TW201217385A - Novel piperidine derivative and pharmaceutical containing same - Google Patents

Abstract

A novel compound that has the effect of promoting insulin secretion from pancreatic ss cells and is useful as a prophylactic and/or therapeutic agent for disorders stemming from hyperglycemia, such as diabetes. A compound represented by general formula (1), a salt thereof, or a solvate of said compound or salt. In the formula, A or B represents a nitrogen atom and the other represents a nitrogen atom or CR8; X represents an oxygen atom, a sulfur atom, -(CH2)n-N(R11)-, or -(CH2)n-CH(R12) -; Z represents a nitrogen atom if Y represents an oxygen atom or a sulfur atom; Z represents an oxygen atom or a sulfur atom if Y represents a nitrogen atom; and R1 through R7 represent hydrogen atoms or other substituents.

Description

201217385 VI. [Technical Field] The present invention relates to an agent having an action of promoting insulin secretion from pancreatic stone cells, and preventing and/or treating a disease caused by hyperglycemia, such as diabetes. [Prior Art] The pancreas is derived from endocrine and exocrine gland tissues of endoderm, which is composed of endocrine cells, acinar cells, and ductal cells. The pancreas belonging to the endocrine cell islets of Langerhans constitute 1 〇/0 of the whole pancreas, and is mainly divided into 4 kinds of cells. That is, the α cells secreting pancreatic ghrelin, secreting cold cells of insulin, synthesizing and secreting 5 cells of somatostatin, synthesizing and secreting pancreatic F cells. Among them, the membrane-secreted membrane has a function of lowering blood sugar in terms of main physiological functions, and is the only hormone that exhibits a blood sugar lowering effect. Insulin is secreted by the rise in perceived blood glucose in the pancreatic cells and released into the portal vein. The released insulin inhibits sugar growth or sugar release in the liver, and plays a role in ensuring the blood glucose level of the living body by promoting sugar intake in fat and muscle tissues belonging to the surrounding tissues. Diabetes is a persistent hyperglycemia state caused by insulin deficiency or its insufficient effect. Diabetes is mainly divided into the following two types: insulin-dependent diabetes mellitus due to abnormal insulin secretion caused by autoimmune diseases (IDDM 'independent dependent diabetes mellitus), and insulin s 100134953 201217385 (Tengdaosu) Resisting) and bowing up persistent high insulin, the membrane-independent diabetes caused by decreased insulin secretion caused by visceral fatigue (inspired by DM, _' this is _ 加加betes mellitus持续 Continuing hyperglycemia caused by diabetes can cause ailments and cause complications in multiple organs. As a representative complication, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, etc. can be cited. The decline in quality (QOL, Quality of Life), the increase in medical expenses, and the decrease in survival rate are considered as problems. The treatment of diabetes is based on exercise therapy, diet therapy, and drug therapy. For use as a drug therapy, for example, promotion:腾_细胞(9) An agent secreted by an island, an agent that improves insulin resistance, A drug that inhibits the absorption of sugar, a drug that promotes the use of sugar, etc. Among them, the Tengdaosu secretion promoting agent can reduce the effect of blood sugar by increasing the blood insulin concentration, so that it is expected to suppress hyperglycemia and improve diabetes, and treat diabetes. In the field, only S& urea-coating agent (SU drug), fast-acting insulin-promoting drug, DPPIV 'dipeptidyl peptidase IV inhibitor (see Non-Patent Document 1), GLP-1 analogue (giucag〇n_like sulphur] is a glucagon-like peptide 1 analog) (see Non-Patent Document 2), etc. However, the most frequently used SU drug in Japan stimulates pancreatic sputum cells and promotes it. Derived insulin secretion (see Non-Patent Document 3), but there is a form of hypothyroidism as a side effect of the 'monthly shape', especially when it is used for elderly people, renal insufficiency, or irregular diet. Also, there are reports. Side effects such as weight gain. Further, when there is 100134953 201217385, it will cause no effect from the initial administration - the second invalid, and the second effect of the clinical effect disappears (refer to the non-patent text) 4), during the period of the period, a kind of insulin secretion promoter which relieves these side effects without impairing the insulin secretion energy and is expected to have a small burden on the dirty stone cells, and the pancreas has a condensation type heterocyclic ring at the 4 position. a piperidine derivative, a compound having 4 main adrenocortical stimulating hormone releasing factor antagonism (patent = 1: 2, 3, 4, 5), a compound having cell proliferation inhibiting activity, etc. 6), etc. A condensed ring compound related to GPR119 has been reported (Patent Documents 7 and 8), but the structure is different from the compound of the present invention. On the other hand, as a compound having a condensed pyridine or a condensed pyrimidine skeleton, a compound having an inhibitory action of the farnesoid X receptor (FXR, Fame S〇 id Xreceptor) has been reported (Patent Document 9), and it is used as a therapeutic agent for metabolic diseases. The compound (patent documents 10 and 11), the compound used as a protein kinase inhibitor (patent documents 12 and 13), and the compound which is used as a therapeutic agent of drug resistance (patent document 14). [PRIOR ART DOCUMENT] [Patent Document 1] [Public Document 1] EP 1 194 853 PCT [Patent Document 2] W02010/058489 vol. [Patent Document 3] EP 1097709 [Patent Document 4] Japanese Patent Laid-Open No. 2001-514260 [ Patent Document 5] Japanese Patent Laid-Open Publication No. 2000-109431 (Patent Document No. 2000) No. 201217385 [Patent Document 6] WO2000/043394 Booklet [Patent Document 7] W02010/088518 Booklet [Patent Document 8] W02010/095663 Booklet [Patent Document 9] WO2009/127321 Booklet [Patent Document 10] WO2007/115822 Booklet [Patent Document 11] W02006/077401 Booklet [Patent Document 12] W02005/113560 Booklet [Patent Document 13] W02009 Booklet No. /070524 [Patent Document 14] Booklet WO04/065389 [Non-Patent Document] [Non-Patent Document 1] J Clin Endocrinol Metab, May 2004, 89 (5): 2078-2084 [Non-Patent Document 2] Regul Pept, 2004, 117 (2): 77-88 [Non-Patent Document 3] The Lancet, Aug 31, 1985, 2: 474-475 [Non-Patent Document 4] The Lancet, Sep 12, 1998, 352: 837-853 SUMMARY OF THE INVENTION (Problem to be Solved by the Invention) An object of the present invention is to provide an insulin having a promotion from pancreatic/5 cells The function of secretion is a compound for use as a prophylactic or therapeutic agent for diseases caused by hyperglycemia such as diabetes. (Means for Solving the Problem) As a study for discovering a compound having insulin-promoting activity, a 100134953 201217385 ring, the inventors of the present invention used a hamster pancreatic cell line HIT-T15 to attract a compound that promotes insulin secretion. As a result, it has been found that the piperidine derivative represented by the formula (丨) has an excellent effect of promoting insulin secretion from pancreatic cells, and is useful as a preventive and therapeutic agent for diabetes, thereby completing the present invention. The invention shown below. [1] A compound or a salt thereof, or a solvate thereof, which is represented by the following formula (1): [Chemical Formula 1]

