.39 (brs, 1 H), 8.25 (s, 1 H), 7.90 (s, 1 H), 7.84 (brs, 1 H), 7.49 (d, 1 H, J = 7.4 Hz), 7.41 (dd, 1 H, J = 7.4, 7.4 Hz), 7.24 (dd, 1 H, J = 7.4, 7.4 Hz), 6.95 (d, 1 H, J = 7.4 Hz), 5.47 (d, 1 H, J = 12.3 Hz), 5.34 (d, 1 H, J = 12.3 Hz), 4.19 (t, 2 H, J = 6.2 Hz), 3.21 to 3.49 (m, 6 H), 1.23 (t, 6 H, J = 7.1 Hz) Example 93

(S)-(+)-3--(2-Chlorophenyl) -1_ [2- (Jethylamino) ethyl]-3-Hydroxy-2-

(1) (S)-(+) — 3— (2-Chloro-Feninole)-1- [2- (Jethylamino) ethynole] -3-Hydroxy-6-Edodo 4_ (Trifluoromethyl) — 1,3-Jihi draw 2H-indole-2-on

3_ (2-Chloro-Feninole)-1- [2- (Jetinoleamino) ethynole]-3-Hydroxy-6-odo-4-(Trifluoromethinole) -1,3-Dihydro-2H-indole- The 2-one (Example 60- (1)) was separated by high performance liquid chromatography to obtain the title compound. The conditions are as follows.

Column: Chiralpak 0D (Daicel Chemical Industries, Ltd.)

Eluent: 6% 2-propanol / hexane

The separated isomers were detected under the following high performance liquid chromatography conditions. Column: Chiralpak AD (particle size 5ζηι, inner diameter 4.6, total length 15cm, Daicel Chemical Industries, Ltd.) Eluate: 10% 2-propanol / hexane

Detection wavelength: 254 nm

Flow rate: 0.5 mL / min

(S) body: 12.7 minutes, [α]. +56.8 (C = 0.26, MeOH)

(R) form: 16.3 minutes, -60.0 (C = 0.33, MeOH)

(2) (S) _ (+)-3- (2-Chlorofur: nil) -1- [2- (Jethylamino) ethyl] -3-hydroxy-2-oxo-4- (trifluoromethyl) indoline -6-carbonitrile

Example 60 In the same manner as in (2), (S) _ (+)-3- (2-chlorophenyl) -tri- [2- (getylamino) ethyl] -3-hydroxy-6-oxide- Synthesized from 4- (trifluoromethyl) -1,3-dihydro-2H-indol-2-one. [a] _D +76.5 (C = 0.31, MeOH)

(3) (S)-(+)-3--(2-Chlorophenyl)-1- [2- (Jethylamino) ethyl] -3-hydroxy-2-oxo-4-(Trifluoromethyl) indoline- 6-carboxamide hydrochloride

Example 60- In the same manner as in (3), (S) _ (+)-3- (2-chloropheninole) -1- [2- (Jetylamino) ethyl] -3-hydroxy-2 -Oxo-4- (trifluoromethyl) indoline-6-force Synthesized from liponitrile. [a] _D +81.4 (C = 0.41, MeOH) Example 94

3- (2-chlorophenyl) -3-hydroxy-2_oxo-1- (2-piperidine_1-ylethyl) -4- (trifluoromethyl) indoline-6-carboxamide hydrochloride

(1) Synthesis of 6-odo-1- (2-piperidine_1-inolechinole) -4- (trimethylomethyl) -1H-indole-2,3-dione

Example 1-In a manner similar to (1), 6-Ed-4- (methyl trifluo) -1H-indole 8

The compound was synthesized from -2,3-dione (Reference Example 4) and 1- (2-cloroethyl) piperidine hydrochloride. H NMR (CDC1 _3, 400顧z) δ 7.75 (s, 1 H), 7.72 (s, 1 H), 3.83 (t, 2 H, J = 6.1 Hz), 2.57 (t, 2 H, J = 6.1 Hz), 2.45 (br, 4 H), 1.53 to 1.58 (m, 4 H), 1.43 to 1.46 (m, 2 H)

(2) 3- (2-chloropheninole) -3-hydroxy-6-iod-1- (2-piperidine-1-ylethyl) -4- (trifluoromethyl) -1,3-dihydro- Synthesis of 2H-indole-2-one

