WO2008084873A1 - Oxime derivative - Google Patents

Abstract

Disclosed is an oxime derivative represented by the formula below or a pharmacologically acceptable salt thereof, which is a novel compound having an excellent glucokinase activation effect and therefore useful as an active ingredient of a pharmaceutical agent for the prevention and/or treatment of a glucokinase-related disease such as diabetes, diabetic complication or obesity. wherein the ring A represents an aryl group or a heteroaryl group; Q represents a cycloalkyl group, a heterocyclic group or the like; the ring T represents a heteroaryl group or a heterocyclic group; R1 represents a hydrogen atom or the like; R2 represents -COR11 or -CR13(OH)R11; R11 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group or the like; R13 represents a hydrogen atom or an alkyl group; R3 and R4 independently represent a hydrogen atom, an alkoxy group or the like; R5 represents a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkyl group or the like; and R6 represents a hydrogen atom or the like.

Description

 TJP2008 / 050467

 1 Description oxime derivatives Technical Field

 The present invention relates to a novel oxime derivative having an excellent darcokinase activating action and useful as a medicine. Background art

Darcokinase (GK) is one of the four hexokinases found in mammals. Hexokinase catalyzes the conversion of glucose to dulcose-6-phosphate, the first step in glucose metabolism. GK is mainly localized in liver parenchymal cells and knee 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 knee β cells are functionally identical due to differences in the sequences of 15 amino acids at the end due to differences in splicing. G 3 hexo other than Κ? Enzyme activity saturates at glucose concentrations below 1 mM, but 0: 111 is 8111] ^, which is the physiological level of blood sugar Therefore, as the blood glucose concentration rises from normoglycemia (5 mM) to postprandial blood glucose (10-15 mM), intracellular glucose metabolism via GK is activated. The hypothesis that it functions as a glucose sensor for spleen β-cells and hepatocytes was proposed (Non-Patent Document 1). G 明 ら か に gene-disrupted mice die soon after birth (Non-patent document 2) Both normal and diabetic mice overexpressing GK are wild-type animals. Lower blood sugar (Non-Patent Document 3). Type II young-onset diabetes of the type II (MODY—2: maturity-onset diabetes of the young type II) A decrease in GK activity in MO DY-2 is thought to cause an increase in blood glucose (Non-patent Document 4). On the other hand, families with GK mutations that increase enzyme activity have been found, and such people exhibit hypoglycemia (Non-patent Document 5). Therefore, GK functions as a glucose sensor in humans and is considered to play 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 3 cells, a glucose uptake enhancing action in the liver, and a liver release inhibiting action. The compound is believed to be useful, for example, in the treatment of type II diabetes.

 Recently, spleen β-cell type dalcokinase has been shown to be localized and distributed in the feeding brain (Ventromedial hypothalamus, VMH) in rat brain.

Approximately 20% of neurons in VMH are called glucose responsive neurons and have traditionally been thought to play an important role in controlling body weight. Intrarat administration of the glucose analog, darcosamine, causes overeating of the rat, resulting in suppression of glucose metabolism. From electrophysiological experiments, the glucose responsive neuron in V MH is stimulated when glucose increases from 5 to 2 O mM, and its activity is blocked by dalcosamine or the like (Non-patent Document 6). The mechanism of glucose sensor of V HM is considered to be the same as that of the knee] 3 cells. Thus, GK activators have the potential to improve obesity and correct hyperglycemia, one of the main problems in type I diabetes.

From the above, the compound having GK activation action is used as a therapeutic agent and / or a therapeutic agent for diabetes or chronic complications of diabetes such as retinopathy, nephropathy, neurosis, ischemic heart disease or arteriosclerosis, and obesity. Useful as a preventive agent. Examples of compounds having GK activating activity include pyridinecarboxylic acid derivatives (Patent Document 1), 2-pyridinecarboxamide derivatives (Patent Document 2), heteroaryl rubamoylbenzene derivatives (Patent Document 3), heteroaryl derivatives ( Patent Document 4), Substituted Alicyclic Methyl Propylacetamide Derivative (Patent Document 5), 5 Monosubstituted Pyrazine or Pyridine Derivative (Patent Document 6), Substituted (Thiazole-2-yl) Amide or Sulfonamide Derivative (Patent Document 7), substituted phenylacetamide derivatives (Patent Document 8) or amide derivatives (Patent Document 9). Further, compounds having an oxime structure are described in Patent Documents 10 to 13 and Non-Patent Documents 7 to 9.

 [Patent Document 1] WO 05/044801

 [Patent Document 2] WO 04/081001

 [Patent Document 3] WO 04/076420

 [Patent Document 4] WO 04/063194

 [Patent Document 5] WO 04/063179

 [Patent Document 6] WO 04/052869

 [Patent Document 7] WO 04/050645

 [Patent Document 8] WOO 3/095438

 [Patent Document 9] WO 03/055482

 [Patent Document 10] WO05Z023761

 [Patent Document 1 1] WOO 1/012189

 [Patent Document 12] WO00 / 026202

 [Patent Document 13] WO 96-no 023763

 [Non-patent document 1] American Journal Physiology, 247 (3Pt2), 1984, p.527-536 [Non-patent document 2] Cell, 83, 1995, p.69-78

[Non-patent literature 3] Proceedings of the National Academy of Sciences of the USA, 93, 1996, p.7225-7230 [Non-Patent Document 4] Nature Genetics, 356, 1992, p. 721-722

[Non-Patent Document 5] New England Journal of Medicine, 338, 1998 'p. 226-230

[Non-Patent Document 6] Diabetes, 48 (9), 1999, p. 1763-72

 [Non-Patent Document 7] Bulletin des Societes Chimiques Beiges, 103 (5-6), 1994, p. 213-18

 [Non-Patent Document 8] Bulletin of the Chemical Society of Japan, 66 (8), 1993, p. 2335-8

 [Non-Patent Document 9] Pharmazie, 43 (8), 1988,. 535-6 Disclosure of the Invention

 An object of the present invention is to provide a novel compound having an excellent action of darcokinase activity useful as an active ingredient of a drug for prevention and Z or treatment of diseases associated with darcokinase such as diabetes, diabetic complications or obesity. Is to provide. As a result of intensive studies on the problems of the present invention, it was found that an oxime derivative represented by the following formula has an excellent darcokinase activating action, and the present invention was completed.

 The present invention includes the following specific embodiments.

 (1) General formula [I]:

 [Wherein, ring A represents aryl or heteroaryl.

 Q represents cycloalkyl, a heterocyclic group, alkyl or alkenyl.

Ring T represents a heteroaryl or hetero ring group. R ¹ is a hydrogen atom, a halogen atom, cycloalkylsulfonyl, alkylsulfonyl, alkylsulfinyl, alkylthio, substituted or unsubstituted tetrazolyl, — COR ¹⁰ or one CR ¹² (OH) R ¹ . Represents.

R ² represents one COR ¹¹ or one CR ¹³ (OH) R ¹¹ .

R ¹⁰ represents an alkyl, cycloalkyl, heteroaryl or heterocyclic group.

R ¹¹ represents a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroaryl or a heterocyclic group.

R ¹² represents a hydrogen atom or alkyl.

R ¹³ represents a hydrogen atom or alkyl.

R ³ and R ⁴ are independently a hydrogen atom, alkoxy, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heteroaryl, alkoxyalkoxy, substituted or unsubstituted cycloalkyl, cyano, substituted or unsubstituted aryl, substituted Alternatively, it represents unsubstituted rubamoyl, hydroxy, alkanoyl, alkylthio, alkoxycarbonyl, substituted or unsubstituted aryloxy, halogen atom, oxo, or substituted or unsubstituted arylcarbonyloxy.

R ⁵ is a hydrogen atom, formyl, halogen atom, oxo, substituted or unsubstituted alkoxy, substituted or unsubstituted aminominosulfonyl, substituted or unsubstituted alkylthio, cyan, substituted or unsubstituted heterocyclic sulfonyl, nitro, substituted Or unsubstituted cycloalkyl, alkoxycarbonyl, alkenyl, alkylsulfonyl, substituted or unsubstituted rubamoyl, substituted or unsubstituted heteroarylthio, substituted or unsubstituted amino, carboxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted Alkyl, substituted or unsubstituted heterocyclic carbonyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted cyclo Alkyloxy, alkanoyl or Represents substituted or unsubstituted alkyl.

R ⁶ represents a hydrogen atom, substituted or unsubstituted alkyl, halogen atom or carboxy. To express. ]

Or an pharmacologically acceptable salt thereof.

(2) The ring is

The oxime derivative according to (1) or a pharmaceutically acceptable salt thereof, which is a heteroaryl or heterocycle group represented by

 (3) Ring T is thiazolyl, thiazo-orthopyridinyl, pyridyl, pyradiel, benzothiazolyl, quinolyl, thiadiazolyl, pyrazolyl, thiazolopyrazinole, thiazo-orthopyrimidinyl, hexahexanothiazolyl or dihydrovirazopyridinyl (1) or (2) The described oxime derivative or a pharmacologically acceptable salt thereof.

 (4) Ring T is thiazolyl, thiazo-orthopyridinyl, pyridyl, pyrazinyl, benzothiazolyl, thiadiazolyl, thiazolovirazinyl, thiazolopyrimidinyl, cyclohexanothiazolyl, or dihydrazolazopyridinyl (1) or (2 ) The described oxime derivative or a pharmaceutically acceptable salt thereof.

 (5) Ring T is thiazolyl, thiazopyridinyl, pyrajur, thiadiazolyl, thiazopyrazuril or thiazolopyrimidyl (1) or (2) the oxime derivative or pharmacologically acceptable Get salt.

 (6) The oxime derivative or the pharmaceutically acceptable salt thereof according to (1) or (2), wherein ring T is thiazolyl or thiazolopyridinyl.

 (7) The oxime derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (6), wherein ring A is aryl.

 (8) The oxime derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (6), wherein ring A is phenyl or pyridyl.

(9) Any of (1) to (8), wherein R ¹ is a hydrogen atom or a halogen atom Oxime derivatives or pharmaceutically acceptable salts thereof.

(10) The oxime derivative according to any one of (1) to (8), wherein R ¹ is a hydrogen atom, or a pharmaceutically acceptable salt thereof.

(1 1) The oxime derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (10), wherein R ^{2 is} COR ¹¹ .

(12) R ¹ . Or an oxime derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (11).

(13) The oxime derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (12), wherein R ¹¹ is substituted or unsubstituted alkyl, or substituted or unsubstituted alkyl.

(14) The oxime derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (13), wherein the substituent of “substituted alkyl” in R ¹¹ is alkoxy.

(1 5) R ¹¹ is methyl, 3-main Tokishipuropiru or cyclopropyl (1) - (1 2) Okishimu derivative or a pharmaceutically acceptable ¾ according to any one of. _Alpha

(16) The oxime derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (15), wherein R ¹² and R ¹³ are hydrogen atoms.

(17) 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 rubamoyl, substituted or unsubstituted heteroarylthio, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or non-substituted The oxime derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (16), which is substituted alkynyl, substituted or unsubstituted heterocyclicoxy, alkanol, or substituted or unsubstituted alkyl. (18) R ⁵ is a hydrogen atom, halogen atom, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted rubermoyl, substituted or unsubstituted amino, substituted or unsubstituted The oxime derivative described in any one of (1) to (16), or a pharmaceutically acceptable salt thereof, which is substituted heterocyclic oxy, alkyl quinole or substituted or unsubstituted alkyl.

(19) R ^{5 is a} halogen atom, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted amino, substituted or unsubstituted heterocyclic, or substituted or unsubstituted alkyl (1 ) The oxime derivative or a pharmacologically acceptable salt thereof according to any one of (16) to (16).

(20) The oxime derivative according to any one of (1) to (16), wherein R ⁵ is substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted heterocyclic or substituted or unsubstituted alkyl, or a derivative thereof Pharmacologically acceptable salt.

(21) The oxime derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (16), wherein R ⁵ is substituted or unsubstituted alkyl.

(22) The substituent of “substituted alkyl” in R ⁵ is a substituted or unsubstituted heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted rubermoyl, hydroxyl, trialkyl. Silyloxy, alkylthio, alkylsulfonyl, substituted or unsubstituted heterocyclicoxy, heteroaryl, substituted or unsubstituted hydroxyimino, halogen atom, carboxy, alkoxyl or alkanoyloxy (1) to (21) Or an pharmacologically acceptable salt thereof.

(23) The oxime derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (16), wherein R ⁵ is substituted or unsubstituted alkoxy.

(24) The substituent of “substituted alkoxy” in R ⁵ is optionally substituted with 1 or 2 groups selected from alkyl, alkoxycarbonyl and optionally substituted with amino, alkoxycarbonyl, mono or dialkyl. Good power An oxime derivative described in any one of (1) to (16) and (2 3), or a pharmacology thereof, which is a heterocyclic group optionally substituted by ruberamoyl, carboxyl, hydroxy, oxo, trialkylsilyloxy or alkoxy Acceptable salt.

(25) The oxime derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (24), wherein R ⁶ is a hydrogen atom, or substituted or unsubstituted alkyl.

(26) The oxime derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (24), wherein R ⁶ is a hydrogen atom.

 (27) A medicament comprising the oxime derivative described in any one of (1) to (26) or a pharmacologically acceptable salt thereof.

 (28) The medicament according to (27), which is a darcokinase activator.

 (29) The medicament according to (27), which is a therapeutic and / or prophylactic agent for diabetes.

(30) The medicament according to (27), which is a therapeutic and Z or preventive agent for chronic complications of diabetes such as retinopathy, nephropathy, neurosis, ischemic heart disease, arteriosclerosis and the like.

 (31) The medicament according to (27), 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, and preferably a fluorine atom or a chlorine atom.

"Alkyl" as a ( "alkylthio", the same. For other groups defined. Hereinafter including "Anorekinore" portion which engages binding with other groups like such as "hydroxyalkyl"), for example 〇 bets ₆ Preferred examples include linear or branched alkyl, and specific examples include methyl, ethyl, propyl, isopropyl, isobutyl, t-butyl, pentyl, hexyl and the like.

The "Arukeniru", for example, c ₂ - _6, preferably include a straight-chain or branched Kusaria Rukeeru of c ₂ _ _4, specifically Bulle, propenyl, isopropenyl, Buteyu Honoré, Penteeru, Hexenyl and the like can be mentioned. As the "alkynyl", for example, C ₂ - _6, preferably C ₂ - ₄ straight or branched Kusaria Rukieru are mentioned in, include Asechireniru, Purobyuru, butynyl, pentynyl, Kishuru like to have specifically .

"Alkoxy" includes, for example _d-6, preferably include 〇 ₄ linear or branched Kusaria alkoxy, specifically main butoxy, ethoxy, propoxy, Isopurobo alkoxy, butoxy, t one butoxy, Penchiruokishi, Hexyloxy and the like can be mentioned.

The "Arukanoiru", for example, C ₂ _ _7, preferably include a straight-chain or branched Zhen Arukanoiru of C ₂ _ _5, specifically Asechiru, propionyl, butyryl, pen Tanoiru and the like.

"Cycloalkyl", for example C ₃ _ _8, preferably C ₃ - ₆ cycloalkyl Le of the like, specifically, cyclopropyl, cyclobutyl, consequent opening pentyl, heptyl is to shea hexyl or consequent opening to click port Can be mentioned. Examples of “aryl” include 6 to 14 membered, preferably 6 to: L 0 membered monocyclic, bicyclic or tricyclic aromatic hydrocarbons, such as phenyl, naphthyl, Examples thereof include phenanthryl and anthryl, and particularly preferred is phenol.

 “Heteroaryl” refers to 4- to 10-membered, preferably 5- to 9-membered, in which 1 to 3 carbon atoms are replaced with a heteroatom independently selected from oxygen, sulfur and nitrogen atoms. And monocyclic or bicyclic aromatic hydrocarbons, such as ceryl, thiazolyl, pyrazolyl, imidazolyl, isoxazolyl, triazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyragel, quinolyl, benzothiazolyl, thiazolo Pyridinyl, thiazolovirazinyl, thiazolopyrimidinyl and the like.

As the “heterocyclic group”, 1 to 3 carbon atoms are independently substituted with a heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom, 4 to 10 members, preferably 4 ~ 9-membered monocyclic or bicyclic non-aromatic hydrocarbons, such as oxetani ^ /, azetidyl, pyrrolidinyl, tetrahydrofl ^ /, dioxolaninore, piperidininore, piperajunole, homopipe Raju / Le, Tetrahydrobila / Le, Thiashi Chlohexinore, Monoreforinole, Thiomonolefolinole, Cyclohexanothiazolinole, Dihydrothiazolopyridinyl, Tetrahydrothiazolopyridinyl and the like. Or, “halogen atom”, “alkyl”, “alkyl”, “alkynyl”, “alkoxy”, “alk force mail”, “cycloalkyl”, “aryl”, “heteroaryl”, “heterocyclic group” As specific examples, those specifically shown in the Examples can be mentioned. The group represented by each symbol of the compound [I] will be described below.

 The “aryl” in ring A is preferably phenyl.

 The “heteroaryl” in ring A is preferably cenyl or pyridyl, particularly preferably pyridyl.

When ring A is a 6-membered ring, the substitution position of R ² is preferably the 4-position.

 Preferable “cycloalkyl” in Q includes, for example, a 5 to 6-membered monocyclic cycloalkyl, and specifically, sucral pentyl, sucral hexyl and the like, and particularly sucral pentyl is preferable.

 As the preferable “heterocyclic group” in Q, for example, a 4- to 6-membered monocyclic group optionally having 1 to 3 heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom Heterocyclic groups are exemplified, and specific examples include oxetanyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, tetrahydroviral, tetrahydrothiobilael, thiaxoxyhexyl and the like, with tetrahydrofuryl being particularly preferred.

