JP2010037337A - Pharmaceutical composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a preventive, remedy for diseases such as diabetes, complication of the same, obesity, etc., in which glucokinase participates. <P>SOLUTION: A medicine is provided comprising a hydrazone derivative represented by formula [I] or a pharmaceutically acceptable salt thereof: [Ring A represents an aryl or heteroaryl. T represents a heteroaryl or a heterocyclic group; R<SP>1</SP>and R<SP>2</SP>each independently represents an H atom, a halogen atom, a cycloalkyl sulfonyl, etc.; R<SP>3</SP>and R<SP>4</SP>are each represents a (substituted)heterocyclic group by combining with a vicinal nitrogen atom. R<SP>5</SP>represents an H atom, a halogen atom, a cyano, a nitro or a tetrazolyl group, etc.; R<SP>6</SP>represents an H atom, etc.]. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a novel hydrazone derivative which has an excellent glucokinase activation action and is useful as a medicine.

  Glucokinase (GK) is one of the four hexokinases found in mammals. Hexokinase catalyzes the conversion of glucose to glucose-6-phosphate, the first step in glucose metabolism. GK is mainly localized in liver parenchymal cells and pancreatic β cells, and plays an important role in glucose homeostasis throughout the body as a rate-limiting enzyme for glucose metabolism in these cells. The forms of the enzyme in liver parenchymal cells and pancreatic β cells are functionally identical, although the N-terminal 15 amino acid sequences differ due to splicing differences. Three hexokinases other than GK saturate the enzyme activity at a glucose concentration of 1 mM or less, but the Km of GK is 8 mM, which is within the physiological range of blood glucose level. Therefore, as the blood glucose concentration increases from normal blood glucose (5 mM) to postprandial blood glucose (10-15 mM), intracellular glucose metabolism through GK is activated. A hypothesis that GK functions as a glucose sensor for pancreatic β cells and hepatocytes has been proposed (Non-Patent Document 1). Later, the results of studies in GK genetically engineered animals have revealed that GK actually plays a crucial role in systemic glucose homeostasis. GK gene-disrupted mice die soon after birth (Non-patent Document 2), but both normal and diabetic mice overexpressing GK showed lower blood glucose levels than wild-type animals (Non-patent Document 3).

  Loss-of-function mutations in the GK gene were found in type II young-onset diabetes of the type II (MODY-2: maturity-onset diabetes of the young type II), and GK activity in MODY-2 It is considered that the decrease in blood pressure causes an increase in blood sugar (Non-patent Document 4). On the other hand, families with GK mutations that increase enzyme activity have been found, and such people show hypoglycemia (Non-Patent Document 5). Therefore, it is considered that GK functions as a glucose sensor even in humans and plays an important role in maintaining glucose homeostasis. Since the compound that activates GK activates the GK sensor system, it can be expected to have an insulin secretion promoting action in β cells, a glucose uptake enhancing action in the liver, and a liver release inhibiting action. May be useful, for example, in the treatment of type II diabetes.

Recently, it has been shown that pancreatic β-cell glucokinase is localized and distributed in the feeding center (Ventromedial hypothalamus, VMH) in the rat brain. About 20% of neurons in VMH are called glucose responsive neurons and have traditionally been thought to play an important role in controlling body weight. Administration of glucose in the brain reduces the amount of food intake in rats, whereas administration of the glucose analog glucosamine in the brain overeats the rats and suppresses glucose metabolism. From the electrophysiological experiment, glucose responsive neurons in VMH are stimulated when glucose increases from 5 to 20 mM, and the activity is blocked by glucosamine or the like (Non-patent Document 6). The glucose sensor mechanism of VHM is thought to be similar to that of pancreatic β cells. Thus, GK activators have the potential to improve obesity and correct hyperglycemia, which is one of the major problems in type II diabetes.
From the above, the compound having a GK activation action is a therapeutic agent and / or prevention of diabetes or chronic complications of diabetes such as retinopathy, nephropathy, neurosis, ischemic heart disease or arteriosclerosis, and obesity. Useful as an agent.
Examples of the compound having a GK activation action include a pyridinecarboxylic acid derivative (Patent Document 1), a 2-pyridinecarboxamide derivative (Patent Document 2), a heteroarylcarbamoylbenzene derivative (Patent Document 3), and a heteroaryl derivative (Patent Document 4). ), Substituted arylcyclopropylacetamide derivatives (Patent Document 5), 5-substituted pyrazine or pyridine derivatives (Patent Document 6), substituted (thiazol-2-yl) amide or sulfonamide derivatives (Patent Document 7), substituted phenylacetamide derivatives (Patent Document 8) or an amide derivative (Patent Document 9).

WO05 / 044801 WO04 / 081001 WO04 / 076420 WO04 / 063194 WO04 / 063179 WO04 / 052869 WO04 / 050645 WO03 / 095438 WO03 / 055482

American Journal Physiology, 247 (3Pt2), 1984, p.527-536 Cell, 83, 1995, p.69-78 Proceedings of the National Academy of Sciences of the U.S.A., 93, 1996, p.7225-7230 Nature Genetics, 356, 1992, p.721-722 New England Journal of Medicine, 338, 1998, p.226-230 Diabetes, 48 (9), 1999, p.1763-72

  An object of the present invention is to provide a novel compound having an excellent glucokinase activating action useful as an active ingredient of a medicament for the prevention and / or treatment of diseases associated with glucokinase such as diabetes, diabetic complications or obesity It is to be. As a result of intensive studies on the problems of the present invention, the present inventors have found that a hydrazone derivative represented by the following formula has an excellent glucokinase activating action, thereby completing the present invention.

［式中、環Ａはアリール又はヘテロアリールを表す。
環Ｔはヘテロアリール又はヘテロ環基を表す。
Ｒ^１は水素原子、ハロゲン原子、シクロアルキルスルホニル、アルキルスルホニル、アルキルスルフィニル、アルキルチオ、置換若しくは非置換テトラゾリル、−ＣＯＲ^１０又は−ＣＲ^１２（ＯＨ）Ｒ^１０を表す。
Ｒ^２は水素原子、ハロゲン原子、シクロアルキルスルホニル、置換若しくは非置換アルキルスルホニル、置換若しくは非置換アルキルチオ、ニトロ、置換若しくは非置換アミノ、置換若しくは非置換アミノスルホニル、置換若しくは非置換ヘテロ環チオ、置換若しくは非置換ヘテロ環スルフィニル、置換若しくは非置換ヘテロ環スルホニル、置換若しくは非置換ヘテロアリールスルホニル、アルケニルオキシ、置換若しくは非置換アルコキシ、置換若しくは非置換アルキルスルフィニル、置換若しくは非置換ヘテロアリール、置換若しくは非置換ヘテロアリールチオ、−ＣＯＲ^１１又は−ＣＲ^１３（ＯＨ）Ｒ^１１を表す。
Ｒ^１０はアルキル、シクロアルキル、ヘテロアリール又はヘテロ環基を表す。
Ｒ^１１は置換若しくは非置換アルキル、置換若しくは非置換シクロアルキル、置換若しくは非置換ヘテロアリール又はヘテロ環基を表す。
Ｒ^１２は水素原子又はアルキルを表す。
Ｒ^１３は水素原子又はアルキルを表す。
Ｒ^３及びＲ^４は独立に、水素原子、置換若しくは非置換アルキル又は置換若しくは非置換ヘテロアリールを表すか、あるいはＲ^３及びＲ^４が連結し隣接する窒素原子と一緒になって置換若しくは非置換ヘテロ環基を形成する。
Ｒ^５は、水素原子、ホルミル、ハロゲン原子、オキソ、置換若しくは非置換アルコキシ、置換若しくは非置換アミノスルホニル、置換若しくは非置換アルキルチオ、シアノ、置換若しくは非置換ヘテロ環スルホニル、ニトロ、置換若しくは非置換シクロアルキル、アルコキシカルボニル、アルケニル、アルキルスルホニル、置換若しくは非置換カルバモイル、置換若しくは非置換ヘテロアリールチオ、置換若しくは非置換アミノ、カルボキシ、置換若しくは非置換ヘテロアリール、置換若しくは非置換アルキニル、置換若しくは非置換ヘテロ環カルボニル、置換若しくは非置換ヘテロ環オキシ、置換若しくは非置換ヘテロ環基、置換若しくは非置換ヘテロ環チオ、置換若しくは非置換シクロアルキルオキシ、アルカノイル又は置換若しくは非置換アルキルを表す。
Ｒ^６は水素原子、置換若しくは非置換アルキル、ハロゲン原子又はカルボキシを表す。］
で示されるヒドラゾン誘導体又はその薬理的に許容し得る塩。 The present invention includes the following specific embodiments.
(1) General formula [I]:

[Wherein, ring A represents aryl or heteroaryl.
Ring T represents a heteroaryl or a heterocyclic group.
R ¹ represents a hydrogen atom, a halogen atom, cycloalkylsulfonyl, alkylsulfonyl, alkylsulfinyl, alkylthio, substituted or unsubstituted tetrazolyl, —COR ¹⁰ or —CR ¹² (OH) R ¹⁰ .
R ² is hydrogen atom, halogen atom, cycloalkylsulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkylthio, nitro, substituted or unsubstituted amino, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted heterocyclic thio, substituted Or unsubstituted heterocyclic sulfinyl, substituted or unsubstituted heterocyclic sulfonyl, substituted or unsubstituted heteroarylsulfonyl, alkenyloxy, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted It represents heteroarylthio, —COR ¹¹ or —CR ¹³ (OH) R ¹¹ .
R ¹⁰ represents an alkyl, cycloalkyl, heteroaryl or heterocyclic group.
R ¹¹ represents a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl or heterocyclic group.
R ¹² represents a hydrogen atom or alkyl.
R ¹³ represents a hydrogen atom or alkyl.
R ³ and R ⁴ independently represent a hydrogen atom, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroaryl, or R ³ and R ⁴ are linked and substituted or unsubstituted together with the adjacent nitrogen atom Heterocyclic groups are formed.
R ⁵ is a hydrogen atom, formyl, halogen atom, oxo, substituted or unsubstituted alkoxy, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkylthio, cyano, substituted or unsubstituted heterocyclic sulfonyl, nitro, substituted or unsubstituted cyclo Alkyl, alkoxycarbonyl, alkenyl, alkylsulfonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted heteroarylthio, substituted or unsubstituted amino, carboxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkynyl, substituted or unsubstituted hetero Ring carbonyl, substituted or unsubstituted heterocyclic oxy, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted cycloalkyloxy, alkanoyl or substituted or non-substituted Represents substituted alkyl.
R ⁶ represents a hydrogen atom, a substituted or unsubstituted alkyl, a halogen atom or carboxy. ]
Or a pharmacologically acceptable salt thereof.

で示される、ヘテロアリール又はヘテロ環基である（１）記載のヒドラゾン誘導体又はその薬理的に許容し得る塩。
（３） 環Ｔがチアゾリル、チアゾロピリジニル、ピリジル、ピラジニル、ベンゾチアゾリル、キノリル、チアジアゾリル、ピラゾリル、チアゾロピラジニル、チアゾロピリミジニル、シクロヘキサノチアゾリル又はジヒドロピラゾピリジニルである（１）又は（２）記載のヒドラゾン誘導体又はその薬理的に許容し得る塩。
（４） 環Ｔが、チアゾリル、チアゾロピリジニル、ピリジル、ピラジニル、ベンゾチアゾリル、チアジアゾリル、チアゾロピラジニル、チアゾロピリミジニル、シクロヘキサノチアゾリル又はジヒドロピラゾロピリジニルである（１）又は（２）記載のヒドラゾン誘導体又はその薬理的に許容し得る塩。 (2) Ring T is

The hydrazone derivative or a pharmaceutically acceptable salt thereof according to (1), which is a heteroaryl or heterocyclic group represented by the formula:
(3) Ring T is thiazolyl, thiazolopyridinyl, pyridyl, pyrazinyl, benzothiazolyl, quinolyl, thiadiazolyl, pyrazolyl, thiazolopyrazinyl, thiazolopyrimidinyl, cyclohexanothiazolyl or dihydropyrazopyridinyl The hydrazone derivative according to (1) or (2) or a pharmaceutically acceptable salt thereof.
(4) Ring T is thiazolyl, thiazolopyridinyl, pyridyl, pyrazinyl, benzothiazolyl, thiadiazolyl, thiazolopyrazinyl, thiazolopyrimidinyl, cyclohexanothiazolyl or dihydropyrazolopyridinyl (1) Or the hydrazone derivative according to (2) or a pharmaceutically acceptable salt thereof.

(5) The hydrazone derivative or a pharmaceutically acceptable salt thereof according to (1) or (2), wherein the ring T is thiazolyl, thiazolopyridinyl, pyrazinyl, thiadiazolyl, thiazolopyrazinyl or thiazolopyrimidinyl .
(6) The hydrazone derivative or a pharmaceutically acceptable salt thereof according to (1) or (2), wherein the ring T is thiazolyl or thiazolopyridinyl.
(7) The hydrazone derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (6), wherein ring A is aryl.

(8) The hydrazone derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (6), wherein ring A is phenyl or pyridyl.
(9) The hydrazone derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (8), wherein R ¹ is a hydrogen atom or a halogen atom.

(10) The hydrazone derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (8), wherein R ¹ is a hydrogen atom.
(11) R ² is cycloalkylsulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkylthio, nitro, substituted or unsubstituted amino, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted The hydrazone derivative according to any one of (1) to (10), which is heterocyclic sulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroarylthio, Its pharmacologically acceptable salt.

(12) The hydrazone derivative or the pharmacology thereof according to any one of (1) to (10), wherein R ² is cycloalkylsulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminosulfonyl, or substituted or unsubstituted heterocyclic sulfonyl. Acceptable salt.
(13) The hydrazone derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (10), wherein R ² is cycloalkylsulfonyl, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted aminosulfonyl.
(14) The hydrazone derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (10), wherein R ² is cycloalkylsulfonyl or substituted or unsubstituted alkylsulfonyl.

(15) The hydrazone derivative according to any one of (1) to (13), wherein the substituent of “substituted aminosulfonyl” in R ² is substituted or unsubstituted alkyl, cycloalkyl, alkoxy, or substituted or unsubstituted heterocycle, or Pharmacologically acceptable salt.

(16) The hydrazone derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (14), wherein the substituent of “substituted alkylsulfonyl” in R ² is alkoxy.
(17) The hydrazone derivative according to any one of (1) to (16), wherein R ³ and R ⁴ are linked to form a substituted or unsubstituted heterocyclic group together with an adjacent nitrogen atom, or a pharmaceutically acceptable salt thereof Possible salt.
(18) The heterocyclic group of “substituted or unsubstituted heterocyclic group formed by combining R ³ and R ⁴ together with the adjacent nitrogen atom” is pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, azetidine, homo The hydrazone derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (17), which is piperazine, homomorpholine or homothiomorpholine.

(19) The substituted heterocyclic substituent of “substituted or unsubstituted heterocyclic group formed by R ³ and R ⁴ together with the adjacent nitrogen atom” is alkyl, alkoxy, hydroxy or oxo (1) to The hydrazone derivative according to any one of (18) or a pharmaceutically acceptable salt thereof.
(20) R ⁵ is a hydrogen atom, formyl, halogen atom, oxo, substituted or unsubstituted alkoxy, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkylthio, cyano, substituted or unsubstituted heterocyclic sulfonyl, nitro, substituted or non-substituted Substituted cycloalkyl, alkoxycarbonyl, alkenyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted heteroarylthio, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic oxy, The hydrazone derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (19), which is alkanoyl or substituted or unsubstituted alkyl.

(21) R ⁵ is a hydrogen atom, a halogen atom, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted hetero The hydrazone derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (19), which is ring oxy, alkanoyl, or substituted or unsubstituted alkyl.
(22) R ¹ is a halogen atom, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted amino, substituted or unsubstituted heterocyclic oxy, or substituted or unsubstituted alkyl Any of the hydrazone derivatives or a pharmaceutically acceptable salt thereof.

(23) The hydrazone derivative according to any one of (1) to (19), wherein R ⁵ is substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted heterocyclic oxy, or substituted or unsubstituted alkyl, or a pharmacological thereof Acceptable salt.
(24) The hydrazone derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (19), wherein R ⁵ is substituted or unsubstituted alkyl.
(25) In R ⁵ , the substituent of “substituted alkyl” is a substituted or unsubstituted heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted carbamoyl, hydroxy, trialkylsilyloxy, alkylthio, The hydrazone derivative or the pharmacology thereof according to any one of (1) to (24), which is alkylsulfonyl, substituted or unsubstituted heterocyclic oxy, heteroaryl, substituted or unsubstituted hydroxyimino, halogen atom, carboxy, alkoxycarbonyl, or alkanoyloxy Acceptable salt.

(26) The hydrazone derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (19), wherein R ⁵ is substituted or unsubstituted alkoxy.
(27) The substituent of “substituted alkoxy” in R ⁵ may be substituted with 1 or 2 groups selected from alkyl and alkoxycarbonyl, and may be substituted with amino, alkoxycarbonyl, mono or dialkyl as appropriate The hydrazone derivative according to any one of (1) to (19) and (26), which is a heterocyclic group optionally substituted by carbamoyl, carboxyl, hydroxy, oxo, trialkylsilyloxy or alkoxy, or a pharmaceutically acceptable salt thereof Possible salt.

(28) The hydrazone derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (27), wherein R ⁶ is a hydrogen atom or substituted or unsubstituted alkyl.
(29) The hydrazone derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (27), wherein R ⁶ is a hydrogen atom.
(30) A medicament comprising the hydrazone derivative according to any one of (1) to (29) or a pharmacologically acceptable salt thereof.
(31) The medicament according to (30), which is a glucokinase activator.
(32) The medicament according to (30), which is a therapeutic agent and / or preventive agent for diabetes.
(33) The medicament according to (30), which is a therapeutic and / or preventive agent for chronic complications of diabetes such as retinopathy, nephropathy, neurosis, ischemic heart disease, arteriosclerosis and the like.
(34) The medicament according to (30), which is an agent for treating and / or preventing obesity.

In the present specification, the following terms have the meanings defined below.
Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom.
“Alkyl” (including “alkyl” moieties bonded to other groups such as “alkylthio”, “hydroxyalkyl”, etc. The same applies to the other groups defined below) includes, for example, C _1-6 C _1-4 linear or branched alkyl is preferable, and specific examples include methyl, ethyl, propyl, isopropyl, isobutyl, t-butyl, pentyl, hexyl and the like.

“Alkenyl” includes, for example, C _2-6 , preferably C _2-4 linear or branched alkenyl, and specifically vinyl, propenyl, isopropenyl, butenyl, pentenyl, hexenyl and the like. .
“Alkynyl” includes, for example, C _2-6 , preferably C _2-4 linear or branched alkynyl, and specific examples include acetylenyl, propynyl, butynyl, pentynyl, hexynyl and the like.
“Alkoxy” includes, for example, C _1-6 , preferably C _1-4 linear or branched alkoxy, specifically methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyl. Examples include oxy and hexyloxy.

Examples of “alkanoyl” include C _2-7 , preferably C _2-5 linear or branched alkanoyl, and specific examples include acetyl, propionyl, butyryl, pentanoyl and the like.
“Cycloalkyl” includes, for example, C _3-8 , preferably C _3-6 cycloalkyl, specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

“Aryl” includes 6 to 14-membered, preferably 6 to 10-membered monocyclic, bicyclic or tricyclic aromatic hydrocarbons, specifically phenyl, naphthyl, phenanthryl, anthryl and the like. In particular, phenyl is preferable.
“Heteroaryl” is a 4- to 10-membered, preferably 5- to 9-membered monocycle in which 1 to 3 carbon atoms are replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen atoms And thienyl, thiazolyl, pyrazolyl, imidazolyl, isoxazolyl, triazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, benzothiazolyl, thiazolopyridinyl, thiazolo Pyrazinyl, thiazolopyrimidinyl and the like.

The “heterocyclic group” is a 4- to 10-membered, preferably 4- to 9-membered single atom in which 1 to 3 carbon atoms are independently substituted with a hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom. Cyclic or bicyclic non-aromatic hydrocarbons, specifically oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, dioxolanyl, piperidinyl, piperazinyl, homopiperazinyl, tetrahydropyranyl, thiacyclohexyl, morpholinyl, thiomorpholinyl, cyclohexanoyl Examples include thiazolyl, dihydrothiazolopyridinyl, tetrahydrothiazolopyridinyl and the like.
Or, as specific examples of “halogen atom”, “alkyl”, “alkenyl”, “alkynyl”, “alkoxy”, “alkanoyl”, “cycloalkyl”, “aryl”, “heteroaryl”, “heterocyclic group” Are specifically shown in the examples.