1- [2- (Jetylamino) ethyl] -4-Fluoro mouth-6-Edro-1H-Indole-2,3-Dione instead of 6-Edro-1- (2-Pyridine-Tyrletyl) The compound was synthesized in the same manner as in Example 1- (2) using -4- (trifluoromethyl) -1H-indole-2,3-dione.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.09 (d, 1 H, J = 7.2 Hz), 7.60 (s, 1 H), 7.55 (s, 1 H), 7.40 (dd, 1 H, J = 7.2, 7.2 Hz), 7.21 to 7.31 (m, 3 H), 4.09 (brs, 1 H), 4.00 to 07 (m, 1 H), 3.72-3.79 (m, 1 H), 2.70 to 2.77 (m, 1 H ), 2.51 to 2.58 (ra, 3 H), 2.39 (m, 2 H), 1.55 to 1.60 (ra, 4 H), 1.45 (m, 2 H)

(3) 3- (2-chloro-2-phenyl) -3-hydroxy-2-oxo-1- (2-piperidine-1-ylethyl) -4- (trifluoromethyl) indoline-6-carbone Synthesis of toril

Example 1 In the same manner as in _____________________________________________ ) -Synthesized from 1,3-dihydro-2H-indole-2-one.

_{¾ NMR (CDC1 3, 400 MHz} ) δ 8.11 (d, 1 H, J = 7.7 Hz), 7.56 (s, 1 H), 7.42 (s, 1 H), 7.42 (dd, 1 H, J = 7.7, 7.7 Hz), 7.31 (dd, 1 H, J = 7.7, 7.7 Hz), 7.23 (d, 1 H, J = 7.7 Hz), 4.89 (brs, 1 H), 4.13 to 4.18 (m, 1 H), 3.72 to 3.78 (m, 1 H), 2.75 to 2.82 (m, 1 H), 2.53 to 2.63 (m, 3 H), 2.38 (m, 2 H), 1.53 to 1.58 (m, 4 H), 1.44 ( m, 2 H)

(4) 3- (2-chloro-2-phenyl) -3-hydroxy-2-oxo-1- (2-piperidine-1-ylethyl) -4- (trifluoromethyl) indoline-6-carboxamide hydrochloride Salt synthesis

Example 1- (4) t In a similar manner, 3_ (2-chlorophenyl) -3-hydroxy-2-oxo-1- (2-piperidine-1-ylethyl) -4- (trifluoromethyl) indoline- Synthesized from 6-carbonitrile. '

_{¾ NMR (DMS0 - d 6,} 400 MHz) δ 10.25 (brs, 1 H), 8.35 (brs, 1 H), 8.15 (s, 1 H), 8.08 (d, 1 H, J = 7.7 Hz), 7.83 (s, 1 H), 7.80 (brs, 1 H), 7.47 (dd, 1 H, J = 7.7, 7.7 Hz), 7.40 (s , 1H), 7.37 (dd, 1H, J = 7.7, 7.7 Hz), 7.30 (d, 1H, J = 7.7 Hz), 4.31 to 4.36 (m, 1H), 4.16 to 4.23 (m, 1 H), 3.67 to 3.71 (m, 1 H), 3.33 to 3.49 (m, 3 H), 2.99 to 3.04 (m, 2 H), 1.72 to 1.81 (m, 5 H), 1.35 to 1.40 (m , 1 H) Formulation example 1

Tablets can be produced, for example, by the following method. mg I tablet

(1) Compound 10 of Example 1

(2) Ratha Tooth 72.5

(3) Corn starch 30

(4) carboxymethylcellulose calcium 5

(5) Hydroxypropyl cellulose (HPL-C) 2

(6) Magnesium stearate 0.5

120 mg in total

The components (1) to (4) are mixed, an aqueous solution of the component (5) is added, granulated, dried, mixed with the component (6), and compressed to form 120 mg tablets. Formulation Example 2

An injection can be produced, for example, by the following method.