The “heteroaryl” in ring T is, for example, a 5- to 9-membered monocyclic ring optionally having 1 to 3 heteroatoms independently selected from an oxygen atom, a sulfur atom, and a nitrogen atom, Bicyclic heteroaryls include thiazolyl, pi Examples include lazolyl, thiadiazolyl, pyridyl, pyrazinyl, benzothiazolyl / le, thiazo oral pyridinyl, thiazolopyrazuril, thiazolopyrimidel, quinolyl and the like. Of these, thiazolyl, thiadiazolyl, pyridyl, pyragel, benzothiazolyl, thiazolopyridyl, thiazolopyridyl, and thiazolopyrimidinyl are preferred, more preferably thiazolyl, thiadiazolyl, pyrazinyl, thiazolopyridinyl, thiazobirazinyl, Zolopyridinyl, more particularly thiazolyl is preferred.

 The “heterocyclic group” in ring T is, 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. A cyclic or bicyclic heterocyclic group, preferably a 9-membered bicyclic heterocyclic group, such as cyclohexanothiazolyl, dihydrothiazolopyridinyl, tetrahydrothiazolopyridinyl. And so on.

As "cycloalkyl" in R ^{1 0} and R ^{1 1} is for example, an 3-4-membered cycloalkyl, specifically cyclopropyl, Shikuropuchiru like, in particular cyclopropyl are preferred.

As the “heterocyclic group” in R ^{1 Q} and R ¹¹ , for example, it may optionally have 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 are mentioned, preferably 5 to 7-membered monocyclic heterocyclic groups, such as azetidinyl, pyrrolidiel, tetrahydrofuryl, piperidinyl, Piperazorenole, morpholinole, thiomorpholinyl, oxazepidinyl and perhydrodiazepier are preferred.

The “aryl” in R ³ and R ⁴ is preferably phenyl. As the “heteroaryl” in R ³ and R ⁴ , for example, it may have 1 to 3 heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom. A cyclic or bicyclic heteroaryl, preferably a 5- to 6-membered monocyclic heteroaryl optionally having 1 to 3 nitrogen atoms, Specifically, pyrazolyl, imidazolyl, thiazolyl, triazolyl, pyridyl, pyrimidyl and the like are preferable, and pyrimidinyl is particularly preferable.

Examples of the “heterocyclic group” in R ³ and R ⁴ include a 5- to 6-membered monocyclic hetero ring group, and specifically include pyrrolidinyl, tetrahydrofuryl, dioxolanyl, piperidinyl, thiacyclohexyl and the like. Can be mentioned.

The “cycloalkyl” in R ³ and R ⁴ is preferably a 3- to 6-membered monocyclic cycloalkyl, specifically, cyclopropyl or cyclopentyl.

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

The substituent in the group represented by each symbol of the compound [I] has the following meanings, for example.

“Substituted amino”, “Substituted aminosulfonyl”, “Substituted aminoalkyl”, “Substituted aminoalkanoyl”, “Substituted power rubamoyl”, “Substituted power rubamoylalkyl”, “Substituted alkyl”, “Substituted alkylthio”, “Substituted” `` Alkyl sulfier '', `` substituted alkyl sulfone '', `` substituted alkoxy '', `` substituted alkanoyl '', `` substituted alkynyl '', `` substituted cycloalkyl '', `` substituted cycloalkyloxy '', `` substituted cycloalkyl force portal '', "Substituted alkylsulfonyl", "Substituted aryl", "Substituted aryloxy", "Substituted arylcarbonyl", "Substituted arylcarbonyl", "Substituted arylsulfol", "Substituted arylalkylcarbonyl", "Substituted heteroaryl", "Substituted heteroarylthio", ""Substitutedheteroarylsulfoel","Substitutedheteroarylalkyl","Substitutedheterocycle","Substitutedheterooxy","Substitutedheterocycle","Substitutedheterocycle"," Substituted heterocyclic sulfinyl, substituted heterocyclic sulfonyl, substituted hydroxyimino, substituted phenyl, substituted pyridyl, substituted thiol Ryozopyridinyl "," Substituted pyrazinyl "," Substituted pyrazolyl "," Substituted imidazolyl ",

“Substituted thiazolyl”, “Substituted benzothiazolyl”, “Substituted quinolyl”, “Substituted thiadiazolyl”, “Substituted pyrazolyl”, “Substituted thiazolopyrazuril”, “Substituted thiazolopyrimidinyl”, “Substituted hexaoxathiazolyl” Nore ”,“ substituted dihydrothiazopyridyl ”,“ substituted triazolyl ”,“ substituted pyrimidinyl ”,“ substituted pyrrolidinyl ”,“ substituted tetrahydrofuryl ”,“ substituted thiacyclohexyl ”,“ substituted cyclopentyl ”,“ substituted pipepentyl ” The substituents in Rajul, Substituted Piperazinylsulfonyl, Substituted Homopiperazinyl, Substituted Piperidinyl, Substituted Morpholyel, Substituted Thiomorpholinyl, Substituted Perhydrodiazebule and Substituted Tezozolyl are ( 1) Hydroxy, alkoxy, Mino, mono- or dialkylamino, rubamoyl, alkyl optionally substituted with tetrahydrofuryl or pyridyl, (2) cycloalkyl, (3) hydroxy, (4) alkoxy, (5) cyano, (6) halogen atom (7) mono- or dialkylamino, (8) an amino optionally substituted with an alkanol, alkoxyalkanol or alkoxycarbonyl, (9) pyridinole, (10) carboxyl, (1 1) formyl, 12) alkanoyl optionally substituted with mono or dialkylamino, hydroxy, alkoxy or alkanoyloxy, (1 3) cycloalkyl carbol, (14) alkoxycarbonyl, (15) year-old xo, (16 ) Alkylsulfoel, (16) Examples specifically shown in Examples and Reference Examples, etc. Can have the same or different 1 to 3 substituents. Further, preferred substituents will be described according to the symbols ( ¹ to! ^ ⁵ and R ¹¹ ) of the compound [I]. The groups of these symbols may have 1 to 3 substituents which are the same or different selected from the groups defined below.

A preferable substituent of “substituted tetrazolyl” in R ¹ includes alkyl. Preferred substituents for “substituted alkyl” in R ^{1 1} are alkoxycarbonyl, alkoxy, cycloalkyl (preferably cyclopropyl), hydroxy, substituted or unsubstituted amino (substituent: alkyl, alkanoyl selected from 1 Or a group of 2), substituted or unsubstituted heteroaryl (preferably imidazolyl, triazolyl) (substituent: alkyl), alkylsulfoel, cyano, substituted or unsubstituted heterocyclic group (preferably tetrahydrofuryl, tetrahydrobiranyl, Dihydro-3H-isoindolyl) (substituents: oxo, dioxo) and the like. Of these, alkoxy, cycloalkynole (preferably cyclopropyl), hydroxy, dialkylamino and the like are more preferable, and alkoxy is particularly preferable.

Preferred substituents for “substituted cycloalkyl” in R ¹¹ include hydroxy; alkyl; oxo; alkanol; hydroxyalkyl; forceful rubamoyl optionally substituted with mono- or dialkyl; heteroaryl; Or an aminosulfonyl optionally substituted with dialkyl; an amino optionally substituted with mono- or alkyl; alkylsulfonyl; alkoxy; alkoxyalkyl. Of these, hydroxy; alkyl; forceful rubamoyl 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 include: hydroxy; alkyl; alkanoyl; hydroxyalkyl; force rubamoyl optionally substituted with mono or dialkyl; heteroaryl; optionally substituted with mono or dialkyl Aminosulfonyl which may be substituted; amino optionally substituted with mono- or dialkyl; alkylsulfonyl; alkoxy; alkoxyalkyl. Of these, hydroxy; alkyl; forceful rubamoyl optionally substituted with mono- or dialkyl; alkoxy; alkoxyalkyl are more preferable, and alkyl is particularly preferable. Preferable substituents for the “substituted heterocycle” in R ³ and R ⁴ include alkoxyl, oxo, alkyl, alkanoyl and the like, and oxo and alkyl are particularly preferable.

Preferred substituents for “substituted heteroaryl” in R ³ and R ⁴ include alkyl; an amino optionally substituted with mono- or dialkyl. Of these, alkyl is more preferred.

Preferred substituents for “substituted cycloalkyl” in R ³ and R ⁴ include benzoinoreoxy, oxo, hydroxy, and alkanoyl. Of these, oxo and hydroxy are more preferred.

Preferred substituents for the “substituted aryl” in R ³ and R ⁴ include alkyl, cyan, halogen atom, alkoxy, mono- or dialkylamino, and particularly preferred are cyan and halogen atoms.

Preferable substituents of “substituent rubermoyl” in R ³ and R ⁴ include alkyl.

“Preferable substituents of substituted aryloxy j in R ³ and R ⁴ include alkyl, cyan, halogen atom, alkoxy, mono- or dialkylamino, and particularly preferred are cyan and halogen atoms.

Preferable substituents of “substituted aryl carbooxy” in R ³ and R ⁴ include alkyl, cyan, halogen atom, alkoxy, mono- or dialkylamino, and the like.

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 May include rubamoyl, ruboxyl, hydroxy, substituted or unsubstituted heterocyclic group (substituent: oxo), trialkylsilyloxy, and alkoxy. this house, Amino optionally substituted with mono or dialkyl as appropriate; strong rubamoyl optionally substituted with mono or dialkyl; hydroxy is more preferred, especially amino optionally substituted with mono or dialkyl; hydroxy is preferred .

A preferable substituent of “substituted aminosulfonyl” in R ⁵ includes alkyl. Therefore, the substituent is monoalkyl or dialkyl, preferably dialkyl.

Preferred substituents for “substituted alkylthio” in R ⁵ include amino optionally substituted with mono or dialkyl; alkoxycarbonylamino; halogen atom; hydroxy; carboxyl; optionally substituted with mono or dialkyl. Rubamoyl which may be included; alkoxycarbonyl. Of these, amino optionally substituted with mono or dialkyl as appropriate; alkoxycarbonylamino; hydroxy; rubamoyl optionally substituted with mono or dialkyl is more preferable, and dialkyl strength rubamoyl is particularly preferable.

A preferable substituent of “substituted heterosulfoyl” in R ⁵ includes 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 “substituent rubermoyl” in R ⁵ include substituted or unsubstituted alkyl (substituent: hydroxyl; cycloalkyl; heterocyclic group; amino optionally substituted with mono- or dialkyl; heteroaryl; 1 or 2 groups selected from the group consisting of cycloalkyl and heteroaryl. Of these, substituted or unsubstituted alkyl (substituent: hydroxy, heterocyclic group, dialkylamino) And 1 or 2 groups selected from heteroaryl), cycloalkyl is more preferred.

A preferable substituent of “substituted heteroarylthio” in R ⁵ includes alkyl.

Preferred substituents of “substituted amino” in R ⁵ include alkyl, substituted or unsubstituted aminoalkyl (substituent: 1 or 2 groups selected from alkyl, alkanol), alkanoyl, hydroxyalkyl, alkoxy force Lupoel. Of these, alkyl, and therefore monoalkyl or dialkyl is more preferable, and dialkyl is particularly preferable.

Preferred substituents for “substituted heteroaryl” for R ⁵ include alkyl.

Preferred substituents for “substituted alkynyl” in R ⁵ include hydroxy, optionally an 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.

Preferred substituents for “substituted heterooxy” in R ⁵ include hydroxy, alkyl, oxo, hydroxyalkyl, alkanoyl. Of these, alkyl and oxo are more preferred.

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

Preferred substituents for “substituted heterocycle” in R ⁵ include hydroxy, alkyl, oxo, hydroxyalkyl, and alkylol. Of these, alkyl and alkanol are more preferred. Preferred substituents for the “substituted alkyl” in R ⁵ include a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted amino, a substituted or unsubstituted alkoxy, a substituted or unsubstituted rubamoyl, a hydroxy, a trialkylsilyloxy, Examples thereof include substituted or unsubstituted alkylthio, substituted or unsubstituted heterocyclicoxy, heteroaryl, substituted or unsubstituted hydroxyimino, and 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 heterocyclicoxy, substituted or unsubstituted hydroxyimino, halogen atom, more preferably substituted or unsubstituted Substituted heterocyclic group, substituted or non-substituted Conversion alkoxy, heterocycle Okishi to substituted or unsubstituted, particularly preferably a substituted or unsubstituted heterocyclic group, substituted or unsubstituted alkoxy, more particularly preferably terrorist ring group to a substituted or unsubstituted.

Preferred substituents of the substituted heterocyclic group which is the substituent of “substituted alkyl” in R ⁵ include alkyl; oxo; alkoxy alkanol; alkanol; alkoxy; anolecaninoreamino; Tri (halogeno) alkanoylamino; honoreminoreamino; alkoxy group lupoelamino; hydroxy; alkyl alkylcarbonyl; tri (halogeno) alkyl; alkoxycarbonyl; formyl; optionally substituted with mono or dialkyl Amino, optionally substituted with mono- or dialkyl as appropriate; alkylsulfol; heteroaryl; alkoxycarbonylalkyl; alkanoloxyalkanoyl; alkoxycarbocarbonyl; Is an aminoalkanoyl optionally substituted with a alkyl; substituted or unsubstituted rubermoyl (substituent: 1 or 2 groups selected from alkyl, alkoxy); hydroxycanol; di (Haguchigeno) Substituted or unsubstituted Heterocyclic force Luponyl (Substituent: oxo); Substituted or unsubstituted hydroxyimino (Substituent: Noreoxycarbonyl); force noreboxinole; hydroxyalkoxy; anorecoxyalkoxy; halogen atom; alkanoyloxy. Of these, alkyl; oxo; alkoxy alkanoinole; alkanol; alkoxy; alkanoylamino; cyclamine alkylcarbonylamino; tri (halogeno) alkanoylamino; formolinalemino; alkoxycarbonylamino; (Halogeno) alkyl; alkoxycarbonyl; formolene; amino optionally substituted with mono- or dialkyl; aminosulfonino optionally substituted with mono- or dialkyl; alkylsulfoyl; heteroaryl; Norequinole; Alkanoyloxynolecaninole; Anolecoxyl power L-Polycarpoel; Aminoalkanoyl optionally substituted with mono or dialkyl; Mono or di as appropriate Carbamoyl optionally substituted by alkyl; hydroxy-force-knol; di (halogeno) -ar force-no-nore; substituted or unsubstituted heterocyclylcarbonyl (substituent: oxo); substituted or unsubstituted hydroxyimino (substituent: More preferably alkyl; oxo; alkoxyalkanoyl; alkanol; formyl; amino optionally substituted with mono- or dialkyl; alkylsulfonyl; alkanoylalkanoyl; mono- or dialkyl as appropriate An amino alkanol optionally substituted with a hydroxy alkanol is more preferred, an alkyl, an alkanoyl, formyl, or a hydrated hydroxy group is more preferred, and an alkyl or alkanol is particularly preferred.

Preferred substituents of the 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, alkyl 1 or 2 groups selected from force-neils); alkoxyalkyl; hydroxyalkynole; alkoxyalkanol; heteroaryl; heteroarylalkyl It is done. Of these, alkyl; rubamoyl alkyl optionally substituted with mono or dialkyl; aminoalkynole optionally substituted with mono or dialkyl; alkoxyalkyl; heteroaryl is more preferable, and alkyl is particularly preferable. Les.

Preferable substituents of substituted alkoxy which is a substituent of “substituted alkyl” in R ⁵ include hydroxy and alkoxy.

Preferable substituents of the substituent ruberamoyl which is a substituent of “substituted alkyl” in R ⁵ include alkyl and alkoxy.

Preferable substituents of substituted heterocyclic oxy, which is a substituent of “substituted alkyl” in R ⁵ , include alkanoyl, alkyl, formyl, cycloalkylcarboyl, alkoxyalkanoyl, and alkylsulfoyl. Of these, aralkyl and alkyl are more preferred, and alkanol is particularly preferred.

A preferred substituent of the substituted hydroxyimino which is the 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 independently selected from an oxygen atom, a sulfur atom and a nitrogen atom. Examples include a 5- to 9-membered monocyclic or bicyclic heterocyclic group which may have a telo atom as appropriate, and preferably have a nitrogen atom of 1 to 3 as appropriate. A monocyclic heterocyclic group such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinole, monoreforinole, thiomonoreforinole, penolehydridozepinyl, octahydropyro mouth [1,2_a] piperazinyl and the like. Of these, piperazil and morpholinyl are more preferable, and piperazinyl is particularly preferable.

The heterocyclic group of “substituted or unsubstituted heterocyclicoxy” which is a substituent of “substituted alkyl” in R ⁵ is independently selected from, for example, an oxygen atom, a sulfur atom and a nitrogen atom. Optionally having 5 to 9 membered monocyclic or bicyclic A 4- to 6-membered monocyclic heterocyclic group optionally having 1 to 3 nitrogen atoms, specifically azetidiel, pyrrolidinyl, piperidinyl, Piperazonole, morpholyl, thiomorpholinyl, perhydrodiazepinyl, octahydropyrrolo [1,2-a] piperazyl and the like. Of these, piperidinyl is preferable. Among the compounds [I], preferred compounds are as follows: ring A is fur; nyl, ring T is 2-thiazolyl or 2-thiazolopyridyl, R ¹ is a hydrogen atom, and R ² is cyclopropylcarboxyl. -R, Al or Alkyl, and R ³ and R ⁴ are both hydrogen atoms, and R ⁵ is appropriately selected from alkyl, oxo, alkanoyl and alkoxyalkanoyl, and hydroxyalkyl 1 And a compound that is piperazinyl-substituted alkyl optionally substituted with ~ 3 substituents.

Other preferred compounds include ring A as a ring, ring T as 2-thiazolopyridyl, R ¹ as a hydrogen atom, R ² as cyclopropylcarbonyl, an alkane or alkoxyal force. R ³ and R ⁴ are both hydrogen atoms, R ⁵ is substituted with 1 or 2 alkyl optionally substituted with amino, alkoxy, 1 or 2 alkyl optionally substituted with amino Or a compound that is an alkylamino substituted with an amino optionally substituted with 1 or 2 alkyl.

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 (A, Q, T, shaku ¹ ~! ^, R ^{1 Q} and R ¹¹ ) include those corresponding to the compounds specifically shown in Examples and Reference Examples. . The compound [I] of the present invention can be a mixture of stereoisomers, or pure or substantially pure It includes each stereoisomer in a nifty form. For example, when the compound of the present invention has one or more asymmetric centers at any carbon atom, the compound [I] may exist in an enantiomer or diastereomer or a mixture thereof. The compound of the present invention includes an isomer or a mixture thereof. In addition, 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.