The groups represented by each symbol of compound [I] will be described below.
The “aryl” in ring A is preferably phenyl.
The “heteroaryl” in ring A is preferably thienyl or pyridyl, and pyridyl is particularly preferable.
When ring A is a 6-membered ring, the substitution position of R2 is preferably the 4-position.

As the “heteroaryl” in the ring T, for example, a 5- to 9-membered monocyclic group optionally having 1 to 3 heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom, Examples thereof include cyclic heteroaryl, and specific examples include thiazolyl, pyrazolyl, thiadiazolyl, pyridyl, pyrazinyl, benzothiazolyl, thiazolopyridinyl, thiazolopyrazinyl, thiazolopyrimidinyl, quinolyl and the like. Of these, thiazolyl, thiadiazolyl, pyridyl, pyrazinyl, benzothiazolyl, thiazolopyridinyl, thiazolopyrazinyl, thiazolopyrimidinyl are preferable, and thiazolyl, thiadiazolyl, pyrazinyl, thiazolopyridinyl, thiazolopyrazinyl In particular, thiazolyl, thiazolopyridinyl, and more particularly thiazolyl are preferred.
As the “heterocyclic group” in the ring T, for example, a 5- to 9-membered monocyclic optionally having 1 to 3 heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom, And bicyclic heterocyclic groups, preferably 9-membered bicyclic heterocyclic groups, such as cyclohexanothiazolyl, dihydrothiazolopyridinyl, tetrahydrothiazolopyridinyl and the like. is there.

Examples of “cycloalkyl” in R ¹⁰ and R ¹¹ include 3 to 4 membered cycloalkyl, specifically cyclopropyl, cyclobutyl and the like, and cyclopropyl is particularly preferable.
As the “heterocyclic group” in R ¹⁰ and R ¹¹ , for example, a 5- to 9-membered single atom optionally having 1 to 3 heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom. Examples thereof include cyclic and bicyclic heterocyclic groups, preferably 5- to 7-membered monocyclic heterocyclic groups, specifically azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxazepidinyl. (Oxazepidinyl) and perhydrodiazepinyl are preferred.

Examples of “cycloalkyl” in R ² include 3 to 4 membered cycloalkyl, specifically cyclopropyl, cyclobutyl and the like, and cyclopropyl is particularly preferable.
As the “heterocyclic group” in R ² , for example, a 5- to 9-membered monocyclic optionally having 1 to 3 heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom, Bicyclic heterocyclic groups are exemplified, and preferably 5 to 7-membered monocyclic heterocyclic groups, specifically azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxazepidinyl (oxazepidinyl) Perhydrodiazepinyl is preferred.
As the “heteroaryl” of R ³ and R ⁴ , for example, a 5- to 9-membered monocycle optionally having 1 to 3 heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom And a bicyclic heteroaryl, preferably a 5- to 6-membered monocyclic heteroaryl optionally having 1 to 3 nitrogen atoms, specifically pyrazolyl, imidazolyl, triazolyl , Pyridyl, or pyrimidyl, and pyrimidyl is particularly preferable.

Examples of preferable combinations of R ³ and R ⁴ include combinations in which one is a substituted alkyl or a substituted or unsubstituted heteroaryl, and the other is a hydrogen atom or an alkyl group.
The heterocyclic group in “R ³ and R ⁴ are linked to form a substituted or unsubstituted heterocyclic group together with the adjacent nitrogen atom” is preferably 0 to 1 oxygen atom, nitrogen other than the nitrogen atom A 5- to 7-membered heterocyclic group containing a hetero atom selected from an atom or a sulfur atom, and preferred heterocyclic groups include pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, homopiperidine, homopiperazine, homo Examples include morpholine and homothiomorpholine. Particularly preferred heterocyclic groups include pyrrolidine, piperidine, piperazine, morpholine, or thiomorpholine.

Examples of the “heterocyclic group” in R ⁵ include a 4 to 6-membered monocyclic heterocyclic group, and specifically, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and the like are preferable.

The substituent in the group represented by each symbol of compound [I] has the following meanings, for example.
“Substituted amino”, “substituted aminosulfonyl”, “substituted aminoalkyl”, “substituted aminoalkanoyl”, “substituted carbamoyl”, “substituted carbamoylalkyl”, “substituted alkyl”, “substituted alkylthio”, “substituted alkylsulfinyl”, “Substituted alkylsulfonyl”, “substituted alkoxy”, “substituted alkanoyl”, “substituted alkynyl”, “substituted cycloalkyl”, “substituted cycloalkyloxy”, “substituted cycloalkylcarbonyl”, “substituted cycloalkylsulfonyl”, “substituted” Aryl, substituted aryloxy, substituted arylcarbonyl, substituted arylcarbonyloxy, substituted arylsulfonyl, substituted arylalkylcarbonyl, substituted heteroaryl, substituted heteroarylthio, Replacement heteroary "Sulfonyl", "substituted heteroarylalkyl", "substituted heterocyclic group", "substituted heterocyclic oxy", "substituted heterocyclic carbonyl", "substituted heterocyclic thio", "substituted heterocyclic sulfinyl", "substituted hetero `` Ring sulfonyl '', `` substituted hydroxyimino '', `` substituted phenyl '', `` substituted pyridyl '', `` substituted thiazolopyridinyl '', `` substituted pyrazinyl '', `` substituted pyrazolyl '', `` substituted imidazolyl '', `` substituted thiazolyl '', `` Substituted benzothiazolyl, substituted quinolyl, substituted thiadiazolyl, substituted pyrazolyl, substituted thiazolopyrazinyl, substituted thiazolopyrimidinyl, substituted cyclohexanothiazolyl, substituted dihydrothiazolopyr "Dinyl", "Substituted triazolyl", "Substituted pyrimidinyl", "Substituted pyrrolidinyl", "Substituted tetra "Drofuryl", "Substituted thiacyclohexyl", "Substituted cyclopentyl", "Substituted piperazinyl", "Substituted piperazinylsulfonyl", "Substituted homopiperazinyl", "Substituted piperidinyl", "Substituted morpholinyl", "Substituted thiomorpholinyl", "Substituted per The substituents in “hydrodiazepinyl” and “substituted tetrazolyl” include (1) alkyl optionally substituted with hydroxy, alkoxy, amino, mono- or dialkylamino, carbamoyl, tetrahydrofuryl or pyridyl, and (2) cyclo Alkyl, (3) hydroxy, (4) alkoxy, (5) cyano, (6) halogen atom, (7) mono- or dialkylamino, (8) amino optionally substituted with alkanoyl, alkoxyalkanoyl or alkoxycarbonyl , (9) pyridyl, (10) carboxyl, (11) formyl, (12) alkanoyl optionally substituted with mono- or dialkylamino, hydroxy, alkoxy or alkanoyloxy, (13) cycloalkylcarbonyl, (14) alkoxy Carbonyl, (15) oxo, (16) alkylsulfonyl, (16) those specifically shown in Examples and Reference Examples, etc., and the same or different 1 to 3 substituents selected from the above groups. Can have.

Furthermore, each preferable substituent is demonstrated according to each symbol (R < ¹ > -R < ⁵ > and R < ¹¹ >) of compound [I]. The groups of these symbols can have the same or different 1 to 3 substituents selected from the groups defined below.

A preferable substituent of “substituted tetrazolyl” in R ¹ includes alkyl.
Preferred substituents for “substituted alkylsulfonyl” in R ² are alkoxycarbonyl, alkoxy, cycloalkyl (preferably cyclopropyl), hydroxy, substituted or unsubstituted amino (substituent: alkyl, alkanoyl 1 or 2 selected from Group), substituted or unsubstituted heteroaryl (preferably imidazolyl, triazolyl) (substituent: alkyl), alkylsulfonyl, cyano, substituted or unsubstituted heterocyclic group (preferably tetrahydrofuryl, tetrahydropyranyl, dihydro-3H- Isoindolyl) (substituents: oxo, dioxo). Of these, alkoxy, cycloalkyl (preferably cyclopropyl), and hydroxy are more preferable, and alkoxy is particularly preferable.
Preferred substituents for “substituted alkylthio” in R ² include alkoxy, cycloalkyl, alkoxycarbonyl, hydroxy, cyano, alkylthio, substituted or unsubstituted heterocyclic groups (preferably tetrahydrofuryl, tetrahydropyranyl, dihydro-3H-isoindolyl). ) (Substituents: oxo, dioxo), heteroaryl (preferably pyridyl). Of these, alkoxy, cycloalkyl, alkoxycarbonyl, hydroxy, cyano, alkylthio, and heteroaryl (preferably pyridyl) are more preferable.

Preferred substituents for “substituted amino” in R ² include heteroarylcarbonyl (preferably pyridylcarbonyl), heteroarylalkanoyl (thienylalkanoyl), cycloalkylcarbonyl, cycloalkylsulfonyl, alkoxycarbonylcarbonyl, heteroarylsulfonyl, alkylsulfonyl Is mentioned. Of these, alkoxycarbonylcarbonyl and alkylsulfonyl are more preferable.

As a preferable substituent of the substituted alkyl which is a substituent of “substituted aminosulfonyl” in R ^2, amino optionally substituted with mono or dialkyl; carbamoyl optionally substituted with mono or dialkyl; hydroxy; Heteroaryl optionally substituted with alkyl; cycloalkyl; alkoxycarbonyl; hydroxyalkoxy; heterocyclic group optionally substituted with alkyl; halogen atom; alkylthio. Of these, amino optionally substituted with mono or dialkyl as appropriate; carbamoyl optionally substituted with mono or dialkyl; hydroxy; alkoxy; cycloalkyl; alkoxycarbonyl; heterocycle optionally substituted with alkyl Group; a halogen atom is more preferred, and hydroxy and alkoxy are particularly preferred.

Examples of the heterocyclic group that is a substituted or unsubstituted alkyl substituent that is a substituent of “substituted aminosulfonyl” in R ² include 1 to 3 heterocycles independently selected from an oxygen atom, a sulfur atom, and a nitrogen atom. Examples thereof include 5 to 9-membered monocyclic and bicyclic heterocyclic groups optionally having atoms, and preferably a 5-membered monocyclic heterocyclic group. Tetrahydrofuryl is particularly preferable.
Preferable substituents of the substituted heterocyclic group that is the substituent of “substituted aminosulfonyl” in R ² include alkyl.

Preferred substituents for “substituted heterocyclethio” in R ² include hydroxy; alkyl; oxo; alkanoyl; hydroxyalkyl; carbamoyl optionally substituted with mono or dialkyl; heteroaryl; optionally substituted with mono or dialkyl. Aminosulfonyl optionally substituted with mono- or dialkyl; alkylsulfonyl; alkoxy; alkoxyalkyl. Of these, hydroxy; alkyl; carbamoyl optionally substituted with mono- or dialkyl; oxo; alkoxy; alkoxyalkyl is more preferable, and alkyl is particularly preferable.
Preferred substituents for “substituted heterocyclic sulfinyl” in R ² include hydroxy; alkyl; oxo; alkanoyl; hydroxyalkyl; carbamoyl optionally substituted with mono or dialkyl; heteroaryl; optionally substituted with mono or dialkyl. Aminosulfonyl optionally substituted with mono- or dialkyl; alkylsulfonyl; alkoxy; alkoxyalkyl. Of these, hydroxy; alkyl; carbamoyl optionally substituted with mono- or dialkyl; oxo; alkoxy; alkoxyalkyl is more preferable, and alkyl is particularly preferable.

Preferred substituents for “substituted heterocyclic sulfonyl” in R ² include hydroxy; alkyl; oxo; alkanoyl; hydroxyalkyl; carbamoyl optionally substituted with mono or dialkyl; heteroaryl; optionally substituted with mono or dialkyl. Aminosulfonyl optionally substituted with mono- or dialkyl; alkylsulfonyl; alkoxy; alkoxyalkyl. Of these, hydroxy; alkyl; carbamoyl optionally substituted with mono- or dialkyl; oxo; alkoxy; alkoxyalkyl are more preferable.

A preferable substituent of “substituted heteroarylsulfonyl” for R ² includes alkyl.
Preferable substituents of “substituted alkoxy” in R ² include cycloalkyl.
A preferable substituent of “substituted alkylsulfinyl” in R ² is selected from alkoxycarbonyl, alkoxy, alkoxyalkyl, cycloalkyl (preferably cyclopropyl), hydroxy, substituted or unsubstituted amino (substituent: alkyl, alkanoyl) 1 or 2 group), substituted or unsubstituted heteroaryl (preferably imidazolyl, triazolyl) (substituent: alkyl), alkylsulfonyl, cyano, substituted or unsubstituted heterocyclic group (preferably tetrahydrofuryl, tetrahydropyranyl, dihydro -3H-isoindolyl) (substituents: oxo, dioxo). Of these, alkoxy, cycloalkyl (preferably cyclopropyl) and hydroxy are more preferable, and hydroxy is particularly preferable.
A preferable substituent of “substituted heteroaryl” in R ² includes alkyl.

As the preferred substituent of “substituted alkyl” in R ¹¹ , alkoxycarbonyl, alkoxy, cycloalkyl (preferably cyclopropyl), hydroxy, substituted or unsubstituted amino (substituent: alkyl, alkanoyl selected from 1 or 2) Group), substituted or unsubstituted heteroaryl (preferably imidazolyl, triazolyl) (substituent: alkyl), alkylsulfonyl, cyano, substituted or unsubstituted heterocyclic group (preferably tetrahydrofuryl, tetrahydropyranyl, dihydro-3H-isoindolyl) ) (Substituents: oxo, dioxo) and the like. Of these, alkoxy, cycloalkyl (preferably cyclopropyl), hydroxy, dialkylamino and the like are more preferable, and alkoxy is particularly preferable.

Preferred substituents for “substituted cycloalkyl” in R ¹¹ are hydroxy; alkyl; oxo; alkanoyl; hydroxyalkyl; carbamoyl optionally substituted with mono or dialkyl; heteroaryl; optionally substituted with mono or dialkyl. Aminosulfonyl optionally substituted with mono or dialkyl; alkylsulfonyl; alkoxy; alkoxyalkyl. Of these, hydroxy; alkyl; carbamoyl optionally substituted with mono- or dialkyl; oxo; alkoxy; alkoxyalkyl is more preferable, and alkyl is particularly preferable.

Preferred substituents for “substituted heteroaryl” in R ¹¹ are hydroxy; alkyl; alkanoyl; hydroxyalkyl; carbamoyl optionally substituted with mono or dialkyl; heteroaryl; optionally substituted with mono or dialkyl. Good aminosulfonyl; amino optionally substituted with mono- or dialkyl; alkylsulfonyl; alkoxy; alkoxyalkyl. Of these, hydroxy; alkyl; carbamoyl optionally substituted with mono- or dialkyl; alkoxy; alkoxyalkyl is more preferable, and alkyl is particularly preferable.

Preferred substituents for “substituted alkyl” in R ³ and R ⁴ include hydroxy, alkoxy, dialkylamino, cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted heteroaryl, particularly preferably Examples include substituted or unsubstituted heteroaryl.
The heterocycle of “substituted or unsubstituted heterocycle” which is a substituent of “substituted alkyl” in R ³ and R ⁴ is, for example, 1 to 3 heterocycles independently selected from an oxygen atom, a sulfur atom and a nitrogen atom. Examples thereof include 4 to 6-membered monocyclic heterocycles optionally having atoms, and specific examples include oxetanyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl and the like. . Tetrahydropyranyl is particularly preferable.

Heteroaryl of “substituted or unsubstituted heteroaryl” which is a substituent of “substituted alkyl” in R ³ and R ⁴ is, for example, 1 to 3 heteroaryls independently selected from an oxygen atom, a sulfur atom and a nitrogen atom 5- to 9-membered monocyclic or bicyclic heteroaryl optionally having atoms, preferably 5 to 6-membered single optionally having 1 to 3 nitrogen atoms Cyclic heteroaryl, specifically pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidyl and the like, with pyrimidyl being particularly preferred.

A substituted heterocyclic ring of “substituted or unsubstituted heterocyclic group formed by R ³ and R ⁴ being joined together with an adjacent nitrogen atom”, “substituted heteroaryl” in R ³ and R ⁴ , and R ³ Preferred substituents for substituted heteroaryl and substituted heterocycle that are substituents of “substituted alkyl” in R ⁴ and R ⁴ include alkyl, hydroxy, oxo, substituted or unsubstituted amino and alkoxy. Particularly preferred are alkyl, hydroxy, oxo, and alkoxy.

Preferred substituents for “substituted alkoxy” in R ⁵ include substituted or unsubstituted amino (substituent: 1 or 2 groups selected from alkyl and alkoxycarbonyl); alkoxycarbonyl; optionally substituted with mono- or dialkyl Carboxamoyl; carboxyl; hydroxy; substituted or unsubstituted heterocyclic group (substituent: oxo); trialkylsilyloxy; alkoxy. Of these, amino optionally substituted with mono or dialkyl as appropriate; carbamoyl optionally substituted with mono or dialkyl; hydroxy is more preferred, and amino optionally substituted with mono or dialkyl as appropriate; hydroxy preferable.

A preferable substituent of “substituted aminosulfonyl” in R ⁵ includes alkyl. Thus, the substituent is monoalkyl or dialkyl, preferably dialkyl.
Preferred substituents for “substituted alkylthio” for R ⁵ include amino optionally substituted with mono or dialkyl; alkoxycarbonylamino; halogen atom; hydroxy; carboxyl; carbamoyl optionally substituted with mono or dialkyl An alkoxycarbonyl. Of these, amino optionally substituted with mono or dialkyl; alkoxycarbonylamino; hydroxy; carbamoyl optionally substituted with mono or dialkyl is more preferable, and dialkylcarbamoyl is particularly preferable.

Preferable substituents of “substituted heterocyclic sulfonyl” in R ⁵ include alkyl.
Preferable substituents of “substituted cycloalkyl” in R ⁵ include amino optionally substituted with mono- or dialkyl.
A preferable substituent of “substituted cycloalkyloxy” in R ⁵ includes amino optionally substituted with mono- or dialkyl.

Preferred substituents for “substituted carbamoyl” in R ⁵ are selected from substituted or unsubstituted alkyl (substituent: hydroxy; cycloalkyl; heterocyclic group; amino optionally substituted with mono- or dialkyl; heteroaryl) 1 or 2 groups), cycloalkyl, and heteroaryl. Among these, substituted or unsubstituted alkyl (substituent: 1 or 2 groups selected from hydroxy, heterocyclic group, dialkylamino, heteroaryl) and cycloalkyl are more preferable.
A preferable substituent of “substituted heteroarylthio” in R ⁵ includes alkyl.

A preferable substituent of "substituted amino" in R ^5, alkyl, substituted or unsubstituted aminoalkyl (substituent: alkyl, 1 or 2 groups selected from alkanoyl), alkanoyl, hydroxyalkyl, alkoxycarbonyl and the like . Of these, alkyl, and therefore monoalkyl or dialkyl is more preferable, and dialkyl is particularly preferable.
A preferable substituent of “substituted heteroaryl” in R ⁵ includes alkyl.

Preferred substituents for “substituted alkynyl” in R ⁵ include hydroxy, amino optionally substituted with mono or dialkyl. Of these, hydroxy and dialkylamino are more preferred.
Preferable substituents of “substituted heterocyclic carbonyl” in R ⁵ include hydroxy, alkyl, oxo, hydroxyalkyl and alkanoyl. Of these, hydroxy, alkyl, and hydroxyalkyl are more preferable.
Preferable substituents of “substituted heterocyclic oxy” in R ⁵ include hydroxy, alkyl, oxo, hydroxyalkyl and alkanoyl. Of these, alkyl and oxo are more preferable.

Preferable substituents of the “substituted heterocyclic group” in R ⁵ include hydroxy, alkyl, oxo, hydroxyalkyl, alkanoyl. Of these, oxo is more preferred.
Preferable substituents of “substituted heterocyclic thio” in R ⁵ include hydroxy, alkyl, oxo, hydroxyalkyl and alkanoyl. Of these, alkyl and alkanoyl are more preferred.