Compound of Example 1 10 mg / vial

Saline 10 mL / vial

Filter sterilize the above components and fill vials that have been previously cleaned and sterilized. Seal with a rubber stopper that has been washed and sterilized in advance, and then use a flip-off cap to make an injection. Test example 1

Evaluation of darrelin antagonism using human GHSR stably expressing cells

Human GHSR (growth hormone secretagogue receptor) The effect of the compounds of the examples on the increase in intracellular calcium ion concentration when ghrelin, an endogenous ligand, was added to cells stably expressing was evaluated.

Human GHSR-expressed CH0-K1 cells (EUR0SCREEN) were placed in a 96-well clear bottom black plate (96_well assay plate, Black plate, Clear Bottom) (Corning) at 2 × 10 ⁴ cells / 100 μΐ ell. seeded, while one Θ in the cell culture device and incubated at _{37 ° C, 5% C0 2} . The composition of the culture solution was Ham's F12 medium containing 10% fetal bovine serum, 100 IU / ral penicilin, 100 μg / ml strepttomycin, 400 μg / ml G418, and 250 ug Zeocin. Calcium fluorescence indicator was taken in one hour before the assay and cultured. As the force fluorescence indicator, a commercially available measurement kit, Calucium Screening Kit (Fluo 3) (Dojindo) was used. After washing the cells,

It was accompanied by calories.

An equal amount of compound prepared with Hanks / Hepes (pH 7.4) to a concentration 10 times the final concentration and darelin (Ghrelin) were combined, and added to cells at 50 μΐ / well. Immediately thereafter, the excitation wavelength of 488 nM was measured 80 times at 1 second intervals using FLIPR (Molecular Devices). The ghrelin antagonism (%) of the compound at a concentration of 10 M was calculated from the maximum value of the fluorescence intensity by subtracting the minimum value from the fluorescence intensity using the following formula.

Gray V antagonist rate (%) = {1- (A-B) I (C-B)} X 100

A: Fluorescence intensity when 10 / Μ concentration of compound and 100 nM darelin were added

B: Fluorescence intensity when no compound and darelin were added

C: Fluorescence intensity when only 100 nM ghrelin was added

Table 1 shows the darellin antagonism (%) of the compounds. It has been observed that the compounds of the present invention antagonize the action of darellin and suppress the elevation of intracellular calcium ions. 8 4

Compound inhibition rate (%) Compound inhibition rate (Compound of Example 1 67 Compound of Example 56 Compound 62 of Example 2 Compound 65 of Example 57 Compound 48 of Example 4 Compound 12 of Example 58 Compound 69 of Example 58 Compound of Example 6 49 Compound of Example 60 59 Compound of Example 7 79 Compound of Example 6 Compound of Example 22 Compound of Example 8 49 Compound of Example 6 2 Compound 46 of Example 19 Compound 39 of Example 6 4 Compound 43 Compound of Example 22 Compound 57 of Example 57 Compound of Example 6 7 29 Compound of Example 23 3 Compound 58 of Example 68 Compound 71 Compound of Example 26 6 Compound of Example 6 9 37 Compound of Example 27 22 Example 70 Compound 46 Example 32 Compound 59 Example 7 Compound 33 Example 33 Compound 17 Example 73 Compound 16 Example 35 Compound 25 Example 7 Compound 14 Example 3 9 Compound 29 Example 7 8 Compound 34 Example 4 2 Compound 15 Example 8 2 Compound 75 Example 4 5 Compound 81 Example 8 7 Compound 12 Example 4 7 Compound 49 Example 8 8 Compound 21 Example 50 Compound 28 Example 8 9 Compound 28 Example 5 1 Compound 32 Example 9 1 Compound 40 Example 5 Compound 3 3 35 Example 9 Compound 4 4 83 Test Example 2

Evaluation of eating using model mice

Using db / db mice known as overeating animals, the effects of the compounds of the examples on the amount of food consumed when the compounds were intraperitoneally administered were evaluated.

One C57BL / Ks J_db / db mouse (male, 16 weeks old, CLEA Japan) was fed per cage. (CE-2, Oriental yeast) and sterilized tap water were fed freely. The weight of the feed was measured twice at the start and end of the observation, and the difference between the feed weight at the start of the observation minus the feed weight at the end of the observation was taken as the amount of food consumed per unit time.

The compound (50 mg / kg) mixed with physiological saline was intraperitoneally administered to db / db mice (administration time 16:00). The feed weight was measured four times 4 days before the start of administration, in the morning on the day of administration, immediately before administration, and 22 hours after administration, for a total of four times. Each treatment group consisted of one or two animals.