(1) [wherein, one of A and B represents a nitrogen atom, and the other represents a nitrogen atom or CR8 (here, R8 represents a hydrogen atom, a halogen atom, a C!-6 alkyl group, a Cw alkoxy group, Amino or ac); D represents a nitrogen atom or CR9 (wherein 'R9 represents a hydrogen atom, a halogen atom, an alkyl group, a C6 alkoxy group, an amine group or a nitro group); E represents a nitrogen atom or CR1G (here' R1G represents a hydrogen atom, a halogen atom, a Cj_6 alkyl group, a (^.6 alkoxy group, an amine group or a Jing group); X represents an oxygen atom, a sulfur atom, -(CH2)nN(Ru)- or -(CH2)n- CH(R12)-(here, R" and Rl2 respectively represent a hydrogen atom or a Cu alkyl group, and η represents no or 1),

S 100134953 7 201217385 γ represents an oxygen atom, a sulfur atom or a nitrogen atom; ζ represents an oxygen atom, a sulfur atom or a nitrogen atom; fluorenyl group, Cl.6 R1 and R3 each independently represent a hydrogen atom, a halogen atom alkoxy group, an amine group or Nitro, or R1 and R11 or R1 and R12 may also form a heterocyclic ring. R2 represents a hydrogen atom, -S(0)R13, -S(〇)2r14, 1〇2, and 15戍^Cl.6, CONR16R17 , aryl, heteroaryl (here, 1113 and rh respectively 〆 〆, C 3 · 8 % of the yard, C 2 · 6 thin, C 2 · 6 block, can take, aryl, amine, A monoamino)amino or di(Ci.6 alkyl group may have an alkyl group wherein R15 represents a Cw alkyl group, and R16 and R17 each independently represent an alkyl group of a gas atom and a substituent); R4 represents a hydrogen atom, a halogen atom, or a C6. An alkyl group or an alkyl group; 1 (R5 and R6 each independently represent a hydrogen atom or a Cy alkyl group; R7 represents a CN6 alkyl group, -C(0)R18, -C(S)R19 , _S(O)2R20, a CVh) aryl group which may have a substituent or a 5_1() heteroaryl group which may have a substituent, and R18 represents a Cw alkyl group which may have a substituent, and a c alkoxy group which may have a substituent Mn alkenyl group which may have a substituent a base, an oxy group which may have a substituent, a C6_10 aryl Cu calcination group which may have a substituent, a Cw cycloalkyloxy group which may have a substituent, a heterocyclic oxy group which may have a substituent, may have a substituent a 5-10 membered heteroaryl or a mono(Ci6 alkyl)amino group, and Rl9 and R20 represent a Cw alkyl group, a halogenated Cm alkyl group, a c3-8 cycloalkyl group, and a mono(Cw 100134953 8 201217385 alkyl) amine group, respectively. It may have a Cw of a substituent. An aryl group or a 5-10 membered heteroaryl group which may have a substituent)]. [2] The compound of the above [1], or a salt thereof, or a solvate thereof, wherein the heterocyclic ring formed by R1 and R11 or R1 and R12 is selected from the following formula: [Chemical 2]

Wherein R21 represents a hydrogen atom, Q-6 alkyl group, -C(0)R22 or -S(0)2R23 (wherein R22 and R23 represent (^_6 alkyl group, C3_8 cycloalkyl group), respectively, wavy line portion The compound of the above [1], or a salt thereof, or a solvate thereof, wherein R1 and R11 or R1 and R12 are formed, and the heterocyclic ring is selected from the group consisting of Description: [Chemical 3]

VA V=\

N-I s 100134953 201217385 is represented by the following formula (la): [4] The compound of the above (1) or a salt thereof, or a solvate thereof, the compound

(wherein R2 to R7 are the same as described above). [5] The compound of the above [1; | or a salt thereof, or a solvate thereof, wherein r

[6] The compound [η or a salt thereof, or a solvate thereof, as described above, which is represented by the following formula (lb): [Chemical 5]