Preferred substituents of “substituted alkyl” in R ⁵ include substituted or unsubstituted heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted carbamoyl, hydroxy, trialkylsilyloxy, substituted or unsubstituted Substituted alkylthio, substituted or unsubstituted heterocyclic oxy, heteroaryl, substituted or unsubstituted hydroxyimino, halogen atom, and more preferably substituted or unsubstituted heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, Hydroxy, substituted or unsubstituted alkylthio, substituted or unsubstituted heterocyclic oxy, substituted or unsubstituted hydroxyimino, halogen atom, more preferably substituted or unsubstituted heterocyclic group, substituted or unsubstituted alkoxy, substituted Or a substituted or unsubstituted heterocyclic group, particularly preferably a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alkoxy group, and still more preferably a substituted or unsubstituted heterocyclic group.

Preferred substituents of the substituted heterocyclic group which is the substituent of “substituted alkyl” in R ⁵ are alkyl; oxo; alkoxyalkanoyl; alkanoyl; alkoxy; alkanoylamino; cycloalkylcarbonylamino; tri (halogeno) alkanoylamino; Amino; alkoxycarbonylamino; hydroxy; cycloalkylcarbonyl; tri (halogeno) alkyl; alkoxycarbonyl; formyl; amino optionally substituted with mono or dialkyl; aminosulfonyl optionally substituted with mono or dialkyl; Heteroaryl; alkoxycarbonylalkyl; alkanoyloxyalkanoyl; alkoxycarbonylcarbonyl; optionally substituted with mono- or dialkyl Optionally substituted aminoalkanoyl; substituted or unsubstituted carbamoyl (substituent: one or two groups selected from alkyl, alkoxy); hydroxyalkanoyl; di (halogeno) alkanoyl; substituted or unsubstituted heterocyclic carbonyl (substituent: Oxo); substituted or unsubstituted hydroxyimino (substituent: alkoxycarbonyl); carboxyl; hydroxyalkoxy; alkoxyalkoxy; halogen atom; alkanoyloxy. Alkoxy; oxo; alkoxyalkanoyl; alkanoyl; alkoxy; alkanoylamino; cycloalkylcarbonylamino; tri (halogeno) alkanoylamino; formylamino; alkoxycarbonylamino; cycloalkylcarbonyl; Amino optionally substituted with mono or dialkyl; aminosulfonyl optionally substituted with mono or dialkyl; alkylsulfonyl; heteroaryl; alkoxycarbonylalkyl; alkanoyloxyalkanoyl; alkoxycarbonylcarbonyl; mono or dialkyl as appropriate An aminoalkanoyl optionally substituted with mono; or optionally substituted with mono or dialkyl Moyl; hydroxyalkanoyl; di (halogeno) alkanoyl; substituted or unsubstituted heterocyclic carbonyl (substituent: oxo); substituted or unsubstituted hydroxyimino (substituent: alkoxycarbonyl) is more preferred, further alkyl; oxo; alkoxyalkanoyl; Alkanoyl; formyl; amino optionally substituted with mono- or dialkyl; alkylsulfonyl; alkanoyloxyalkanoyl; aminoalkanoyl optionally substituted with mono- or dialkyl; hydroxyalkanoyl is more preferred, and alkyl, alkanoyl, formyl Hydroxyalkanoyl is more preferable, and alkyl and alkanoyl are particularly preferable.

Preferred substituents of substituted amino which is a substituent of “substituted alkyl” in R ⁵ are alkyl; carbamoylalkyl optionally substituted with mono- or dialkyl; substituted or unsubstituted aminoalkyl (substituent: alkyl, alkanoyl) Alkoxyalkyl; hydroxyalkyl; alkoxyalkanoyl; heteroaryl; heteroarylalkyl. Of these, alkyl; carbamoylalkyl optionally substituted with mono or dialkyl; aminoalkyl optionally substituted with mono or dialkyl; alkoxyalkyl; heteroaryl is more preferable, and alkyl is particularly preferable.

Preferable substituents of substituted alkoxy which is a substituent of “substituted alkyl” in R ⁵ include hydroxy and alkoxy.
Preferable substituents of the substituted carbamoyl which is the substituent of “substituted alkyl” in R ⁵ include alkyl and alkoxy.
Preferable substituents of the substituted heterocyclic oxy that is the substituent of “substituted alkyl” in R ⁵ include alkanoyl, alkyl, formyl, cycloalkylcarbonyl, alkoxyalkanoyl, and alkylsulfonyl. Of these, alkanoyl and alkyl are more preferable, and alkanoyl is particularly preferable.

A preferable substituent of the substituted hydroxyimino which is a substituent of “substituted alkyl” in R ⁵ includes alkoxycarbonyl.
The heterocyclic group of the “substituted or unsubstituted heterocyclic group” which is the substituent of “substituted alkyl” in R ⁵ is, for example, 1 to 3 heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom 5 to 9-membered monocyclic and bicyclic heterocyclic groups which may optionally have 4 to 6-membered monocyclic which may optionally have 1 to 3 nitrogen atoms may be mentioned. A cyclic heterocyclic group, specifically azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, perhydrodiazepinyl, octahydropyrrolo [1,2-a] piperazinyl, and the like. Of these, piperazinyl and morpholinyl are more preferable, and piperazinyl is particularly preferable.

As the heterocyclic group of “substituted or unsubstituted heterocyclic oxy” which is a substituent of “substituted alkyl” in R ⁵ , for example, 1 to 3 heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom 5 to 9-membered monocyclic and bicyclic heterocyclic groups which may optionally have 4 to 6-membered monocyclic which may optionally have 1 to 3 nitrogen atoms may be mentioned. A cyclic heterocyclic group, specifically azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, perhydrodiazepinyl, octahydropyrrolo [1,2-a] piperazinyl, and the like. Of these, piperidinyl is more preferable.

Among the compounds [I], as a preferable compound, ring A is phenyl, ring T is 2-thiazolyl or 2-thiazolopyridyl, R ¹ is a hydrogen atom, and R ² is cyclopropylsulfonyl or alkoxy. Alkylsulfonyl, R ³ and R ⁴ together with the adjacent nitrogen atom form morpholine or pyrrolidine, R ⁵ is optionally substituted with 1 to 3 substituents selected from alkyl, oxo, alkanoyl and alkoxyalkanoyl And compounds that are piperazinyl-substituted alkyl.

As another preferred compound, ring A is phenyl, ring T is 2-thiazolopyridyl, R ¹ is a hydrogen atom, R ² is cyclopropylsulfonyl or alkoxyalkylsulfonyl, R ³ and R ⁴ forms a morpholine or pyrrolidine together with the adjacent nitrogen atom, and R ⁵ may be substituted with 1 or 2 alkyl, substituted with amino, substituted with 1 or 2 alkyl Examples include compounds that are amino substituted with good amino, or alkylamino substituted with amino optionally substituted with 1 or 2 alkyls.

Other preferable specific compounds among the compounds [I] of the present invention include the compounds described in any of Examples and Reference Examples. Furthermore, specific examples of each group (ring A, T, R ^{1 to} R ⁶ , R ¹⁰ and R ¹¹ ) include those corresponding to the compounds specifically shown in Examples and Reference Examples.

  The compound [I] of the present invention includes a mixture of stereoisomers or each stereoisomer in a pure or substantially pure form. For example, when the compound of the present invention has one or more asymmetric centers at any carbon atom, the compound [I] can exist in an enantiomer or diastereomer or a mixture thereof. The compound of the present invention includes an isomer or a mixture thereof. When the compound [I] of the present invention contains a double bond, geometric isomers (cis isomer, trans isomer) can exist, and the compound [I] of the present invention contains an unsaturated bond such as carbonyl. In some cases, tautomers can exist, but the compounds of the present invention include all these isomers or mixtures thereof. In the hydrazone part of the compound [I] of the present invention, a geometric isomer may exist, but a trans isomer (E isomer) is preferable.

  Examples of the pharmacologically acceptable salt of Compound [I] include inorganic acid salts such as hydrochloride, sulfate, phosphate and hydrobromide, acetate, fumarate, oxalate, citric acid, and the like. Organic acid salts such as acid salts, methanesulfonic acid salts, benzenesulfonic acid salts, tosylate salts and maleic acid salts. Moreover, when it has a substituent such as carboxyl, examples of the salt include salts with bases such as alkali metal salts such as sodium salt or potassium salt or alkaline earth metal salts such as calcium salt. The pharmacologically acceptable salt of the compound [I] of the present invention also includes an inner salt, and the compound [I] and the salt thereof can be in the form of a solvate such as a hydrate thereof.

  Compound [I] of the present invention or a pharmacologically acceptable salt thereof can be formulated into a pharmaceutical composition containing a therapeutically effective amount of the present compound and a pharmaceutically acceptable carrier. Pharmacologically acceptable carriers include diluents, binders (syrup, gum arabic, gelatin, sorbit, tragacanth or polyvinylpyrrolidone), excipients (lactose, sucrose, corn starch, potassium phosphate, sorbit or glycine) , Lubricants (magnesium stearate, talc, polyethylene glycol or silica), disintegrants (potato starch) and wetting agents (sodium lauryl sulfate).

  The compound [I] of the present invention or a pharmacologically acceptable salt thereof can be administered orally or parenterally and can be used in an appropriate pharmaceutical preparation. Suitable pharmaceutical preparations for oral administration include solid preparations such as tablets, granules, capsules or powders, or liquid, suspension or emulsion forms. Suitable pharmaceutical preparations for parenteral administration include suppositories, or injection solutions or infusion preparations using distilled water for injection, physiological saline or aqueous glucose solution, or inhalants.

  The compound [I] of the present invention or a pharmacologically acceptable salt thereof or a pharmaceutical preparation thereof can be used in combination with one or more other drugs selected from antidiabetic drugs and antihyperglycemic drugs. In this case, the concept of the term “combination” is used when administering these other drugs at the same time or separately at an arbitrary interval, and when they are formulated together with these other drugs and administered as a single pharmaceutical preparation. Is mentioned. Such other drugs include sulfonylureas (e.g. glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, glyoxepide, acetohexamide, glyboneuride, tolbutamide, tolazamide, carbutamide, glyquidone, glyhexamide, fenbutamide, tolcyclamide, etc.) Biguanides (eg, metformin, phenformin, buformin, etc.), glucagon antagonists (eg, peptide or non-peptide glucagon antagonists), glucosidase inhibitors (eg, acarbose, miglitol, etc.), insulin sensitivity enhancers (eg, troglitazone, rosiglitazone) , Pioglitazone, etc.), anti-obesity drugs (eg, sibutramine, orlistat, etc.).

  The dose of the compound [I] of the present invention or a pharmacologically acceptable salt thereof varies depending on the administration method, patient age, body weight or pathological condition, but is usually about 0.01 to about 100 mg / kg per day, preferably Is about 0.1 to about 10 mg / kg.

［式中、環Ａ、Ｔ、Ｒ^１〜Ｒ^６は前記定義と同じ］
化合物［ＩＩ］と化合物［ＩＩＩ］との反応は、適当な溶媒中、縮合剤の存在又は非存在下に実施することができる。縮合剤としては、Ｎ−エチル−Ｎ’−（３−ジメチルアミノプロピル）カルボジイミド、Ｎ，Ｎ’−ジシクロヘキシルカルボジイミド、１−メチル−２−ブロモピリジニウムヨージド、Ｎ，Ｎ’−カルボニルジイミダゾール、ジフェニルホスホリルアジド、ベンゾトリアゾール−１−イルオキシトリス（ジメチルアミノ）ホスフォニウムヘキサフルオロホスフェート、４−（４，６−ジメトキシ[１.３.５]トリアジン−２−イル）−４−メチルモルホリニウムクロリド、フルオロ−Ｎ，Ｎ，Ｎ’，Ｎ’−テトラメチルホルムアミジニウムヘキサフルオロホスフェート等をいずれも好適に用いることができる。溶媒としては、水、メタノール、イソプロパノール、エタノール、塩化メチレン、ＴＨＦ、ＤＭＦ、ジメチルアセトアミド、クロロホルム等を単一、又は混合溶媒としていずれも好適に使用することができる。反応は-78℃〜100℃下、好ましくは-25〜25℃で好適に進行する。塩基として、炭酸カリウム、炭酸ナトリウム、炭酸水素ナトリウムやトリエチルアミン、Ｎ，Ｎ−ジイソプロピルエチルアミン、Ｎ−メチルモリホリン、ピリジン、Ｎ，Ｎ−ジメチルアミノピリジン、ピコリン、ルチジン等を、又、添加剤として、Ｎ-ヒドロキシスクシンイミド、又は３−ヒドロキシ−３，４−ジヒドロ−４−オキソ−１，２，３−ベンゾトリアゾール、Ｎ，Ｎ−ジメチルアミノピリジン、Ｎ-ヒドロキシベンゾトリアゾール等を加えることにより、反応の進行を促進することができる。 Compound [I] of the present invention can be produced by the following method.

[Wherein, ring A, T, and R ^{1 to} R ⁶ are the same as defined above]
The reaction of compound [II] and compound [III] can be carried out in a suitable solvent in the presence or absence of a condensing agent. As the condensing agent, N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide, N, N′-dicyclohexylcarbodiimide, 1-methyl-2-bromopyridinium iodide, N, N′-carbonyldiimidazole, diphenyl Phosphoryl azide, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 4- (4,6-dimethoxy [1.3.5] triazin-2-yl) -4-methylmorpholinium Any of chloride, fluoro-N, N, N ′, N′-tetramethylformamidinium hexafluorophosphate and the like can be suitably used. As the solvent, water, methanol, isopropanol, ethanol, methylene chloride, THF, DMF, dimethylacetamide, chloroform and the like can be suitably used as a single or mixed solvent. The reaction suitably proceeds at -78 ° C to 100 ° C, preferably at -25 to 25 ° C. As a base, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, N, N-dimethylaminopyridine, picoline, lutidine, etc., and as an additive, By adding N-hydroxysuccinimide, or 3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazole, N, N-dimethylaminopyridine, N-hydroxybenzotriazole, etc. Progress can be promoted.

The reaction from compound [II] to compound [I] can also be carried out by converting compound [II] into a reactive intermediate such as acid chloride or mixed acid anhydride and then reacting with compound [III]. can do. Conversion to acid chloride is achieved by using triphenylphosphine in the presence of thionyl chloride, phosphorus oxychloride, phosphorus pentachloride or carbon tetrachloride, and conversion to mixed acid anhydride is diphenylphosphoryl chloride, methanesulfonyl. Any of chloride, ethyl chloroformate, isobutyl chloroformate and the like can be suitably used in the presence of a base such as triethylamine. As the solvent, methylene chloride, chloroform, THF, DMF and the like can be suitably used singly or as a mixed solvent. The reaction suitably proceeds at -78 ° C to 100 ° C, preferably at -25 to 25 ° C. In the reaction of these reactive intermediates with the compound [II], methylene chloride, chloroform, tetrahydrofuran, DMF, etc. can be suitably used as a solvent either alone or as a mixed solvent. It proceeds suitably at 100 ° C, preferably at -25 to 25 ° C.
Moreover, compound [I] can also be manufactured by making it react like the below-mentioned (LL) using the mixture whose hydrazone part is a cis-trans body as compound [II].

［式中、Ｚ^１はハロゲン原子を表し、Ｚ^２はアルコキシを表し、その他の記号は同一意味を有する。］
化合物［ＸＩ］と化合物［ＸＩＩ］の反応は、適当な溶媒（クロロホルム、塩化メチレン等）中、酸（塩化アルミニウム等）の存在下で実施することができる。
化合物［ＸＩＩＩ］とヒドラジン[ＸＶ]またはその適当な酸との塩の反応は、適当な溶媒（メタノール、クロロホルム等）中、塩基共存下、又は非共存下で実施することができる。用いる塩基としてはピリジン、ピコリン、ルチジン、Ｎ，Ｎ-ジメチルアニリン、トリエチルアミン等が挙げられる。生成するヒドラゾンが、シス体−トランス体の混合物である場合は、シリカゲルカラムカラムクロマトグラフィにより分離することができ、シス体は、酸（トリフルオロ酢酸、酢酸、塩酸、硫酸、リン酸等）で処理することで、所望のトランス体若しくはシス体−トランス体の混合物に変換することができる。
このようにして得られた生成物は、塩基（水酸化ナトリウム等）で処理して、Ｚ^２部分を加水分解することにより、化合物〔ＩＩ〕とすることができる。この際、化合物[ＸＩＶ]としてヒドラゾン部がシス体−トランス体の混合物を用いて、後述の（ＫＫ）と同様に反応させることで、化合物［ＩＩ］を製造することもできる。
また、化合物［ＸＩＩＩ］は、先に塩基（水酸化ナトリウム等）で処理して、Ｚ^２部分を加水分解し、［ＸＶＩ］に導いたのち、ヒドラジンと[ＸＶ]と適当な溶媒（メタノール、塩化メチレン、クロロホルム、ＤＭＦ等）中、塩基共存下、又は非共存下で反応させることにより、化合物〔ＩＩ〕とすることができる。
化合物［ＸＶ］は、例えばOrganic Synthesis II,211(1943)、Organic Synthesis II,290(1943)、Organic Synthesis II,418(1943)、Organic Synthesis II,460(1943)、Organic Synthesis V, 893(1973), Organic Synthesis V, 542(1988)等の通常の方法により、芳香族又は脂肪族アミンをニトロソ化し還元することによって、製造できる。または、一方を保護したヒドラジンとハロゲン化ヘテロアリール又はアルキルハライドを、適当な溶媒（クロロホルム、塩化メチレン、テトラヒドロフラン等）中、塩基存在下で反応させることにより、製造できる。 Compound [II] can be produced by the following method.

[Wherein, Z ¹ represents a halogen atom, Z ² represents alkoxy, and other symbols have the same meaning. ]
The reaction of compound [XI] and compound [XII] can be carried out in the presence of an acid (such as aluminum chloride) in an appropriate solvent (such as chloroform or methylene chloride).
The reaction of the salt of compound [XIII] and hydrazine [XV] or a suitable acid thereof can be carried out in a suitable solvent (such as methanol or chloroform) in the presence or absence of a base. Examples of the base used include pyridine, picoline, lutidine, N, N-dimethylaniline, triethylamine and the like. When the hydrazone to be produced is a mixture of cis isomer and trans isomer, it can be separated by silica gel column column chromatography, and the cis isomer is treated with an acid (trifluoroacetic acid, acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, etc.). By doing so, it can be converted into a desired trans form or a mixture of cis form and trans form.
The product thus obtained can be converted to compound [II] by treating with a base (sodium hydroxide or the like) and hydrolyzing the Z ² moiety. In this case, compound [II] can also be produced by reacting hydrazone moiety as compound [XIV] in the same manner as (KK) described later using a mixture of cis isomer and trans isomer.
Compound [XIII] is first treated with a base (such as sodium hydroxide) to hydrolyze the Z ² moiety and lead to [XVI], and then hydrazine, [XV] and a suitable solvent (methanol, Compound [II] can be obtained by reacting in methylene chloride, chloroform, DMF, etc.) in the presence or absence of a base.
Compound [XV] is, for example, Organic Synthesis II, 211 (1943), Organic Synthesis II, 290 (1943), Organic Synthesis II, 418 (1943), Organic Synthesis II, 460 (1943), Organic Synthesis V, 893 (1973) ), Organic Synthesis V, 542 (1988), and the like, and can be produced by nitrosating and reducing an aromatic or aliphatic amine. Alternatively, it can be produced by reacting one of the protected hydrazines with a halogenated heteroaryl or alkyl halide in an appropriate solvent (chloroform, methylene chloride, tetrahydrofuran, etc.) in the presence of a base.

Compound [I] can be further converted by the following method.
(A) among the objective compound [I], a compound containing a sulfinyl (SO) or sulfonyl (SO ₂₎ in the upper R1~R6 and ^{R 11} of the present invention, converts the corresponding sulfide compound into a sulfinyl or sulfonyl compound Can be produced by oxidation using any conventional method. For example, this oxidation can be carried out by treating with an oxidizing agent in a suitable solvent (methylene chloride, chloroform, THF, methanol, water or the like or a mixed solvent thereof). As an oxidizing agent, peroxy acids such as hydrogen peroxide, m-chlorobenzoic acid, peracetic acid, and oxone (registered trademark) (“potassium peroxyhydrogensulfate / dipotassium sulfate / potassium hydrogensulfate” manufactured by DuPont) are used. An acid can be preferably used, and this reaction can be preferably carried out at -78 ° C to 100 ° C.