(C-D) I {(A-B) / 4} X 100 (%)

A Feed weight measured 4 days before administration

B: Feed weight measured in the morning on the day of administration

C: Feed weight measured immediately before administration

D: Feed weight measured 22 hours after administration The amount of food consumed in the saline-administered group was 98%, whereas the drug-administered group in Example 6 was 75%, and the %, Marked suppression of feeding. Industrial applicability

-The derivative represented by the formula (1), a prodrug thereof, or a pharmaceutically acceptable salt thereof is used as a food intake regulator effective for the treatment, prevention, and improvement of diabetes, obesity, etc. lj can be used.

Claims

Claim formula (1)

[Wherein, R ¹ , R ² , R ³ and R ⁴ independently of one another are a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, Optionally substituted heteroaryl, optionally substituted heteroaryl, halogen atom, cyano, nitro, carboxy, hydroxyl group, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkanol, substituted Optionally substituted alkoxycarbyl, optionally substituted sulfamoyl, optionally substituted sorbamoyl, optionally substituted ureido, optionally substituted alkylthio, optionally substituted alkylsulfinyl, optionally substituted Alkylsulfonyl, optionally substituted alkylsulfo-lamino, or optionally substituted alkanoylamino It is. However, all of R ¹ , R ² , R ³ and R ⁴ cannot be hydrogen atoms at the same time.

X represents C—R ⁶ or a nitrogen atom.

R ⁶ represents one OW ² , —NW ² R ¹³ or a fluorine atom.

When W ² is present in the formula (1), one of W ¹ and W ² represents a hydrogen atom, an alkyl or one Y ¹ -CONCR ¹ MR ¹² , and the other represents a formula (2): 87

R ⁹

C- (CH ₂ ) _m-

Or equation (3):

Represents.

When W ² is not present in the formula (1), W ¹ is a hydrogen atom, alkyl, —Y ¹ -CON (R ¹¹ ) R ^{X 2} , the formula (2), the formula (2a) or the formula (3) Represents

n represents 0, 1, 2 or 3, and m represents 0, 1, 2 or 3.

Y ¹ represents a single bond or Ci to C ₃ alkylene.

R ⁷ and R ⁸ independently of one another represent a hydrogen atom, an optionally substituted alkyl or an optionally substituted cycloalkyl or, together with the adjacent nitrogen atom, Represents a saturated heterocyclic group which may be substituted.

R ⁹ and R ¹⁰ independently of ^one another represent a hydrogen atom or an optionally substituted alkyl, or together with an adjacent carbon atom, an optionally substituted, cycloalkylene or Represents an optionally substituted saturated heterocyclic group.

R ^{8 represents a} hydrogen atom, an optionally substituted alkyl or an optionally substituted cycloalkyl, R ¹ . When R represents a hydrogen atom or an alkyl which may be substituted, R ⁷ and R ⁹ may be taken together with an adjacent nitrogen atom, carbon atom and — (CH ₂ ) _m — It may represent a good saturated heterocyclic group.

R ^{9 a} and R ¹ ° ^a, independently of one another, represent a hydrogen atom or alkyl.

R ⁷ and R ^{9 a} is together such connexion, nitrogen atom P粦接, together with the carbon atom and one (CH ₂₎ _m one, may represent a saturated heterocyclic group which may be substituted.

R ¹¹ and R ¹² independently of ^one another represent a hydrogen atom or alkyl, or Or together with an adjacent nitrogen atom represents an optionally substituted saturated heterocyclic group.

R ¹³ represents a hydrogen atom or alkyl.

k represents 0 or 1.

Y ² represents cycloalkylene, optionally substituted arylene, or optionally substituted heteroarylene.

X represents C one R ^6, R ⁶ is - representative of the OW ² or a NW ² R ^{1 3,} and W ^2, such together substituents present in the ortho position of the bond to X of R ⁵ connexion, Forming a heterocyclic ring which may be newly substituted, and formula (4):

It may be.

Y ³ represents an oxygen atom or NR ¹³ , and Y ⁴ represents CC ₃ alkylene.

].