(wherein R1 represents a hydrogen atom, a halogen atom, a Cw alkyl group, a Ci 6 alkoxy group, an amine group or a nitro group, and R2 to R7 are the same as defined above). [7] The compound of any one of the above [1] to [6] or a salt thereof, or a solvate thereof, which is selected from the group consisting of the following compounds: 4 - (7 - (5 - (methyl) With the base). 哚 哚 -1 - - - 异 4 4 [4,5 - d ] u _ 4 base) piperidine-1-carboxylic acid tert-butyl ester, 3- (1- (5 - chloropyrimidinyl) piperidine, 4 100134953 10 201217385 yl)-7-(5-(methylsulfonyl) porphyrin _ 1 _yl)isoxazo[4,5-d]pyrimidine, 3-( 1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-7-(5-(indolylsulfonyl) porphyrin-1-yl)isoxazo[4,5- d]pyrimidine, 3-(1-(5-bromopyrimidin-2-yl)piperidinyl)-7-(5-(methylsulfonyl)porphyrin-1 1 -yl)isoxazo[4 , 5 d]pyrimidine, - 3-(1_(5-fluoropyrimidin-2-yl)piperidin-4-yl)-7-(5-(methylsulfonyl)porphyrin-1-yl) Isoxazolo[4,5-flavored pyridyl, 2-(4-(7-(5-(methylsulfonyl) porphyrin-1- 1 -yl) iso[[,5-d] °密α-3-yl)σ辰.定-1 _yl)β-bite ethyl citrate, 2-(4-(7-(5-(methylsulfonyl)porphyrin-1-yl) ) Iso-azolo[4,5-d]pyrimidin-3-yl)piperidine-i-yl)pyrimidine_5-carboxylic acid, 7-(5-(methylsulfonyl) σ 哚 哚 -1- -1--1-yl)-3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine _4_yl)isoxazo[4,5-d] mouth σ疋, 2-(4-(7-(5-(methyl sulphate)) α 弓 朵 朵 丨 基 基 基 异 唾 4 4 [4,5-d]pyrimidin-3-yl) α 啶 啶-ΐ_yl)pyrimidine_5-alcohol, 3_(丨_(5•methoxypyrimidin-2-yl)bistidin-4-yl)-7-(5-(methylsulfonyl)吲哚琳丨 基 基 基 。 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4-yl)isoxazolo-μ,5-d]pyrimidine, 7-(5-(methylsulfonyl) porphyrin-1-yl)-3-(1-(5-(trifluoromethyl) Pyridin-2-yl)piperidine-4-yl)isoxazo[4,5-d]pyrimidine, 4-(7-(5-(methylsulfonyl)D porphyrinyl)isoindole Isopropyl [4,5-d]pyrimidin-3-yl)piperidine-1-carboxylic acid, 4_(7_(5-(methylsulfonyl) °bendolin small base) [4,5 threatening bite winter base octopus biting small acid ethyl ester, 4-(7-(5-(methylsulfonyl). 引哚琳小基) 异十坐Μ Μ 密 密 -3-3 -yl)piperidine-hydrazine-carboxylic acid 2_fluoroethyl ester, 4_(7_(5-(methylsulfonyl)carinphyrin)-yl)isoazolo[4,5-d]pyrimidine-3 -base) 2-methoxyethyl pyridinecarboxylate, 100134953 11 201217385 4-(7-(5-(indolylsulfonyl)porphyrin _i_yl)isoxazolo[4,5-d]pyrimidinyl) Tetrahydro-2H-pentan-4-yl pyridinecarboxylate, 2-(4-(7-(5-(methylsulfonyl) fluorene)-isoxazo[4,5 Bite-3-yl)-bite-l-kimididine_5-carboxylate allyl ester, 4_(7-(5(methylsulfinyl)porphyrin-丨-yl)isoxazole[4 , 5-d] bite _3_ base) brigade bite small hydroxy acid third vinegar, 7_(5_(methylsulfinyl) 引木琳1基)_3-(1-(5_(difluorometh) Base) mouth ratio mouth _2_ base) 〇 bottom mouth fixed _4_ base) different mouth and other saliva [4,5 Qingmi bite, 2,2_ dimethyl small (4_(7_(5_(methyl) Sulfonyl). Phenidinoline-1-yl)iso-p-[4,5-d]pyrimidin-3-yl)piperidinyl)propane ketone, (7 ((2fluoro-4-(methyl sylvanyl))phenyl) Amino)iso-[]-and--3-yl)piperidinecarboxylic acid tert-butyl vinegar, hydrazine (2-fluoro-4-[(methylsulfonyl)phenyl) 3-(1-(5-( Difluoromethyl)11密0定_2_基)11底11定_4_基)异1}号唾和[4,5·^ Pyridine _7_amine, Nm (methyl scutellaria ) phenyl traitor (1) is called fluoroindolyl) pyridine _2-yl) piperidine _4_yl) isocido[4,5-d]-7-amine, 4-(7-((2·fluoride) _4_ 甲基 to the base of the phenyl group) and the singularity of the singularity of the squid and the ^-^ mouth bite-^ 2_ gas ice methyl stone yellow brewing base) phenyl) amine base) sitting and [4,5_(four) bite _3_ base) brigade bite - bitter acid 2,2,2_trifluoroethyl ester, 4- (7-((2-Fluoro-4-ylsulfonyl)phenyl)amino)isoxazo[4,5♦ 密_____) 唆 , wu, 〗 2 gas vinegar, 4__气_心基顿基)phenyl)amino)iso-salt[ο♦密咬_3_基)派咳小竣西文新戊 ga, 4-(7-((2-fluoro-) 4-methylsulfonyl)phenyl)amino)isoxazo[4,5♦ dense bite _3_ base) bite small acid to recognize difluorocyclohexane酉, 4_(7|Fluoromethyl hydrazino)phenyl)amino)iso-sand and Μ♦ 密密冬基)〇辰啶100134953 201217385-1-carboxylic acid oxetane-3- Base ester, 4-(7-((2-fluoro-4-(decylsulfonyl)phenyl)amino)isoxazo[4,5-d]pyrimidin-3-yl)piperidine _; [_Carboxylic acid (3- mercapto oxetane-3-yl) decyl ester, 4-(7-((2-fluoro-4-methylsulfonyl)phenyl)amino)isoxazole And [4,5-d]pyrimidin-3-yl) pie bite _i_ phenylate, 4-(7-((2-fluoro-4-indolyl) oxime) (iso)oxazolo[4,5-d]pyrimidin-3-yl)piperidinecarboxylic acid nitrophenyl ester, (4-(7-((2-fluoro-4-(methylsulfonyl))phenyl) Amino)iso 11th oxazolo[4,5-flamodin-3-yl)pyridinyl)(D-pyridyl-2-yl)methanone, 4 (7(tetra)methyl decyl)phenoxy) Alien sitting and [4,5 threatening bite _3_ base) brigade bite tridecyl citrate, heart (7-(2_fluoro_4_(methylsulfonyl)phenoxy)isoxazole And [4,5-d]pyrimidin-3-yl)piperidinecarboxylic acid tert-butyl ester, 4_(7_(4_(ih_tetrazole_ι_yl)phenoxy)) [4,5· (4) Bite the winter base) Pie bite + a few acid third vinegar, and 4 servant methyl-7_ (5-(methyl continued basal (Iv) -1- yl) -1Η-. And the ratio of sialic [4,3 ♦ adhesion-3-yl) trip bite _ι_ betray acid tert-butyl acetate. [8] A pharmaceutical composition comprising the compound of any one of the above (1) to (7), or a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier. (9) The insulin secretion-promoting agent according to any one of the above (1) to (7), or a salt thereof, or a solvate thereof, as an active ingredient. [10] A blood sugar lowering agent which comprises the compound of any one of the above (1) to (7) or a salt thereof or a solvate thereof as an active ingredient. A preventive and/or therapeutic agent for diabetes according to any one of the above (1) to (7), or a salt thereof, or a solvate thereof, as an active ingredient. [12] A method for promoting insulin secretion, which is characterized in that an effective amount of 100134953 is administered.

The compound of any one of the above [1] to [7], or a salt thereof, or a solvate thereof. [13] A blood sugar lowering method, which comprises administering an effective amount of the compound of any one of the above [1] to [7], or a salt thereof, or a solvate thereof. [14] A method for the prophylaxis and/or treatment of diabetes, which comprises administering an effective amount of the compound of any one of the above [1] to [7] or a salt thereof, or a solvate thereof. [15] The compound of any one of the above [1] to [7] or a salt thereof, or a solvate thereof, for promoting insulin secretion. [16] The compound of any one of the above [1] to [7] or a salt thereof, or a solvate thereof, for use in lowering blood sugar. [17] The compound of any one of the above [1] to [7], or a salt thereof, or a solvate thereof, for use in the prevention and/or treatment of diabetes. [18] The compound according to any one of the above [1] to [7], or a salt thereof, or a solvate thereof, for use in the manufacture of an insulin secretion promoter, a blood sugar lowering agent or a diabetes preventing and/or therapeutic agent. (Effect of the Invention) The piperidine derivative of the present invention or a salt thereof, or a solvate thereof, has an orally administrable low molecular compound which strongly promotes the action of insulin secretion from the pancreas/3 cells, and is useful as A disease caused by hyperglycemia of a mammal including a human, such as a preventive and/or therapeutic agent for diabetes. [Embodiment] In the present specification, examples of the "halogen atom" include a fluorine atom and 100134953 14