 Examples of the pharmacologically acceptable salt of compound [I] include inorganic acid salts such as hydrochloride, sulfate, phosphate and hydrobromide, acetate, fumarate, oxalate, and queen. And organic acid salts such as acid salts, methanesulfonate, benzenesulfonate, tosylate, and maleate. In addition, when it has a substituent such as carboxyl, the salt includes, for example, a base such as an alkali metal salt such as a sodium salt or an alkaline salt or an alkaline metal salt such as a calcium salt. Of the salt. The pharmacologically acceptable salt of the compound [I] of the present invention 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. The compound [I] of the present invention or a pharmaceutically 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), lubricant (magnesium stearate, talc, polyethylene glycol or silica), disintegrating agent (potato starch) and wetting agent (sodium lauryl sulfate).

The compound [I] of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and can be used in an appropriate pharmaceutical preparation. Orally administered Suitable pharmaceutical preparations for this purpose include, for example, solid preparations such as tablets, granules, capsules or powders, or liquid, suspension or emulsion forms. Suitable pharmaceutical preparations for parenteral administration include suppositories, or injectable solutions or infusion preparations using distilled water for injection, physiological saline or aqueous buducose, or inhalants. The compound [I] of the present invention, 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 term “combination” includes the concept of administration together with these other drugs at the same time or separately at an arbitrary interval, and administration together with these other drugs as a single pharmaceutical preparation. There are cases. Such other drugs include snorephoninoreurea (eg, daliprid, glimepiride, dalipiride, glipizide, chlorpropamide, gliclazide, glyoxepide, acetohexamide, daliborneuride, tolptamide, tolazamide , Carpamide, darikidon, darifexamide, fenptamide, tolcyclamide, etc., biguanide (eg, methonoremine, phenphonolemin, bufonoremin, etc.), gnore gon'antagonist (eg, peptide or non-peptide) Glucagon 'antagonists), dalcosidase inhibitors (eg, acarporte, miglitol, etc.), insulin sensitizers (eg, troglitazone, rosiglitazone, pioglitazone), anti-obesity agents (eg, sibutramine) Orurisutatsuto, etc.) and the like.

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. Yes, preferably from about 0.1 to about lOra g Z kg. The compound [I] of the present invention can be produced by the following method.

[In the above reaction formula, Z ¹ is a halogen atom, hydroxy or alkoxy, Z ² is a hydrogen atom or alkyl, Z ³ is hydroxy, a halogen atom or aryl sulfonyloxy, alkylsulfonyloxy, Z ⁴ is halogen Atom, dialkoxyboryl, dihydroxyboryl or trialkylstannyl, lithium, z ⁵ is a hydrogen atom, halogen atom, dialkoxyboryl, dihydroxypolyl or trialkylstanyl, lithium, and the other symbols are as described above. Have the same meaning. ]

(1) The reaction for producing compound [VI] (Z ² is alkyl) from compound [VII] (Z ⁵ is a hydrogen atom) and compound [VIII] (Z ¹ is a halogen atom, Z ² is alkyl) It can be carried out under so-called Friedel-Crafts reaction conditions. For example, this reaction can be carried out in the presence of a suitable acid (such as aluminum chloride) in a suitable solvent (such as black mouth form, methylene chloride, nitromethane).

Compound [VI] (Z ² is alkyl) can also be a compound [VII] (Z ⁵ is Jiarukoki Shiboriru, dihydric de port Kishiborinore or trialkyl stannyl) with the compound [VIII] (Z ¹ is a halogen atom, Z ² is alkyl ) In a suitable solvent (THF, methyl chloride, dioxane, water, DMF, toluene, 1,2-dimethoxetane, etc., or a mixture thereof) in a metal catalyst (for example, dichlorobis (trifurphosphine) paradium, tetrakis (Triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, dichloro [1,1, _bis (diphenylphosphino) phenolacene] palladium, etc.) This process proceeds favorably at -78 ° C to 200 ° C.

In addition, compound [VI] (Z ² is alkyl) can also be combined with compound [VII] (Z ⁵ is lithium) and compound [VIII] (Z ¹ is alkoxy, Z ² is alkyl) with a suitable solvent (THF, Dioxane, DMF, toluene, 1,2-dimethoxetane, etc., or a mixture thereof), and this step can be preferably carried out at -78 ° C to 200 ° C. . In addition, when compound [VII] (Z ⁵ is a halogen atom), compound [VI] (Z ² is alkyl) is used in an appropriate solvent (THF, jetyl ether, toluene, 1,2-dimethoxetane, etc.) or a mixture thereof), suitable alkyl lithium (n- butyl lithium, sec- butyl lithium, t chromatography Bed butyllithium, etc.) using a compound [VII] (Z ⁵ is a halogen atom) the compound [VII] (Z ⁵ Can be prepared by reacting with compound [VIII] (Z ¹ is alkoxy, Z ² is alkyl) in the same manner as described above. And (2) Compound [VI] (Z ² is alkyl), reaction of the hydroxyl § Min or a salt thereof with the appropriate acid (hydrochloride, sulfate, etc.), to convert the ketone to hydroxy I Mino Any conventional method can be used. For example, this reaction can be carried out in the presence or absence of a base in an appropriate solvent (alcohol solvent such as methanol or ethanol, or THF, dioxane, water, or a mixed solvent thereof). Examples of the base used in this reaction include pyridine, picoline, lutidine, N, N-dimethylaniline, and triethylamine. The oxime produced in the cis form or a mixture of the cis form and the trans form can be converted into the desired trans form by treatment with an acid (trifluoroacetic acid, acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, etc.). The oxime produced by the reaction described below can also be converted to the desired trans form by treating in the same manner as described above.

(3) with the compound [IV] (Z ² is alkyl), reaction of a compound Z ³ is hydroxy [V] can be carried out in a suitable solvent (THF, methylene chloride, etc.) in, triphenyl phosphinite down the presence, By using an activator (jetylazodicarboxylate, diisopropylazodicarboxylate, etc.) or using cyanomethyltri_n-butylphosphorane in the absence of triphenylphosphine (so-called Mitsunobu reaction). Can be implemented. In addition, the reaction with the compound [V] wherein Z ³ is a halogen atom, arylsulfonyloxy or alkylsulfonyloxy is carried out by using an appropriate solvent (acetone, ethanol, THF, dimethylsulfoxide, DMF, dioxane, N , N-dimethylacetamide, N-methylpyrrolidone or the like or a mixed solvent thereof) in the presence of a base such as potassium carbonate, potassium t-butoxide, sodium hydride, cesium carbonate. The product thus obtained can be obtained by any conventional method for hydrolyzing an alkoxy carbonate to carboxyl, for example, a suitable solvent (alcohol solvent such as methanol or ethanol, THF, dioxane, water, etc., or a mixed solvent thereof) in, hydroxide Ihirichiumu, sodium hydroxide, and treated with potassium carbonate or the like by hydrolyzing Z ² group, the compound [II] (Z ² can be converted to a hydrogen atom). (4) The reaction between compound [II] (Z ² is a hydrogen atom) and compound [III] can be carried out by using any conventional method for the formation of amides commonly used in peptide synthesis and the like. It can be carried out in a solvent in the presence or absence of a condensing agent. As condensing agents, N-ethyl-1-N '— (3-dimethylaminopropyl) carpositimide, N, N, dicyclohexenorenoreidoimido, 1-methinole-2-bromopyridinumuomoide, N, N'— Levoenorethymidazolene, Dipheninophosphorinoleaide Zide, Benzotriazole 11-Iloxytris (Dimethylamino) Phosphonium Hexafnoreo Oral Phosphate, 4-(4, 6-Dimethoxy 1, 3, 3, 5-to Riazine _ 2—Inole) 14-Methylmorpholinum chloride, Funoleo mouth _N, N, N,, N'-Tetramethylformamidinum hexafluorophosphate Can be used. As the solvent, water, methanol, isopropanol, ethanol, methylene chloride, THF, dioxane, DMF, dimethylacetamide, black mouth form and the like can be suitably used as a single or mixed solvent. This reaction preferably proceeds at _78 ° C to 100 ° (more preferably from -25 ° C to 25 ° C.) As a base, an inorganic base such as carbonated lithium, sodium carbonate, sodium hydrogen carbonate, or triethylamine, Organic bases such as diisopropylethylamine, N-methylmorpholine, pyridine, N, N-dimethylaminopyridine, picoline, lutidine, etc. are added. As additives, N-hydroxysuccinimide, 3-hydroxy 3,4-Dihydr Draw 4-Oxo 1, 2, 3 Addition of benzotriazolone, N, N-dimethylaminopyridine, N-hydroxybenzotriazole, etc. to promote the progress of this reaction Can do.

The reaction from compound [II] (Z ² is a hydrogen atom) to compound [I] converted compound [II] (Z ² is a hydrogen atom) into a reactive intermediate such as an acid chloride or mixed acid anhydride. Thereafter, the reaction can be carried out by reacting with compound [III]. Conversion to the acid chloride is thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, or tetra It can be suitably carried out by using triphenylphosphine in the presence of carbon chloride, and conversion to a mixed acid anhydride can be carried out using diphenylphosphoryl chloride, jetylphosphorus didate, methanesulfoalkoxide, This can be carried out by using ethyl formate, isobutyl formate, etc. in the presence of a base such as triethylamine. As the solvent, methylene chloride, black-form, THF, DMF and the like can be suitably used as single or mixed solvents. This reaction preferably proceeds at −78 ° C. to 100 ° C., more preferably _25 ° C. to 25 ° C. The reaction between the acid chloride or mixed acid anhydride thus obtained and compound [III] involves the presence of a base such as pyridine, tritylamine, N, N-dimethylaminopyridine, disopropylethylamine, etc. Preferably at −78 ° C. to 100 ° C., more preferably at −25 ° C. to 25 ° C., and methylene chloride, black form, THF, DMF, etc. are used as a single or mixed solvent. It can be used suitably.

(5) The reaction between compound [VI] (Z ² is a hydrogen atom or alkyl) and compound [III] is the same as the reaction of (4) above when Z ² is a hydrogen atom, or Z ^{When 2} is alkyl, it can be carried out via the following compound [VI ′] and compound [X,].

Conversion of compound [VI] (Z ² is alkyl) to compound [VI '] (Z ² is a hydrogen atom) can be accomplished by any conventional method for reducing ketones to alcohols, such as suitable solvents (water, methanol, ethanol). Arbitrary hydrolysis of alkoxycarbonyl to carboxyl after treatment with a reducing agent such as zinc borohydride, sodium triacetoxyborohydride, sodium borohydride, etc. For example, by hydrolyzing the Z ² group by treating with lithium hydroxide, sodium hydroxide, etc. in a suitable solvent (methanol, ethanol, THF, dioxane, water, etc. or a mixed solvent thereof). Can be implemented. The reaction between compound [VI '] (Z ² is a hydrogen atom) and compound [III] is the same as the reaction in (4) above. Can be applied. Conversion of compound [X '] to compound [X] can be accomplished by any conventional method for oxidizing alcohols to ketones, for example, in an appropriate solvent (dimethylsulfoxide, chloroform, methylene chloride, etc.), an activator such as oxalyl chloride, etc. Oxidizing agent (activated manganese dioxide, sulfur trioxide monopyridine complex, 1-hydroxy-1) in the presence or absence of potassium or base (triethylamine etc.) by dimethyl sulfoxide oxidation (Swern oxidation) using , 2—Benzodoxol _ 3 (1 H) —On 1 1-oxide, 1, 1, 1—Triacetoxy 1, 1—Dihydr draw 1, 2—Benzo-doxolol 1 3 (1 H) 1 on, black It can be carried out by using pyridinium chromate, pyridinium dichromate, etc.).

(6) The reaction from compound [X] to compound [I X] can be carried out in the same manner as the reaction in (2) above.

 (7) The reaction from compound [I X] and compound [V] to compound [I] can be carried out in the same manner as the reaction in the above (3).

(8) The reaction between compound [VI] and compound [XI] is carried out by using O-substituted hydroxylamine or a salt thereof as a substitute for hydroxylamine in the reaction (2) above. The reaction can be carried out in the same manner as in the above reaction (2) by using ruxylamine, cycloalkyloxyamine, heterocyclic oxyamine, benzyloxyamine and the like.

 (9) The reaction between compound [X] and compound [XI] can be carried out in the same manner as the reaction in (8) above.

(10) The reaction of compound [XI] and compound [VIII] (Z ¹ is a halogen atom or a hydroxyl group, Z ² is an alkyl) is any conventional method for amide formation usually used in peptide synthesis, for example, The reaction can be carried out in the same manner as the reaction (4) above.

(1 1) The reaction from compound [XIII] (Z ² is alkyl) to compound [XII] (Z ⁴ is a hydrogen atom) is any conventional method for converting an amide to halomino, preferably literature: WO9520569 For example, a compound [XIII] (Z ² is alkyl) in a suitable solvent (acetonitrile, chloroformate, methylene chloride, THF, or a mixed solvent thereof), halogenating agent (phosphorus oxychloride, phosphorus pentachloride, etc.) ) And can be implemented. This reaction can also be carried out in the presence of triphenylphosphine by using carbon tetrachloride, carbon tetrabromide, N-prosuccinic acid imide, N-mouth succinic acid imide, iodine, or the like.

(1 2) The reaction of compound [XII] (Z ² is alkyl) and compound [VII] to compound [II] (Z ² is alkyl) is carried out by using a suitable solvent (for example, dioxane) when Z ⁵ is dihydroxyboryl. In the presence of a base (sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, etc.) in toluene, THF, 1,2-dimethoxetane, methanol, ethanol, DMF, N-methylpyrrolidone, etc. or a mixed solvent thereof) , Metal catalysts (eg, dichlorobis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, dichloro [1, 1, monobis (diphenyl phosphino) phenolic] (E.g. palladium). wear. This reaction suitably proceeds under an inert gas stream such as argon at room temperature to 200 ° C or under microwave irradiation. Compound [I] can be further converted by the following method.

(A) Among the target compounds [I] of the present invention, a compound containing sulfiel (SO) or sulfonyl (so ₂ ) on R ¹ ! ^ ⁶ converts the corresponding sulfido compound into a sulfinyl or sulfonyl compound. It can be produced by oxidation using any conventional method to achieve this. For example, this oxidation can be carried out by treating with an oxidizing agent in an appropriate solvent (methylene chloride, chloroform, THF, methanol, water or a mixed solvent thereof). As oxidizing agents, peroxy acids such as hydrogen peroxide, m-chlorobenzoic acid, peracetic acid, and oxone (registered trademark) ("Peroxyhydrogensulfuric acid lithium / disulfuric acid lithium / hydrogensulfuric acid hydrogenum mixture" DuPont And the like. The reaction can be preferably carried out at −78 ° C. to 100 ° C.

(B) among the objective compound [I], formula at ¹ ~ ^ ⁶ above: one ^{_{CH 2 N (R 11) (}} R 12)

[Wherein R ¹¹ and R ¹² are substituents of the substituted amino group described herein, or R ¹¹ and R ¹² are combined with the nitrogen atom of the amino group to form an oxygen atom. A heterocyclic group having 1 to 3 heteroatoms independently selected from a sulfur atom and a nitrogen atom, wherein the heterocyclic group may be substituted]

And a compound having a group represented by the formula: HN (R ¹¹ ) (R ¹² ) [wherein the symbols have the same meaning as described above]

(In the following description, this compound means "substituted or unsubstituted amine", and the group after removing a hydrogen atom from this substituted or unsubstituted amine is "substituted or unsubstituted amine". 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 is By using a reducing agent (sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, etc.) at -78 ° C-100 ° C It can implement suitably.

(C) In the target compound [I], the nitrogen atom on R ¹ ! ^ ⁶ is substituted or unsubstituted alkanoyl such as alkanoyl, cyclyl alkylcarbonyl, alkoxyalkanoyl, alkanoyloxycanol, etc. A compound that is simply substituted with a substituted or unsubstituted alkyl group is also a compound in which the corresponding nitrogen atom is unsubstituted (eg R ⁵ is piperazinylmethyl, piperazinylcarbonyl or pipera). It can also be produced by alkanoylation of a compound such as dinylsulfonyl. The alkanoylation can be produced by using any conventional method of amide formation that is usually used for peptide synthesis and the like. For example, the alkanoylation can be carried out using a base (triethylamine, pyridine, etc.) in a suitable solvent (methylene chloride, TI-IF, DMF, N, N-dimethylacetamide, chloroform or a mixed solvent thereof). It can be suitably carried out by using an acid chloride, an acid anhydride or an ester in the presence or absence at -78 ° C to 100 ° C. This reaction can also be carried out, for example, in a suitable solvent in the presence or absence of a condensing agent. As condensing agents, N-ethyl 1 N '— (3 -dimethylaminopropyl) carbodiimide, N, N ′ -dioxyhexyl carbodiimide, 1-methyl 1 2 _bromopyridyum-muzide, N, N' — Canoleboninorethymidazolone, dipheninophosphorinoleazide, benzotriazole- 1-yloxytris (dimethylamino) phosphoyuhexafluorophosphate, 4- (4,6-dimethoxy [1.3.5] triazine-2 -Inole) _ 4-Methylmorpholinum chloride, Fluoro N, N, N,, N, 1 Tetramethylform amidinium hexafluorophosphate it can. As a solvent, water, methanol, isopropanol, ethanol, salt methylene chloride, THF, DMF, N, N-dimethylacetamide, chloroform, etc. can be preferably used as a single or mixed solvent. it can. Genuine The reaction preferably proceeds at -78 ° C to 100 ° C, more preferably at -25 ° C to 25 ° C. As the base, potassium carbonate, sodium carbonate, sodium hydrogen carbonate or triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, N, N-dimethylaminopyridine, picoline, lutidine, etc. are added, and as an additive, N -Hydroxy succinimide or 3-hydroxy 3,4-dihydro _4 monoxo — 1, 2, 3-benzotriazole, N, N-dimethylaminopyridine, N-hydroxybenzotriazole, etc. By adding, the progress of this reaction can be promoted.