(B) Of the target compound [I], on R ^{1 to} R ⁶ , the formula: —CH ₂ N (R ²¹ ) (R ²² )
[Wherein R ²¹ and R ²² are substituents of the substituted amino group described in the present specification, or R ²¹ and R ²² are combined with a nitrogen atom of the amino group to form an oxygen atom, sulfur A heterocyclic group having 1 to 3 heteroatoms independently selected from an atom and a nitrogen atom (wherein the heterocyclic group may be substituted)]
In addition the compound having a group represented, with a compound corresponding site is formyl, the ^{formula: HN (R 21) (R} 22)
[Wherein the symbols have the same meaning as above]
(In the following description, this compound means “substituted or unsubstituted amine”, and the group after removing the hydrogen atom from this substituted or unsubstituted amine is “substituted or unsubstituted amino”. Can also be produced by so-called “reductive amination”. This reaction can be carried out by any conventional method of reductive amination. For example, this reaction may be carried out by reducing agents (sodium borohydride, sodium triacetoxyborohydride, cyano) at −78 ° C. to 100 ° C. in an appropriate solvent (methanol, methylene chloride, chloroform, acetic acid or the like or a mixed solvent thereof). By using sodium borohydride or the like, it can be suitably carried out.

(C) In the target compound [I], the nitrogen atom on R ^{1 to} R ⁶ is substituted or unsubstituted alkanoyl (hereinafter simply referred to as substituted or unsubstituted alkanoyl) such as alkanoyl, cycloalkylcarbonyl, alkoxyalkanoyl, alkanoyloxyalkanoyl, etc. Compounds also substituted by the corresponding alkanoylation of compounds in which the corresponding nitrogen atom is unsubstituted (such as, for example, compounds wherein R ⁵ is piperazinylmethyl, piperazinylcarbonyl or piperazinylsulfonyl). You can also The alkanoylation can be produced by using any conventional method of amide formation usually used for peptide synthesis and the like. For example, the alkanoylation is carried out in a suitable solvent (methylene chloride, THF, DMF, N, N-dimethylacetamide, chloroform or a mixed solvent thereof) in the presence or absence of a base (triethylamine, pyridine, etc.) at −78 ° C. To 100 ° C. by using acid chloride, acid anhydride or ester. This reaction can also be carried out, for example, in a suitable solvent in the presence or absence of a condensing agent. As condensing agent, N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide, N, N′-dicyclohexylcarbodiimide, 1-methyl-2-bromopyridinium iodide, N, N′-carbonyldiimidazole, diphenylphosphoryl Azide, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 4- (4,6-dimethoxy [1.3.5] triazin-2-yl) -4-methylmorpholinium chloride, fluoro -N, N, N ', N'-tetramethylformamidinium hexafluorophosphate or the like can be preferably used. As the solvent, water, methanol, isopropanol, ethanol, methylene chloride, THF, DMF, N, N-dimethylacetamide, chloroform or the like can be suitably used as a single or mixed solvent. This reaction preferably proceeds at -78 ° C to 100 ° C, more preferably at -25 ° C to 25 ° C. As a base, potassium carbonate, sodium carbonate, sodium hydrogen carbonate or triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, N, N-dimethylaminopyridine, picoline, lutidine and the like are added, and as an additive, N-hydroxysuccinimide or 3 Addition of -hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazole, N, N-dimethylaminopyridine, N-hydroxybenzotriazole, etc. can promote the progress of this reaction. it can.

(D) Among the target compounds [I], a substituted or unsubstituted aminocarbonyl on R ^{1 to} R ⁶ , that is, a compound having a substituted or unsubstituted carbamoyl is substituted or unsubstituted with a compound whose corresponding site is carboxy It can be produced by reacting with an amine. This reaction can be carried out in the same manner as in the above reaction (C).
(E) Among the target compounds [I], a compound in which R ⁵ or R ⁶ has a substituted or unsubstituted alkoxymethyl or a substituted or unsubstituted heteroarylmethyl is also a compound in which the corresponding site is hydroxymethyl. After conversion to alkanoylmethyl, preferably acetyloxymethyl by the usual method of chemical conversion, substituted or unsubstituted alkanol, cycloalkanol, alkylthio, or a heterocyclic compound having a hydroxyl group, or substituted or substituted having a hydrogen atom on the nitrogen atom It can also be produced by condensing an unsubstituted heteroaryl compound such as pyrazole. This condensation reaction is carried out in the presence of an acid (p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, etc.) without solvent or in an appropriate solvent (THF, dioxane, methylene chloride, chloroform, toluene, benzene, etc.) It can be suitably carried out at −78 ° C. to 200 ° C. in the presence, more preferably at 25 ° C. to 100 ° C.

(F) Among the target compounds [I], a compound having hydroxymethyl on R ^{1 to} R ⁶ can reduce a compound whose corresponding site is formyl by any conventional method for reducing formyl to alcohol. Can be manufactured. For example, this reaction can be carried out by using a reducing agent (sodium borohydride, sodium triacetoxyborohydride, diborane, diisobutylaluminum hydride, aluminum hydride) in an appropriate solvent (methanol, ethanol, methylene chloride, chloroform, dioxane, THF, etc.). Lithium or the like) can be suitably used at −78 ° C. to 100 ° C.
(G) Among the target compounds [I], a compound having a carboxyl on R ^{1 to} R ⁶ is obtained by oxidizing a compound in which the corresponding site is formyl by any conventional method for oxidizing formyl to carboxyl. Can be manufactured. The oxidation is performed by, for example, using an oxidizing agent (sodium chlorite, potassium permanganate, pyridinium dichromate, etc.) in a suitable solvent (DMF, dimethyl sulfoxide, acetone, t-butanol, water, methylene chloride, chloroform, etc.). It can implement suitably by using at -78 to 100 degreeC.

(H) Among the target compounds [I], a compound having an alkoxycarbonyl on R ^{1 to} R ⁶ is a compound in which the corresponding site is carboxyl by any conventional method for esterifying carboxyl to alkoxycarbonyl. It can also be produced by esterification. The esterification is performed by, for example, acid (sulfuric acid, hydrochloric acid, p-toluenesulfonic acid) in a suitable solvent (methanol, ethanol, isopropanol, t-butanol, etc.) at -78 ° C to 200 ° C, more preferably 0 ° C. It can implement suitably by using at -100 degreeC.
Furthermore, esterification can also be carried out by using a halogenating agent (oxalyl chloride, thionyl chloride, etc.) in a suitable solvent (methylene chloride, chloroform, THF, dioxane, etc.) to convert a carboxyl compound into a reaction intermediate such as an acid halide. After the conversion, it can also be carried out by using alkanol (methanol, ethanol, isopropanol, etc.) at -78 ° C to 200 ° C.

(I) Among the target compounds [I], a compound having a carboxyl on R ^{1 to} R ⁶ can also hydrolyze a compound whose corresponding site is alkoxycarbonyl by any conventional method of ester hydrolysis. Can also be manufactured. The hydrolysis is carried out by adding a base (sodium hydroxide, potassium hydroxide, potassium carbonate, lithium hydroxide, etc.) in an appropriate solvent (alcohol solvent such as methanol or ethanol or dioxane, THF, water or the like or a mixed solvent thereof). It can implement suitably by using at -78 degreeC-200 degreeC, More preferably, 0 degreeC-100 degreeC.
Furthermore, the hydrolysis is also preferably carried out by using an acid (sulfuric acid, hydrochloric acid, etc.) at −78 ° C. to 200 ° C. in an appropriate solvent (THF, dioxane, acetic acid, water, etc. or a mixed solvent thereof). You can also.

(J) Of the target compound [I], a compound having formyl on R ^{1 to} R ⁶ is also produced from a compound in which the corresponding site is carboxyl by any conventional method for reducing carboxyl to aldehyde. You can also. In this reaction, an acid halide is synthesized using a halogenating agent (oxalyl chloride, thionyl chloride, etc.) in a suitable solvent (methylene chloride, chloroform, THF, etc. or a mixed solvent thereof), and then the acid halide is subjected to a hydrogen atmosphere. It can be suitably carried out by reduction with a metal catalyst (palladium carbon, platinum dioxide, etc.) at -78 ° C to 200 ° C.
(K) Among the target compound [I], a compound having hydroxymethyl on R ^{1 to} R ⁶ can be produced by using any conventional method of reduction reaction of ester or carboxylic acid to alcohol. For example, this reaction can be carried out by reducing the corresponding carboxyl or alkoxycarbonyl at a suitable solvent (methylene chloride, chloroform, THF, etc.) at −78 ° C. to 200 ° C. with a reducing agent (sodium borohydride, diborane, lithium aluminum hydride, hydrogen For example, diisobutylaluminum chloride).

(L) Among the target compounds [I], a compound having a carboxyl on R ^{1 to} R ⁶ can be produced by using a conventional method for oxidizing a primary alcohol to a carboxylic acid. For example, this reaction may be carried out by converting a compound whose corresponding site is hydroxymethyl into an oxidizing agent (chromium trioxide, dichromic acid) in an appropriate solvent (methylene chloride, acetone, chloroform, DMF, etc.), for example, at 0 ° C. to 100 ° C. It can be preferably carried out by treating with pyridinium or the like.

(M) Among the target compounds [I], compounds having amino on R ^{1 to} R ⁶ can be produced by using any conventional method for reducing nitro to amine. For example, in this reaction, a compound in which the corresponding site is nitro in a suitable solvent (methanol, ethanol, DMF, THF, dioxane, etc.) in a hydrogen atmosphere at −78 ° C. to 200 ° C. is converted to a metal catalyst (palladium carbon, dioxide dioxide). For example, platinum).
Further, this step is more preferably at −78 ° C. to 200 ° C. in an appropriate solvent (alcohol solvent such as methanol or ethanol or methylene chloride, chloroform, THF, dioxane, acetic acid, water, or a mixed solvent thereof). Can be suitably carried out by using a reducing agent (such as stannous chloride, iron, zinc, etc.) at 0 to 100 ° C.

(N) Among the target compounds [I], a compound having halogenosulfonyl on R ^{1 to} R ⁶ is obtained by reacting a compound in which the corresponding site is amino under the so-called Sandmayer reaction conditions, via a diazonium salt. It can be produced by sulfonylation. The formation of a diazonium salt is, for example, the presence of an appropriate acid (hydrochloric acid, sulfuric acid, etc.) and / or an additive (cupric chloride, etc.) in an appropriate solvent (water, methylene chloride, chloroform, THF, etc. or a mixed solvent thereof). It can be suitably carried out by using an oxidizing agent (sodium nitrite, isoamyl nitrite, tert-butyl nitrite, etc.) at -78 ° C to 200 ° C in the absence or absence. Subsequent halogenosulfonylation can be carried out by referring to (MM) described later.

(O) Among the target compounds [I], a compound having a substituted or unsubstituted aminosulfonyl on R ^{1 to} R ⁶ is also a reaction of a compound whose corresponding site is halogenosulfonyl with a substituted or unsubstituted amine. Can also be manufactured. This reaction is carried out in a suitable solvent (methylene chloride, chloroform, THF, dioxane, water, etc.) in the presence or absence of a base (pyridine, triethylamine, sodium hydroxide, sodium carbonate, etc.) at −78 ° C. to 200 ° C. It can implement suitably.
(P) Among the target compounds [I], compounds having alkylthio, cycloalkylthio, or heterocyclic thio on R ^{1 to} R ⁶ are also described in, for example, literature (Young RN, et al., Tetrahedron Lett., 1984, 25 ( 17), 1753.) In the same manner as described in the above, after converting a compound in which the corresponding site is methylsulfinyl to thiol, a base (sodium hydride, cesium carbonate, potassium carbonate, potassium t-butoxide, triethylamine, Alkylating agent (haloalkyl, halocycloalkyl, haloheterocyclic compound, alkyl mesylate, cycloalkyl mesylate, heterocyclic mesylate, alkyl tosylate, cycloalkyl tosylate, in the presence or absence of diazabicycloundecene, etc.) It can also be produced by reacting with a heterocyclic tosylate or the like.

(Q) Among the target compound [I], a compound having a substituted or unsubstituted alkanoylamino on R ^{1 to} R ⁶ can also be produced by alkanoylating a compound in which the corresponding site is amino. The alkanoylation can be carried out in the same manner as the reaction (C) above. Moreover, this alkanoylation can be implemented with the compound whose corresponding site | part is a secondary amine and a primary amine.
(R) Among the target compounds [I], compounds having substituted sulfonylamino such as alkylsulfonylamino, heteroarylsulfonylamino, heterocyclic sulfonylamino and the like on R ^{1 to} R ⁶ are also compounds in which the corresponding site is amino Can also be produced by sulfonylation. The sulfonylation may be carried out in a suitable solvent (water, THF, methylene chloride, chloroform, etc.) in the presence or absence of a base (triethylamine, diisopropylethylamine, pyridine, etc.) at −78 ° C. to 200 ° C. it can. Also, the sulfonylation can be carried out with a compound in which the corresponding site is a secondary amine or a primary amine.

(S) Among the target compounds [I], a compound having a secondary alcohol on R ^{1 to} R ⁶ can be produced by using any conventional method for converting a ketone to a secondary alcohol. For example, this reaction can be carried out in the same manner as in the reaction (K) above for a compound having a corresponding oxo.

(T) Among the target compounds [I], a compound having oxo on R ^{1 to} R ⁶ can be produced by using any conventional method for converting a secondary alcohol into a ketone. For example, this reaction is carried out by dimethyl sulfoxide oxidation (Swern oxidation) using an activating agent such as oxalyl chloride in an appropriate solvent (dimethyl sulfoxide, chloroform, methylene chloride, etc.), or in the presence of a base (triethylamine, etc.) or In the absence of oxidizing agent (activated manganese dioxide, sulfur trioxide-pyridine complex, 1-hydroxy-1,2-benziodoxol-3 (1H) -one-1-oxide, 1,1,1-tri And acetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one, pyridinium chlorochromate, pyridinium dichromate, etc.).

(U) Among the target compounds [I], a compound having a secondary alcohol on R ^{1 to} R ⁶ is produced by using any conventional method for converting a compound having formyl to a secondary alcohol. Can do. For example, in this reaction, the corresponding formyl compound and metal reagent (alkyl magnesium halide, alkyl lithium, dialkyl zinc, etc.) are used in an appropriate solvent (THF, toluene, diethyl ether, etc.) at −78 ° C. to 100 ° C. It can implement suitably.

(V) Among the target compound [I], a compound having hydroxyamidino on R ^{1 to} R ⁶ can be produced by using any conventional method for converting a cyano group into a hydroxyamidino group. For example, in this reaction, a compound having a corresponding cyano and hydroxylamine (or a salt thereof with an appropriate acid) are heated at 0 ° C. to 100 ° C. in an appropriate solvent (water, methanol, ethanol, etc. or a mixed solvent thereof). The reaction can be suitably carried out by reacting in the presence or absence of a base (sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium t-butoxide, triethylamine, pyridine, etc.).

(W) Among the target compound [I], a compound having an unsubstituted carbamoyl on R ^{1 to} R ⁶ can be produced by using any conventional method for converting a cyano group into an unsubstituted carbamoyl group. For example, in this reaction, a compound having a corresponding cyano is converted to a base (sodium hydroxide, potassium hydroxide) at −20 ° C. to 100 ° C. in an appropriate solvent (water, methanol, ethanol, isopropanol, etc., or a mixed solvent thereof). , Potassium t-butoxide, etc.).
(X) Of the target compound [I], a compound having a tertiary alcohol on R ^{1 to} R ⁶ is produced, for example, by reacting a corresponding compound having oxo under the conditions (U) above. Can do.

(Y) Among the target compounds [I], the production of a compound having an optically active secondary alcohol on R ^{1 to} R ⁶ can be carried out by arbitrarily dividing the secondary alcohol compound by an enzymatic transesterification method. It can be carried out by using a conventional method. For example, in this production, the corresponding racemic secondary alcohol is converted to an enzyme at −78 ° C. to 100 ° C. in an appropriate solvent (t-butyl methyl ether, hexane, diisopropyl ether, THF, diethyl ether, water, etc.). It can be preferably carried out by treating with an acyl donor (such as vinyl acetate) in the presence of (such as lipase PS).

(Z) The production of the compound having alkyl on R ^{1 to} R ⁶ among the target compound [I] can be carried out by using a so-called catalytic hydrogenation method. For example, this compound can be obtained by reacting a compound having a corresponding alkenyl with a metal catalyst (palladium carbon, carbon dioxide, methanol, ethanol, DMF, THF, acetic acid or the like or a mixed solvent thereof) at 0 ° C. to 200 ° C. in a hydrogen atmosphere. It can be suitably manufactured by treating with platinum dioxide or the like.
(AA) Among the target compounds [I], the production of a compound having 1,2-diol on R ^{1 to} R ⁶ is, for example, an appropriate solvent (water, acetone, THF, acetonitrile, ethyl acetate or the like, or a mixed solvent thereof) ), The compound having the corresponding alkenyl is treated with an oxidizing agent (osmium tetroxide, ruthenium tetroxide, sodium periodate, etc.) at 0 ° C. to 100 ° C., and can be suitably carried out.

(BB) Among the target compound [I], the production of a compound having a halogen atom on R ^{1 to} R ⁶ can be carried out by using any conventional method for halogenating an alcohol. For example, this production is suitably carried out by treating the corresponding alcohol with carbon tetrabromide in the presence of triphenylphosphine at 0 ° C. to 100 ° C. in a suitable solvent (methylene chloride, chloroform, etc.). be able to.
(CC) Among the target compounds [I], the production of a compound having unsubstituted and substituted alkylthio, heteroarylthio or arylthio on R ¹ , R ² , R ⁵ or R ⁶ is performed by converting the thiol form to an aryl halide, halogen This can be done by using any conventional method of coupling with a heteroaryl bromide, aryl triflate or heteroaryl triflate. For example, this production can be carried out at 0 ° C. to 200 ° C. in the presence or absence of a base (triethylamine, diisopropylamine, etc.) in a suitable solvent (dioxane, toluene, THF, 1,2-dimethoxyethane, etc. or a mixed solvent thereof). In the presence of a metal catalyst (tetrakis (triphenylphosphine) palladium, etc.), the compound having a corresponding halogen atom or triflate is treated with a thiol (hydroxyalkylthiol, dialkylaminoalkylthiol, etc.) to suitably carry out. Can do.

(DD) Among target compounds [I], the production of a compound having mono-substituted or di-substituted alkylamino on R ^{1 to} R ⁶ can be carried out, for example, by using a suitable solvent (methanol, ethanol, dioxane, toluene, THF, 1, 2 A compound having a corresponding haloalkyl in the presence or absence of a base (triethylamine, diisopropylamine, etc.) in a dimethoxyethane, It can be preferably carried out by treating with methylamine or the like. In addition, a compound having dimethylamino is obtained by converting a compound having a corresponding haloalkyl to N- (trimethylsilyl) at 0 ° C. to 200 ° C. in an appropriate solvent (methanol, ethanol, dioxane, toluene, THF, 1,2-dimethoxyethane, etc.). ) It can manufacture suitably by processing with dimethylamine.

(EE) Among the target compounds [I], the production of a compound having alkynyl on R ¹ , R ² , R ⁵ or R ⁶ is carried out by combining an aryl halide, a halogenated heteroaryl, an aryl triflate or a heteroaryl triflate with an alkyne. It can be carried out by using any conventional method of so-called Sonogashira coupling reaction with the compound having it. For example, the preparation may be carried out in the presence of a base (triethylamine, diisopropylamine, etc.) and / or a copper salt (eg cuprous iodide) in a suitable solvent (dioxane, toluene, THF, 1,2-dimethoxyethane, etc.), or Treating a compound having a corresponding halogen atom with an alkyne (propargyl alcohol, N, N-dimethylpropargylamine, etc.) in the presence of a metal catalyst (tetrakis (triphenylphosphine) palladium, etc.) in the absence of 0 ° C. to 200 ° C. By doing so, it can be suitably implemented.

(FF) Among target compounds [I], the production of a compound having tetrazolyl on R ^{1 to} R ⁶ can be carried out by using any conventional method for converting a cyano group into a tetrazolyl group. For example, this production is carried out in the presence of a base (triethylamine, diisopropylamine, etc.) or a salt (triethylamine hydrochloride, etc.) in a suitable solvent (methanol, ethanol, DMF, dioxane, toluene, THF, 1,2-dimethoxyethane, etc.) Alternatively, it can be suitably carried out by treating a compound having a corresponding cyano with metal azide (sodium azide, tributyltin azide, trimethylsilyl azide) at 0 ° C. to 200 ° C. in the absence.
(GG) Among the target compound [I], the production of a compound having O-alkoxycarbonylhydroxyimine on R ^{1 to} R ⁶ is carried out by using an appropriate solvent (DMF, dioxane, toluene, THF, 1,2-dimethoxyethane, etc. ) Or by treating a compound having a corresponding hydroxyimine with an alkyl chlorocarbonate (such as ethyl chlorocarbonate) in the absence of a solvent in the presence or absence of a base (pyridine, triethylamine, etc.) at 0 ° C. to 200 ° C. It can implement suitably.