201217385 Chlorine, bromine or iodine atoms. In the present specification, the term "ΓΓ" is used to mean an alkyl group having a carbon number of 1 to 6 in a straight or branched chain, and examples thereof include a mercapto group, an ethyl group, a n-propyl group, an isopropyl group, and a positive group. Butyl, isobutyl, second butyl-butyl, n-pentyl, 2-methylbutyl, 2,2-methylpropyl, n-hexyl and the like. In the present specification, 'the so-called r  Ci 2 alkyl group” means a Gw group substituted by the same or different one to the maximum number of argon atoms which may be substituted, and examples thereof include a monofluoromethyl group and a di a fluorene group. A group, a trifluoromethyl group, a monomethyl sulfhydryl group, a dichloromethyl group, a trimethyl sulfhydryl group, a mono- fluorenyl group, a single nail group or a tris-ethyl group. In the present specification, the term "(wei)" is a monocyclic, polycyclic or condensed cyclic ring system having a carbon number of 3 to 8, preferably a carbon number of 3 to 6. A cycloalkyl group, for example, may be listed as a "c26 dilute group". In the present specification, as a "c26 dilute group", it may be listed as a "c26 dilute group". For example, an ethyl group, a propionyl-i-alkenyl group, a (7) alkenyl group, a dilute group (dilyl group), an isopropyl group, a butane-small-small group, a n2-ene group (crotonyl), butyl like _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 1·Small base, pentane _2_ ene small base, pentylene _3_ thin base, pentylene · 4 · roasted small base, 3-mercaptobutylene small base, 3-methyl, hexane Xiaogui | base, hexane--2, dilute base, hexene, hexanyl-4, alkenyl, hexane-5-en-1-yl, 4-methylpentane_3_ Alkenyl and the like. 100134953 15 201217385 In the present specification, 'as a C2_6 fast base', for example, B. _ 、, 丙烧-1-快-1-yl, propyl-2-non-1-yl (block propyl) ,丁丁_ι_妒1, butyl -3-phenyl-1-yl, 1-methylpropan-2-low-1-yl, pentane acetylene 丨 基 基, 戍 -4- Alkyn-1-yl, hexan-1-yl-1-yl, hexa-5-fast-1-yl and the like. In the case of the "C" alkoxy group, the methoxy group, the ethoxy group, the n-propoxy group, the isopropoxy group, the n-butoxy group, the isobutoxy group, and the Dibutoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy and the like. In the present specification, examples of the "CM cycloalkyloxy group" include a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, and a cyclooctyl group. Baseoxy. In the "V2_6 alkenyloxy group", examples of the "C2_6 alkenyloxy group" include a vinyloxy group, a propane-1-en-1-yloxy group (propyleneoxy group), and a propane olefin small oxygen. (allyloxy), isopropenyloxy, butanyloxymethane, butan-2-en-1-yloxy (crotonyloxy), butane-3-enyloxy, 2 methylpropan-2-en-1-yloxy, 1_mercaptopropoxyoxy, pentacene-1-diyloxy, pentane-2· ene small oxy, pentane _3 _ Phytosyloxy, pentan-4-en-1-yloxy, 3-methylbutane 2-2-ene·丨-yloxy, methylbutyrol-3-ene·1·yloxy Base, hexanes, acetophenoxy, hexanyl-2-yloxy, hexanyl-1-yloxy, hexa-butoxyloxy, hexanyl Alkoxy group, 4-nonylpentane-3-ene-1-anthraceneoxy group, and the like. In the present specification, examples of the "Ci6 alkylthio group" include: methyl 100134953 16 201217385 thiol, ethylthio, n-propylthio, isopropylthio, n-butylthio, and iso Butylthio, second butylthio, tert-butylthio, n-pentylthio, isopentylthio, neopentylthio, n-hexylthio, isohexylthio and the like. In the present specification, the term "mono(Cu alkyl)amino group" means a group in which one alkyl group is bonded to a nitrogen atom, and examples thereof include a mercaptoamine group, an ethylamine group, a propylamine group, and a different group. Alanine, butylamino, second butylamino, tert-butylamino, n-pentylamino, isoamylamino, neopentylamino, n-hexylamino, isohexylamino and the like. In the present specification, the term "di(CV6 alkyl)amino group" means a group in which two identical or different alkyl groups are bonded to a nitrogen atom, and examples thereof include a diammonium group and a mercapto group. Amino group, diethylamino group, mercaptopropylamino group, ethylpropylamino group, dipropylamino group, diisopropylamino group, dibutylamino group and the like. In the present specification, examples of the "C6_1()aryl group) include a phenyl group, a naphthyl group, and a foundation. In the present specification, the term "substituted sulfonyl" refers to a "Cu alkylsulfonyl group" in which an alkyl group is bonded via a sulfonyl group (-S02-), and a halogenated alkyl group is bonded via a sulfonyl group. "C2_6-6-enyl alkenyl group bonded to the C3-8 cycloalkylsulfonyl group" and a c2_6 alkenyl group bonded via a sulfonyl group by a C3-8 cycloalkyl group "C2_6 alkynylsulfonyl group" in which a sulfonyl group, a c2_6 alkynyl group is bonded via a sulfonyl group, an "amine sulfonyl group" bonded to an amine group via a sulfonyl group, and a mono(CJ _ 6 alkyl group) A mono-(Ci_6 alkyl)amine sulfonyl group or a bis(C^alkyl)amine sulfonyl group bonded to an amine group or a di(Ci_6 alkyl)amino group via a sulfonyl group, and an aryl group via a sulfonate "c6_1() arylsulfonyl) bonded to the thiol group. 100134953 17 201217385 In the present specification, examples of the "cN6 alkylsulfonyl group" include a mercaptosulfonyl group, an ethylsulfonyl group, a n-propylsulfonyl group, an isopropylsulfonyl group, and a n-butyl group. Sulfosyl, isobutylsulfonyl, t-butylsulfonyl, tert-butyl sulphate, n-decyl base, isoamyl acid, neodecyl, 2_ Nonylbutylsulfonyl, 1-methylbutylsulfonyl, 1-ethylpropylsulfonyl, 2.2-dimethylpropyl schulphate, n-hexylsulfonyl, 4-decylpentyl ruthenium , 3-methylpentylsulfonyl, 2-methylpentylsulfonyl, 1-decylpentylsulfonyl, 3.3-dimercaptobutylsulfonyl, 2,2-dimethylbutyl Sulfosyl, 1,1-dimethylbutylsulfonyl, 1,2-didecylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,3-di A butyl sulfonyl group, a 1-ethylbutyl sulfonyl group, a 2-ethylbutyl fluorenyl group, and the like. In the present specification, examples of the "halogenated Ck-burning basestone" include a fluoromethylsulfonyl group, a difluoromethylsulfonyl group, a trifluoromethylsulfonyl group, and a chloromethylsulfonyl group. Bromomethylsulfonyl group, iodomethylsulfonyl group, 2,2,2-trifluoroethyllithic acid group, and the like. In the present specification, examples of the "(:3_8 cycloalkylsulfonyl) group include a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a cyclopentylsulfonyl group, a cyclohexylsulfonyl group, and a ring. Heptylsulfonyl group, cyclooctylsulfonyl group, etc. In the present specification, examples of the "c2_6 alkenylsulfonyl group" include a vinylsulfonyl group, a propenylsulfonyl group, and an allylsulfonate. In the present specification, as the "c2_6 alkynylsulfonyl group", for example, 100134953 18 201217385, a fast-curing basestone, a propyl sulfonyl group, etc. Examples of the "mono(Cu alkyl)aminesulfonyl group" include a mercaptosulfonyl group, an ethylaminesulfonyl group, a propylaminesulfonyl group, an isopropylaminesulfonyl group, and a butyl group. Aminesulfonyl, t-butylamine sulfonyl, tert-butylamine sulfonyl, pentylamine sulfonyl, hexylamine sulfonyl, etc. In the present specification, as "di(CV6 alkyl) Examples of the amine sulfonyl group include a dimercaptosulfonyl group, a methyl ethylamine sulfonyl group, a diethylamine sulfonyl group, a dipropylamine sulfonyl group, and a diisomeric group. In the present specification, examples of the "C6.10 arylsulfonyl group" include a benzenesulfonyl group, an anthracenesulfonyl group, and a naphthalenesulfonate. In the present specification, the term "heterocyclic ring" means a saturated or unsaturated heterocyclic ring of 4 to 10 members which may have at least one nitrogen atom, oxygen atom or sulfur atom, for example.可 吼 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比.啼σ sit, 吼 啥, 啥 _, 嘻 嘻 、, tetrahydro 喧 、, tetrahydroisoindole. Lin, 丨 朵 α, ° 引 咐 咐, ° bottom α, α bottom σ ketidine, two Hydrogen ratio biting, indoline sigma ketone, ° ratio °, 淋 、, 咬 嗟, 嗟 吱, 吱 、, benzofuran, benzothiophene, tetrahydro thiol, tetrahydrofuran, oxetane In the present specification, the "5-10 membered heteroaryl group" means a 5- to 10-membered monocyclic or polycyclic ring containing one to four hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. Aromatic heterocyclic group For example, a furyl group, a porphinyl group, a sigma base, a sigma group, an iso-β, a thiol group, a fluorenyl group, an isoindole group, a sigma σ sitting group, a π ratio α sitting group, and a π number are exemplified. Di-sigma sitting, sputum sigma, trisal, four saliva