2. R ¹ , R ² , R ³ and R ⁴ independently of each other, hydrogen atom, optionally substituted alkyl, optionally substituted alkyl, optionally substituted alkyl, substituted Optionally substituted halogen, halogen atom, cyano, nitro, carboxy, optionally substituted alkoxy, optionally substituted alkanoyl, optionally substituted alkoxycarbonyl, optionally substituted alkylsulfinyl or substituted ^2. The compound according to claim 1, or a prodrug thereof, or a pharmaceutical agent thereof, which is alkylsulfonyl (however, all of I ¹ , R ² , R ³ and R ⁴ cannot be hydrogen atoms at the same time). An eating control agent comprising an acceptable salt as an active ingredient.

3. R ¹ , R ² , R ³ and R ⁴ independently of each other a hydrogen atom, an optionally substituted alkyl, an optionally substituted rubamoyl, carboxy, halogen atom Child, anoreoxy, or 1 c≡C- (CH ₂ ) _p — Q (p represents 1 or 2, Q is a hydroxyl group, an optionally substituted amino, an optionally substituted rubamoyl, an optionally substituted Represents a saturated heterocyclic group, alkylsulfonyl, alkanoylamino, alkylsulfonylamino or alkylureido. (However, all of R ¹ R ² , R ³ and R ⁴ cannot be hydrogen atoms at the same time.) And a prodrug thereof or a pharmaceutically acceptable salt thereof as an active ingredient. ·

4. The eating control agent comprising, as an active ingredient, the compound according to claim 1, wherein R ² and R ⁴ are both hydrogen atoms, a prodrug thereof, or a pharmaceutically acceptable salt thereof.

5. R ² and R ⁴ are both hydrogen atoms, R ¹ is a trifluoromethyl, nodogen, methyl, or methoxy, and R ³ is a hydrogen atom of carbamoyl, carboxy, halogen or one C The compound according to claim 3, which is ≡C_ (CH ₂ ) _p -Q (p and Q have the same meanings as in claim 3), a prodrug thereof, or a pharmaceutically acceptable salt thereof. Feeding regulator as an active ingredient.

6. The compound according to claim 1, wherein R ² and R ⁴ are both hydrogen atoms, R ¹ is trifluoromethyl, a fluorine atom, a chlorine atom or a bromine atom, and R ³ is rubamoyl. An intake control agent comprising a prodrug or a pharmaceutically acceptable salt thereof as an active ingredient.

7. R ⁵ forces optionally substituted Fueeru, naphthyl which may be substituted, indolyl which may be substituted, a Yoibe Nzocheniru be also be base Nzofuraniru or substituted substituted, of claims 1 to 6 An eating control agent comprising, as an active ingredient, the compound according to any one of the above, a oral drug thereof, or a pharmaceutically acceptable salt thereof.

8. R ⁵ force An optionally substituted phenyl, optionally substituted 2-naphthyl or optionally substituted 7-benzofuranyl, wherein the substituent is substituted with a halogen atom, trifluoromethyl, alkoxy or a hydroxyl group. And the substituent is one or more of which may be the same or different, or the compound according to any one of claims 1 to 6 or a compound thereof. An eating control agent comprising prodrug or a pharmaceutically acceptable salt thereof as an active ingredient.

9. X is C—R ⁶ , R ^{6 is} —OW ² or one NHW ² , one of W ¹ and W ² is a hydrogen atom or alkyl, and the other is a compound of formula (2): 90

— (CH ₂ ) _n -C- (CH ₂ ) _m -N (2)

R ^{10 8}

Or equation (3):

(k, n, m, R ⁷ , R ⁸ , R ⁹ and R ¹ ° have the same meanings as in claim 1), wherein the compound according to any one of claims 1 to 8 or An eating control agent comprising the prodrug or a pharmaceutically acceptable salt thereof as an active ingredient.

10. X is C—R ⁶ , R ⁶ is —OW ² or one NHW ² , W ¹ is hydrogen atom or methyl, W ² force formula (5): R ⁷ ′

— (CH ₂ ) _n -C- (CH ₂ ) _m -N (5)

^ o 'R ⁸ '

(n and m have the same meanings as in claim 1. R ⁷ ′ and R ⁸ ′ are, independently of each other, a force which is an alkyl which may be substituted, or taken together to form an adjacent nitrogen. R ⁹ ′ and R ¹ ′ represent a hydrogen atom together with a hydrogen atom, and R ⁹ ′ and R ¹ ′ are hydrogen atoms. An eating control agent comprising a compound, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

1 1. The compound according to any one of claims 1 to 8, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, which is represented by the formula (2), wherein W ¹ force S is an active ingredient. Eating regulators.