(D) Among the target compounds [I], a substituted or unsubstituted aminocarbon on R ¹ ! ^ ⁶ , that is, a compound having a substituted or unsubstituted rubamoyl group is replaced with a compound whose corresponding site is force loxy. Alternatively, it can be produced by reacting with an unsubstituted 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 may be any compound in which the corresponding site is hydroxymethyl. A heterocyclic compound having a substituted or non-substituted ar forceanol, a cycloalkanol, an alkylthio, or a hydroxyl group after being converted into an aralkylylmethyl, preferably acetyloxymethyl by a conventional method of esterification of Alternatively, it can also be produced by condensing a substituted or unsubstituted heteroaryl compound having a hydrogen atom on a nitrogen atom, such as virazole. This condensation reaction is carried out in the absence of a solvent or in an appropriate solvent (THF, dioxane, methylene chloride, chlorophonolem, tonoleene, benzene, etc.), in the presence of an acid (p-tonoleensenophonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, etc.). Alternatively, it can be suitably carried out in the absence of -78 ° C to 200 ° C, more preferably 25 ° C to 100 ° C.

(F) Among the target compounds [I], a compound having hydroxymethyl on 1 ^ to ¹⁶ can reduce a compound having a corresponding site of formyl by any conventional method for reducing formyl to alcohol. Can be manufactured. For example, this reaction is Reducing agent (sodium borohydride, sodium triacetoxyborohydride, diporane, diisoptylaluminum hydride, lithium aluminum hydride, etc.) in appropriate solvents (methanol, ethanol, methylene chloride, black mouth form, dioxane, THF, etc.) ) At −78 ° C. to 100 ° C. (G) Of the target compound [I]! A compound having a carboxyl on 尺 to ⁶ can be produced by oxidizing a compound in which the corresponding site is formyl by any conventional method of acidifying formyl to carboxyl. The oxidation can be carried out, for example, in an appropriate solvent (DMF, dimethyl sulfoxide, acetone, t-ptanol, water, methylene chloride, black mouth form, etc.), an oxidizing agent (sodium chlorite, potassium permanganate, pyridinium dichromate). Etc.) at −78 ° C. to 100 ° C.

(H) Among the target compounds [I], a compound having alkoxycarbonyl on R i R ⁶ is also 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. For the esterification, for example, acid (sulfuric acid, hydrochloric acid, _P- toluenesulfonic acid) in a suitable solvent (methanol, ethanol, isopropanol, t-butanol, etc.) is more preferable at -78 ° C to 200 ° C. Can be preferably carried out by using at 0 ° C to 100 ° C.

 Furthermore, esterification can also be carried out by reacting a carboxyl compound with an acid halide using a halogenating agent (oxalyl chloride, thionyl chloride, etc.) in an appropriate solvent (methylene chloride, chloroform, THF, dioxane, etc.). After conversion to an intermediate, it can also be carried out by using an alkenol (methanol, ethanol, isopropanol, etc.) at _78 ° C to 200 ° C.

(I) Among the target compounds [I], compounds having carboxyls on 1 ^ to ¹⁶ are also hydrolyzed by any conventional method of estenoreca-hydrolysis in which the corresponding site is alkoxycarbonyl. It can also be manufactured. The hydrolysis is In a suitable solvent (alcohol solvent such as methanol or ethanol or dioxane, THF, water or a mixed solvent thereof), base (sodium hydroxide, potassium hydroxide, potassium carbonate, lithium hydroxide, etc.) is -78 ° C ~ It can be suitably carried out by using at 200 ° C, more preferably from 0 ° C to 100 ° C.

 Furthermore, hydrolysis is also preferably performed 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). It can also be implemented.

(J) among the objective compound [I], a compound having a formyl on 1 ^ to 1 ⁶ also manufactured in any conventional method for the reduction of the force Rupokishiru aldehyde, the corresponding site is from a compound is carboxyl You can also This reaction is carried out by synthesizing an acid halide using a halogenating agent (eg, oxalyl chloride, thionyl chloride, etc.) in an appropriate solvent (methylene chloride, chloroformate, THF, etc. or a mixed solvent thereof). It can be suitably carried out by reducing the acid halide with a metal catalyst (palladium carbon, platinum dioxide, etc.) at _78 ° C to 200 ° C in a hydrogen atmosphere.

(K) Among the target compounds [I], a compound having hydroxymethyl on R ¹ ! ^ ⁶ can be produced by using any conventional method for the reduction reaction of ester or carboxylic acid to alcohol. . For example, in this reaction, the corresponding carboxyl or alkoxycarbonyl is reduced to a reducing agent (sodium borohydride, diborane, dioxane, etc.) at -78 ° C to 200 ° C in an appropriate solvent (methylene chloride, black mouth form, THF, etc.) It can be preferably carried out by treating with aluminum lithium hydride, diisoptyl aluminum hydride, etc.).

(L) Of the target compound [I]! A compound having a carboxyl on ^ ¹ to! ^ ⁶ can be produced by using a conventional method for oxidizing a primary alcohol to a carboxylic acid. For example, in this reaction, a compound in which the corresponding site is hydroxymethyl in an appropriate solvent (methylene chloride, acetone, chloroform, DMF, etc.), for example, at 0 ° (: to 100 ° C) is used as an oxidizing agent (3 Chromium oxide, pyridinium dichromate, etc.) 8050467

 37 and more preferably.

(M) Of the target compound [I]! ^ Compound having an amino on-scale ⁶ can be prepared by using any conventional method of reduction to Amin nitro. For example, in this reaction, a compound with a corresponding nitro compound as a metal catalyst (palladium) in a suitable solvent (methanol, ethanol, DMF, THF, dioxane, etc.) under a hydrogen atmosphere at _78 ° C to 200 ° C. Carbon, platinum dioxide, etc.).

 In addition, this step can also be performed at -78 ° C to 200 ° C in an appropriate solvent (alcohol solvents such as methanol and ethanol, or methylene chloride, chloroform, THF, dioxane, acetic acid, water, etc., or a mixed solvent thereof). More preferably, it can be suitably carried out by using a reducing agent (such as stannous chloride, iron, zinc, etc.) at 0 ° C to 100 ° C.

(N) Of the target compound [I], a compound having halogenosulfonyl on 1 ^ to ¹⁶ is obtained by reacting a compound in which the corresponding site is an amino group under the so-called S and mayer reaction conditions. It can be produced by halogenosulfuration via a salt. Formation of the diazonium salt can be achieved by, for example, using an appropriate acid (hydrochloric acid, sulfuric acid, etc.) and Z or an additive (cupric chloride, etc.) in an appropriate solvent (water, methylene chloride, chloroform, THF, or a mixed solvent thereof). ) In the presence or absence of -78 ° C. to 200 ° C., by using an oxidizing agent (such as sodium nitrite, isoamil nitrite, and 1 t-butyl nitrite). Subsequent halogenosulfonylation can be carried out by adding a sulfonating agent (sulfur dioxide, sodium bisulfite, etc.) to the obtained reaction solution at -78 ° C to 200 ° C.

(O) Of the target compound [I], a compound having a substituted or unsubstituted aminosulfonyl on 1 ^ to ¹⁶ also reacts a compound having a corresponding site of halogenosulfonyl with a substituted or unsubstituted amine. J? Can also be manufactured. This reaction is carried out in the presence of a base group (pyridine, triethylamine, sodium hydroxide, sodium carbonate, etc.) in an appropriate solvent (methylene chloride, chloroform, THF, dioxane, water, etc.). It can be suitably carried out at -78 ° C to 200 ° C in the presence or absence.

(P) Of the target compound [I]! Compounds with alkylthio, cycloalkylthio, and heterocyclicthio on ^ ¹ ~! ^ ⁶ are also described, for example, in the literature (Young RN, et al., Tetrahedron Lett., 1984, 25 (17), 1753.) In the same way as above, after converting the compound whose corresponding site is methylsulfier to thiol, there is a base (sodium hydride, cesium carbonate, potassium carbonate, potassium t-butoxide, triethylamine, diazabisulfandundene, etc.) Under or in the absence of alkylating agents (haloalkyls, halocycloalkyls, nochole heterocyclic compounds, alkyl mesylate, cycloalkyl mesylate, heterocyclic mesylate, alkyl tosylate, cycloalkyl tosylate, heterocyclic tosylate Etc.) can also be produced.

(Q) Of the target compound [I]! A compound having a substituted or unsubstituted alkanoylamino on ^ to ⁶ can also be produced by alkanoylating a compound in which the corresponding site is amino. The alkanoich can be carried out in the same manner as the reaction (C) above. Further, the alkanoylation can be carried out with a compound in which the corresponding site is a secondary amine or a primary amine.

(R) among the objective compound [I], R ¹ ~: alkylsulfonyl El § Mino on R ^6, Te lower reel sulfo El amino, substituted sulfo, such as heterocyclic Suruhoniruamino to - compounds with Rua amino or It can also be produced by sulfonylating a compound in which the corresponding site is an amino. The sulfonylation is carried out in a suitable solvent (water, THF, methylene chloride, black mouth form, etc.) in the presence or absence of a base (triethylamine, diisopropyl pyrethylamine, pV gin, etc.) at -78 ° C to Can be performed at 200 ° C. The sulfoleation can be carried out with a compound in which the corresponding site is a secondary amine and also a primary amine.

(S) Of the target compound [I]! A compound with a secondary alcohol on ^ ¹ to! ^ ⁶ is prepared by using any conventional method for converting a ketone to a secondary alcohol. 08 050467

39. For example, this reaction can be carried out in the same manner as the above reaction (K) with a compound having a corresponding oxo.

(T) Among the target compounds [I], compounds having oxo on 1 ^ to ¹⁶ can be produced by using any conventional method for converting a secondary alcohol to a ketone. For example, this reaction can be carried out using dimethyl sulfoxide oxidation (Swern oxidation) using an activating agent such as oxalyl chloride in an appropriate solvent (dimethyl sulfoxide, black mouth form, methylene chloride, etc.), or a base (triethyla In the presence or absence of oxidants (activated manganese dioxide, sulfur trioxide mono-pyridine complex, 1-hydroxy 1,2-benzobenzoxo 1 3 (1 H) 1 on 1 1 oxide 1, 1, 1-triacetoxy 1,1-dihydr draw 1,2-benzodoxol-3 (1 H) 1-on, pyridinium dichromate, pyridinium dichromate, etc.) . .

(U) Among the target compounds [I], R ¹ ~! A compound having a secondary alcohol on ⁶ can be produced by using any conventional method for converting a compound having formyl to a secondary alcohol. For example, this reaction can be carried out in a suitable solvent (THF, toluene, jetyl ether, etc.) at -78 ° C to 100 ° C with the corresponding formyl compound and metal reagent (alkylmagnesium halide, alkyllithium, Dialkyl dumbbell etc.) can be preferably used.

(V) Of the target compound [I]! ^ Compounds on ^1-6 having hydroxyamidino can be produced Ri by the using any conventional method for converting Shiano group hydroxyamidino group. For example, in this reaction, a compound having a corresponding cyano and hydroxylamine (or a salt thereof with an appropriate acid) are mixed in an appropriate solvent (water, methanol, ethanol, etc. or a mixed solvent thereof) at 0 ° C to 100 ° C. It is preferably carried out by reacting in the presence or absence of a base (sodium carbonate, potassium carbonate, sodium hydroxide, hydroxy hydroxide, potassium t-ptoxide, .triethylamine, pyridine, etc.) at ° C. Can do. (W) Among the target compounds [I], a compound having unsubstituted rubamoyl on ¹ to! ^ ⁶ is produced by using any conventional method for converting a cyano group to an unsubstituted rubamoyl group. can do. For example, in this reaction, a compound having the corresponding cyano is converted into a base (sodium hydroxide, water, water) at −20 ° C. to 100 ° C. in an appropriate solvent (water, methanol, ethanol, isopropanol, etc., or a mixed solvent thereof). It can be suitably carried out by treatment with oxidizing power, such as oxidizing power, or power, t-butoxide.

(X) Of the target compound [I]! A compound having a tertiary alcohol on ^ to ⁶ can be produced, for example, by reacting a compound having a corresponding oxo under the above-mentioned conditions (U).

(Y) Of the target compound [I], the production of a compound having an optically active secondary alcohol on ⁶ can be carried out by any conventional method for dividing the secondary alcohol compound by enzymatic transesterification. It can be implemented by using. For example, the preparation can be carried out in a suitable solvent (t-butyl methyl ether, hexane, diisopropyl ether, THF, jetyl ether, water, etc.) at -78 ° C to 100 ° C at the corresponding racemic second. The treatment can be suitably carried out by treating the secondary alcohol with an acyl donor (such as bulacetic acid) in the presence of an enzyme (such as lipase PS).

(Z) Of the target compound [I],! The production of a compound having alkyl on ^ ¹ to! ^ ⁶ can be carried out by using a so-called catalytic hydrogenation method. For example, this compound can be obtained by converting a compound having the corresponding alkenyl into a metal catalyst in a suitable solvent (methanol, ethanol, DMF, THF, acetic acid or the like or a mixed solvent thereof) at 0 ° C to 200 ° C in a hydrogen atmosphere. By treating with (palladium carbon, platinum dioxide, etc.), it can be suitably produced.

(AA) Among the target compounds [I], a compound having 1,2-diol on 1 ^ to ¹⁶ can be produced by, for example, using a suitable solvent (water, acetone, THF, acetonitrile, ethyl acetate, etc. or a mixture thereof) In the solvent, at 0 ° C to 100 ° C, the corresponding alkenyl-containing compound is oxidant (osmium tetroxide, ruthenium tetroxide, sodium periodate 7

41 etc.) can be suitably carried out.

(BB) Of the target compound [I]! The production of a compound having a halogen atom on ^ ~ ⁶ can be carried out by using any conventional method for halogenating alcohols. For example, in this production, the corresponding alcohol is treated with carbon tetrafluoride in the presence of triphenylphosphine in an appropriate solvent (methylene chloride, black mouth form, etc.) at 0 ° C to 100 ° C. It can implement suitably.

(CC) among the objective compound [I], RR ^2, preparation of R ⁵ or an unsubstituted and substituted § alkylthio on R ^6, Heteroari one Lucio or compounds having a § Li one Lucio are halogenated Ariru the thiols body It can be carried out by using any conventional method of coupling with halogenated heteroaryl, aryltriflate or heteroaryltriflate. For example, this production is carried out in the presence or absence of a base (triethylamine, disopropylamine, etc.) in an appropriate solvent (dioxane, toluene, THF, 1,2-dimethoxetane, etc. or a mixed solvent thereof) 0 ° Suitable by treating a compound having a corresponding haloaryl with a thiol (hydroxyalkylthiol, dialkylaminoalkylthiol, etc.) in the presence of a metal catalyst (tetrakis (triphenylphosphine) palladium, etc.) at C to 200 ° C. Can be implemented.

(DD) Among the target compounds [I], the production of compounds having mono- or di-substituted alkylamino on R ¹ ! ^ ⁶ can be carried out by using, for example, an appropriate solvent (methanol, ethanol, dioxane, toluene, THF, 1, 2-dimethoxetane, etc.) In the presence or absence of a base (triethylamine, disopropylamine, etc.) or at 0 ° C to ²⁰⁰ ° C, the corresponding haloalkyl-containing compound is mono- or di-substituted. It can be preferably carried out by treatment with an alkylamine (dimethylamine, jetylamine, methylamine, etc.). A compound having dimethylamino is a compound having a corresponding haloalkyl at 0 ° C to 200 ° C in an appropriate solvent (eg, methanol, ethanol, dioxane, toluene, THF, 1,2-dimethoxetane). - (bird Methylsilyl) It can be preferably produced by treatment with dimethylamine.

(EE) Among the target compounds [I], the production of a compound having alkynyl on RR ² , R ⁵ or R ⁶ can be carried out by using halogenated aryl, halogenated heteroaryl, aryl triflate or heteroaryl triflate and alkyne. It can be carried out by using any conventional method of so-called bacterial head coupling reaction with the compound having the above-mentioned compounds. For example, this production is carried out in the presence of a base (such as triethylamine or diisopropylamine) and / or a copper salt (such as cuprous iodide) in a suitable solvent (such as dioxane, toluene, THF, 1,2-dimethoxetane). In the absence or presence of a metal catalyst (tetrakis (triphenylphosphine) palladium, etc.) in the presence of 0 ° C to 200 ° C, alkyne (propargyl alcohol, N, N-dimethylpropargylamine) Etc.) can be suitably carried out.

(FF) Of the target compound [I], a compound having tetrazolyl on scales ¹ to! ^ ⁶ can be produced by using any conventional method for converting a cyano group into a tetrazolyl group. For example, this production can be carried out in a suitable solvent (methanol, ethanol, DMF, dioxane, toluene, TI-IF, 1,2-dimethoxetane, etc.), salt (triethylamine, diisopropylamine, etc.) or salt (triethylamine). Mine hydrochloride, etc.) In the presence or absence, the corresponding cyano-containing compound is treated with metal azide (sodium azide, triptyltin azide, trimethylsilyl azide). It can implement suitably by doing.

(GG) Among the target compounds [I], the production of compounds with O-alkoxy carbonyl oximine on 1 ^ to ¹⁶ can be carried out using suitable solvents (DMF, dioxane, toluene, THF, 1, 2-dimethoxetane, etc.) or in the absence of a base, in the presence or absence of a base (pyridine, triethylamine, etc.) or at 0 ° C to 200 ° C, the corresponding hydroxyimine compound can be converted to an alkyl carbonate. Treated with ethyl ether etc.) It can implement suitably.

(HH) Of the target compound [I], the production of a compound having aryl or heteroaryl on RR ² , R ⁵ or R ⁶ uses any conventional method of so-called Still coupling or Suzuki force coupling reaction. Can be implemented. For example, in this production, a base (triethylamine, disopropylamine, sodium tertbutoxide, sodium carbonate, cesium carbonate, in a suitable solvent (dioxane, toluene, THF, 1,2-dimethoxetane etc. or a mixed solvent thereof) In the presence or absence of potassium phosphate, etc. 0. At C ~ 200 ° C, metal catalysts (eg dichlorobis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) paradium), tris (dibenzylideneaceton) dipalladium, dichloro [1,1 'bis (Diphenylphosphino) Phenolsene] Palladium, palladium acetate, etc.) In the presence, the corresponding haloaryl-containing compounds are araryltrialkyltin, heteroarrenoretanoloxytin, arenorezig droxyborane, heteroaryldihydroxyborane, aryl It can be suitably carried out by treating with catechol borane, heteroaryl catechol borane and the like.