S 100134953 19 201217385 Basis, ° ratio ° base, mouth ° base, ° ratio ° well base, ° 荅 基 base, benzo oxamethane, isobenzofuranyl, benzothienyl, fluorenyl, isoindole Mercapto, carbazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzopyrene. Sitting base, benzo and σ number two. Sitting on the base, benzo.塞二σ坐基, benzotrisyl, 喧琳基, isoindolin, zhonglin, 喧α sitin, 啥 淋, π 井, 奈 定 定, 嘌呤 base, 喋The bite base, furan 吼 σ determinate, α 塞 并 并 比 咬 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比In the present specification, the term "saturated heterocyclic group" means a saturated heterocyclic group of 4 to 6 members containing one to four hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. For example, σ ratio π base, σ ratio σ each lining, σ m sigma sigma, and mouth squaring. Lin Ji, 11 is better than Jun σ, D is more than Jun Lin, sent bite base, and sent a base. Lead D-linyl, iso-linyl, °-lin, tetrahydro σ-decyl, tetrahydro-α-fumonyl, oxacyclobutyl and the like. In the present specification, the term "C6_1()aryl CV6 alkoxy group" means a group in which the above Cm alkoxy group is bonded to a phenyl group, a naphthyl group or a base. For example, a phenyl-Cw alkoxy group, a naphthyl-Cm alkoxy group, and a base-Cw alkoxy group can be mentioned. More specifically, a benzyloxy group, a phenethyloxy group, a naphthylmethyl group, etc. are mentioned. In the present specification, examples of the "substituent" in the CV6 alkyl group which may have a substituent include a halogen atom, a c3-8 cycloalkyl group, a C6 alkoxy group, a mono(CV6 alkyl)amino group, and a (^_6 alkyl)amino, di(C2_6 alkenyl)amine, mono(C3_8cycloalkyl)amine, C2-7 alkoxycarbonyl, amine, carboxyl, cyano, 20 100134953 201217385 Amine oxime, An amine yellow base, a thiol group, a moth group, a 5_1 member heteroaryl group, a saturated heterocyclic group, etc. The substituent may have 1 to 4. Further, the carbon number of the 6 oxy group (C2·7) The number including the carbonyl carbon. In the present specification, the q-6 methoxy group which may have a substituent, the c2_6 oxy group which may have a substituent, and the epoxy group which may have a silk are taken. Examples of the radical "" include a halogen atom, a c3 8 cycloalkyl group, a k alkoxy group, an early (C1_6 alkyl)amino group, a di(C1-6 alkyl)amino group, and a di(1)2.6 alkenyl group. Amino, mono(c3-8cycloalkyl)amine, c2-7 alkoxy group, amine group, decyl soil, cyano group, amine amide group, amine hetero group, thio group, nitro group, 5, a heteroaryl dihomocyclic heterocyclic group. These substituents may have four. Further, the carbon number of the carbonyl group (C2_7) represents a number including the county carbon. In the present specification, it is a <5> member heteroaryl group which may have a silky wire and a substituent which may have a substituent, and may have a substituent. An aryloxy group which may have a substituent (: _ aryl Ci), an oxy group, and a "substituent" which may have a substituted base, and examples thereof include a halogen atom and a 6" c3-8 cycloalkyl group. ώCi 6 county, C6 6 dilute group, C2 6 alkynyl group, yl group, 6 alkyl) amine group, bis(cl-6 alkyl)amino group, bis(C26 alkenyl group, base, early ( C3_8 cycloalkyl)amine, dioxaboroalkyl, oxamorpholinyl, 疋 、, ^ II. Sitylene, C2-7 alkoxy group, amine group, carboxyl group, cyano group... And an amine hydrazino group, a hydrazine group, a nitro group, etc. The substituents may have 4 groups. Further, the substituents may further have a substituent. 〜 As R1 and R3, a hydrogen atom, a halogen atom, The base is preferably a hydrogen atom, an i atom or a U group. Among them, r1 is more preferably a dentate atom or a Cw alkyl group, and R3 is more preferably a hydrogen atom. In the formula (1), 'as R^r3 The ruthenium atom is preferably a fluorine atom. In the formula (1), as the Ci 6 alkyl group in R1 and R3, a Q 4 alkyl group is preferred, and a methyl group is more preferred. In the formula (1), R2, preferably a hydrogen atom, _s(〇)r13, _s(〇)2R14, -co2r15 Or -conr1 V7' is more preferably a hydrogen atom, _s(0)r13, _s(〇)2Rl4. In the formula (1), as R4, 5 and R6, a hydrogen atom is preferred. In the formula (1), as R7, Preferably, _c(〇)Rl8, _c(s)r19, -s(o)2R2G, a C61Q aryl group which may have a substituent or a 5-10 membered heteroaryl group which may have a substituent is more preferably _c (〇) r18, _s(〇) 2r20 or a 5-10 membered heteroaryl group which may have a substituent. In the formula (1), R18 in -C(〇)R18 in R7 preferably has a C. 6 alkoxy group of a substituent, a (^^ alkenyloxy group which may have a substituent, a CM()aryloxy group which may have a substituent, a c3 8 cycloalkyloxy group which may have a substituent, A C61G aryl Cl-6 alkoxy group which may have a substituent, a heterocyclic oxy group which may have a substituent, a 5-10 membered heteroaryl group or a mono(Cm alkyl)amino group which may have a substituent may more preferably have a substituted c16 alkoxy group. In the formula (1), 'as R7, preferably c 6 alkoxy group, halogenated ci-6 alkoxy group, C6_1G aryl alkoxy group or mono (CV6 alkyl group) The amine group is more preferably a mono(Ci 6 alkyl)amino group. In the formula (1), R20 in the _S(〇) 2r20 in R7 is preferably c! _6 100134953 22