(HH) Among the target compounds [I], the production of a compound having aryl or heteroaryl on R ¹ , R ² , R ⁵ or R ⁶ is carried out by any conventional method of so-called Stille coupling or Suzuki coupling reaction. It can be implemented by using. For example, this production is carried out in a suitable solvent (dioxane, toluene, THF, 1,2-dimethoxyethane or the like or a mixed solvent thereof) in a base (triethylamine, diisopropylamine, sodium t-butoxide, sodium carbonate, cesium carbonate, potassium phosphate). Etc.) In the presence or absence, at 0 ° C. to 200 ° C., a metal catalyst (for example, dichlorobis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium), tris (dibenzylideneacetone) dipalladium, dichloro [1 , 1′-bis (diphenylphosphino) ferrocene] palladium, palladium acetate, etc.), the corresponding haloaryl-containing compound is converted into aryltrialkyltin, heteroaryltrialkyltin, aryldihydroxyborane, heteroaryldihydroxyl Borane, aryl catechol borane, by treatment with a heteroaryl catechol borane, can be preferably carried out.

(II) In each of the above reactions, a protecting group is appropriately introduced or removed, and finally the desired compound [I] can be obtained. Such a method for introducing and removing a protecting group can be carried out according to the description of Protective Groups in Organic Synthesis Third Edition (Theodora W. Green and Peter G. Wuts).
(JJ) Alternatively, the present compound [I] is optionally subjected to any reaction of the above (A) to (II) with respect to compound [II] to compound [XVI] at an appropriate stage in each step of the production. By doing so, it can also be synthesized.

［式中、Ｃｙは有機環状基（例えば、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリール、置換若しくは非置換のシクロアルキル、又は置換若しくは非置換のヘテロ環）を表し、Ａｌｋｙｌはアルキルを表し、Ｒ^Ｘ、及びＲ^Ｙはそれぞれ独立して有機基を表すか、あるいは、Ｒ^Ｘ及びＲ^Ｙが連結し隣接する窒素原子と一緒になって環状の有機基を形成する。］
シス体（ヒドラゾン部とカルボキシル基又はアルコキシカルボニル基の位置関係がシスである化合物。以下、この項で同じ）−トランス体の混合物である化合物［ＸＩＶａ］を、トランス体の反応速度が、シス体の反応速度より速い事を利用し、選択的に加水分解することによりトランス体化合物である［Ｅ−ＩＩａ］を得ることができる。加水分解の条件としては、アルカリ加水分解が好ましい。アルカリ加水分解の条件としては、塩基は、水酸化ナトリウム、水酸化カリウム、炭酸カリウム、水酸化リチウム等のような、水酸化アルカリ金属、水酸化マグネシウム、水酸化カルシウムのような水酸化アルカリ土類金属が好ましく、溶媒はメタノール、エタノール等のアルコール系溶媒又はジオキサン、ＴＨＦ、水等又はその混合溶媒が好ましい。反応温度は-78℃〜200℃にて行え、好ましくは-20℃〜100℃、より好ましくは0℃〜25℃が好ましい。反応時間は、１０分間から７日間で行え、好ましくは１時間から４８時間、より好ましくは１時間から２４時間反応させるか、薄層クロマトグラフィー、高速液体クロマトグラフィー等でモニタリングし反応時間を決めるのが好ましい。Ｃｙは、Ｒ^１及びＲ^２を有する環Ａが好ましい。Ｒ^Ｘ及びＲ^Ｙは、好ましくは、それぞれＲ^３及びＲ^４である。［Ｚ−ＸＩＶａ］と［Ｅ−ＸＩＩａ］は転溶、又はイオン交換樹脂若しくはカラムクロマトグラフィーによる精製等で、良好に分離できる。
なお、本方法に従って、化合物［ＩＩ］も製造できる。 (KK)

[Wherein Cy represents an organic cyclic group (for example, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycle), and Alkyl represents alkyl R ^X and R ^Y each independently represent an organic group, or R ^X and R ^Y are connected to form a cyclic organic group together with the adjacent nitrogen atom. ]
Compound [XIVa], which is a mixture of a cis isomer (a compound in which the positional relationship between a hydrazone moiety and a carboxyl group or an alkoxycarbonyl group is cis; hereinafter the same in this section) -trans isomer is converted to a cis isomer. [E-IIa], which is a trans isomer compound, can be obtained by selective hydrolysis utilizing the fact that the reaction rate is faster than the above. As the hydrolysis conditions, alkaline hydrolysis is preferable. The conditions for alkaline hydrolysis include bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, lithium hydroxide and the like, and alkaline earth hydroxides such as alkali metal hydroxide, magnesium hydroxide and calcium hydroxide. Metal is preferable, and the solvent is preferably an alcohol solvent such as methanol or ethanol, dioxane, THF, water or the like, or a mixed solvent thereof. The reaction temperature can be -78 ° C to 200 ° C, preferably -20 ° C to 100 ° C, more preferably 0 ° C to 25 ° C. The reaction time can be 10 minutes to 7 days, preferably 1 hour to 48 hours, more preferably 1 hour to 24 hours, or monitoring by thin layer chromatography, high performance liquid chromatography or the like to determine the reaction time. Is preferred. Cy is preferably ring A having R ¹ and R ² . R ^X and R ^Y are preferably R ³ and R ⁴ respectively. [Z-XIVa] and [E-XIIa] can be separated satisfactorily by phase transfer or purification by ion exchange resin or column chromatography.
In addition, according to this method, compound [II] can also be manufactured.

［式中、Ｗａは水素又は有機基（置換若しくは非置換のアルキル等）を表し、Ｗｂは水素、置換若しくは非置換のアルキル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリール、置換若しくは非置換のシクロアルキル、又は置換若しくは非置換のヘテロ環を表し、Ｒ^Ｘ、及びＲ^Ｙはそれぞれ独立して有機基を表すか、あるいは、Ｒ^Ｘ及びＲ^Ｙが連結し隣接する窒素原子と一緒になって環状の有機基を形成し、その他の記号は同一意味を有する。］
シス体（ヒドラゾン部とカルボキシル基又は置換若しくは非置換のカルバモイル基の位置関係がシスである化合物。以下、この項で同じ）−トランス体の混合物である化合物［ＩＩａ］を、トランス体の反応速度が、シス体の反応速度より速い事を利用し、選択的にアミド化反応を行うことによりトランス体化合物である［Ｅ−Ｉａ］を得ることができる。アミド化反応は常法により行え、好ましくは（Ｃ）に記載した方法が挙げられる。反応時間は、１０分間から７日間で行え、好ましくは１時間から４８時間、より好ましくは１時間から２４時間反応させるか、薄層クロマトグラフィー、高速液体クロマトグラフィー等でモニタリングし反応時間を決めるのが好ましい。Ｃｙは、Ｒ^１及びＲ^２を有する環Ａが好ましい。Ｗａは好ましくはアルキル又は水素であり、水素が特に好ましい。Ｗｂは好ましくはＲ^５及びＲ^６を有する環Ｔである。Ｒ^Ｘ及びＲ^Ｙは、好ましくは、それぞれＲ^３及びＲ^４である。［Ｚ−ＩＩａ］と［Ｅ−Ｉａ］は転溶、又はイオン交換樹脂若しくはカラムクロマトグラフィーによる精製等で、良好に分離できる。
なお、本方法に従って、化合物［Ｉ］も製造できる。 (LL)

[Wherein, Wa represents hydrogen or an organic group (substituted or unsubstituted alkyl, etc.), Wb represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Represents an unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycle, and R ^X and R ^Y each independently represent an organic group, or R ^X and R ^Y are linked together with an adjacent nitrogen atom To form a cyclic organic group, and other symbols have the same meaning. ]
Compound [IIa], which is a mixture of a cis isomer (a compound in which the positional relationship between a hydrazone moiety and a carboxyl group or a substituted or unsubstituted carbamoyl group is cis, hereinafter the same in this section) -trans isomer, However, by utilizing the fact that the reaction rate is faster than that of the cis isomer, selective amidation reaction can be performed to obtain [E-Ia] which is a trans isomer compound. The amidation reaction can be carried out by a conventional method, preferably the method described in (C). The reaction time can be 10 minutes to 7 days, preferably 1 hour to 48 hours, more preferably 1 hour to 24 hours, or monitoring by thin layer chromatography, high performance liquid chromatography or the like to determine the reaction time. Is preferred. Cy is preferably ring A having R ¹ and R ² . Wa is preferably alkyl or hydrogen, with hydrogen being particularly preferred. Wb is preferably a ring T having R ⁵ and R ⁶ . R ^X and R ^Y are preferably R ³ and R ⁴ respectively. [Z-IIa] and [E-Ia] can be satisfactorily separated by dissolution or purification by ion exchange resin or column chromatography.
In addition, according to this method, compound [I] can also be manufactured.

(MM) A halogenosulfonylating agent (sulfur dioxide, sodium hydrogen sulfite, etc., alkali metal nitrite, alkali metal hydrogen nitrite, in the presence of an additive (cupric chloride, etc.) to the salt of aryldiazonium or heteroaryldiazonium , Alkaline earth metal nitrite) can be converted to halogenosulfonylaryl or halogenosulfonylheteroaryl. When a nitrite (an alkali metal nitrite, an alkali metal hydrogen nitrite, an alkaline earth metal nitrite, or the like) is used as the halogenosulfonylating agent, weighing is preferable. The reaction solvent is preferably an acid selected from hydrochloric acid, hydrobromic acid, and hydroiodic acid, and acetic acid, sulfuric acid, water, THF, ethyl acetate, or a mixed solvent thereof can be mixed as appropriate. The reaction temperature can be carried out at -78 ° C to 200 ° C, preferably -20 ° C to 100 ° C, more preferably -20 ° C to 30 ° C. It can also be carried out by adding a halogenosulfonylating agent and an additive to the reaction solution of aryldiazonium salt or heteroaryldiazonium salt which can be produced from arylamine or heteroarylamine or a salt thereof according to (N). Note that aryl and heteroaryl in (MM) may have 1 to 5 substituents.

Experimental example

Glucokinase activation action The glucokinase activity does not directly measure the produced glucose-6-phosphate, but 6-phosphogluconic acid by glucose-6-phosphate dehydrogenase, which is a conjugate enzyme of glucose-6-phosphate. It was investigated by measuring the amount of NADPH produced when saponin was produced. As the glucokinase enzyme, human liver type GST-GK expressed in E. coli was used. The activity was measured according to the following procedure. Specifically, 30 mM MgCl ₂ , 30 mM KCl, 1 mM DTT, 5 mM NADP (Nacalai), 0.7 mU / mL G6PDH (Roche 737-232 grade II from yeast), 0.17 μL / mL GST-GK was used as the reaction solution. A 30 mM HEPES buffer (pH 7.4) was prepared. The evaluation compound was dissolved in DMSO and added to the reaction solution so that the final concentration was 0.01 to 100 μM (5% DMSO). Glucose (final concentration 5 mM) was added as a substrate, and ATP (final concentration 5 mM) was added to initiate the reaction. The reaction temperature was 30 ° C., and the production of NADPH was monitored by the change in absorbance at 340 nm. The increase in absorbance for 10 minutes from the start of the reaction was measured, and the blank corrected one was defined as GK activity (mOD / min). The EC ₅₀ value was calculated from the GK activity value at the time of adding the evaluation compound at each concentration.

  Since the compound [I] of the present invention or a pharmacologically acceptable salt thereof has an excellent glucokinase activating action, diseases involving glucokinase such as diabetes, particularly type II diabetes, or retinopathy, nephropathy It is useful for the prevention or treatment of chronic complications of diabetes such as neurosis, ischemic heart disease or arteriosclerosis, and obesity.

  The present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited to these. In the examples, APCI represents atmospheric pressure chemical ionization mass spectrum and ESI represents electrospray ionization mass spectrum. In the present specification, THF represents tetrahydrofuran, DMF represents dimethylformamide, and DMSO represents dimethyl sulfoxide. In the examples, Me represents a methyl group, Et represents an ethyl group, Ac represents an acetyl group, and Boc represents a t-butoxycarbonyl group.

（１）塩化アルミニウム67.0 g(503 mmol)の塩化メチレン溶液(380 ml)に塩化グリオキシル酸メチル48.9 g(399 mmol)を氷冷下加え、そのまま３０分攪拌後、シクロプロピルフェニルスルフィド（１−Ａ）50 g(333 mmol)の塩化メチレン溶液(60 ml)を加えた後、氷冷浴を外し室温で１．５時間攪拌した。反応液を氷に注いだ後、塩化メチレン層を分液、減圧下濃縮した。残渣を酢酸エチルに溶解し、水、飽和重曹水、飽和食塩水で順次洗浄、硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をヘキサンで結晶化させることにより、化合物（１−Ｂ）69.5 g(収率88%)を淡黄色結晶として得た。MS(m/z)APCI:237[M+H]⁺ Example 1

(1) To a methylene chloride solution (380 ml) of 67.0 g (503 mmol) of aluminum chloride, 48.9 g (399 mmol) of methyl glyoxylate was added under ice-cooling. ) After adding 50 g (333 mmol) of methylene chloride solution (60 ml), the ice-cooled bath was removed and the mixture was stirred at room temperature for 1.5 hours. After pouring the reaction solution onto ice, the methylene chloride layer was separated and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with water, saturated aqueous sodium hydrogen carbonate, and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from hexane to obtain 69.5 g (yield 88%) of compound (1-B) as pale yellow crystals. MS (m / z) APCI: 237 [M + H] ⁺

(2) An aqueous solution (513 ml) of Oxon ^TM 178 g (289 mmol) in a methanol: THF (1: 1) solution (1480 ml) of the above compound (1-B) 57.0 g (241 mmol). After dropping, the ice bath was removed at the same temperature for 1 hour, and the mixture was further stirred at room temperature for 12 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from diethyl ether to obtain 44.3 g (yield 69%) of compound (1-C) as pale yellow crystals. MS (m / z) APCI: 286 [M + H] ⁺

(3) A methanol solution (160 ml) of 16.7 g (62.1 mmol) of the above compound (1-C), 9.89 g (80.7 mmol) of aminopyrrolidine hydrochloride and 8.37 ml (99.3 mmol) of pyridine at 65 ° C. for 6 hours. The mixture was further stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the resulting residue, followed by saturated aqueous sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, and purified by NH silica gel column chromatography using ethyl acetate as an elution solvent. Toluene was added to the residue obtained by concentrating the eluate under reduced pressure, and the remaining pyridine was removed by azeotropic distillation under reduced pressure. The residue was purified by silica gel chromatography (50-67% ethyl acetate-hexane) to give 10.4 g (yield 50%) of compound (1-D) (E: Z = 5: 1) as a pale yellow solid. It was.

(4) To a methanol solution (250 ml) of 16.7 g (49.8 mmol) of the above compound (1-D), 99.5 ml (199 mmol) of 2N aqueous sodium hydroxide solution was added under ice cooling, and further at the same temperature for 1 hour. Stir at room temperature for 26 hours. Diethyl ether (700 ml) and water (300 ml) were added to the residue obtained by concentrating the reaction solution under reduced pressure. After separating the aqueous layer, the organic layer was further extracted with water (300 ml). To the combined aqueous layer, 2N hydrochloric acid (99.5 ml) was carefully added and extracted three times with chloroform. 2N hydrochloric acid (20 ml) was further added to the aqueous layer, and the mixture was extracted twice with chloroform. The combined extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude crystals were pulverized in THF-diethyl ether and collected by filtration to give compound (1-E) ( E-isomer) 14.2 g (yield 87%) was obtained as colorless crystals. MS (m / z) ESI: 321 [MH] ^-

(5) 42 mg (0.13 mmol) of the above compound (1-E), 72 mg (0.40 mmol) of 5-methoxy [1,3] thiazole [5,4-b] pyridin-2-amine, and 4- ( N, N-dimethylamino) pyridine (37 mg, 0.27 mmol) in chloroform solution (2 ml) was stirred at room temperature with 28.6 g (184 mmol) of N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide hydrochloride. A chloroform solution (0.54 ml) was added, and the mixture was stirred overnight at the same temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was vigorously stirred for 10 minutes. The organic layer was separated and concentrated under reduced pressure. The obtained residue was pulverized in methanol-THF-DMSO-diethyl ether, collected by filtration, and washed with diethyl ether to give 41 mg (yield 65%) of compound (1-F) as a colorless solid.
MS (m / z) APCI: 486 [M + H] ⁺

（１）化合物（１−Ｃ２）10.0 g(35.4 mmol)の１６％塩酸(100ml)溶液を２４時間加熱還流した。冷却後、反応液を減圧下濃縮し、得られた残渣をトルエン中で粉砕することにより、化合物（２−Ａ）9.0 g(定量的)を無色固体として得た。MS(m/z)ESI:253[M-H]^- Example 2

(1) A solution of 10.0 g (35.4 mmol) of compound (1-C2) in 16% hydrochloric acid (100 ml) was heated to reflux for 24 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residue was pulverized in toluene to obtain 9.0 g (quantitative) of Compound (2-A) as a colorless solid. MS (m / z) ESI: 253 [MH] ^-

(2) A methylene chloride solution of 2.54 g (9.99 mmol) of compound (2-A) and 1.02 g (9.99 mmol) of 4-aminomorpholine was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was crystallized in methylene chloride-diethyl ether to give 2.32 g of compound (2-B) (E: Z = 4.2: 1) (69% yield). ) Was obtained as colorless crystals. MS (m / z) ESI: 337 [MH] ^-
(3) Compound (2-B) 169 mg (0.50 mmol), 2-amino-5-fluorothiazole hydrochloride 231 mg (1.50 mmol), and 4- (N, N-dimethylamino) pyridine 91 mg (0.75 mmol) N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide (0.136 ml, 0.75 mmol) was added to a methylene chloride solution at room temperature, and the mixture was stirred at the same temperature for 24 hours. The reaction solution was purified by silica gel column chromatography (2 to 10% methanol-containing chloroform) to obtain 65 mg (yield 30%) of compound (2-C) (E-isomer) as a colorless solid. MS (m / z) APCI: 439 [M + H] ⁺

The following compounds were obtained by the same treatment as in the synthesis methods described in the present specification and the examples.