12. is W ¹ force equation (5), the compound also properly its prodrug or food regulatory intake and their pharmaceutically acceptable salts as an active ingredient, according to any one of claims 1-8 Agent.

13. X is C—R ⁶ , R ⁶ is one OW ² or one NHW ² , W ¹ is hydrogen atom or methyl, W ² force formula (6): (6)

(n and m are as defined in claim 1. R ⁷ ″ and R ⁸ are each independently methyl or ethyl, or together with an adjacent nitrogen atom R ⁹ ′ and R ¹ ° ′ represent a hydrogen atom.) The compound according to claim 1, or a prodrug thereof, or a prodrug thereof. An eating control agent comprising a pharmaceutically acceptable salt of the above as an active ingredient.

14. is a W ¹ 1 Formula (6), the compound also properly its prodrug or food regulatory intake and their pharmaceutically acceptable salts as an active ingredient, according to any one of claims 1-8 Agent.

15. W ¹ force formula (7):

(k represents 0 or 1. R ⁷ ′ and R ⁸ ′ are, independently of one another, an optionally substituted alkyl, or together with an adjacent nitrogen atom, Y ² ′ represents cyclohexylene, cyclopentylene, cyclobutylene, or phenylene; and Y ² ′ represents cyclohexylene, cyclopentylene, cyclobutylene, or phenylene. An eating control agent comprising the compound described above, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

16. W ¹ force formula (8):

(k represents 0 or 1. R ⁷ ″ and R ⁸ , independently of each other, are methyl or ethyl, or together, together with an adjacent nitrogen atom, represent piperidine or pyrrolidine Y ² represents cyclohexylene or cyclobutylene.) The compound according to any one of claims 1 to 8, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient. Feeding regulator.

17. Equation (9)

[Wherein, R ¹ R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and W ¹ have the same meaning as in claim 1. The dietary control comprising an optical isomer of the compound according to any one of claims 1 to 16 or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Agent.

18.R ¹ force S trifluoromethyl, chlorine atom or fluorine atom, R ² is hydrogen atom, R ³ is hydrogen atom, R is hydrogen atom, X is C-R ⁶ R ⁵ is an optionally substituted fuel, and R ⁶ is a hydroxyl group, the compound according to any one of claims 1 to 17, or a prodrug thereof, or a pharmaceutically acceptable salt thereof. Feeding regulator as an active ingredient.

19. R ¹ is a chlorine atom or a fluorine atom, R ² is a hydrogen atom, R ³ is a carbamoyl, R ⁴ is a hydrogen atom, X is a nitrogen atom, and R ⁵ is substituted 17. A compound comprising the compound according to any one of claims 1 to 8, 11, 12, or 14 to 16, or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Food regulator.

20. X is C one R ^6, R ⁶ is a fluorine atom, 'also properly its prodrug compound according to claim 1, wherein or food regulatory intake and their pharmaceutically acceptable salts as an active ingredient, Agent.

21. An eating control agent comprising, as an active ingredient, the compound according to claim 1 or a prodrug thereof, or a pharmaceutically acceptable salt thereof, which is of the formula (4).

22. The food intake regulator according to any one of claims 1 to 21, which is an agent for treating or preventing diabetes.

23. The eating control agent according to any one of claims 1 to 21, which is an agent for treating or preventing an eating disorder.

.

24. The method according to any one of claims 1 to 21, which is an agent for treating or preventing obesity. Eating regulator.

25. The food intake regulator according to any one of claims 1 to 21, which is an agent for treating or preventing hyperlipidemia.

26. Equation (1a):

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and W ¹ have the same meaning as in claim 1. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

27. Equation (4):

^{Wherein, 1 ^, 1 2, 1} 3, R 4, R 5, W 1, Υ 3 Contact good beauty Upsilon ⁴ has the same meaning and significance in claim 1. Or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

28. A medicament comprising the compound according to any one of claims 26 to 27 or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.