201217385 Alkyl, halogenated Ci_6 alkyl, c3-8 cycloalkyl, c6_10 aryl which may have a substituent or a 5-10 membered heteroaryl which may have a substituent. In the formula (1), as a 5- to 10-membered heteroaryl group of the 5-10 membered heteroaryl group which may have a substituent in R7, it is preferred that the ratio is σ-based, αα-based, and ρ-numbered . Further, the substituent moiety is preferably a halogen atom, a Cw alkyl group or a halogenated CV6 alkyl group, more preferably a gas atom, an ethyl group, an isopropyl group or a trifluoromethyl group, still more preferably a chlorine atom or a group B. base. In the formula (1), the hetero ring formed as R1 and R11 or R1 and R12 is preferably a heterocyclic ring selected from the group consisting of:

Wherein R21 represents a hydrogen atom, a Cu alkyl group, -C(0)R22 or -S(0)2R23 (wherein R22 and R23 respectively represent a CV6 alkyl group or a C3_8 cycloalkyl group), and a wavy line portion indicates A and E aromatic rings], more preferably 100134953 23 201217385 [Chem. 7]

Better yet [Chemical 8]

In the formula (1), R11 or R12 is preferably a hydrogen atom. In the formula (1), the CN6 alkyl group in R13 or R14 is preferably a CK4 alkyl group, more preferably a methyl group. In the formula (1), the C6_10 aryl group which may have a substituent in R13 or R14 is preferably a phenyl group or a fluorenylmethyl group, and more preferably a p-tolylmethyl group. In the formula (1), as the alkoxy group which may have a substituent in R18, a methoxy group, an ethoxy group, an isopropoxy group, a third butoxy group, a 2-fluoroethoxy group, and 2 are preferable. -methoxyethoxy, (3-methyloxetan-3-yl)methoxy, 1,1,1-trifluoro-2-methylpropan-2-yloxy, 2, 2,2-Trifluoroethoxy, 2,2,2-trichloroethoxy. In the formula (1), as the C3_8 cycloalkyloxy group which may have a substituent in R18, a C3_6 cycloalkyloxy group which may have 1 to 3 halogen atoms may be substituted, and more preferably a 4-fluorocyclic ring. Hexyloxy, 4,4-difluorocyclohexyloxy. In the formula (1), as the C2_6 alkenyloxy group which may have a substituent in R18, 100134953 24 201217385 is preferably a C2_4 dilute oxy group, more preferably a propidyl-2-en-1-yloxy group ( Dilute propoxy). In the formula (1), as the C6_10 aryloxy group in R18, a phenoxy group or a p-nitrophenoxy group is preferred. In the formula (1), as the C6_10 aryl Cm alkoxy group in Rl8, it is preferred that the - group Ci-6 hexyloxy group is more preferably an oxy group. In the formula (1), as the 5_1 member heteroaryl group which may have a substituent in R18, a thiol group is preferred. In the formula (1), as the mono(Cl-6 alkyl)amino group in R18, a mono(Cm alkyl)amino group is preferred as the third butylamino group. In the formula (1), the mono(Cl-6 alkyl)amino group in R19 is preferably a mono)amino group, more preferably a third butylamino group. In the formula (1), as the Ci_6 alkyl group in r2〇, a Cm alkyl group is preferred, and an n-butyl group is more preferred. In the formula (1), as the halogenated Cl 6 alkyl group in R20, a halogenated Ci 4 alkyl group is more preferably a di-halomethyl group. In the formula (1), the Cs_8 cycloalkyl group in R20 is preferably a C36 cycloalkyl group, more preferably a cyclopropyl group or a cyclohexyl group. In the formula (1), as the aryl group which may have a substituent in R20, a phenyl group which may have a substituent is preferable. The substituent moiety is preferably a halogenated Cu-based (difluoroindenyl group or the like) or a cK6 alkoxy group (anthraceneoxy group or the like). In the formula (1), as a heteroaryl group which may have a substituent in R20, 100134953 25 201217385 is preferably an anthracene group. In the general formula (1), as the incorporation and 3, A is a nitrogen atom, and in the case of a money material, it is a case where A is CH, and B is a nitrogen atom, more preferably A and (iv) a nitrogen atom. Clear

Preferably, CH = (1) is preferably a nitrogen atom, and CHM (tetra) is CH. In the formula (1), X is preferably a nitrogen atom or an oxogen atom. , in (1), 'as E' is preferably a nitrogen atom, ch or c^, more preferably a nitrogen in the formula (1), and as Y, preferably an oxygen atom, a sulfur atom, a nitrogen atom, more preferably an oxygen atom. Atom, and more oxygen atoms. In the above, "as z" is preferably an oxygen atom, a sulfur atom or a nitrogen atom, more preferably an oxygen atom or a nitrogen atom, still more preferably a nitrogen atom. In the ', Ε = Γ), 'as a ring structure containing D and E' is more preferably a benzene ring (CH in the case of D and (d)). Further, in the general formula (1), as the % structure including A, B, and YAZ, the following structure is more preferable:

R4 R4 N^N \λ N人N l| I //\y^~ 〇~N , N-N 100134953 26 201217385 More preferably the following structure: [Chem. 10]

(wherein R4 is the same as above). Among the piperidine derivatives represented by the formula (1), the compounds represented by the following (1 hook or "b) are particularly preferred.