 (I I) 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 in Protective Groups in Organic Synthesis Third Edition (Theodora W. Green and Peter G. uts).

 (JJ) Alternatively, the present compound [I] can also be used in the above steps (A) to (II) for compound [II] to compound [XIII] at an appropriate stage in each step of (1) to (13). It can also be synthesized by appropriately carrying out any reaction. Experimental example

Darcokinase activation

Darcokinase activity is directly measured by the glucose monophosphate produced. 08 050467

 However, the amount of NADPH produced when 6-phosphodarconic acid was produced from dalcose-6-phosphate by glucose-6-phosphate dehydrogenase, a conjugated enzyme, was measured. As the darukoki-Ize enzyme, human liver type GST-GK expressed in E. Coli was used. GK activity was measured according to the following procedure.

As the reaction _{solution, 25 raM MgCl 2, 25 mM} KC1, 1 mM DTT, 5 mM NADP (Roche), 16. 64 / ig / raL G6PDH ( yeast Roche 737-232 grade II) and 2. 8 μ g / ml A 25 mM HEPES buffer (pH 7.4) containing GST-GK was prepared. The evaluation compound dissolved in DMSO was added to the reaction solution so that the final concentration was 0.001 to 100 μΜ (5% DMSO). To this, 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 15 minutes from the start of the reaction was measured, and the value corrected for blank was taken as GK activity (mOD / min). The EC ₅₀ value was calculated from the GK activity value at each concentration of the evaluation compound.

Since the compound [I] of the present invention or a pharmacologically acceptable salt thereof has an excellent darcokinase activating action, diseases involving dalcokinase such as diabetes, particularly type II diabetes, or retinopathy, kidney It is useful for the prevention or treatment of chronic diabetic complications such as symptom, neurosis, ischemic heart disease or arteriosclerosis, and obesity. BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described in more detail with reference to the following examples and reference examples, but the present invention is not limited thereto. In the examples, APCI is the atmospheric pressure chemical ionization mass 67

 45 kutonore (atmospheric pressure chemical ionization mass spectrum), E S I stands for electrospray ionization mass spectrum. In the present specification, DMF represents N, N-dimethylformamide, and THF represents tetrahydrofuran. Example

(1) A solution of (4-nitrophenol) ethyl acetate 70.0 g (314 mmol), hydroxylamine hydrochloride 32.7 g (470 mmol) and pyridine 37.2 g (470 mmol) in ethanol (700 ml) was heated for 13 hours. Refluxed. After cooling the reaction mixture, the precipitate is collected by filtration, 2008/050467

 46 The mixture was washed with a mixed solvent of ice-cold etanol-rugetyl ether. The crystals were dried under reduced pressure to give 21.7 g (yield 29%) of (1-B) as a pale yellow solid.

MS (m / z) ESI: 237 [M-H]-

(2) 33.7 g (244 mmol) of potassium carbonate and (S) — 3—tetrahydrofuranonoic acid under ice-cooling in a DMF (400 ml) solution of 29.0 g (122 mmol) of the above compound (1 1 B) Lou p

-Toluenesulfonic acid ester 44.3 g (183 mmol) was sequentially added, and the mixture was stirred at the same temperature for 10 minutes and at room temperature for 18 hours. The reaction mixture was filtered through Celite, and the insoluble material was washed with ethyl acetate. The combined filtrate was washed with water, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with dilute brine and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 55.2 g of the compound (11C) as crude crystals. The obtained crude crystals (1-C) were used in the next reaction without purification.

(3) 2N of the above compound (1-C) in a mixture of 55.2 g (122 mmol) of THF (435 ml), ethanol (145 ml) and water (72.5 ml) under ice-cooling. Aqueous sodium hydroxide solution (102 ml, 0.23 mmol) was added dropwise, and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, water (500 ml) was added to the residue, and the mixture was washed 3 times with ethyl acetate (200 ml). 2N hydrochloric acid (104 ml) was added to the aqueous layer to adjust the pH to 2 to 3, and the mixture was further extracted twice with ethyl acetate. The combined organic layer was dried over magnesium sulfate, and the organic solvent was distilled off under reduced pressure. The oily residue was dissolved in ethyl acetate, hexane was added to the solution until it became cloudy under heating, and the mixture was stirred at room temperature for 16 hours. The precipitated crystals were collected by filtration, washed with a mixed solvent of ethyl acetate and hexane (1: 2), and dried under reduced pressure at 40 ° C. to obtain the above compound (1 1 D) I ⁸ · 2 g ((1 1 A yield of 53%) from B) was obtained as colorless crystals.

MS (m / z) ESI: 279 [M-H] "

(4) Potassium carbonate powder was added to a solution of the above compound (11D) 21.5 g (76.7 ol) in DMF (358 ml) under ice cooling and stirred for 10 minutes. Furthermore, 5.75 ml (92. 1 mmol) of odomethane was added dropwise at the same temperature, and the mixture was stirred at room temperature for 3 hours and 30 minutes. The reaction mixture was filtered through celite to remove insolubles, and the insolubles were washed with ethyl acetate. Combined elution The solution was washed 3 times with water, and the aqueous layer was re-extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 23.9 g of the above compound (1-E) as a crude colorless oil. The obtained crude colorless oil (11E) was used in the next reaction without purification. MS (m / z) APCI: 295 [M + H] ⁺

(5) Add 28.6 g (384 mmol) of tin chloride dihydrate to a solution of 23.9 g (76.7 olol) of the above compound (1 1 E) in ethanol (271 ml) at room temperature. In addition, the mixture was stirred at the same temperature for 15 hours. Ethanol was distilled off under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the residue. The insoluble matter was removed by Celite filtration, and the insoluble matter was washed with ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and then concentrated under reduced pressure. The resulting crude crystals were powdered by stirring in ethyl acetate in hexane overnight and collected by filtration. The crystals were washed with ethyl acetate hexane (1: 3) and dried under reduced pressure to obtain 14.4 g (yield 71%) of compound (1-F) as pale yellow powder crystals. MS (m / z) APCI: 265 [M + H] ⁺

 (6) Dissolve the above compound (11F) 8, 03 g (30.4 mmol) in a mixed solvent of concentrated hydrochloric acid (80 ml) and water (26 ml), and add sodium nitrite under ice-cooling. 34 g (33.4 mmol) in aqueous solution

(21 ml) was added and stirred at the same temperature for 30 minutes. Next, 15.2 g (91.1 mmol) of an aqueous solution of potassium iodide (32 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Ice water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The extract was filtered with Bond Elut JR-NH ₂ (VARIA), and the carrier was eluted with ethyl acetate. The combined eluate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate hexane) to obtain 9.10 g of compound (1-G) (yield 80%). Obtained as a yellow oil.

MS (m / z) APCI: 376 [M + H] ⁺

(7) Under an argon atmosphere, sodium formate 816 mg (12.0 mmol) _N N, N-diisopropylethylamine 1.4 ml (8.04 raraol) and acetic anhydride 0.76 ml (8.04 mmol) ) Of DMF suspension at room temperature for 1 hour, the above compound (1_G) 1.50 g (4.00 mmol), lithium chloride 508 mg (12.0 mmol) and tris (dibenzylidene) Seton) A solution of dipalladium (0) 183 rag (0.20 .ol) in DMF was added, and the mixture was heated and stirred at 80 ° C. for 15 hours. The reaction mixture was cooled, diluted with ethyl acetate, filtered through Celite to remove insoluble materials, and the insoluble materials were washed with ethyl acetate. The combined eluate was washed 3 times with 1 N hydrochloric acid, and extracted with a saturated aqueous sodium hydrogen carbonate solution into the organic layer. Wash the aqueous layer 3 times with ethyl acetate, then add 1 N hydrochloric acid to the aqueous layer! H 2 to 3 and extracted 3 times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% tananol chloroform) to obtain 1.09 g (yield 93%) of the compound (11H) as a colorless oil. MS (ra / z) ESI: 292 [MH]-

(8) The above compound (l—H) 1.00 g (3.41 ramol), N-ethylyl N ′ — (3-dimethylaminopropyl) carbodiimide hydrochloride 1. 31 g (6. 82 mmol) And 1-hydroxybenzotriazole 922 rag (6. 82 mmol) in DMF (10 ml) solution under ice-cooling, N, O-dimethylhydroxyamine hydrochloride 499 mg (5. 12 mmol) and N, N-diisopropylethylamine 0.89 ml (5.11 mmol) was added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted 3 times with ethyl acetate. The extract was washed 3 times with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel gel chromatography (67% ethyl acetate monohexane) to give 2.88 g (yield 85%) of compound (1-1) as a colorless oil. MS (m / z) APCI: 337 [M + H] ⁺

(9) 850 mg (2.53 ol) of the above compound (1-1) in a mixed solvent of THF (13 ml), methanol (2.5 ml) and water (1 ml) under ice-cooling, 2 N aqueous sodium hydroxide solution 1.26 ml (2.52 mmol) was added, and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and water were added to the residue. After separating the aqueous layer, the organic layer was further extracted with water. The combined aqueous layer was acidified with 2N hydrochloric acid (1.27 ml) and extracted twice with ethyl acetate. The extract was dried over sodium sulfate and concentrated under reduced pressure to obtain 765 mg (yield 94%) of the compound (1_J) as a colorless oil. MS (m / z) ESI: 321 [M—H 643 [2M-H] —

 (10) Above compound (1- J) 720 mg (2.23 mmol) 2-Amino mono 5-Fluoro-thiazole hydrochloride 691 mg (4.47 mmol), and 4 mono (N, N-dimethylamino) Pyridine 382 mg (3.13 To the solution of thigh ol) in black mouth form (11 ml), add N-ethyl N '— (3-dimethylaminopropyl) carbodiimide 570 / z 1 (3.14 mmol) at room temperature, Stir for hours. A 10% aqueous taenoic acid solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed twice with 10% aqueous citrate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel force ram chromatography (07% methanol-chloroform) to obtain Compound (11K) 336 rag (yield 36%) as a pale yellow solid.

MS (ra / z) APCI: 423 [M + H] ⁺

(1 1) In a THF solution (2.0 ml) of the above compound (1 K) 100 rag (0.24 mmol) in an argon atmosphere, cyclopropylmagnesium bromide 2.5 ml (0.5M; 1.25 mmol) was added, and the mixture was stirred at 120 for 1 hour and further at 0 ° C for 1 hour. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (45 70% ethyl acetate) and then purified by NH silica gel chromatography (0 4% methanol-chloroform) to give 146 mg of compound (1-L) (yield 8 ⁸ ° / ₀ ) was obtained as a colorless powdered solid.

MS (m / z) APCI: 404 [M + H] ⁺ Example 2

The corresponding starting material compound was treated in the same manner as in Example 1 to obtain the following compound.

Example 3

(1) Under argon atmosphere, the above compound (1 -G) 1.70 g (4.53 mmol) _s tributyl (1-ethoxybiyl) tin 1.68 ml (4.97 ol ol) and bis (triphenolinolephosphine) palladium (II ) A 1,4_dioxane solution (26 ml) of 318 rag (0 · 453 mraol) was heated and stirred at 80 ° C. for 4 hours. After cooling the reaction mixture, impurities are removed by Celite filtration, and then the filtrate is passed through Bond Elut JR-NH ₂ (VARIAN) and concentrated under reduced pressure to give compound (3-A) as a crude solid. And used in the next reaction without purification.

(2) The above compound (3-A) was dissolved in 1,4-dioxane (20 ml), 3% hydrochloric acid (5 ml) was added, and the mixture was stirred at room temperature for 32 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and then under reduced pressure. Concentrated. The residue was purified by NH silica gel chromatography (25% ethyl acetate-hexane) to obtain 1.09 g (yield 83%) of compound (3-B) as a pale yellow oil. MS (ra / z): APCI: 292 [M + H] ⁺

 (3) Dissolve 1.00 g (3.43 mmol) of the above compound (3-B) in a mixed solvent of THF (10 ml), methanol (2 ml), and water (1 ml) and add 2 N sodium hydroxide under ice-cooling. 1.9 ml (3.80 ol) of an aqueous solution was added and stirred at the same temperature for 30 minutes. Water was added to the residue obtained by concentrating the reaction mixture under reduced pressure, and the mixture was washed twice with jetyl ether. The aqueous layer was separated and the organic layer was further extracted with water. The combined aqueous layer was acidified with 2N hydrochloric acid (1.95 ml), and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain 929 mg (yield 98%) of compound (3-C) as a pale yellow oil. MS (ra / z) ESI: 276 [M—H]-, 553 [2M-H] "

 (4) The above compound (3_C) 150 rag (0.54 mmol), 2_amino-5-fluorothiazonole hydrochloride 125 mg (0.81 瞧 ol), and 4— (N, N-dimethylamino) pyridine 86 mg (0.70 mmol) N-ethyl-N ′-(3-jetylaminopropyl) carbodiimide 128/1 (0.70 mmol) was added to a solution of chloroform (2.3 ml) at room temperature and stirred at the same temperature for 16 hours. The reaction mixture was directly purified by silica gel column chromatography (0-5% methanol-chloroform) to obtain 73 mg (yield 36%) of the compound (3 1 D) as a colorless powder solid.

MS (m / z) APCI: 378 [M + H] ⁺ Examples 4 to 9

 [Examples 4 and 5] The corresponding starting materials were treated in the same manner as in Example 3 to obtain the compounds of Examples 4 and 5 above.

(Example 4) MS (m / z) APCI: 584 [M + H] ⁺

(Example 5) MS (m / z) APCI: 598 [M + H] ⁺

 [Example 6]

 Compound 470 rag (0.81 mmol) of Example 4 was dissolved in formic acid (3 ml) and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH silica gel chromatography (0 to 3% methanol / chloroform form) to obtain 200 mg (yield 50%) of the compound of Example 6 above as a yellow powder. Obtained as a solid.

MS (m / z) APCI: 484 [M + H] ⁺

 [Example 7]

The corresponding starting material compound was treated in the same manner as in Example 6 to obtain the compound of Example 7. MS (m / z) APCI: 498 [M + H] ⁺

 [Example 8]

140 mg (0.29 mmol) of the compound of Example 6 was dissolved in black mouth form (2.5 ml), 37% formalin solution (0.5 ml) and sodium triacetoxypolyhydride at room temperature. 0467

 53

123 mg (0.58 olol) was added and stirred at the same temperature for 1 hour. Ice water was added to the reaction mixture, and the mixture was extracted twice with black mouth form. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel chromatography (0-2% methanol-chloroform) to obtain 154 mg (quantitative) of the compound of Example 8 as a pale yellow solid. MS (m / z) APCI: 498 [M + H] ⁺

 [Example 9]

The corresponding starting material compound was treated in the same manner as in Example 6 to obtain the compound of Example 9 above. MS (m / z) APCI: 512 [M + H] ⁺ Example 1 0

(1) Compound (1—H) of Example 1 in a solution of 1.40 g (4.77 mmol) in methylene chloride (15 ml) at 0 ° C with oxalyl chloride 520 μ 1 (5.96 mraol) and DMF (catalyst amount: 1 drop) was added dropwise in order, and the mixture was stirred at room temperature for 1 hour. Further, 2.91 ml (33.4 mraol) of oxalinole chloride was added dropwise, and the mixture was stirred at room temperature for 2 hours. The above compound (10-A) was obtained as a crude brown viscous oil by distilling off the solvent of the reaction mixture under reduced pressure. 08050467

 54 Used for the next reaction.

 (2) Under an argon atmosphere, add 0.5M cyclopropyl magnesium promide to a suspension of copper iodide (I) 1.07 g (5.64 ramol) in THF (10 ml) at 78 ° C over 5 minutes. Added. The reaction mixture was heated to 0 ° C over 1 hour and stirred at the same temperature for 1 hour. The reaction mixture was cooled to 78 ° C, a solution of compound (10-A) (4.77 raraol) in THF (10 ml) was added dropwise, stirred at the same temperature for 10 minutes, and then warmed to room temperature over 2 hours. The mixture was warmed and stirred overnight at the same temperature. 5% Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The residue obtained by concentrating under reduced pressure was separated and purified with a silica gel chromatography (0 to 40% ethyl hexane acetate), and the above compound (E form: 10-B) 172 mg (yield 11%) ) And the above compound (Z form: 10-C) were obtained as yellow oils, respectively.

(E body: 10— B) MS (m / z) APCI: 318 [M + H] ⁺

(Z body: 10 -C) MS (m / z) APCI: 318 [M + H] ⁺

(3) The above compound (Z form: 10-C) 570 rag (1.80 ol) was dissolved in 4.0 ml of dioxane and 4.0 ml (16 ramol) of 4N hydrogen chloride-dioxane solution and stirred at room temperature for 2 hours. The reaction mixture was neutralized by adding saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (10-40% ethyl acetate). ) 177 rag (yield 31%) was obtained as a colorless oil. MS (m / z) APCI: 318 [M + H] ⁺

(4) Dissolve the above compound (E form: 10-B) 366 rag (1.15 mmol) in a mixed solvent of T HF (2 ml), methanol (1 ml), and water (1 ml). In C, 2N aqueous sodium hydroxide solution 690 1 (1.38 mmol) was added, and the mixture was stirred at the same temperature for 1 hour 30 minutes. 2N hydrochloric acid 690 1 (1.38 ol) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. Concentrate under reduced pressure, add toluene to the residue, azeotrope twice and remove water to remove the above compound (10—D) 346 mg (concentration). 99%) was obtained as a yellow solid. MS (m / z) ESI: 302 [M—H] ", 605 [2M-H]-(5) To a solution of the above compound (1 0—D) 85 mg (0.28 mmol) in black mouth form (2.0 ml) 5— (3-Dimethylaminopropoxy) — [1,3] thiazolo [5, 4-b] pyridin-2-amine and molecular 4s A (powder, 5 microns) (Aldrich) And stirred at room temperature for 15 minutes, followed by N-ethyl-N '— (3-dimethylaminopropyl) carbodiimide hydrochloride 70 mg (0.36 olol) and 4- (N, N-dimethylamino) pyridine at 0 ° C 45 mg (0.36 mmol) was added, stirred at the same temperature for 30 minutes, and stirred at room temperature for 22 hours.The reaction mixture was diluted with chloroform and diluted with Celite, and the combined filtrate was NH silica gel. Purification by chromatography (0-: L 5% methanoyl lauryl acetate) gave 61 mg (yield 40%) of the above compound (10-E) as a colorless solid.