MS(m/z)APCI:413/415[M+H]⁺ Example 6

MS (m / z) APCI: 413/415 [M + H] ⁺

MS(m/z)APCI:431[M+H]⁺ Example 13

MS (m / z) APCI: 431 [M + H] ⁺

MS(m/z)APCI:380[M+H]⁺ Example 14

MS (m / z) APCI: 380 [M + H] +

MS(m/z)APCI:567[M+H]⁺ Example 27

MS (m / z) APCI: 567 [M + H] ⁺

MS(m/z)ESI:406[M+H]⁺ Example 28

MS (m / z) ESI: 406 [M + H] ⁺

MS(m/z)APCI:406[M+H]⁺ Example 29

MS (m / z) APCI: 406 [M + H] ⁺

MS(m/z)APCI:453/455[M+H]⁺ Example 30

MS (m / z) APCI: 453/455 [M + H] ⁺

MS(m/z)APCI:397/399[M+H]⁺ Example 36

MS (m / z) APCI: 397/399 [M + H] ⁺

MS(m/z)APCI:401[M+H]^＋ Example 37

MS (m / z) APCI: 401 [M + H] ⁺

MS(m/z)APCI:422[M+H]⁺ Example 49

MS (m / z) APCI: 422 [M + H] ⁺

MS(m/z)APCI:477[M+H]⁺ Example 58

MS (m / z) APCI: 477 [M + H] ⁺

MS(m/z)ESI:540[M+H]⁺ Example 59

MS (m / z) ESI: 540 [M + H] ⁺

MS(m/z)ESI:504[M+H]⁺ Example 60

MS (m / z) ESI: 504 [M + H] ⁺

MS(m/z)ESI:420[M+H]⁺ Example 61

MS (m / z) ESI: 420 [M + H] ⁺

MS(m/z)ESI:450[M+H]⁺ Example 62

MS (m / z) ESI: 450 [M + H] ⁺

MS(m/z)ESI:498[M+H]⁺ Example 63

MS (m / z) ESI: 498 [M + H] ⁺

MS(m/z)ESI:512[M+H]⁺ Example 64

MS (m / z) ESI: 512 [M + H] ⁺

MS(m/z)APCI:564[M+H]⁺ Example 65

MS (m / z) APCI: 564 [M + H] ⁺

MS(m/z)APCI:451[M+H]⁺ Example 66

MS (m / z) APCI: 451 [M + H] ⁺

MS(m/z)APCI:394/396[M+H]⁺ Example 67

MS (m / z) APCI: 394/396 [M + H] ⁺

Example 68

To a solution of the compound of Example 58 in 1.90 g (3.99 mmol) in ethanol (20 ml) was added 1N aqueous sodium hydroxide solution (5 ml), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was acidified with 2N hydrochloric acid (10 ml), and the precipitate was collected by filtration to give the above compound (1.73 g, yield 97%) as a colorless solid. MS (m / z) APCI: 449 [M + H] ⁺

実施例６８の化合物100 mg(0.223 mmol)のＴＨＦ(5 ml)溶液に、０℃でＮ−メチルモルホリン37.0μl(0.337 mmol)及びクロロギ酸イソブチル43.5μl(0.337 mmol)を順次加え、同温で３０分間撹拌した。更に、２ＮジメチルアミンのＴＨＦ溶液335μl(0.670 mmol)を加え、同温で１時間、室温で４０時間撹拌した。反応混合物に水(2 ml)を加え、クロロホルムを溶出溶媒として用いChem Elut(VARIAN社)でろ過した。併せた溶出液を減圧下濃縮し、残渣をシリカゲルクロマトグラフィーによって精製（３〜１０％メタノール−クロロホルム）することにより、上記化合物46 mg(収率45%)を淡黄色固体として得た。MS(m/z)APCI:462[M+H]⁺ Example 69

To a solution of 100 mg (0.223 mmol) of the compound of Example 68 in THF (5 ml), N-methylmorpholine (37.0 μl, 0.337 mmol) and isobutyl chloroformate (43.5 μl, 0.337 mmol) were sequentially added at 0 ° C. at the same temperature. Stir for 30 minutes. Furthermore, 2N dimethylamine in THF (335 μl, 0.670 mmol) was added, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 40 hours. Water (2 ml) was added to the reaction mixture, and the mixture was filtered through Chem Elut (VARIAN) using chloroform as an elution solvent. The combined eluate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (3 to 10% methanol-chloroform) to obtain 46 mg (yield 45%) of the above compound as a pale yellow solid. MS (m / z) APCI: 462 [M + H] ⁺

実施例６８の化合物100 mg(0.223 mmol)、２−（４−モルホリニル）エチルアミン44μl(0.335 mmol)、及び１−ハイドロキシベンゾトリアゾール52 mg(0.391 mmol)の塩化メチレン(5 ml)溶液に、０℃下、Ｎ−エチル−Ｎ’−（３−ジメチルアミノプロピル）カルボジイミド59μl(0.34 mmol)を加え、同温で１０分間、更に室温で３時間撹拌した。反応混合物に水(500μl)を加え、酢酸エチル(30 ml)を溶出溶媒として用いChem Elut(VARIAN社)及びBond Elut JR-NH₂(VARIAN社)を通してろ過した。併せた溶出液を減圧下濃縮し、残渣をシリカゲルクロマトグラフィーで精製（３〜１０％メタノール−クロロホルム）することにより、上記化合物89 mg(収率72%)を無色固体として得た。MS(m/z)APCI:561[M+H]⁺ Example 70

To a solution of 100 mg (0.223 mmol) of the compound of Example 68, 44 μl (0.335 mmol) of 2- (4-morpholinyl) ethylamine and 52 mg (0.391 mmol) of 1-hydroxybenzotriazole in methylene chloride (5 ml) was added at 0 ° C. Then, 59 μl (0.34 mmol) of N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide was added, and the mixture was stirred at the same temperature for 10 minutes and further at room temperature for 3 hours. Water (500 μl) was added to the reaction mixture, and the mixture was filtered through Chem Elut (VARIAN) and Bond Elut JR-NH ₂ (VARIAN) using ethyl acetate (30 ml) as an elution solvent. The combined eluate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (3 to 10% methanol-chloroform) to obtain 89 mg (yield 72%) of the above compound as a colorless solid. MS (m / z) APCI: 561 [M + H] ⁺

The following compounds were obtained by the same treatment as in the synthesis methods described in the present specification and the examples.

MS(m/z)APCI:534[M+H]⁺ Example 113

MS (m / z) APCI: 534 [M + H] ⁺

MS(m/z)APCI:518[M+H]⁺ Example 114

MS (m / z) APCI: 518 [M + H] ⁺

MS(m/z)APCI:550[M+H]⁺ Example 115

MS (m / z) APCI: 550 [M + H] ⁺

MS(m/z)APCI:566[M+H]⁺ Example 116

MS (m / z) APCI: 566 [M + H] ⁺

実施例１０の化合物50 mg(0.12 mmol)のメタノール(1 ml)溶液に、０℃で水素化ホウ素ナトリウム23 mg(0.37 mmol)を加え、室温で３０分間撹拌した。反応混合物にアセトン(1 ml)を加え、減圧下濃縮し、残渣をシリカゲルクロマトグラフィーで精製（２〜１０％メタノール−クロロホルム）することにより、上記化合物46 mg(収率92%)を無色固体として得た。MS(m/z)APCI:409[M+H]⁺ Example 117

To a solution of 50 mg (0.12 mmol) of the compound of Example 10 in methanol (1 ml), 23 mg (0.37 mmol) of sodium borohydride was added at 0 ° C. and stirred at room temperature for 30 minutes. Acetone (1 ml) was added to the reaction mixture, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (2-10% methanol-chloroform) to give 46 mg (92% yield) of the above compound as a colorless solid. Obtained. MS (m / z) APCI: 409 [M + H] ⁺

対応原料化合物を実施例１１７と同様に処理して、上記化合物を無色固体として得た。MS(m/z)APCI:435[M+H]⁺ Example 118

The corresponding starting material compound was treated in the same manner as in Example 117 to obtain the above compound as a colorless solid. MS (m / z) APCI: 435 [M + H] ⁺

実施例１８の化合物212 mg(0.49 mmol)及び１−メチルピペラジン66μl(0.594 mmol)の塩化メチレン(10 ml)溶液に、０℃でトリアセトキシヒドロホウ酸ナトリウム156 mg(0.736 mmol)を加え、同温で５分間、室温で４時間撹拌した。反応混合物に、更に１−メチルピペラジン66 μl(0.594 mmol)及び０℃でトリアセトキシヒドロホウ酸ナトリウム156 mg(0.736 mmol)を順次加え、室温で１８時間撹拌した。飽和炭酸水素ナトリウム水溶液(2 ml)を加え、室温で１０分間激しく撹拌した。反応混合物をChem Elut(VARIAN社)に通し、２０％メタノール−クロロホルム混合溶媒(30 ml)で溶出した。併せた溶出液を減圧下濃縮し、残渣をシリカゲルクロマトグラフィーで精製（９．１％メタノール−クロロホルム）し、エタノールで洗浄することにより、上記化合物141 mg(収率56%)を無色固体として得た。MS(m/z)APCI:517[M+H]⁺ Example 119

To a solution of 212 mg (0.49 mmol) of the compound of Example 18 and 66 μl (0.594 mmol) of 1-methylpiperazine in methylene chloride (10 ml) was added 156 mg (0.736 mmol) of sodium triacetoxyhydroborate at 0 ° C. Stir at warm for 5 minutes and at room temperature for 4 hours. To the reaction mixture, 66 μl (0.594 mmol) of 1-methylpiperazine and 156 mg (0.736 mmol) of sodium triacetoxyhydroborate were sequentially added at 0 ° C. and stirred at room temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution (2 ml) was added and stirred vigorously at room temperature for 10 minutes. The reaction mixture was passed through Chem Elut (VARIAN) and eluted with 20% methanol-chloroform mixed solvent (30 ml). The combined eluate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (9.1% methanol-chloroform) and washed with ethanol to obtain 141 mg (yield 56%) of the above compound as a colorless solid. It was. MS (m / z) APCI: 517 [M + H] ⁺

The following compounds were obtained by the same treatment as in the synthesis methods described in the present specification and the examples.

実施例１３２の化合物313 mg(0.52 mmol)の１，４−ジオキサン(5 ml)懸濁液に、室温下、４Ｎ塩化水素ジオキサン溶液(5 ml)を加えて、同温で２４時間激しく撹拌した。反応混合物に水(10 ml)を加えて希釈し、クロロホルム(20 ml)で洗浄した。水層に１０％炭酸ナトリウム水溶液(10 ml)を加え塩基性とし、クロロホルム(20 ml)で3回抽出した。併せたクロロホルム層を硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。残渣を酢酸エチル(10 ml)−ジエチルエーテル(20 ml)の混合溶媒中で粉砕し、ろ取することにより上記化合物208 mg(収率80%)を淡黄色固体として得た。MS(m/z)APCI:503[M+H]⁺ Example 154

To a suspension of 313 mg (0.52 mmol) of the compound of Example 132 in 1,4-dioxane (5 ml) was added 4N hydrogen chloride dioxane solution (5 ml) at room temperature, and the mixture was vigorously stirred at the same temperature for 24 hours. . The reaction mixture was diluted with water (10 ml) and washed with chloroform (20 ml). The aqueous layer was made basic by adding 10% aqueous sodium carbonate solution (10 ml), and extracted three times with chloroform (20 ml). The combined chloroform layers were dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was pulverized in a mixed solvent of ethyl acetate (10 ml) -diethyl ether (20 ml) and collected by filtration to obtain the above compound (208 mg, yield 80%) as a pale yellow solid. MS (m / z) APCI: 503 [M + H] ⁺

The following compounds were obtained by the same treatment as in the synthesis methods described in the present specification and the examples.

MS(m/z)APCI:460[M+H]⁺ Example 155

MS (m / z) APCI: 460 [M + H] ⁺

MS(m/z)APCI:517[M+H]⁺ Example 156

MS (m / z) APCI: 517 [M + H] ⁺

実施例１５４の化合物の３塩酸塩（中和する前の粗成生物）60 mg(0.098 mmol)及びＮ，Ｎ−ジイソプロピルエチルアミン77μl(0.44 mmol)のクロロホルム(3 ml)溶液に、氷冷下プロピオニルクロライド12μl(0.13 mmol)を加え、同温で１時間、室温で6時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液(1 ml)を加え、室温で1時間撹拌した。硫酸ナトリウムで乾燥し、Bond Elut JR-NH₂(VARIAN社)に通して酢酸エチル、及び９％メタノール−クロロホルム混合溶媒で溶出した。併せた溶出液を減圧下濃縮し、残渣をシリカゲルクロマトグラフィーで精製（０〜１０％メタノール−クロロホルム）することにより上記化合物48 mg(収率88%)を無色固体として得た。MS(m/z)APCI:559[M+H]⁺ Example 157

To a solution of the trihydrochloride of the compound of Example 154 (crude product before neutralization) 60 mg (0.098 mmol) and N, N-diisopropylethylamine 77 μl (0.44 mmol) in chloroform (3 ml) was added propionyl under ice-cooling. 12 μl (0.13 mmol) of chloride was added, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 6 hours. A saturated aqueous sodium hydrogen carbonate solution (1 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The extract was dried over sodium sulfate, passed through Bond Elut JR-NH ₂ (VARIAN), and eluted with ethyl acetate and a 9% methanol-chloroform mixed solvent. The combined eluate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0 to 10% methanol-chloroform) to obtain 48 mg (yield 88%) of the above compound as a colorless solid. MS (m / z) APCI: 559 [M + H] ⁺

The following compounds were obtained by the same treatment as in the synthesis methods described in the present specification and the examples.

MS(m/z)APCI:559[M+H]⁺ Example 162

MS (m / z) APCI: 559 [M + H] ⁺

MS(m/z)APCI:557[M+H]⁺ Example 163

MS (m / z) APCI: 557 [M + H] ⁺

実施例１５４の化合物の３塩酸塩（中和する前の粗生成物）60 mg(0.098 mmol)及びＮ，Ｎ−ジイソプロピルエチルアミン154μl(0.98 mmol)のクロロホルム(3 ml)溶液に、氷冷下、無水トリフルオロ酢酸38μl(0.27 mmol)を加え、同温で１時間、室温で終夜撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液(1 ml)を加え、室温で1時間撹拌した。硫酸ナトリウムで乾燥し、Bond Elut JR-NH₂(VARIAN社)に通して酢酸エチル、及び９％メタノール−クロロホルム混合溶媒で溶出した。併せた溶出液を減圧下濃縮し、残渣をシリカゲルクロマトグラフィーで精製（０〜１０％メタノール−クロロホルム）することにより、上記化合物46 mg(収率78%)を淡黄色粉末として得た。MS(m/z)APCI:599[M+H]⁺ Example 164

To a solution of the trihydrochloride of the compound of Example 154 (crude product before neutralization) 60 mg (0.098 mmol) and N, N-diisopropylethylamine 154 μl (0.98 mmol) in chloroform (3 ml) under ice-cooling, 38 μl (0.27 mmol) of trifluoroacetic anhydride was added, and the mixture was stirred at the same temperature for 1 hour and at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution (1 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The extract was dried over sodium sulfate, passed through Bond Elut JR-NH ₂ (VARIAN), and eluted with ethyl acetate and a 9% methanol-chloroform mixed solvent. The combined eluate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0 to 10% methanol-chloroform) to obtain 46 mg (yield 78%) of the above compound as a pale yellow powder. MS (m / z) APCI: 599 [M + H] ⁺

実施例１５４の化合物の３塩酸塩（中和する前の粗生成物）60 mg(0.098 mmol)及びＮ，Ｎ−ジイソプロピルエチルアミン77 μl(0.44 mmol)のぎ酸メチル(3 ml)溶液を室温で２４時間攪拌した。反応液をBond Elut JR-NH₂(VARIAN社)に通して酢酸エチル、及び９．１％メタノール−クロロホルム混合溶媒で溶出した。併せた溶出液を減圧下濃縮し、残渣をシリカゲルクロマトグラフィーで精製（０〜１０％メタノール−クロロホルム）することにより上記化合物39 mg(収率75%)を淡黄色アモルファスとして得た。MS(m/z)APCI:531[M+H]⁺ Example 165

A solution of the trihydrochloride of the compound of Example 154 (crude product before neutralization) 60 mg (0.098 mmol) and N, N-diisopropylethylamine 77 μl (0.44 mmol) in methyl formate (3 ml) was stirred at room temperature. Stir for 24 hours. The reaction solution was passed through Bond Elut JR-NH ₂ (VARIAN) and eluted with ethyl acetate and 9.1% methanol-chloroform mixed solvent. The combined eluates were concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0 to 10% methanol-chloroform) to obtain 39 mg (yield 75%) of the above compound as a pale yellow amorphous. MS (m / z) APCI: 531 [M + H] ⁺

実施例１５４の化合物の３塩酸塩60 mg(0.098 mmol)及びＮ，Ｎ−ジイソプロピルエチルアミン77 μl(0.444 mmol)のアセトニトリル(3 ml)溶液を氷冷し、クロロぎ酸ｐ−ニトロフェニルを加えた後、室温で終夜攪拌した。反応液にアセトニトリル(1.5 ml)及び４０％メチルアミン水溶液(4.5 ml)を加え、室温で２２時間攪拌した。反応液に飽和食塩水を加え、酢酸エチルで２回抽出を行った。抽出液を併せ、有機層を飽和食塩水で洗い、硫酸ナトリウムで乾燥後、Bond Elut JR-NH₂(VARIAN社)に通して酢酸エチルで溶出した。溶出液を減圧下濃縮し、残渣をシリカゲルクロマトグラフィーで精製（０〜１０％メタノール−クロロホルム）することにより上記化合物48 mg(収率87%)を淡黄色粉末として得た。MS(m/z)APCI:560[M+H]⁺ Example 166

A solution of trihydrochloride 60 mg (0.098 mmol) of the compound of Example 154 and N, N-diisopropylethylamine 77 μl (0.444 mmol) in acetonitrile (3 ml) was ice-cooled, and p-nitrophenyl chloroformate was added. Thereafter, the mixture was stirred at room temperature overnight. Acetonitrile (1.5 ml) and 40% aqueous methylamine solution (4.5 ml) were added to the reaction mixture, and the mixture was stirred at room temperature for 22 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The extracts were combined, the organic layer was washed with saturated brine, dried over sodium sulfate, passed through Bond Elut JR-NH ₂ (VARIAN) and eluted with ethyl acetate. The eluate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0 to 10% methanol-chloroform) to obtain 48 mg (yield 87%) of the above compound as a pale yellow powder. MS (m / z) APCI: 560 [M + H] ⁺

実施例１５４の化合物52.0 mg(0.103 mmol)の水(1 ml)懸濁液に４Ｎ塩化水素ジオキサン溶液103 μl(0.412 mmol)を加え、氷冷下シアン酸カリウム25.2 mg(0.310 mmol)を加えた後、室温で２０時間攪拌した。反応液を酢酸エチルで希釈し、飽和食塩水で洗浄、硫酸ナトリウムで乾燥、減圧下濃縮した。残渣をシリカゲルクロマトグラフィーで精製（０〜１０％メタノール−クロロホルム）することにより上記化合物41 mg(収率72%)を淡黄色粉末として得た。MS(m/z)APCI:546[M+H]⁺ Example 167

To a suspension of 52.0 mg (0.103 mmol) of the compound of Example 154 in water (1 ml) was added 103 μl (0.412 mmol) of 4N hydrogen chloride dioxane solution, and 25.2 mg (0.310 mmol) of potassium cyanate was added under ice cooling. Thereafter, the mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% methanol-chloroform) to obtain 41 mg (yield 72%) of the above compound as a pale yellow powder. MS (m / z) APCI: 546 [M + H] ⁺

実施例６５の化合物770 mg(1.37 mmol)、ヒドラジン一水和物343 mg(6.85 mmol)、エタノール(10 ml)及びＴＨＦ(10 ml)の混合物を室温で２４時間攪拌した。反応液に飽和重曹水を加え、クロロホルムで抽出を３回行った。抽出液を併せ、硫酸ナトリウムで乾燥後、減圧下濃縮した。ＮＨ−シリカゲルクロマトグラフィーで精製（７５〜１００％クロロホルム−ヘキサン）し、得られた粗結晶を５０％酢酸エチル−ヘキサンで洗浄することにより、上記化合物510 mg(収率86%)を無色粉末として得た。MS(m/z)APCI:434[M+H]⁺ Example 168

A mixture of 770 mg (1.37 mmol) of the compound of Example 65, 343 mg (6.85 mmol) of hydrazine monohydrate, ethanol (10 ml) and THF (10 ml) was stirred at room temperature for 24 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The extracts were combined, dried over sodium sulfate, and concentrated under reduced pressure. Purification by NH-silica gel chromatography (75-100% chloroform-hexane) and washing of the resulting crude crystals with 50% ethyl acetate-hexane gave the above compound 510 mg (yield 86%) as a colorless powder. Obtained. MS (m / z) APCI: 434 [M + H] ⁺

実施例１１の化合物260 mg(0.65 mmol)のメタノール(10 ml)懸濁液を氷冷し、塩化ヒドロキシルアンモニウム135 mg(1.94 mmol)及び２８％ナトリウムメトキシドメタノール溶液374 mg(1.94 mmol)を加えた後、加熱環流を１２時間行った。反応混合物を室温に冷却し、水を加え析出物をろ取、乾燥することにより上記化合物218 mg(収率77%)を無色粉末の単一の異性体として得た。MS(m/z)APCI:437[M+H]⁺ Example 169

A suspension of 260 mg (0.65 mmol) of the compound of Example 11 in methanol (10 ml) was ice-cooled, and 135 mg (1.94 mmol) of hydroxylammonium chloride and 374 mg (1.94 mmol) of 28% sodium methoxide methanol solution were added. Then, heating reflux was performed for 12 hours. The reaction mixture was cooled to room temperature, water was added, and the precipitate was collected by filtration and dried to obtain the above compound (218 mg, yield 77%) as a single isomer of a colorless powder. MS (m / z) APCI: 437 [M + H] ⁺