(wherein R1 represents a hydrogen atom, a dentate atom, a Cw alkyl group, a Ci6 alkoxy group, an amine group or a nitro group, and R2 to R7 are the same as defined above). Further, as a bite derivative represented by the formula (1) As a preferable compound, a compound selected from the group consisting of 4-(7-(5-(methyl sulphate)) D-introduced π-dot-!-yl)iso^, etc. , 5_d]e close bite _4· 100134953 27 Η 201217385 base) piperidine-1-carboxylic acid tert-butyl ester (Example 1), 3-(1-(5-chloropyrimidin-2-yl)piperidine- 4-yl)-7-(5-(indolylsulfonyl) porphyrin-1-yl)isoxazo[4,5-d]pyrimidine (Example 2), 3-(1-(5) -ethylpyrimidin-2-yl)piperidin-4-yl)-7-(5-(methylsulfonyl) porphyrin-1-yl)isoxazo[4,5-d]pyrimidine ( Example 3), 3-(1-(5-Bromopyrimidin-2-yl)piperidin-4-yl)-7-(5-(methylsulfonyl) porphyrin-1-yl)isoindole Zoxao[4,5-d]pyrimidine (Example 4), 3-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)-7-(5-(methylsulfonyl) ) is porphyrin-1-yl)isoxazolo[4,5-d]pyrimidine (Example 5), 2-(4-(7-(5-(methylsulfonyl)) porphyrin- 1-yl)isoxazolo[4,5-d]pyrimidin-3-yl)piperidin-1-yl)pyrimidine 5-carboxylic acid ethyl ester (Example 6), 2-(4-(7-(5-(methylsulfonyl) porphyrin-1-yl)isoxazo[4,5-d] Pyrimidin-3-yl)piperidin-1-ylpyrimidine-5-carboxylic acid (Example 7), 7-(5-(indolylsulfonylpolypyridin-1-yl)-3-(1) -(5-(Trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)isoxazo[4,5-d]pyrimidine (Example 8), 2-(4-(7-( 5-(indolylsulfonyl) porphyrin-1-yl)isoxazo[4,5-d]pyrimidin-3-yl)piperidin-1-yl)pyrimidine-5-ol (Example 9 , 3-(1-(5-Methoxypyrimidin-2-yl)piperidin-4-yl)-7-(5-(indolylsulfonyl)] | porphyrin-1-yl)isoindole Zizo[4,5-d]pyrimidine (Example 10), 7-(5-(indolylsulfonyl)porphyrinyl)-3-(1-(5-phenylpyrimidin-2-yl) Piperidin-4-yl)isoxazo[4,5-d]pyrimidine (Example 11), 7-(5-(indolylsulfonyl)porphyrin-1-yl)-3-( 1-(5-(trifluoromethyl)acridine 100134953 28 201217385 -2-yl) brigade -4-yl) heterogeneous sitting and [4,5_吓密α定(Example η), 4- (7-(5-(methyl-stone-branched). 引引流__ι_基)iso-[S, and [4,5_d]a dimethyl) piperidine-1-carboxylic acid isopropyl ester ( Example 13), 4-(7-(5-(methyl fluorenyl)).引倍淋_1_基)iso, oxazo [4,5_ illusion. dense. Ethyl-piperidine-1-carboxylic acid ethyl ester (Example 14), 4- 4-(7-(5-(methyl fluorenyl) tenth linne group) is iso-sit and [^ phantom spray. 2-fluoroethyl piperidine-1-carboxylate (Example 15), 4-(7-(5-(methylsulfonyl) porphyrin)-isoxazole [4,5-d]pyrimidin-3-yl)piperidine-1-carboxylic acid 2-methoxyethyl ester (Example 16), 4-(7-(5-(methyl sulfonyl))-puroline Azolo[4,5_d]c cleavage-3_yl)pyrazine-1-carboxylic acid tetrahydro-2H-11 decano-4-yl ester (Example 17), 2-(4-(7-( 5-(indolylsulfonyl)dopruline _ι_yl)isoxazoloindole-3-yl) ° bottom bite -1 yl y dense. _5_l-acid dilute propyl ester (example μ ), 4-(7-(5(Methyl continuation), σ_^σ 坐[4,5_d]^ σ-3-yl)piperidine-1-carboxylic acid Butyl ester (Example 19), 7-(5-(methylsulfinyl) is called porphyrin small group)_3_(1_(5-(trifluoromethyl). Ratio ' °疋_2·yl)a Bottom-biting ice base) iso-n-number π sit-and-set (Example 20), 2,2-monomethyl-1_(4_(7_(5_(曱基石黄醯基) porphyrin small group) isoxazole [4 , 5_d]pyrimidin-3-yl)piperidin-1-yl)propan-1-one (Example 21), 4_(7-((2.fluoro-4-(A) Phytosulfonyl)phenyl)amino)isoxazo[4,5-d]pyridin-3-yl)-branched 丨·carboxylic acid tert-butyl ester (Example 22), N-(2-fluoro -4·(methylsulfonyl)phenyl)-3-(1_(5-(trifluoromethyl)pyrimidine_2·100134953 29 201217385 yl)piperidin-4-yl)isoxazo[4,5 -d]pyrimidine-7-amine (Example 23), N-(2-fluoro-4-(methylsulfonyl)phenyl)-3-(1-(5-(trifluoromethyl)acridine) 2-yl)piperidin-4-yl)isoxazo[4,5-d]-7-amine (Example 24), 4-(7-((2-fluoro-4-indolyl)sulfonate Phenyl)amino)isoxazo[4,5-d]pyrimidin-3-yl)piperidine-1-carboxylic acid 1,1,1-trifluoro-2-methylpropan-2-yl Ester (Example 25), 4-(7-((2-fluoro-4-indolylsulfonyl)phenyl)amino)isoxazo[4,5-d]pyrimidin-3-yl)piperidine 2-carboxylic acid 2,2,2-trifluoroethyl ester (Example 26), 4-(7-((2-fluoro-4-methylsulfonyl)phenyl)amino)isoxazole [4,5-d]pyrimidin-3-yl)piperidine-1-carboxylic acid 2,2,2-trichloroethyl ester (Example 27), 4-(7-((2-fluoro-4-indole) (1,5-(4-) (2-fluoro-4-indolylsulfonyl)phenyl Amino)isoxazo[4,5-d]pyrimidin-3-yl)piperidine-1-carboxylic acid 4,4-difluorocyclohexyl ester (Example 29), 4-(7-(( 2-fluoro-4-mercaptosulfonyl)phenyl)amino)iso). Isooxa[4,5-d]pyrimidin-3-yl)piperidine-1-carboxylic acid oxetan-3-yl ester (Example 30), 4-(7-((2-fluoro-) 4-(indolylsulfonyl)phenyl)amino)isoxazo[4,5-d]pyrimidin-3-yl)piperidine-1-carboxylic acid (3-methyloxetane- 3-yl)methyl ester (Example 31), 4-(7-((2-fluoro-4-indolylsulfonyl)phenyl)amino)isoxazo[4,5-d]pyrimidine- 3-yl) piperidine-1-carboxylic acid phenyl ester (Example 32), 4-(7-((2-fluoro-4-indolylsulfonyl)phenyl)amino)isoxazo[4] , 5-d]pyrimidine 100134953 30 201217385 -3-yl) piperidine-1-carboxylic acid 4-nitrophenyl ester (Example 33), (4-(7-((2-fluoro-4-(fluorenyl)) Sulfo]phenyl)amino)isoxazo[4,5-d]pyrimidin-3-yl)piperidin-1-yl) (pyridin-2-yl)anthone (Example 34) , 4-(7-(4-(indolylsulfonyl)phenoxy)isoxazo[4,5-d]pyrimidin-3-yl)piperidine-1-carboxylic acid tert-butyl ester Example 35), 4-(7-(2-Fluoro-4-(methylsulfonyl)phenoxy)isoxazo[4,5-d]pyrimidin-3-yl)piperidine-1-carboxylate Tert-butyl acid ester (Example 36), 4-(7-(4-(1Η-tetrazol-1-yl)phenoxy)isoxazo[4,5-d]pyrimidin-3-yl) Piperidine-1-carboxylic acid third Ester (Example 37), and 4-(1-methyl-7-(5-(indolylsulfonyl)-indolyl-1-yl)-1Η-°-pyrazolo[4,3-d] Pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (Example 38). Where geometric isomers or optical isomers are present in the compounds of the invention, such isomers also include In the range of the present invention, the separation of the isomers is carried out by a usual method. The salt of the compound represented by the formula (1) is not particularly limited as long as it is a pharmaceutically acceptable salt. When it is considered as an acidic compound, for example, a metal salt or a soil test metal salt of Na, Shu, Zhen, #5, and tridecylamine, triethylamine, pyridine, mercaptopyridine, N- a salt of an organic base such as decyl pyrrolidine, N-mercaptopiperidine or N-mercaptomorpholine, etc. When the compound is regarded as a basic compound, for example, a hydrochloride or a hydrobromide salt, An acid addition salt of a mineral acid such as a hydroiodide, a sulfate, a nitrate or a phosphate; a benzoate, an oxime sulfonate, an ethanesulfonate, a besylate, a p-toluenesulfonate, 100134953 31 201217385 顺An acid addition salt of an organic acid such as a sebacate, a fumarate, a tartrate, a citrate or an acetate, etc. As a solvate of the compound represented by the formula (1) or a salt thereof, For example, a hydrate or the like is not limited thereto. Further, a compound which is metabolized in a living body and converted into a compound represented by the formula (丨), that is, a so-called prodrug is also included in the present invention. The group which is used as a drug to form the compound of the present invention may be exemplified by "Progress in Medicine", Life Science Medical, 1985, Vol. 5, p. 2157 - page 2161; The basis of the molecular design of the 19th volume of the "Development of Pharmaceuticals", Guangchuan Bookstore, 1990, p. pp. pp. 198. The compound represented by the above formula (1), or a salt thereof, or a solvate thereof can be produced by various known methods, and is not particularly limited, and can be produced, for example, according to the reaction step described below. Further, when the following reaction is carried out, the functional groups other than the reaction site are protected in advance, and are appropriately deprotected at an appropriate level. As protection and deprotection conditions, refer to the commonly used methods (eg Protective Groups in Organic Synthesis Third)