MS (m / z) ESI: 538 [M + H] ⁺

Example 1 1-; L 3

 Corresponding raw material compounds were treated in the same manner as in Examples 10 and 6, respectively.

13 compounds and the compounds of Examples 14 and 15 were obtained.

 Example RMS (m / z)

11-(CH2) ₂ -N (CH ₃ ) COO-t-Bu ESI: 610 [M + H] ⁺

12-(CH2) ₂ -N (CH ₃ ) 2 ESI: 524 [M + H] ⁺

13-(CH2) ₃ -N (CH ₃ ) COO-t-Bu ESI: 624 [M + H] ⁺

14-(CH2) ₂ -NH-CH ₃ APCI: 510 [M + H] +

15-(CH ₂ ) ₃ -NH-CH ₃ APCI: 524 [M + H] ⁺ 67

 56 Example 16

The above compound (1-L) ^. [^ (. ^. [^.] Methanol! ^^^ Sodium borohydride 69 mg (1.82 mmol) was added to the solution at 0 ° C and stirred for 1 hour at the same temperature. 1N hydrochloric acid was added to the reaction mixture. Concentrated under reduced pressure Water was added to the residue, extracted three times with ethyl acetate, the combined organic layers were washed with saturated brine and dried over sodium sulfate, concentrated under reduced pressure, and the residue was combined with NH silica gel chromatography. (0-10% ethyl chloroacetate) yielded 110 mg (yield 92%) of the compound (16-A) as a colorless powder solid MS (m / z) APCI: 406 [ M + H] ⁺ Examples 17-20

The corresponding starting compound was treated in the same manner as in Example 16 to obtain the following compound.

Example RMS (m / z)

Example

Treatment as in the above example gives the following compound:

 L9P0S0 / 8 0ZdT / lJd

81 "80 / 800∑: OAV

63

9

.9l70S0 / 800Zdf / X3d £ L8 80 / 800Z OAV

Reference example 1

H ls' II HCI

 S to CHO

2-t-Ptyloxycarbonylaminothiazole 88.0 g (439 mmol) in THF 1760 ml- ⁷ 8 ° C 1.59M n-Butyllithium hexane solution 729 ml (1159 mmol) 2 The solution was added dropwise over 0 minutes, and the temperature was raised to -10 ° C over 1 hour. -After cooling to 78 ° C again, DM F (102 ml, 1320 mmol) was added all at once. Remove the acetone-dry ice bath and stir for 30 minutes. Then pour the reaction mixture into 1000 ml of cold water and add 2000 ml of ethyl acetate. 8 050467

 67 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 with ethyl acetate to obtain 74.8 g of 2-tert-propylcarbonylcarbonylaminothiazole-5-carboaldehyde. mp. 173-175. C MS (m / z) APCI: 229 (M + H) +

 Add 322 ml of trifluoroacetic acid to a solution of 62.5 g (282 mmol) of 2-tert-butyloxycarbonylaminothiazobenzene as above in 322 ml of methylene chloride over 20 minutes under ice-cooling. Added. The reaction mixture was stirred at room temperature for 2 hours and the solvent was distilled off. To this was added 50 ml of black mouth form, and then 300 ml of 4N hydrogen chloride-dioxane solution was added dropwise under ice cooling. After distilling off the solvent, the residue was washed with ethyl acetate and collected to obtain 41.3 g of the title compound as a monohydrochloride salt.

mp. 190- 194 ° C (Disassembly) MS (m / z) APCI: Not detected Reference Example 2

H ₂ N- <HCI

2-t-petite / leoxycanoleponinoleaminothiazonole 60.0 g (299 mmol) in THF 1200 ml to 1.5 9 M n-butyllithium in hexane 428 ml (659 mmol) was added dropwise over 20 minutes, and the temperature was raised to -10 ° C over 1 hour. After cooling again to −78 ° C., 142 g of N-fluorobenzenesulfonyl chloride (449 mmol) was added all at once. Remove the acetone-dry ice bath, stir for 30 minutes, pour the reaction mixture into 1000 ml of cold water, add 1200 ml of ethyl acetate, separate the layers, and wash the organic layer successively with 2 N hydrochloric acid, water, and saturated brine. The extract was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (15% ethyl acetate: hexane = 3: 1), recrystallized with jetyl ether, ² — t-Butyloxycarbonamino 5-fluoro This gave 45.1 g of thiazole.

mp. 157-159 ° C MS (m / z) APCI: 219 (M + H) ⁺ Add 190 ral trifluoroacetic acid dropwise to 190 ml of methylene chloride in 2 ml of 2-tert-butinoreoxycanolebonylamino-5-funoleo-thiazonole 38.0 g (174 mmol) under ice-cooling for 20 minutes. Added. Stir at room temperature for 2.5 hours and concentrate. To this was added 20 ml of black mouth form, and 180 ml of 4N hydrogen chloride-dioxane solution was added dropwise under ice cooling. After concentration, the residue was washed with ethyl acetate and collected to give 24.6 g of the title compound as the monohydrochloride salt. mp. 142-144. C (Disassembly) MS (m / z) APCI: 119 (M + H) ⁺ Reference Example 3

 (1) After adding 28% aqueous solution at room temperature to 400 ml of an aqueous solution of 80.0 g (486 mmol) of the compound of Reference Example 1 at 80 ° C., the precipitated crystals are collected and dried to obtain a free aldehyde. It was.

 (2) The above product was suspended in 600 ml of methanol, 27.6 g (729 mmol) of sodium hydrogen hydride was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. After adding 30 ml of acetone and 50 ml of water to the reaction mixture, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (20-25% methanol-chloroform). —Hydroxymethylthiazole (45.2 g, yield 71%) was obtained.

MS (m / z) APCI: 131 (M + H) ⁺

 (3) 45.2 g of the above product was dissolved in 2 M hydrogen chloride / methanol solution and stirred at 60 ° C. for 5 hours. After the reaction mixture was concentrated, the residue was solidified with a mixture of methanol and jetyl ether to obtain 49.8 g (yield 79%) of the title compound as a monohydrochloride.

MS (m / z) APCI: 145 (M + H) ⁺ Reference Example 4 S input N input OH

 5-Methoxy [1,3] thiazolo [5,4 b] Pyridine-2-amin 5.0 g (27.6 mmol) was dissolved in 50 ml of 30% hydrogen bromide monoacetic acid and stirred at 130 ° C for 3 hours. . After cooling to room temperature, the solvent was distilled off under reduced pressure, the residue was solidified with jetyl ether, and 2-amino [1, 3] thiazolo [5, 4 b] pyridine 1 5 _ol dihydrobromide 9.11 g (Quantitative) was obtained as colorless crystals.

MS (m / z) APCI: 168 (M + H) ⁺ Reference Example 5

 Stir a solution of 1.18 g (3.59 mmol) of the compound of Reference Example 4, dimethylaminoethyl chloride hydrochloride hydrochloride 569 rag (3.95 mmol) and 6.43 g (19.75 mmol) of cesium carbonate in 30 ml of DMF at 60 ° C for 2 hours. did. After cooling to room temperature, 2.26 ml (39.5 mmol) of acetic acid was added, diluted with water until a homogeneous solution was obtained, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH-silica gel; 50% ethyl acetate-hexane) to obtain 273 rag of the title compound (yield 32%) as pale yellow crystals.

MS (m / z) APCI: 239 (Reading) ⁺ Reference Example 6

A solution of 1.54 g (4.68 (ol) of Reference Example 4, 0.571 ml (5.15 mmol) of bromoethyl acetate and 6.86 g (21.06 mmol) of cesium carbonate was stirred for 30 minutes at room temperature. Then, 2.47 ml (43.2 raraol) of acetic acid was added, diluted with water until a homogeneous solution was obtained, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH-silica gel; ethyl acetate) and solidified with diisopropyl ether to obtain the title compound 862 rag (yield 67%) as colorless crystals.

MS (m / z) APCI: 254 (M + H) ⁺ Reference Example 7

 The corresponding raw material mixture was treated in the same manner as in Reference Example 5 to obtain the title compound.

MS (m / z) APCI: 282 (M + H) Reference Example 8

To a solution of 862 mg (3.40 mmol) of Reference Example 6 in 20 ml of THF, 222 mg (10.21 mraol) of lithium borohydride was added at room temperature, and the mixture was stirred as it was for 24 hours. To the reaction mixture was added 10% hydrochloric acid to decompose excess reagent, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with a 20% methanol-chloroform solution, the organic layer was separated, and the solvent was distilled off. The obtained residue was purified by squeezing force genoleum chromatography (5 to 20% methanol-luke mouth form) to obtain 369 mg (yield 51%) of the title compound as colorless crystals. MS (m / z) APCI: 212 (arm) + The above compound was synthesized by the following alternative method

 (8-a) ((88--bb)) (8-c)

(1) 13.55 g (98.0 mmol) of carbonated lithium was added to 20 ml of a DMF solution of 5.18 g (32.7 mmol) of compound (8-a) and 20.28 g (327 mmol) of ethylene glycol, and stirred at room temperature for 2 hours. 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 with ethyl acetate-hexane to obtain 5.59 g (yield 93%) of compound (8-b) as yellow crystals. MS (APCI): 185 (M + H) ⁺

(2) Add 0.50 g of 10 ^o / _o Pd_C to 50 ml of an ethanol solution of 5.57 g (30.25 mmol) of compound (8-b), stir vigorously for 2 hours under a hydrogen stream, and concentrate the reaction mixture under reduced pressure. As a result, a crude amine compound was obtained.

 (3) To 100 ml of an acetic acid solution of the above amine compound, 17.64 g (182 mmol) of potassium thiocynate was added, 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; methanol-chloroform == 20: 1-10: 1) and triturated with ethyl acetate. Then, 5.55 g (yield 87%) of the compound (8_c) was obtained as colorless crystals.

MS (APCI): 212 (M + H) ⁺ Reference Example 9

Treat the compound of Reference Example 4 with 2-promoacetamide in the same manner as in Reference Example 5. 08050467

72 The following compound was obtained. MS (m / z) APCI: 225 (M + H) ⁺ Reference Example 10

The compound of Reference Example 4 was treated with 2-bromo-Ν-methylacetamide in the same manner as in Reference Example 5 to obtain the title compound. MS (m / z) APCI: 239 (M + H) ⁺ Reference Example 1 1

 (1) To a solution of 1380 mg (3.02 mmol) of the compound of Reference Example 9 in 40 ml of THF, 1.17 g (30.8 mmol) of lithium aluminum hydride was added at room temperature, and the mixture was stirred at room temperature for 20 hours. Excess reagent was decomposed with 30% aqueous ammonia solution, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by sili-gel gel force ram chromatography (30% aqueous ammonia: methanol: chloroform = 0.1: 1: 5) to obtain 150 mg of an amine form.

 (2) To a suspension of 150 mg (0.713 tnmol) of the compound obtained in (1) above in 10 ml of THF, dissolve 187 mg (0.856 mmol) of di-t-butinoresicarbonate in 5 ml of THF at room temperature. The mixture was further stirred at room temperature for 90 minutes. A 30% aqueous ammonia solution was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes, diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0-5% methanol / chloroform) to obtain 177 mg (yield 9%: 2 steps) of the title compound as a colorless solid.

MS (m / z) APCI: 311 (M + H) ⁺ _T The above compound was synthesized in alternative shown below

S input Ν Boc

 (1) Compound (8-a) 15.0 g (94.6 mraol) and N— (t_butoxycarboninole) ethanolamine 30.50 g (189.2 mmol) in DMF solution 150 ml in potassium carbonate

26.15 g (189.2 mmol) was added little by little, and the mixture was stirred at 50-60 ° C for 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over sodium sulfate. After the activated carbon treatment, the solution was concentrated under reduced pressure, and the residue was crystallized with diisopropyl pill ether to obtain 11.86 g (yield 44%) of the compound (ll_a). MS (m / z) APCI: 284 (M + H) ⁺

 (2) To 10 ml of an ethyl acetate solution of 1.08 g (3.81 mmol) of the above compound was added 128 mg of 10% Pd—C, and the mixture was vigorously stirred at room temperature for 1 hour under a normal pressure hydrogen stream. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 1.09 g of a crude amine compound.

 (3) Add 1.87 g (19.3 mmol) of potassium acetate and 2.22 g (22.8 mraol) of potassium thiocyanate to 20 ml of the above acetic acid solution of the amine compound, and add bromine while cooling in an ice-water bath.

0.234 ml (4.57 mmol) was added dropwise and then stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water, aqueous sodium sulfite solution and saturated brine, and dried over sodium sulfate. After the activated carbon treatment, the mixture was concentrated under reduced pressure, and the residue was crystallized with ethyl hexane acetate to obtain 516 mg of the above compound (44% yield over 2 steps). MS (m / z) APCI: 311 (M + H) ⁺ Reference Example 1 2

The compound of Reference Example 10 was treated in the same manner as in Reference Example 11 to give the title compound as colorless crystals. MS (ra / z) APCI: 325 (M + H) ^{+ The} above compound was also synthesized by the following alternative method

(1) 100 ml of dimethyl sulfoxide solution of compound (8-a) 10.0 g (63.08 mmol) and N— (t-ptoxycarbonyl) mono-N-methylethanolamine 16.55 g (94.6 mmol) was cooled in an ice-water bath. While adding forceurium tert-butoxide 10.62 g (94.6 mmol) little by little, the mixture was 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 21.76 g of the compound (12-a). MS (m / z) APCI: 298 (M + H) ⁺

(2) The compound obtained in (1) above was reacted in the same manner as in Alternative Method (2) of Reference Example 11 to obtain a crude amine. MS (m / z) APCI: 268 (M + H) ⁺

(3) The compound obtained in (2) above was treated in the same manner as in Alternative Method (3) of Reference Example 11 to obtain the above compound. MS (m / z) APCI: 325 (M + H) + Reference Example 1 3

(1) Black mouth sulfuric acid 80.0 g (687 mmol) was cooled with water, 2-acetamidothiazole 20.00 g (140.6 mmol) 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 jetyl ether. Extract 67

 75 Washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give 9.41 g of the crude product (13-b) as a yellow solid.

 (2) A 2 M aqueous solution of dimethylamine 7.2 ml (14.3 mraol) and 3 ml of pyridine was ice-cooled and compound (13-b) 1. 50 g was added in several portions. Stir for 5 minutes at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0 to 10% methanol-chloroform).

(13-c) 677 mg was obtained as a yellow powder.

(3) 6N Hydrochloric acid was added to 447 mg of the above compound, and the mixture was stirred at 110 ° C for 1 hr. 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 Compound (13_d) 283 rag (9% yield over 3 steps) as a yellow powder. MS (m / z) APCI: 208 (M + H) + Reference Example 1 4

Methylbiperazine was used in the same manner as in Reference Example 13 to obtain the title compound (yield 3% over 3 steps). MS (m / z) APCI: 263 (M + H) ⁺

(1) 2-t-Ptyloxycarbonylaminothiazole-5-cal of Reference Example 1 To 100 ml of THF solution of 4.37 g (19.1 mmol) of aldehyde, 9.14 ml (45.9 mmol) of ethylphosphonoacetate and 5.16 g (45.9 mmol) of strong tert-butoxide were added at room temperature and stirred at the same temperature overnight. Heated to reflux for hours. The reaction mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, treated with activated carbon, concentrated under reduced pressure, and the residue was crystallized with ethyl hexane acetate (1: 5) to give compound (15-a) 4.13 g (yield 72%) was obtained as colorless crystals.

MS (ra / z) APCI: 299 (M + H) ⁺

 (2) A mixture of 4.10 g (13.74 mmol) of the above compound, 5.0 g of 10% Pd / C, 50 ml of ethyl acetate and 50 ml of acetic acid was vigorously stirred at room temperature for 24 hours in a hydrogen stream. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and then azeotroped several times with toluene to obtain 4.05 g (yield 98%) of the compound (15-b) as colorless crystals.

MS (m / z) APCI: 301 (M + H) ⁺

 (3) A solution of 4.03 g (13.42 mmol) of the above compound in ethanol (20 ml), THF (40 ml) and water (20 ml) was ice-cooled, and 2N sodium hydroxide solution (16.1 ml)

(32.2 mmol) was added dropwise. The mixture was stirred at the same temperature for 2 hours and then at room temperature for 3 hours. The mixture was poured into a mixture of aqueous citrate solution and ethyl acetate, 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 crystallized from diisopropyl ether to obtain 3.16 g (yield 86%) of compound (15-c) as colorless crystals.

MS (ESI): 271 (M-H) "

(4) 10 ml of DMF solution of the above compound 589 mg (2.16 mmol) and 1-hydroxybenzotriazole 584 mg (4.33 mmol) was ice-cooled, and N-ethyl-N, mono (3-dimethylaminopropyl) carpositimide hydrochloride 1.04 g (5.40 mmol) was added, and the mixture was stirred at the same temperature for 15 minutes and then at room temperature for 1 hour. The reaction mixture was ice-cooled again, 5 ml of 50% aqueous methylamine solution was added, and the mixture was stirred at the same temperature for 10 minutes and at room temperature for 1 hour. Reaction mixture 50467

 The mixture was poured into a mixture of ethyl acetate and saturated brine, and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. The residue was concentrated under reduced pressure, and the residue was crystallized with ethyl acetate-hexane (1:10) to obtain 597 mg (yield 92%) of the compound (15-d) as colorless crystals.