実施例１８の化合物600 mg(1.39 mmol)のピリジン(4 ml)溶液に塩化ヒドロキシルアンモニウム106 mg(1.53 mmol)を一度に加え、室温で３０分間攪拌した。反応液を６０℃に加熱し、無水酢酸262 μg(2.78 mmol)を加え、同温で２時間攪拌した。反応液を室温に冷却し、減圧下濃縮後、残渣に水(10 ml)を加え、ジクロロメタン(10 ml)で２回抽出を行った。抽出液を併せ、硫酸ナトリウムで乾燥し、減圧下濃縮後、残渣をシリカゲルクロマトグラフィーで精製（０〜５％メタノール−クロロホルム）することにより、粗結晶452 mgを得た。この粗結晶250 mgを酢酸エチル−イソプロピルエーテル（１：２）で再結晶することにより、上記化合物189 mg(収率58%)を淡黄色粉末として得た。MS(m/z)APCI:430[M+H]⁺ Example 170

106 mg (1.53 mmol) of hydroxylammonium chloride was added at once to a solution of the compound of Example 18 in 600 mg (1.39 mmol) in pyridine (4 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was heated to 60 ° C., 262 μg (2.78 mmol) of acetic anhydride was added, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, water (10 ml) was added to the residue, and the mixture was extracted twice with dichloromethane (10 ml). The extracts were combined, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0-5% methanol-chloroform) to give 452 mg of crude crystals. By recrystallizing 250 mg of the crude crystals with ethyl acetate-isopropyl ether (1: 2), 189 mg (yield 58%) of the above compound was obtained as a pale yellow powder. MS (m / z) APCI: 430 [M + H] ⁺

実施例１７０の化合物を用い、実施例１６９と同様に処理し、上記化合物を得た。MS(m/z)APCI:463[M+H]⁺ Example 171

The above compound was obtained in the same manner as in Example 169, using the compound of Example 170. MS (m / z) APCI: 463 [M + H] ⁺

実施例６６の化合物110 mg(0.237 mmol)の塩化メチレン(3 ml)溶液を氷冷し、６５％ｍ−クロロ過安息香酸101 mg(0.378 mmol)を加え、同温度で４０分間攪拌した。反応液に亜硫酸ナトリウム水溶液を加え、クロロホルムで３回抽出を行った。抽出液を併せて硫酸ナトリウムで乾燥し、減圧下濃縮を行った。残渣をシリカゲルクロマトグラフィーで精製（０〜７％メタノール−クロロホルム）した後、５０％酢酸エチルヘキサンで結晶化することにより上記化合物51 mg(収率44%)を得た。MS(m/z)APCI:483[M+H]⁺ Example 172

A solution of 110 mg (0.237 mmol) of the compound of Example 66 in methylene chloride (3 ml) was ice-cooled, and 101 mg (0.378 mmol) of 65% m-chloroperbenzoic acid was added, followed by stirring at the same temperature for 40 minutes. A sodium sulfite aqueous solution was added to the reaction solution, followed by extraction with chloroform three times. The extracts were combined, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-7% methanol-chloroform), and then crystallized with 50% ethyl acetate hexane to obtain 51 mg (yield 44%) of the above compound. MS (m / z) APCI: 483 [M + H] ⁺

実施例１７２において、シリカゲルクロマトグラフィーにおいて別途得られた化合物を、５０％酢酸エチルヘキサン中から結晶化することにより、上記化合物47 mg(収率43%)を得た。MS(m/z)APCI:467[M+H]⁺ Example 173

In Example 172, the compound separately obtained by silica gel chromatography was crystallized from 50% ethyl acetate hexane to obtain 47 mg of the above compound (yield 43%). MS (m / z) APCI: 467 [M + H] ⁺

The following compounds were obtained by the same treatment as in the synthesis methods described in the present specification and the examples.

  The following compounds can be produced by the same treatment as in the synthesis methods described in the present specification and the examples.

  The following compounds were obtained by the same treatment as in the synthesis methods described in the present specification and the examples.

（１）上記化合物（１−ａ）88.0 g(439 mmol)のＴＨＦ溶液1760 mlに−７８℃でｎ−ブチルリチウム（１．５９Ｍ）のヘキサン溶液729 ml(1159 mmol)を２０分かけて滴下して加え、１時間かけて−１０℃まで昇温した。−７８℃に再度冷却後ＤＭＦ102 ml(1320 mmol)を一度に加えた。アセトン−ドライアイス浴を外し、３０分撹拌後、反応混合物を冷水1000 mlに注ぎ、酢酸エチル2000mlを加えた。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣を酢酸エチルで再結晶することにより、上記化合物（１−ｂ）74.8 gを得た。MS(m/z)APCI:229[M+H]⁺
（２）上記化合物（１−ｂ）64.5 g(282 mmol)の塩化メチレン322 ml溶液に、氷冷下２０分かけてトリフルオロ酢酸322 mlを滴下した。反応混合物を室温で２時間撹拌し、溶媒を留去した。これにクロロホルム50 mlを加え、次いで氷冷下４Ｎ塩化水素−ジオキサン溶液300 mlを滴下した。溶媒留去後、残渣を酢酸エチルで洗浄、乾燥し、上記化合物（１−ｃ）41.3 gを一塩酸塩として得た。MS(m/z)APCI:検出されず Reference example 1

(1) 729 ml (1159 mmol) of a hexane solution of n-butyllithium (1.59 M) was dropped into 1760 ml of the above compound (1-a) 88.0 g (439 mmol) in THF at −78 ° C. over 20 minutes. In addition, it heated up to -10 degreeC over 1 hour. After cooling again to −78 ° C., 102 ml (1320 mmol) of DMF was added all at once. After removing the acetone-dry ice bath and stirring for 30 minutes, the reaction mixture was poured into 1000 ml of cold water, and 2000 ml of ethyl acetate was added. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was recrystallized from ethyl acetate to obtain 74.8 g of the above compound (1-b). MS (m / z) APCI: 229 [M + H] ⁺
(2) To a solution of 64.5 g (282 mmol) of the above compound (1-b) in 322 ml of methylene chloride was added dropwise 322 ml of trifluoroacetic acid over 20 minutes under ice cooling. The reaction mixture was stirred at room temperature for 2 hours and the solvent was distilled off. To this was added 50 ml of chloroform, and then 300 ml of 4N hydrogen chloride-dioxane solution was added dropwise under ice cooling. After the solvent was distilled off, the residue was washed with ethyl acetate and dried to obtain 41.3 g of the above compound (1-c) as a monohydrochloride salt. MS (m / z) APCI: Not detected

（１）上記化合物（１−ａ）60.0 g(299 mmol)のＴＨＦ溶液1200 mlに−７８℃でｎ−ブチルリチウムのヘキサン溶液（１．５９Ｍ）428 ml(659 mmol)を２０分かけて滴下して加え、１時間かけて−１０℃まで昇温した。−７８℃に再度冷却後、Ｎ−フルオロベンゼンスルホニルイミド142 g(449 mmol)を一度に加えた。アセトン−ドライアイス浴を外し、３０分撹拌後、冷水(1000 ml)に反応混合物を注ぎ、酢酸エチル(1200 ml)を加えて分液した。有機層を２Ｎ塩酸、水及び飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（１５％酢酸エチル：ヘキサン）で精製した後、ジエチルエーテルで再結晶し、上記化合物（２−ａ）45.1 gを得た。
MS(m/z)APCI:219[M+H]⁺
（２）上記化合物（２−ａ）38.0 g(174 mmol)の塩化メチレン(190 ml)溶液に、氷冷下２０分かけてトリフルオロ酢酸(190 ml)を滴下して加えた。室温で２．５時間撹拌し、濃縮した。残渣にクロロホルム(20 ml)を加え、氷冷下、４Ｎ塩酸−ジオキサン溶液(180 ml)を滴下して加えた。濃縮後、残渣を酢酸エチルで洗浄、乾燥し、上記化合物（２−ｂ）24.6 gを一塩酸塩として得た。MS(m/z)APCI:119[M+H]⁺ Reference example 2

(1) n-Butyllithium hexane solution (1.59M) 428 ml (659 mmol) was added dropwise over 20 minutes to 1200 ml of a THF solution of 60.0 g (299 mmol) of the above compound (1-a). In addition, it heated up to -10 degreeC over 1 hour. After cooling again to −78 ° C., 142 g (449 mmol) of N-fluorobenzenesulfonylimide was added all at once. After removing the acetone-dry ice bath and stirring for 30 minutes, the reaction mixture was poured into cold water (1000 ml), and ethyl acetate (1200 ml) was added to separate the layers. The organic layer was washed successively with 2N hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (15% ethyl acetate: hexane) and then recrystallized from diethyl ether to obtain 45.1 g of the above compound (2-a).
MS (m / z) APCI: 219 [M + H] ⁺
(2) To a methylene chloride (190 ml) solution of 38.0 g (174 mmol) of the above compound (2-a), trifluoroacetic acid (190 ml) was added dropwise over 20 minutes under ice cooling. Stir at room temperature for 2.5 hours and concentrate. Chloroform (20 ml) was added to the residue, and 4N hydrochloric acid-dioxane solution (180 ml) was added dropwise under ice cooling. After concentration, the residue was washed with ethyl acetate and dried to obtain 24.6 g of the above compound (2-b) as a monohydrochloride salt. MS (m / z) APCI: 119 [M + H] ⁺

（１）アルゴン雰囲気下、既知の化合物（ＷＯ０２／１４３１２）（３−ａ）9.30 g(30.6 mmol)をトルエン(100 ml)に溶解し、ビス（トリブチルすず）35.5 g(61.2 mmol)及びテトラキス（トリフェニルホスフィン）パラジウム（０）1.77 g(1.53 mmol)を加え、１２０℃で２日間攪拌した。反応混合物を室温に冷却し、ＮＨシリカゲルカラムクロマトグラフィーで直接に精製（５０％酢酸エチルヘキサン）後、更にシリカゲルクロマトグラフィーで精製（０〜１７％酢酸エチルヘキサン）することにより、スズ化合物（３−ｂ）10.70 g(収率75%)を淡黄色液体として得た。MS(m/z)APCI:465/467/469[M+H]⁺
（２）アルゴン雰囲気下、上記スズ化合物（３−ｂ）10.7 g(22.9 mmol)、Ｎ，Ｎ−ジイソプロピルエチルアミン5.19 ml(29.8 mmol)、炭酸カリウム189 mg(1.37 mmol)、トリス（ジベンジリデンアセトン）ジパラジウム（０）1.05 g(1.14 mmol)及びＴＨＦ(100 ml)の混合物を氷冷し、クロログリオキシル酸エチル3.83 g(34.3 mmol)をゆっくり滴下した後、氷浴を外し室温で４時間攪拌した。反応混合物にジエチルエーテル(15 ml)、飽和フッ化カリウム水溶液(50 ml)及び水(10 ml)を加え、室温で終夜攪拌した後、混合物をセライト濾過した。濾液を減圧下濃縮することで有機溶媒を留去した後、得られた水溶液にジエチルエーテルを加え、不溶物を再びセライト濾過後、濾液を分液した。水層をジエチルエーテルで２回抽出し、先の有機層と抽出液を併せて、水及び飽和食塩水で順次洗浄後、硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルクロマトグラフィーで精製（３０％酢酸エチルヘキサン、次いで１０％メタノール−クロロホルム）することにより、ケトエステル体（３−ｃ）0.93 g(収率15%)を淡黄色粉末として得た。MS(m/z)APCI:279[M+H]⁺ Reference example 3

(1) Under an argon atmosphere, a known compound (WO02 / 14312) (3-a) 9.30 g (30.6 mmol) is dissolved in toluene (100 ml), and bis (tributyltin) 35.5 g (61.2 mmol) and tetrakis ( Triphenylphosphine) palladium (0) 1.77 g (1.53 mmol) was added, and the mixture was stirred at 120 ° C. for 2 days. The reaction mixture was cooled to room temperature, purified directly by NH silica gel column chromatography (50% ethyl acetate hexane), and further purified by silica gel chromatography (0 to 17% ethyl acetate hexane) to give a tin compound (3- b) 10.70 g (75% yield) was obtained as a pale yellow liquid. MS (m / z) APCI: 465/467/469 [M + H] ⁺
(2) Under an argon atmosphere, 10.7 g (22.9 mmol) of the tin compound (3-b), 5.19 ml (29.8 mmol) of N, N-diisopropylethylamine, 189 mg (1.37 mmol) of potassium carbonate, tris (dibenzylideneacetone) A mixture of dipalladium (0) 1.05 g (1.14 mmol) and THF (100 ml) was ice-cooled, and 3.83 g (34.3 mmol) of ethyl chloroglyoxylate was slowly added dropwise, the ice bath was removed, and the mixture was stirred at room temperature for 4 hours. . Diethyl ether (15 ml), saturated aqueous potassium fluoride solution (50 ml) and water (10 ml) were added to the reaction mixture, and the mixture was stirred overnight at room temperature, and then the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to distill off the organic solvent, diethyl ether was added to the resulting aqueous solution, the insoluble material was filtered through Celite again, and the filtrate was separated. The aqueous layer was extracted twice with diethyl ether, and the previous organic layer and the extract were combined, washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% ethyl acetate hexane, then 10% methanol-chloroform) to obtain a ketoester (3-c) 0.93 g (yield 15%) as a pale yellow powder. MS (m / z) APCI: 279 [M + H] ⁺

（１）クロロ硫酸80.0 g(687 mmol)を氷冷し、２−アセトアミドチアゾール（４−ａ）20.00 g(140.6 mmol)を数回に分けて加え、次いで混合物を１００℃で終夜撹拌した。反応混合物を室温に冷却後、氷水に注ぎ、ジエチルエーテルで抽出した。抽出液を水及び飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、減圧下濃縮することにより、粗生成物（４−ｂ）9.41 gを黄色固体として得た。
（２）２Ｍジメチルアミン水溶液7.2 ml(14 mmol)とピリジン3 mlの混合物を氷冷し、化合物（４−ｂ）1.50 gを数回に分けて加え、同温度で１５分間、室温で終夜撹拌した。反応混合物を減圧下濃縮し、残渣をシリカゲルクロマトグラフィー（０〜１０％メタノール−クロロホルム）で精製することにより、粗生成物（４−ｃ）677 mgを黄色粉末として得た。
（３）上記化合物（４−ｃ）447 mgに６Ｎ塩酸を加え、１１０℃で１時間撹拌した。反応混合物を室温まで冷却し、減圧下濃縮した。残渣に水及びアンモニア水を加え、塩基性とし、析出した結晶を集めて乾燥し、化合物（４−ｄ）283 mg(3工程で収率9%)を黄色粉末として得た。MS(m/z)APCI:208[M+H]⁺ Reference example 4

(1) 80.0 g (687 mmol) of chlorosulfuric acid was ice-cooled, and 20.00 g (140.6 mmol) of 2-acetamidothiazole (4-a) was added in several portions, and then the mixture was stirred at 100 ° C. overnight. The reaction mixture was cooled to room temperature, poured into ice water, and extracted with diethyl ether. The extract was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give 9.41 g of a crude product (4-b) as a yellow solid.
(2) A mixture of 7.2 ml (14 mmol) of 2M dimethylamine aqueous solution and 3 ml of pyridine was ice-cooled, 1.50 g of compound (4-b) was added in several portions, and the mixture was stirred at the same temperature for 15 minutes and at room temperature overnight. did. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0-10% methanol-chloroform) to give 677 mg of a crude product (4-c) as a yellow powder.
(3) 6N hydrochloric acid was added to 447 mg of the compound (4-c), and the mixture was stirred at 110 ° C. for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water and aqueous ammonia were added to the residue to make it basic, and the precipitated crystals were collected and dried to obtain 283 mg of compound (4-d) (9% yield over 3 steps) as a yellow powder. MS (m / z) APCI: 208 [M + H] ⁺

対応原料化合物を参考例４と同様に処理し、上記化合物を得た。 Reference Example 5

The corresponding starting material compound was treated in the same manner as in Reference Example 4 to obtain the above compound.

（１）化合物（６−ａ）10.0 g(63.1 mmol)及びＮ−（−ブトキシカルボニル）−Ｎ−メチルエタノールアミン16.55 g(94.6 mmol)のジメチルスルホキシド溶液100 mlを氷水浴で冷却しながらカリウムｔ−ブトキシド10.6 g(94.6 mmol)を少しずつ加え、室温で５０分間撹拌した。反応混合物を酢酸エチルで希釈した後、水及び飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。活性炭処理した後、混合物を減圧下濃縮することにより粗生成物（６−ｂ）21.8 gを得た。MS(m/z)APCI:298[M+H]⁺
（２）上記化合物（６−ｂ）18.5 gの酢酸エチル溶液200 mlに１０％パラジウム炭素（ドライ）1.00 gを加え、混合物を常圧水素雰囲気下、室温で激しく３時間撹拌した。反応混合物を濾過して、濾液を減圧下濃縮し、粗アミン体（６−ｃ）17.1 gを得た。MS(m/z)APCI:268[M+H]⁺
（３）上記アミン体（６−ｃ）20.1 gの酢酸溶液250 mlに酢酸カリウム31.0 g(319 mmol)及びチオシアン酸カリウム36.8 g(379 mmol)を加え、氷水浴で冷却しながら臭素3.40 ml(66.4 mmol)を滴下して加え、次いで室温で２時間撹拌した。反応混合物を酢酸エチルで希釈して、水、亜硫酸ナトリウム水溶液及び飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。活性炭処理後、溶媒を減圧下留去し、残渣を酢酸エチルで結晶化して、上記化合物（６−ｄ）13.36 g(3工程で収率65%)を得た。MS(m/z)APCI:325[M+H]⁺ Reference Example 6

(1) While cooling 100 ml of a dimethyl sulfoxide solution of 10.0 g (63.1 mmol) of compound (6-a) and 16.55 g (94.6 mmol) of N-(-butoxycarbonyl) -N-methylethanolamine in an ice-water bath, potassium t -Butoxide 10.6 g (94.6 mmol) was added little by little, and it stirred at room temperature for 50 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After the activated carbon treatment, the mixture was concentrated under reduced pressure to obtain 21.8 g of a crude product (6-b). MS (m / z) APCI: 298 [M + H] ⁺
(2) 1.00 g of 10% palladium carbon (dry) was added to 200 ml of an ethyl acetate solution of 18.5 g of the above compound (6-b), and the mixture was vigorously stirred at room temperature for 3 hours under an atmospheric hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 17.1 g of a crude amine compound (6-c). MS (m / z) APCI: 268 [M + H] ⁺
(3) 3250 g (319 mmol) of potassium acetate and 36.8 g (379 mmol) of potassium thiocyanate were added to 250 ml of an acetic acid solution of 20.1 g of the above amine compound (6-c), and 3.40 ml of bromine with cooling in an ice-water bath ( 66.4 mmol) was added dropwise and then stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water, aqueous sodium sulfite solution and saturated brine, and dried over sodium sulfate. After the activated carbon treatment, the solvent was distilled off under reduced pressure, and the residue was crystallized from ethyl acetate to obtain 13.36 g of the above compound (6-d) (yield: 65% in 3 steps). MS (m / z) APCI: 325 [M + H] ⁺

対応原料化合物を参考例６と処理し、上記化合物を得た。 Reference Example 7

The corresponding starting compound was treated with Reference Example 6 to obtain the above compound.