MS (m / z) APCI: 300 (M + H) ⁺

(5) To 6 ml of formic acid solution of the above compound 202 rag (0. 675 mmol) was added 2 ml (8 mmol) of 4N hydrogen chloride-dioxane solution, and the mixture was stirred at room temperature for 8 hours. Jet ether was added to the reaction mixture and stirred at room temperature, and the resulting crystals were collected and washed with jet ether. To this crystal, 2 ml (8 mmol) of 4N hydrogen chloride monodioxane solution and 10 ml of diethyl ether were added, and the mixture was further stirred at room temperature overnight. The crystals were collected and washed with JETLE TERTEL to obtain 175 mg of compound (15-e) as colorless crystals in a quantitative yield. MS (m / z) APCI: 200 (+ H) ⁺

Reference Example 1 6

 Dihydrochloric acid ¾

Ammonia water and saturated saline were added to 173 mg (0.734 圆 ol) of the compound of Reference Example 15 (15-e), and the mixture was extracted several times with black mouth form. The extract was dried over sodium sulfate and concentrated under reduced pressure to give 112 mg (76% yield) of free colorless crystals. 3 ml of a THF solution of the above compound 112 rag (0. 560 mmol) was ice-cooled, lithium aluminum hydride 65 trig (1.71 mmol) was added, and the mixture was stirred at the same temperature for 1 hour and then at room temperature for 1 hour. Ammonia water was added to the reaction mixture, and the mixture was stirred at room temperature overnight. After adding sodium sulfate, the mixture was filtered. The filtrate was concentrated under reduced pressure, the obtained residue was dissolved in ethyl acetate, 0.5 ml (1 mmol) of 4 N salt-hydrogen-dioxane solution and jetyl ether were added, and the mixture was stirred at room temperature. The precipitate was collected and dried to give the title compound 98 rag (yield 68%) as a colorless powder.

MS (m / z) APCI: 186 (M + H) Reference Example 1 7

2-Amino-1-Promopyrazine 2.00 g (11.5 mmol), Cyclopropinorephoronic acid 1.28 g (14.9 olol), Palladium acetate 258 mg (1.15 隱 ol), Tricycloto A mixture of 644 mg (2. 30 mmol) of xyzolephosphine and 8.50 g (40. 23 mmol) of tripotassium phosphate in 53 ml of toluene-water (20: 1) was heated to reflux for 18 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer is washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to purify the residue by silica gel column chromatography (50 to 100% ethyl acetate in hexane). The title compound (329 mg, yield 21%) was obtained as a colorless powder. MS (ra / z) APCI: 136 (M + H) + Reference Example 1 8

DMF solution of 188 mg (l. 25 ramol) of t-butyldimethylchlorosilane in 4 ml of DMF solution of 176 mg (0.833 mmol) of compound of Reference Example 8 and 188 mg (2.76 mmol) of imidazole 2 ml was added dropwise and stirred at room temperature overnight. 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 chromatographed on silica gel (40-70% ethyl acetate-hexane). Purification gave 172 mg (64% yield) of the title compound as colorless crystals. MS (m / z) APCI: 326 (M + H) ⁺ Reference Example 19

2N-amino-5-bromothiazole hydrobromide 3.00 g (11.5 mmol) and 2-dimethylaminoethanethiol monohydrochloride 2.45 g (17.31 mmol) in water 15 ml-ethanol 20 ml solution at room temperature with 1 N Aqueous sodium hydroxide solution (23.5 ml, 23.5 mmol) was added, and the mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to saturate sodium chloride, and the mixture was extracted several times with ethyl acetate. The extract was dried with magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (NH-silica genomic; methanol: chloroform = 49: 1 to 19: 1). Compound 2.10 g (89% yield) was obtained as a brown solid. MS (m / z) APCI: 204 (M + H) ⁺ Reference Example 20

The title compound was obtained by using 3-mercapto-4-monomethyl-1,4H-1,2,4-triazole in the same manner as in Reference Example 19.

MS (m / z) APCI: 214 (M + H) ⁺ Reference Example 21

The title compound was obtained by using 2_mercaptoethanol in the same manner as in Reference Example 19. MS (m / z) APCI: 177 (M + H) + Reference Example 22

By using 3-mercaptopropanol in the same manner as in Reference Example 19, the title compound was obtained. MS (m / z) APCI: 191 (M + H) ⁺ Reference Example 23

2—amino _ 5—promothiazole hydrobromide 5.50 g (21.2 mmol), tert-butyl-N— (2-mercaptoethyl) carbamate 5.25 g (29.6 mmol) and ethanol in a mixture of ethanol 80 ral Under cooling, 1,8-diazabicyclo [5.4.0] -7-7undecene 7.73 g (50.8 mmol) was added, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with water and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate: hexane = 3: 1) to obtain 5.72 g (yield 98%) of the title compound as a colorless powder.

MS (m / z) APCI: 276 (M + H) ⁺ Reference Example 24 50467

 81

 (1) DMF solution of 1.00 g (3. 30 mmol) of compound (24-a) synthesized according to known methods (B. Koren et al., Heterocycles, 1987, 26 (3) 689.) : 10 ml of water, 4.50 g (66.2 mmol) of sodium formate and 200 mg of 10% Pd—C were added to 40 ml of the solution, and the mixture was stirred at 85 ° C. for 14 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was acidified with an aqueous citrate solution. The precipitated crystals were collected and dried to obtain 720 mg of compound (24-b) (yield 97%) as a yellow powder.

MS (m / z) APCI: 225 (M + H) ⁺

(2) 20 ml of 10% aqueous sodium hydroxide solution was added to 700 mg (3.12 mmol) of the above compound, and the mixture was stirred at 100 ° C for 4.5 hours. The reaction mixture was cooled to room temperature, neutralized with 10% hydrochloric acid, and the precipitate was removed by filtration. The filtrate was extracted with ethyl acetate, the extract was concentrated under reduced pressure, and the resulting residue was washed with jetyl ether to obtain 228 mg (yield 48%) of compound (24-c) as a yellow powder. MS (m / z) APCI: 153 (M + H) ⁺ Reference Example 2 5

 (1) Compound (25-a) 482 mg (2. 09 mmol), 2, 5— synthesized according to known methods (B. Koren et al., Heterocycles, 1987, 26 (3) 689.) Hexanedione 0. 490 ral

(4. 17 ml), -Toluene sulphonic acid monohydrate 40 mg (0.21 mmol) and tonolein 5 ml were heated to reflux for 3 hours while removing water with a Dei-Stark apparatus. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and a small amount of methanol, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. Residue after concentration under reduced pressure Was purified by silica gel chromatography (NH-sili-force gel; ethynole acetate: hexane = 10: 1, then ethyl acetate) to obtain 598 mg (yield 93%) of compound (25-b) as light brown crystals. .

MS (ra / z) APCI: 309/311 (M + H) ⁺

 (2) A solution of the above compound 533 mg (1.72 mmol) in methanol 15 ml-DMF 15 ml was ice-cooled, sodium methoxide 464 mg (8.60 mmol) was added, and the mixture was stirred at room temperature for 42 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After treatment with activated charcoal, the mixture is concentrated under reduced pressure to give a compound

(25-c) 339 mg (yield 76%) was obtained as brown crystals.

MS (m / z) APCI: 261 (M + H) ⁺

 (3) 30 ml of an aqueous suspension of the above compound 330 mg (1.27 mmol) was ice-cooled, 30 ml of trifluoroacetic acid was added, and the mixture was stirred at 60 ° C. for 4 hours. The reaction mixture is then cooled to room temperature, concentrated under reduced pressure, and the residue is azeotroped with toluene and purified by silica gel throat matrix (NH-silica gel; methanol: throat form = 1:20 to 1: 5). The obtained crude crystals were washed with ethyl acetate-hexane (1: 3) to obtain 154 mg (yield 67%) of compound (25-d) as reddish brown crystals.

MS (m / z) APCI: 183 (M + H) ⁺ Reference Example 26

Add 1.00 g (10.5 mmol) of 5-aminobilimidine to 25 ml of acetic acid solution of 6.10 g (63 mmol) thiocyanate and add 3 ml of acetic acid solution of 1.08 ml (21.0 mmol) bromine while cooling in an ice bath. The mixture was then stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with saturated aqueous sodium hydrogen carbonate and concentrated under reduced pressure. To the residue THF was added and the mixture was dried over magnesium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel chromatography (methanol: chloroform = 1: 20-1 to 10) to give the title compound 287 trig (yield 18%). Was obtained as a yellow powder. MS (m / z) APCI: 153 (M + H) ⁺

Reference Example 2 7

NCS purchase CI NCS

 (27-a) (27-b) (27-c)

 (1) Known methods (T. Takahashi et al., Chemical & Pharmaceutical Bulletin,

1958, 6, 334.) 20 ml of a methanol suspension of 1.00 g (4.62 mmol) of compound (27-a) synthesized according to 1) was cooled to -40 ° C and 28% sodium methoxide was added. A methanol solution (0.305 ml, 4.85 mmol) was added and stirred at the same temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (15-35% ethyl acetate-hexane) to give 194 mg (yield 20%) of compound (27-b) as a yellow powder.

(2) In 6 ml of acetic acid solution of the above compound 6 ⁶ 3 mg (3.12 mmol), iron powder 6 ⁸ mg at room temperature

(12.2 mmol) was added, and the mixture was stirred at 60 ° C for 4 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate and the mixture was filtered through celite. The filtrate was concentrated, the residue was diluted with ethyl acetate, saturated aqueous sodium hydrogen carbonate was added, and insoluble material was removed by filtration. The filtrate was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate) to obtain 231 mg (yield 41%) of compound (27-c) as a yellow powder. MS (ra / z) APCI: 183 (M + H) ⁺

Reference Example 2 8

 (28-a) (28-b) (28-c) (28-d)

 (1) Compound (28-a) 3.05 g (16.4 mtnol), 2,5 monohexanedione 3.85 ml (32.9 mtnol), p-toluenesulfonic acid monohydrate 313 mg (1.64 mmol) in 30 ml of tolylene 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 (ethyl acetate: hexane = 1: 10) to obtain 3.84 g (yield 89%) of compound (28-b) as light brown crystals.

MS (m / z) APCI: 264/266 (M + H) ⁺

(2) The above compound 600 mg (2.27 mmol) Bis (dibenzylideneaceton) paradium 131 mg (0.227 ramol), 2-dicyclohexylenorephosphono-1, 2- (N, N, dimethylamino) biphenylenore 89 mg ( 0.226 mmol) and sodium tertbutoxide 437 mg (4.55 mmol) in 10 ml of toluene, 6.81 ml (13.6 mmol) of 2M dimethylamine in THF at room temperature under argon flow, and stirred at the same temperature for 5 days did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-35% ethyl acetate-hexane) to obtain 419 mg (yield 68%) of compound ( ² 8-c) as brown crystals.

MS (m / z) APCI: 273 (M + H) ⁺

(3) A 30 ml suspension of 410 mg (1.51 mmol) of the above compound in water was cooled with water, 30 ml of trifnoreo oral acetic acid was added, and the mixture was stirred at 50 ° C. for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and then treated with activated carbon. After concentration under reduced pressure, the residue was crystallized with ethyl acetate: hexane (3: 1) to give compound (28-d) 194 mg (Yield 66%) was obtained as a colorless powder. MS (m / z) APCI: 195 (+ H) Reference Example 29

2-Amino _ 5—Bromopyrazine 2.61 g (15.0 謹 ol), t-Puttynorecarbamate 2.11 g (18.0 mmol), Copper iodide (I) 290 mg (1.50 mmol),, Ν'-Dimethylolethylene A mixture of 260 mg (3.00 mmol) of diamine, 4.15 g (30.0 mmol) of potassium carbonate and 80 ml of dioxane was heated to reflux for 16 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The extract was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (30-80% ethyl hexane acetate) to give the title compound (yield 18%) as colorless. Obtained as a powder. MS (m / z) APCI: 211 (M + H) ⁺ Reference Example 30

 (30-b) (30-c)

(1) Dioxane suspension of 1.86 g (7.05 mmol) of compound (28-b), 6.14 g (14.1 mmol) of t-butyldimethyl (triptylstanylmethoxy) silane and 495 mg (0.701 mmol) of dichlorobis (triphenylphosphine) palladium 20 ml of the solution was heated to reflux for 41 hours under an argon flow. After the reaction mixture is cooled to room temperature, activated carbon is added. The mixture was filtered and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The extract was dried over sodium sulfate and concentrated under reduced pressure to give 10.44 g of compound (30_a) as a yellow oil.

 (2) A mixture of the above compound 10.4 g in 60 ml of water was ice-cooled, 60 ml of trifluoroacetic acid was added, and the mixture was stirred at 50 ° C. for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the resulting residue, the mixture was saturated with sodium chloride, and extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was azeotroped with toluene and crystallized with a mixed solvent of ethyl acetate: hexane to give 1.10 g of the compound (30-b) as a brown powder. Got as.

(3) To 30 ml of DMF solution of the above compound 1.10 g and imidazole 1.54 g (22.6 mmol), 1.70 g (11.3 mmol) of t-butyldimethylchlorosilane was added under ice cooling, Stir at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine, and dried over sodium sulfate. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (NH-silica gel; 60-100% ethyl acetate), 354 mg of compound (30-c) (16% yield over 3 steps) ) Was obtained as pale yellow crystals. MS (m / z) APCI: 296 (M + H) ⁺ Reference Example 3 1

2-Amino-1-5-Phodopyridine 1.00 g (4.55 mmol), Methyl thioglycolate 0. 482 g (4.55 ol), Tris (dibenzylideneacetone) Dipalladium 208 mg (0. 227 mmol) ), A mixture of bis (2-diphenyl-norephosphinophenyl) etherole 245 mg (0. 455 mmol) and potassium tert-butoxide 561 mg (5.00 mmol) in 20 ml of toluene under a stream of argon. The mixture was stirred at ° C for 3 hours. After cooling the reaction mixture to room temperature, 8050467

 87 Celite filtration was performed, and the filtrate was concentrated under reduced pressure. Silica gel chromatography of the residue

Purification by (NH-silica gel, 0 to 3% methanol-chloroform) gave 268 mg (yield 30%) of the title compound as a pale yellow solid. MS (ra / z) APCI: 199 (M + H) ⁺ Reference Example 32

(1) Compound (32-a), (S) 1-acetylyl-2-methylbiperazine hydrochloride and diisopropylethylamine were treated in the same manner as in Example 2 to obtain compound (32-b). MS (m / z) APCI: 349 (M + H) ⁺

(2) The compound obtained in (1) above was treated in the same manner as in Example 138- (2) to obtain compound (32-c). MS (m / z) APCI: 249 (M + H) ⁺ Reference Example 33

 (1) A mixture of 2.00 g (7.58 mmol) of the compound of Reference Example 28 (28-b) and 7.74 g (75.8 mmol) of N, N, N '—trimethylethylenediamine was stirred at 125 ° C for 15 hours. did. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH-silica gel; 15-35% ethyl acetate-hexane) to obtain 2.33 g of compound (33-a) (yield 93%). It was.

MS (m / z) APCI: 330 (M + H) ⁺ 08050467

88

(2) To 2 ml of a methanol solution of 530 mg (1.61 ramol) of the above compound was added 3.3 ml of 10% hydrochloric acid, and the mixture was stirred at 60 ° C. for 19 hours. The reaction mixture was cooled to room temperature, neutralized with sodium hydrogen carbonate, and concentrated under reduced pressure. To the residue was added black mouthform, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude crystals were washed with ethyl acetate-ethyl ether to obtain Compound (33-b) 201 rag (yield 50%).

MS (m / z) APCI: 252 (M + H) ⁺

The corresponding starting compound was treated in the same manner as in Reference Example 33, Reference Example 11- (2), Reference Example 18 or a combination thereof to obtain the following compounds.

 Reference example RMS (m / z)

33-4 ヽ N ^ / ^{0_Si (Me) 2t_Bu} APCI: 325 [M + H]

 H

Reference Example 34

(1) Compound (28-b) 500 mg (1.90 瞧 ol), t-Putylcarbamate 333 mg (2.84 mmol), Cesium carbonate 1235 mg (3.79 mmol), Palladium acetate (II) 21.3 mg (0.095 mmol), 4, 5-bis (diphenylphosphino) 9,9-dimethylxanthene 87.7 mg (0.152 mmol) and dioxane 5 ml were stirred at 100 ° C. for 15 hours under an argon atmosphere. The reaction mixture was cooled to room temperature, water was added, the mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel chromatography (5-15% ethyl acetate-hexane) to obtain 727 mg (quantitative) of the compound (34-a). MS (ra / z) APCI: 345 (M + H) ⁺

 (2) 4 ml of DMF solution of the compound 633 mg (1.84 mmol) obtained in (1) above was ice-cooled, 0.126 ml (2.02 mmol) of methyl oxalate and 110 mg of 60% sodium hydride

(2.76 mmol) was sequentially added and stirred at the same temperature for 10 minutes. The reaction mixture is poured into water and extracted with ethyl acetate, the extract is concentrated under reduced pressure, and the residue is chromatographed on silica gel.

Purification with (NH-silica gel, 0-10% ethyl acetate hexane) gave 556 mg (84% yield) of compound (34-b). MS (m / z) APCI: 359 (M + H) ⁺

(3) A mixture of the compound 556 mg (1.55 mmol) _s 10% hydrochloric acid 7 ral and methanol 6 ml obtained in (2) above was stirred at 75 ° C. for 23 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added, the mixture was extracted with chloroform, and the extract was concentrated under reduced pressure to obtain 300 mg (quantitative) of the compound (34-c). MS (m / z) APCI: 181 (M + H) ⁺ Reference Example 35

 The compound of Reference Example 34 (34-a) was treated in the same manner as in Reference Example 34 (3) to obtain the title compound. MS (m / z) APCI: 167 (M + H). Reference Example 36

The corresponding starting compounds were reacted in the same manner as in Reference Example 11 or Reference Example 12 to obtain the following compounds.

 Reference example RMS (m / z)

36-5 ^ot APCI: 339 [M + H] '

Reference Example 3 7

2-Amino_4 monochloromethylthiazole hydrochloride 2.00 g (10.8 mmol) of dioxane suspension 15 ml of N-methylbiperazine 12 ml (108 mmol) was added and stirred at room temperature for 10 hours did. To the reaction mixture was added 5 ml of saturated aqueous sodium hydrogen carbonate, the organic layer was separated with Chem Elut 1010 (registered trademark, manufactured by VARIAN), and the column was eluted with black mouth form. The eluate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH 1 silica gel; 2% methanol monochloroform) to obtain 1.18 g of the above compound (yield 52%). MS (m / z) APCI: 213 (M + H) ⁺ Reference Example 38

The corresponding starting material compound was treated in the same manner as in Reference Example 38 to obtain the above compound.