（１）上記の化合物（６−ａ）30.0 g(94.6 mmol)、Ｎ，Ｎ−ジメチルエタノールアミン22.7 ml(227.1 mmol)、炭酸カリウム52.3 g(378.5 mmol)及びＤＭＦ(150 ml)の混合物を６０℃で２時間攪拌した。反応混合物を室温に冷却後セライト濾過した。濾液を減圧下濃縮して得られた残渣に、水を加え酢酸エチルで２回抽出を行った。抽出液を合わせ飽和食塩水で洗浄し、乾燥（硫酸ナトリウム）、活性炭処理後、減圧下濃縮して、粗ニトロ化合物（８−ａ）36.10 gを得た。
（２）上記粗ニトロ化合物（８−ａ）36.10 gのメタノール溶液(300 ml)にドライ１０％パラジウム炭素（ドライ）5.0 gを加え、水素雰囲気下５時間激しく攪拌した。反応液を濾過し、濾液を減圧下濃縮することにより、粗アミン体（８−ｂ）31.96 gを得た。
（３）上記粗アミン体（８−ｂ）31.96 gの酢酸溶液(300 ml)にチオシアン酸カリウム 110.3 g(1135 mmol)を加え、氷浴で冷却しながら臭素 10.2 ml(199 mmol)を滴下し、次いで室温で２．５日間攪拌した。反応液を減圧下濃縮し、トルエン共沸後、残渣に水及び飽和重曹水を加え、更に塩化ナトリウムを加えた。セライト濾過後、濾液に２８％アンモニア水を加え水層をアルカリ性にした後に、クロロホルムで抽出を４回行った。抽出液を合わせ、硫酸ナトリウムで乾燥、溶媒留去した。残渣をメタノールに溶解、活性炭処後、減圧下濃縮し、残渣を酢酸エチルで洗浄することにより、化合物（８−ｃ）22.2 g(3工程で収率49%)を淡赤色粉末固体として得た。MS(m/z)APCI:239[M+H]⁺ Reference Example 8

(1) A mixture of the above compound (6-a) 30.0 g (94.6 mmol), N, N-dimethylethanolamine 22.7 ml (227.1 mmol), potassium carbonate 52.3 g (378.5 mmol) and DMF (150 ml) Stir for 2 hours at ° C. The reaction mixture was cooled to room temperature and filtered through celite. Water was added to the residue obtained by concentrating the filtrate under reduced pressure, and the mixture was extracted twice with ethyl acetate. The extracts were combined, washed with saturated brine, dried (sodium sulfate), treated with activated carbon, and concentrated under reduced pressure to obtain 36.10 g of a crude nitro compound (8-a).
(2) 5.0 g of dry 10% palladium carbon (dry) was added to 36.10 g of the crude nitro compound (8-a) in methanol (300 ml), and the mixture was vigorously stirred in a hydrogen atmosphere for 5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 31.96 g of a crude amine compound (8-b).
(3) 110.3 g (1135 mmol) of potassium thiocyanate was added to 31.96 g of acetic acid solution (300 ml) of the crude amine compound (8-b), and 10.2 ml (199 mmol) of bromine was added dropwise while cooling in an ice bath. And then stirred at room temperature for 2.5 days. The reaction solution was concentrated under reduced pressure, azeotroped with toluene, water and saturated aqueous sodium hydrogen carbonate were added to the residue, and sodium chloride was further added. After filtration through Celite, 28% aqueous ammonia was added to the filtrate to make the aqueous layer alkaline, followed by extraction with chloroform four times. The extracts were combined, dried over sodium sulfate, and evaporated. The residue was dissolved in methanol, treated with activated carbon, concentrated under reduced pressure, and the residue was washed with ethyl acetate to obtain 22.2 g of compound (8-c) (49% yield over 3 steps) as a light red powder solid. . MS (m / z) APCI: 239 [M + H] ⁺

対応原料化合物を参考例８と処理し、上記化合物を得た。 Reference Example 9

The corresponding starting compound was treated with Reference Example 8 to obtain the above compound.

２−アミノ−４−ニトロ安息香酸メチル4.3 g(22 mmol)の酢酸エチル(21 ml)、濃塩酸(39 ml)の混合溶液に、亜硝酸ナトリウム1.61 g(23 mmol)の水溶液(10 ml)を氷浴で冷却しながら滴下し、同温で３０分間撹拌した。塩化銅（ＩＩ）二水和物1.76 g(10 mmol)、亜硫酸水素ナトリウム23 g(220 mmol)、酢酸28 ml及び濃塩酸10 mlの混合液を滴下し、室温で３０分間撹拌した。反応液を、氷に注ぎ析出した塩化スルホニル体をろ取し、水洗した。得られた塩化スルホニル体を、飽和アンモニア水に、室温で加え、同温で２日間撹拌した。濃塩酸で、ｐＨを１〜２にし、酢酸エチルで抽出し、抽出液を水及び飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣を酢酸エチル−ヘキサンでろ取することにより、上記化合物3.0 g(収率60%)で得た。MS(m/z):227[M‐H]⁺ Reference Example 10

To a mixed solution of methyl 2-amino-4-nitrobenzoate 4.3 g (22 mmol) in ethyl acetate (21 ml) and concentrated hydrochloric acid (39 ml), an aqueous solution (10 ml) of sodium nitrite 1.61 g (23 mmol) Was added dropwise while cooling in an ice bath and stirred at the same temperature for 30 minutes. A mixture of copper (II) chloride dihydrate 1.76 g (10 mmol), sodium hydrogen sulfite 23 g (220 mmol), acetic acid 28 ml and concentrated hydrochloric acid 10 ml was added dropwise and stirred at room temperature for 30 minutes. The reaction solution was poured into ice, and the precipitated sulfonyl chloride was collected by filtration and washed with water. The obtained sulfonyl chloride was added to saturated aqueous ammonia at room temperature and stirred at the same temperature for 2 days. The pH was adjusted to 1-2 with concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was collected by filtration with ethyl acetate-hexane to give the above compound (3.0 g, yield 60%). MS (m / z): 227 [M−H] ⁺

対応原料化合物を参考例８と処理し、上記化合物を得た。 Reference Example 11

The corresponding starting compound was treated with Reference Example 8 to obtain the above compound.

対応原料化合物を参考例８と処理し、上記化合物を得た。 Reference Example 12

The corresponding starting compound was treated with Reference Example 8 to obtain the above compound.

（１）化合物（６−ａ）5.18 g(32.7 mmol)及びエチレングリコール２０．３ ｇ(327 mmol)のＤＭＦ(20 ml)溶液に炭酸カリウム13.6 g(98.0 mmol)を加え、室温で２時間撹拌した。反応混合物を酢酸エチルで希釈した後、有機層を水及び飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。減圧下濃縮した残渣を酢酸エチル−ヘキサンで再結晶化することにより、化合物（１２−ａ）5.59 g(収率93%)を黄色結晶として得た。MS(m/z)APCI:185[M+H]⁺
（２）化合物（１２−ａ）5.57 g(30.3 mmol)のエタノール溶液50 mlに１０％パラジウム炭素0.50 gを加え、水素気流下２時間激しく撹拌し、反応混合物を減圧下濃縮することにより、粗アミン体を得た。
（３）上記アミン体の酢酸溶液(100 ml)にチオシアン酸カリウム17.6 g(182 mmol)を加え、氷浴で冷却しながら臭素1.62 ml(31.8 mmol)を滴下し、次いで室温で終夜撹拌した。反応混合物を減圧下濃縮し、トルエンで共沸後、残渣をシリカゲルクロマトグラフィー（ＮＨ−シリカゲル；５〜９％メタノール−クロロホルム）で精製し、酢酸エチルでトリチュレーションし、化合物（１２−ｂ）5.55 g(収率87%)を無色結晶として得た。MS(m/z)APCI:212 [M+H]⁺
（４）上記化合物175 mg(0.833 mmol)及びイミダゾール188 mg(2.76 mmol)のＤＭＦ(4 ml)溶液に、氷冷下ｔ−ブチルジメチルクロロシラン188 mg(1.25 mmol)のＤＭＦ(2 ml)溶液を滴下し、室温で終夜撹拌した。反応混合物を酢酸エチルで希釈し、水及び飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。減圧下濃縮後、残渣をシリカゲルクロマトグラフィー（４０〜７０％酢酸エチル−ヘキサン）で精製し、化合物（１２−ｃ）172 mgを無色結晶として得た。MS(m/z)APCI:326 [M+H]⁺ Reference Example 12

(1) To a solution of compound (6-a) 5.18 g (32.7 mmol) and ethylene glycol 20.3 g (327 mmol) in DMF (20 ml) was added potassium carbonate 13.6 g (98.0 mmol), and the mixture was stirred at room temperature for 2 hours. did. After the reaction mixture was diluted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over sodium sulfate. The residue concentrated under reduced pressure was recrystallized from ethyl acetate-hexane to obtain 5.59 g (yield 93%) of compound (12-a) as yellow crystals. MS (m / z) APCI: 185 [M + H] ⁺
(2) To 50 ml of an ethanol solution of 5.57 g (30.3 mmol) of the compound (12-a), 0.50 g of 10% palladium on carbon was added, stirred vigorously for 2 hours under a hydrogen stream, and the reaction mixture was concentrated under reduced pressure to give a crude product. An amine body was obtained.
(3) 17.6 g (182 mmol) of potassium thiocyanate was added to an acetic acid solution (100 ml) of the amine compound, 1.62 ml (31.8 mmol) of bromine was added dropwise while cooling in an ice bath, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and the residue was purified by silica gel chromatography (NH-silica gel; 5-9% methanol-chloroform), triturated with ethyl acetate, and compound (12-b) 5.55 g (yield 87%) was obtained as colorless crystals. MS (m / z) APCI: 212 [M + H] ⁺
(4) A solution of 175 mg (0.833 mmol) of the above compound and 188 mg (2.76 mmol) of imidazole in DMF (4 ml) is mixed with a solution of 188 mg (1.25 mmol) of t-butyldimethylchlorosilane in DMF (2 ml) under ice cooling. The solution was added dropwise and stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (40-70% ethyl acetate-hexane) to obtain 172 mg of compound (12-c) as colorless crystals. MS (m / z) APCI: 326 [M + H] ⁺

（１）化合物（１３−ａ）3.05 g(16.4 mmol)、２，５−ヘキサンジオン3.85 ml(32.9 mmol)、ｐ−トルエンスルホン酸一水和物313 mg(1.64 mmol)のトルエン30 ml中の混合物をDean-Stark装置で水を除去しながら、６時間加熱還流した。反応混合物を室温まで冷却後、酢酸エチルで希釈し、飽和重曹水及び飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。減圧下濃縮後、残渣をシリカゲルクロマトグラフィー（９％酢酸エチル−ヘキサン）で精製し、化合物（１３−ｂ）3.84 g(収率89%)を淡褐色結晶として得た。MS(m/z)APCI:264/266[M+H]⁺
（２）上記化合物（１３−ｂ）1.00 g(3.79 mmol)及びＮ，Ｎ−ジメチルエチレンジアミン3.34 g(37.0 mmol)の混合物を１２０℃で１５時間攪拌した。反応混合物を室温に冷却し、ＮＨシリカゲルクロマトグラフィーで精製（３０〜６０％酢酸エチル−ヘキサン）で精製することにより化合物（１３−ｃ）を黄色粉末として得た。MS(m/z)APCI:316[M+H]⁺
（３）上記化合物（１３−ｃ）500 mg(1.59 mmol)、メタノール(2.0 ml)及び１０％塩酸(3.3 ml)の混合物を６０℃で１９時間攪拌した。反応混合物を室温に冷却し、炭酸水素ナトリウム粉末を加えて中性とした後、減圧下濃縮を行った。残渣をクロロホルムで希釈し、硫酸マグネシウムで乾燥後、減圧下濃縮を行った後、残渣を酢酸エチル−ジエチルエーテルの混合溶媒で洗浄することにより、上記化合物（１３−ｄ）を褐色粉末として得た。MS(m/z)APCI:238[M+H]⁺ Reference Example 13

(1) Compound (13-a) 3.05 g (16.4 mmol), 2,5-hexanedione 3.85 ml (32.9 mmol), p-toluenesulfonic acid monohydrate 313 mg (1.64 mmol) in 30 ml toluene The mixture was heated to reflux for 6 hours while removing water with a Dean-Stark apparatus. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (9% ethyl acetate-hexane) to obtain 3.84 g (yield 89%) of compound (13-b) as light brown crystals. MS (m / z) APCI: 264/266 [M + H] ⁺
(2) A mixture of 1.00 g (3.79 mmol) of the above compound (13-b) and 3.34 g (37.0 mmol) of N, N-dimethylethylenediamine was stirred at 120 ° C. for 15 hours. The reaction mixture was cooled to room temperature and purified by NH silica gel chromatography (30-60% ethyl acetate-hexane) to give compound (13-c) as a yellow powder. MS (m / z) APCI: 316 [M + H] ⁺
(3) A mixture of the above compound (13-c) 500 mg (1.59 mmol), methanol (2.0 ml) and 10% hydrochloric acid (3.3 ml) was stirred at 60 ° C. for 19 hours. The reaction mixture was cooled to room temperature, neutralized with sodium hydrogen carbonate powder, and concentrated under reduced pressure. The residue was diluted with chloroform, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with a mixed solvent of ethyl acetate-diethyl ether to give the compound (13-d) as a brown powder. . MS (m / z) APCI: 238 [M + H] ⁺

  The present invention provides a novel compound having an excellent glucokinase activating action useful as an active ingredient of a medicament for the prevention and / or treatment of diseases associated with glucokinase such as diabetes, diabetic complications or obesity. Can do.

Claims (33)

Formula [I]:

[Wherein, ring A represents aryl or heteroaryl.
Ring T represents a heteroaryl or a heterocyclic group.
R ¹ represents a hydrogen atom, a halogen atom, cycloalkylsulfonyl, alkylsulfonyl, alkylsulfinyl, alkylthio, substituted or unsubstituted tetrazolyl, —COR ¹⁰ or —CR ¹² (OH) R ¹⁰ .
R ² is hydrogen atom, halogen atom, cycloalkylsulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkylthio, nitro, substituted or unsubstituted amino, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted heterocyclic thio, substituted Or unsubstituted heterocyclic sulfinyl, substituted or unsubstituted heterocyclic sulfonyl, substituted or unsubstituted heteroarylsulfonyl, alkenyloxy, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted It represents heteroarylthio, —COR ¹¹ or —CR ¹³ (OH) R ¹¹ .
R ¹⁰ represents an alkyl, cycloalkyl, heteroaryl or heterocyclic group.
R ¹¹ represents a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl or heterocyclic group.
R ¹² represents a hydrogen atom or alkyl.
R ¹³ represents a hydrogen atom or alkyl.
R ³ and R ⁴ independently represent a hydrogen atom, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroaryl, or R ³ and R ⁴ are connected to form a substituted or unsubstituted group together with the adjacent nitrogen atom. Forms a substituted heterocyclic group.
R ⁵ represents a hydrogen atom, formyl, halogen atom, oxo, substituted or unsubstituted alkoxy, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkylthio, cyano, substituted or unsubstituted heterocyclic sulfonyl, nitro, substituted or unsubstituted cycloalkyl , Alkoxycarbonyl, alkenyl, alkylsulfonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted heteroarylthio, substituted or unsubstituted amino, carboxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocycle Carbonyl, substituted or unsubstituted heterocyclic oxy, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted cycloalkyloxy, alkanoyl or substituted or unsubstituted Represents a substituted alkyl.
R ⁶ represents a hydrogen atom, a substituted or unsubstituted alkyl, a halogen atom or carboxy. ]
Or a pharmacologically acceptable salt thereof. Ring T is

The medicament according to claim 1, which is a heteroaryl group or a heterocyclic group represented by the formula: The ring T is thiazolyl, thiazolopyridinyl, pyridyl, pyrazinyl, benzothiazolyl, quinolyl, thiadiazolyl, pyrazolyl, thiazolopyrazinyl, thiazolopyrimidinyl, cyclohexanothiazolyl or dihydropyrazopyridinyl. Or the medicine according to 2. The ring T is thiazolyl, thiazolopyridinyl, pyridyl, pyrazinyl, benzothiazolyl, thiadiazolyl, thiazolopyrazinyl, thiazolopyrimidinyl, cyclohexanothiazolyl or dihydropyrazolopyridinyl. Medicine. The medicament according to claim 1 or 2, wherein the ring T is thiazolyl, thiazolopyridinyl, pyrazinyl, thiadiazolyl, thiazolopyrazinyl or thiazolopyrimidinyl. The medicine according to claim 1 or 2, wherein the ring T is thiazolyl or thiazolopyridinyl. Ring A is aryl, The pharmaceutical of any one of Claims 1-6. The medicine according to any one of claims 1 to 6, wherein ring A is phenyl or pyridyl. The pharmaceutical according to any one of claims 1 to 8, wherein R ¹ is a hydrogen atom or a halogen atom. The pharmaceutical according to claim 1 to 8 R ¹ is a hydrogen atom. R ² is cycloalkylsulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkylthio, nitro, substituted or unsubstituted amino, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted heterocyclic thio, substituted or unsubstituted heterocyclic sulfonyl The pharmaceutical according to any one of claims 1 to 10, which is substituted, unsubstituted heteroarylsulfonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylthio. The pharmaceutical according to any one of claims 1 to 10, wherein R ² is cycloalkylsulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminosulfonyl or substituted or unsubstituted heterocyclic sulfonyl. The pharmaceutical according to any one of claims 1 to 10, wherein R ² is cycloalkylsulfonyl, substituted or unsubstituted alkylsulfonyl or substituted or unsubstituted aminosulfonyl. The pharmaceutical according to any one of claims 1 to 10, wherein R ² is cycloalkylsulfonyl or substituted or unsubstituted alkylsulfonyl. Substituent is substituted or unsubstituted alkyl of "substituted aminosulfonyl" in R ^2, cycloalkyl, alkoxy or substituted or unsubstituted heterocyclic ring a medicament according to any one of claims 1 to 13 is. The pharmaceutical according to any one of claims 1 to 14 substituents of the "substituted alkylsulfonyl" in R ² is alkoxy. The pharmaceutical according to any one of claims 1 to 16, wherein R ³ and R ⁴ are linked to form a substituted or unsubstituted heterocyclic group together with an adjacent nitrogen atom. The heterocyclic group “substituted or unsubstituted heterocyclic group formed by combining R ³ and R ⁴ together with the adjacent nitrogen atom” is pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, azetidine, homopiperazine, homo The pharmaceutical according to any one of claims 1 to 17, which is morpholine or homothiomorpholine. Any substituents of the substituted heterocycle of "substituted or unsubstituted heterocyclic group R ³ and R ⁴ form together with the adjacent nitrogen atom" is alkyl, alkoxy, of claims 1 to 18 is hydroxy or oxo Or a pharmaceutical according to any one of the above. R ⁵ is a hydrogen atom, formyl, halogen atom, oxo, substituted or unsubstituted alkoxy, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkylthio, cyano, substituted or unsubstituted heterocyclic sulfonyl, nitro, substituted or unsubstituted cycloalkyl , Alkoxycarbonyl, alkenyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted heteroarylthio, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic oxy, alkanoyl or substituted Or the medicine according to any one of claims 1 to 19, which is unsubstituted alkyl. R ⁵ is a hydrogen atom, a halogen atom, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted heterocyclic oxy, The medicament according to any one of claims 1 to 19, which is alkanoyl or substituted or unsubstituted alkyl. The pharmaceutical according to any one of claims 1 to 19, wherein R ⁵ is a halogen atom, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted amino, substituted or unsubstituted heterocyclic oxy, or substituted or unsubstituted alkyl. . The pharmaceutical according to any one of claims 1 to 19, wherein R ⁵ is substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted heterocyclic oxy, or substituted or unsubstituted alkyl. The pharmaceutical according to any one of claims 1 to 19, wherein R ⁵ is substituted or unsubstituted alkyl. The substituent of “substituted alkyl” in R ⁵ is substituted or unsubstituted heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted carbamoyl, hydroxy, trialkylsilyloxy, alkylthio, alkylsulfonyl, substituted Or the pharmaceutical of any one of Claims 1-24 which is unsubstituted heterocyclic oxy, heteroaryl, substituted or unsubstituted hydroxyimino, a halogen atom, carboxy, alkoxycarbonyl, or alkanoyloxy. The pharmaceutical according to any one of claims 1 to 19, wherein R ⁵ is substituted or unsubstituted alkoxy. The substituent of “substituted alkoxy” in R ⁵ is amino, alkoxycarbonyl optionally substituted with one or two groups selected from alkyl and alkoxycarbonyl, carbamoyl optionally substituted with mono- or dialkyl, carboxyl 27. The pharmaceutical according to any one of claims 1 to 19 and 26, which is a heterocyclic group optionally substituted with hydroxy, oxo, trialkylsilyloxy or alkoxy. The pharmaceutical according to any one of claims 1 to 27, wherein R ⁶ is a hydrogen atom or substituted or unsubstituted alkyl. R < ⁶ > is a hydrogen atom, The pharmaceutical in any one of Claims 1-27.
. The medicament according to any one of claims 1 to 29, which is a glucokinase activator. The medicament according to any one of claims 1 to 29, which is a therapeutic agent and / or a preventive agent for diabetes. The medicament according to any one of claims 1 to 29, which is a therapeutic and / or preventive agent for chronic complications of diabetes such as retinopathy, nephropathy, neurosis, ischemic heart disease, arteriosclerosis and the like. The medicament according to any one of claims 1 to 29, which is a therapeutic and / or prophylactic agent for obesity.