MS (ra / z) APCI: 227 (M + H) ⁺ Reference Example 39

Compound of Reference Example 1 10.00 g (60.7 mtnol), (S) 1-2-Methyl-1 monoacetylylperazine hydrochloride 15.0 g (85.0 mmol) and diisopropylethylamine 26.0 ml (149 mmol) To the solution, 18.0 g (85.0 mraol) of triacetoxyhydrogen fluoride was added and stirred at room temperature for 17 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with black mouth form. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (6% methanol-chloroform) and crystallized from ethyl acetate-jetyl ether. %). MS (m / z) APCI: 255 (M + H) ⁺ Reference Example 40

 The corresponding starting material compound was treated in the same manner as in Example 39 to obtain the above compound.

MS (m / z) APCI: 213 (M + H) ⁺ Reference Example 41

16 ml of a DMF solution of 1.61 g (7.70 mraol) of the compound of Reference Example 29 was ice-cooled, and 945 tng (8.42 mmol) of potassium t-butoxide was added, followed by stirring at room temperature for 10 minutes. The reaction mixture was ice-cooled again, 572 ml (9.19 mmol) of methyl iodide was added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with black mouth form. The extract was washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (NH-silica gel, 10-35% ethyl acetate-hexane) to obtain 1.51 g of the above compound (yield 88%).

MS (m / z) APCI: 225 (M + H) ⁺ Reference Example 42

2-amino-5-bromopyrazine 5.00 g (28.74 mmol), 2-pyrrolidinone 10.90 ml (143.7 mmol), cuprous iodide 1.10 g (5.75 mmol), (1 R, 2 R) — (1) 1 1, A mixture of 2-diaminocyclohexane 1.38 ml (11.50 匪 .1), potassium carbonate 7.94 g (57.5 mmol) and dioxane 86 ml was stirred at 120 ° C. for 17 hours under a stream of argon. The reaction mixture was cooled to room temperature, ethyl acetate-methanol (10: 1) was added, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5% methanol-chloroform) and crystallized from jetyl ether to obtain 2.77 g (yield 54%) of the above compound.

MS (m / z) APCI: 179 (M + H) + Reference example 4 3

1_t-Butoxycarbolulu 4-acetinolepipiperidine 4.60 g (17. 69 mtnol) and 2-amino 5-bromothiazole hydrobromide were reacted in the same manner as in Reference Example 19. The above compound was obtained. MS (ra / z) APCI: 316 (M + H) ⁺ Reference Example 4 4

 2-Methoxyethanol 55 ml under ice-cooling, 60% sodium hydride 1.83 g (45. 8 ramol), 2-amino 5-bromopyrazine 7.00 g (40. 23 mtnol) and copper powder 2.91 g (53.9 mtnol) was sequentially added, and the mixture was stirred in a sealed tube at 160 ° C for 2 hours. After cooling to room temperature, water, aqueous ammonia and ethyl acetate were added and stirred, then filtered through Celite, and the filtrate was extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40% ethyl acetate-hexane) to obtain 2.74 g (yield 40%) of the title compound.

MS (m / z) APCI: 170 (M + H) ⁺ corresponding raw material compound treated in the same manner as in Reference Example 4 4, Reference Example 1 1 1 (2) or Reference Example 1 8 or an appropriate combination thereof, The following compounds were obtained:

[Reference Example 4 4-1] H ₂ N 丫

l _{N 0 to} 0 _S i (Me) ₂ tB _{U MS} () _{Apcl: 270}

[Reference Example 44 1 2]

H ₂ N 丫

NO MS (m / z) APCI: 154 (M + H) ⁺ Reference Example 45

(1) (S) 1_Acetyl-2-methylbiperazine hydrochloride 0.800 g (4.50 mmol) and diisopropylethylamine 1.81 ml (10.4 olol) in 10 ml of DMF solution were ice-cooled to give compound (45-a) And stirred at the same temperature for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (acetic Echiru) to give compound (45-b) 0.930 g (7 ^6% yield). MS (m / z) APCI: 350 (M + H) ⁺

(2) The compound obtained in (1) above was reacted in the same manner as in Example 138- (2) to obtain compound (45-c). MS (m / z) APCI: 250 (M + H) ⁺ Reference Example 46

 The corresponding starting compound was treated with 2-amino-6-hydroxybenzothiazole in the same manner as in Reference Example 5 to obtain the following compound.

[Reference Example 46-1]

MS (m / z) APCI: 325 (M + H)- [Reference Example 4 6-2]

MS (m / z) APCI: 324 (M + H) + Reference Example 4 7

(1) Compound (47-a) 1. 50 g (5. 63 mraol) and N, N-dimethylethanolamine 535 mg (6.00 mmol) in THF (20 ml) were ice-cooled and triphenylphosphine 1.57 g (6.00 mmol) and jetylazodicarboxylate 1.04 g (6.00 mmol) were added and stirred at the same temperature overnight. Ethyl oxalate and dilute hydrochloric acid were added to the reaction mixture, and the aqueous layer was separated and made basic with an aqueous sodium hydroxide solution. After extraction with ethyl acetate, the extract was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (40-60% Aceton-Cloform form), washed with diisopropyl ether, and compound ( 47-b) 606 mg (yield 32%) was obtained as a colorless powder.

 (2) To 5 ml of methanol solution of the compound (47-b) 337 mg (1.0 mraol) obtained in (1) above, add 2.5 ml of 4 M hydrogen chloride / dioxane solution at room temperature. Stir overnight at warm temperature. The reaction mixture is concentrated under reduced pressure, and the residue is washed with jetyl ether.

302 mg (yield 97%) of (47-c) was obtained as a colorless powder.

MS (m / z) APCI: 238 (M + H) ⁺ Reference Example 4 8

Corresponding raw material compounds were reacted in the same manner as in the alternative method of Reference Example 11, the alternative method of Reference Example 12 or the method of Reference Example 53, and the following compounds were obtained.

Reference example RMS (m / z)

48-3 N APCI: 253 [M + H] ⁺

H Reference Example 4 9

 (1) 2 M dimethylamine THF solution in a mixture of Reference Example 2 5 compound (25-b) 1.0 g (3.23 mmol) and T Η F (10 ml) 16.2 ml (32.4 mmol ) Was added and stirred at room temperature for 40 hours. The reaction solution was treated with activated carbon and concentrated under reduced pressure to obtain 827.5 g (yield 94%) of the above compound (49_a) as a powder. MS (m / z) APCI: 274 (M + H) +

(2) The above compound (49-a) was treated in the same manner as in Reference Example 25— (3) to give compound (49-b). MS (m / z) APCI: 196 (M + H) ⁺

Reference Example 50 N,

S people _{N 0} ~ N ヽ

 (25-b) (50-a) (50-b)

(1) Reference Example 2 Compound (25-b) of 5 (2.45 mmol) in a solution of 1.5 g (4.85 mmol) in dimethylacetamide (22 ml) at room temperature with 2.43 ml (24.25 mmol) and sodium carbonate 1.54 g (14. 55 mraol) were added, followed by stirring at 60 ° C. for 2 days. The reaction mixture was cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure, and to the residue were added jetyl ether and saturated brine. After liquid separation, the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (NH-silica gel; 10 to 40% ethyl acetate hexane) to obtain the above. Compound (50_a) 1.46 g (yield 95%) was obtained as a pale yellow viscous body. MS (m / z) APCI: 318 (M + H) ⁺

(2) The above compound (50-a) was treated in the same manner as in Reference Example 25— (3) to give compound (50-b). MS (m / z) APCI: 240 (M + H) ⁺ Reference Example 51

 (51 -a) (51 -b) (51 -c)

(1) The above compound (51-a) synthesized by a known method (KELLY TA, MCNEIL DW, Tetrahedron Lett., 35 (48), 9003-9006 (1994).) ) To give the above compound (51-b). MS (m / z) APCI: 210 (M + H) ⁺

(2) The above compound (51-b) was treated in the same manner as in Reference Example 53- (3) to obtain compound (51-c). MS (m / z) APCI: 267 (M + H) ⁺ Reference Example 52

 (1) A DMF (200 ml) solution of the compound (51-a) 8.54 g (35.7 mmol) described above was permanently cooled, and 2.29 g (57.3 mmol) of 60% sodium hydride was added little by little. For 20 minutes. 2.90 ml (46.6 mmol) of methyl iodide was added dropwise, and the mixture was stirred at the same temperature for 15 minutes and at room temperature for 1 hour. The reaction mixture is ice-cooled again, water is added slowly, and extraction is performed several times with ethyl acetate. The extracts are combined and washed successively with 5% hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, and saturated brine. After drying with sodium sulfate, the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (17% ethyl acetate hexane) to obtain 8.88 g (yield 88%) of the above compound (52-a) as a yellow solid.

MS (m / z) APCI: 254 (M + H) ⁺ (2) Treated in the same manner as in Alternative Method (3) of Reference Example 11 to obtain the above compound (51-b). MS (m / z) APCI: 224 (M + H) ⁺

(3) The compound (52-b) was treated in the same manner as in the alternative method (3) of Reference Example 5 to obtain the compound (52-c). MS (m / z) APCI: 281 (M + H) ⁺ Reference Example 5 3

The compound described in Reference Example 5 was synthesized by another method shown below.

―People 0- ^N , ―

(53-a) (53-b)

 (53-c)

 (1) The above compound (53- a) 15.0 g (94. 6 mmol), N, N-dimethylethanolamine 22.7 ml (227. 1 mmol), Potassium carbonate 53. 31 g (378. 5 mmol) and DM F (150 ml) were stirred at 60 ° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through celite. To the residue obtained by concentrating the filtrate under reduced pressure, water was added and extracted twice with ethyl acetate. The extracts were combined and washed with saturated brine. After drying (sodium sulfate), treatment with activated carbon, and concentration under reduced pressure, 36.10 g of a crude nitro compound (53-b) was obtained.

(2) 10% palladium on carbon (5.0 g) was added to a methanol solution (300 ml) of 36.10 g of the crude double-ended compound, 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 (53-c).

(3) To the acetic acid solution (300 ml) of the above crude amine compound 31.96, add 110.3 g (1135 ramol) thiocyanate, and bromine 10.2 ml (198.7 mmol) while cooling in an ice bath. And then stirred at room temperature for 2.5 days. The reaction mixture 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. Celite filtration, filtration After 28% ammonia water was added to the solution to make the aqueous layer alkaline, extraction was carried out four times with a black mouth form. The extracts were combined, dried over sodium sulfate, and evaporated. The residue was dissolved in methanol, treated with activated charcoal, concentrated under reduced pressure, and the residue was washed with ethyl acetate to give 22.39 g of the title compound (yield 49% in 3 steps) as a pale red powder. It was. MS (m / z) APCI: 239 [M + H] + Industrial Applicability

 INDUSTRIAL APPLICABILITY According to the present invention, there is provided a novel compound having an excellent darcokinase activating action useful as an active ingredient of a medicament for the prevention and Z or treatment of dalcokinase-related diseases such as diabetes, diabetic complications or obesity. The

Claims

 [Wherein, ring A represents aryl or heteroaryl.

 Q represents cycloalkyl, a heterocyclic group, alkyl or alkenyl.

 Ring T represents a heteroaryl or heterocyclic ring group.

R ¹ is a hydrogen atom, a halogen atom, a cycloalkyl / lephonyl, an aralkylsulfonyl, an alkylsulfinyl, an alkylthio, a substituted or unsubstituted tetrazolyl, —COR ¹ . Or one CR ¹² (OH) R ^1C) .

R ² represents one COR ¹¹ or one CR ¹³ (OH) R ¹¹ .

R ¹⁰ represents an alkyl, cycloalkyl, heteroaryl or heterocyclic group. R ¹¹ represents substituted or unsubstituted alkyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or heterocyclic ring group.

R ¹² represents a hydrogen atom or alkyl.

R ¹³ represents a hydrogen atom or alkyl.

R ³ and R ⁴ are independently a hydrogen atom, alkoxy, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heteroaryl, alkoxyalkoxy, substituted or unsubstituted cycloalkyl, cyano, substituted or unsubstituted aryl, substituted Or unsubstituted carbamoyl, hydroxyl, alkanoyl, alkylthio, alkoxycarbol, substituted or unsubstituted aryloxy, halogen atom, oxo or substituted Or unsubstituted arylylcarbonyloxy.

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 cycloanolenoquinoles, anorecoxicanoleni, anorekeninore, anorequinolesnorehoninore, substituted or unsubstituted rubermoyl, substituted or unsubstituted heteroarylthio, substituted or unsubstituted amino, substituted lpoxy, Substituted or unsubstituted heteroaryl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic, substituted or unsubstituted heterocyclic group, substituted or unsubstituted Substituted heterocyclic thio, substituted or unsubstituted cycloalkyloxy Represents alkanoyl or substituted or unsubstituted alkyl.

R ⁶ represents a hydrogen atom, a substituted or unsubstituted alkyl, a halogen atom or carboxy. ]

Or an pharmacologically acceptable salt thereof.

2.

2. The oxime derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is a heteroaryl or heterocycle group represented by the formula:

 3. The ring T is thiazolyl, thiazolopyridinyl, pyridyl, pyrazinyl, benzothiazolyl, quinolyl, thiadiazolyl, virazolyl, thiazoloviradiel, thiazopyrimidinyl, cyclohexanothiazolyl or dihydrovirazopyrigel Or the oxime derivative according to 2, or a pharmaceutically acceptable salt thereof.

4. Ring T is thiazolyl, thiazolopyridinyl, pyridyl, pyrazinyl, benzothiazolyl, thiadiazolyl, thiazopyrazuril, thiazolopyrimidyl, hexahexazothiazolyl or dihydropyrazomouth pyridier 2. The oxime derivative or a pharmaceutically acceptable salt thereof according to 2.

 5. The oxime derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the ring T is thiazolyl, thiazolopyridyl, pyrajur, thiadiazolyl, thiazorobirazinyl or thiazopyrimidier.

 6. The oxime derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein ring T is thiazolyl or thiazopyridyl.

 7. The oxime derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein ring A is aryl.

 8. The oxime derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein ring A is phenyl or pyridyl.

9. The oxime derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R ¹ is a hydrogen atom or a halogen atom.

10. The oxime derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R ¹ is a hydrogen atom.

11. The oxime derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 10, wherein R ^{2 is} COR ¹¹ .

12. The oxime derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R ¹⁰ is alkyl or cycloalkyl.

13. The oxime derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R ¹¹ is substituted or unsubstituted alkyl, or substituted or unsubstituted cyclalkyl.

14. The oxime derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein the substituent of “substituted alkyl” in R ¹¹ is alkoxy.

15. The oxime derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R ¹¹ is methyl, 3-methoxypropyl or cyclopropyl.

16. The oxide according to any one of claims 1 to 15, wherein R ¹² and R ¹³ are hydrogen atoms. Shim derivatives or pharmacologically acceptable salts thereof.

1 7. R ⁵ is a hydrogen atom, honoleyl, halogen atom, oxo, substituted or unsubstituted alkoxy, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkylthio, cyan, substituted or unsubstituted heterocyclic sulfonyl, nitro, substituted Or unsubstituted cycloalkyl, alkoxycarbonyl, alkenyl, substituted or unsubstituted rubamoyl, substituted or unsubstituted heteroarylthio, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkynyl, The oxime derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, which is substituted or unsubstituted heterocyclic oxy, alkanol, or substituted or unsubstituted alkyl.

1 8. R ⁵ is a hydrogen atom, halogen atom, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted rubamoyl, substituted or unsubstituted amino, substituted or unsubstituted The oxime derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, which is a substituted heterocyclic oxy, an alkanol, or a substituted or unsubstituted alkyl.

1 9. R ⁵ is a halogen atom, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted amino, substituted or unsubstituted heterocyclic or substituted or unsubstituted alkyl. Or an pharmacologically acceptable salt thereof.

20. The oxime derivative according to any one of claims 丄 to 16, wherein R ⁵ is substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted heterocyclic or substituted or unsubstituted alkyl Pharmacologically acceptable salt.

21. The oxime derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein R ⁵ is substituted or unsubstituted alkyl.

2 2. The substituent of “substituted alkyl” in R ⁵ is substituted or unsubstituted heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or Is unsubstituted rubamoyl, hydroxy, trialkylsilyloxy, alkylthio, alkylsulfonyl, substituted or unsubstituted heterocyclicoxy, heteroaryl, substituted or unsubstituted hydroxyimino, halogen atom, force alkoxy, alkoxy force, or alkyl 2. The oxime derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, which is a strong neuroxy.

2 3. Okishimu derivative or a pharmaceutically acceptable salt of any of R ⁵ is claim 1-1 6 is a substituted or unsubstituted alkoxy.

2 4. The substituent of “substituted alkoxy” in R ⁵ is an amino, alkoxycarbonyl, optionally mono- or dialkyl optionally substituted with one or two groups selected from alkyl, alkoxy group The heterocyclic group optionally substituted with rubamoyl, carboxyl, hydroxy, oxo which may be substituted, trialkylsilyloxy or alkoxy, or any one of claims 1 to 16 and 23 Or an pharmacologically acceptable salt thereof.

25. The oxime derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, wherein R ⁶ is a hydrogen atom or substituted or unsubstituted alkyl.

2 6. R ⁶ is Okishimu derivative or a pharmaceutically acceptable salt of any of claims 1-2 4 is a hydrogen atom.

 27. A medicament comprising the oxime derivative according to any one of claims 1 to 26 or a pharmacologically acceptable salt thereof.

 28. The medicament according to claim 27, which is a darcokinase activator.

 29. The medicament according to claim 27, which is an agent for treating and / or preventing diabetes.

 30. The medicament according to claim 27, which is a therapeutic and Z or prophylactic agent for chronic complications of diabetes such as reticulopathy, nephropathy, neurosis, ischemic heart disease, arteriosclerosis and the like.

 3. The pharmaceutical according to claim 27, which is an agent for treating and / or preventing obesity.