Edition, John Wiley & Sons, Inc., 1999). Further, in each step, the reaction can be carried out by a usual method (for example, the method described in Comprehensive Organic Transformations Second Edition, John Wiley & Sons, Inc; 1999), and the separation can be suitably selected or combined with crystallization. The recrystallization, chromatography, and the like are usually carried out by the method of 100134953 32 201217385. (Manufacturing method of the compound represented by the formula (1)) The compound represented by the formula (1) of the present invention can be produced by the method described in the following reaction scheme. [Reaction Path Figure 1] [Chemical 12]

(1) (wherein A, B, D, E, X, Y, Z, Ri, R2, R3, R4, R5, R6, and R7 have the same meanings as in the above formula (1), and W1 represents a leaving group) ( The Al) Al step is a dehydrating condensing agent such as PdBOP in the presence of a compound (2) in a solvent and in the presence of (stuppyrazin-1-yloxy)triazolopyridinium hexafluorophosphate (PyBOP). A step of producing a compound (3) by reacting a sulfhydrylating agent such as sulfonium chloride. The base is not particularly limited, and for example, an alkali metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate or carbonic acid can be used; 1,8-diazabicyclo[5.4.0]undec-7-ene ( DBU), 1,5-diazabicyclo[4.3.0]壬-5- 100134953 33 201217385 olefin (DBN), 1,4-diazabicyclo[2,2,2]octane (DABC〇), Organic tests such as triethylamine, N,N-diisopropylethylamine, diisopropylamylamine, tridecylamine, and the like. Preferred is fluorene, 8-diazabicyclo[5.4.0]undec-7-ene (DBU). The solvent is not particularly limited, and examples thereof include N,N-dimethylformamide, di-n-tetrahydrofuran, acetonitrile, propionitrile, chloroform, and dichlorocarbyl, etc., which may be used singly or in combination. Fortunately, the father is a mixture of tetrahydrofurfuran or tetrahydrofuran and dichlorohydrazine. The reaction temperature is preferably 〇~15〇°c, more preferably 1〇~3〇. The reaction time is preferably from 5 minutes to 48 hours, more preferably from 10 minutes to 2 hours. The step (A-2) A-2 is a step of producing a compound (1) by reacting the compound (3) with a compound (4) in a solvent in the presence of a base. There are no special restrictions on the secrets. For example, hydrogen (10), hydrogen, potassium hydride, etc. can be used for metallurgy: metal, metal sodium, gold, etc.; gas oxidation clock, sodium oxychloride,

Potassium hydroxide and other hydroquinone test metals; carbonic acid clock, sodium carbonate, carbonic acid K acid, metal oxides; diisopropyl (10) test, diisopropyl sodium, diisopropyl guanamine potassium, six Lithium decylamino lithium, hexamethylene dimercaptoamine, hexamethyldimonylamino potassium, sodium butoxide sodium butoxy 2 = keili, second butyl clock, third Butyl material. (4): The solvent is not particularly limited, and examples thereof include hydrazine, hexamethylene carbamide, bismuth, tetrahydrofuran, acetonitrile, propionitrile, and the like, which may be used singly or in combination. More preferred is Ν·dimethyl ketone. The reaction temperature is preferably 〇~(9) of 50 to 1 Torr. The reaction time is preferably 5 minutes % by hour, more preferably 10 minutes to 4 hours. Eth. 100134953 34 201217385 In addition to the above methods, the compound represented by the formula (1) of the present invention can also be produced by the method described in the following reaction scheme of Fig. 2. I; reaction pathway diagram 2] [Chemical 13]

(B-1) R4

(5)

(wherein A, B, D, E, X, Y, Z, Ri, R2, R3, R4, R5, R6, and R7 have the same meanings as in the above formula (1), and W2 represents a leaving group) (Bl The step B1 is a step of producing a compound (5) by reacting the compound (2) in the presence or absence of a solvent with an i-forming agent such as phosphonium chloride (POCl3) in the presence or absence of a base. The halogenating agent to be used is not particularly limited, and for example, phosphonium chloride, phosphonium chloride/phosphorus pentachloride, ruthenium, osmium-dimethylformamide/grass chloride, and the like can be used. Preferred is phosphonium chloride. As the base, hydrazine, hydrazine-dimercaptoaniline, hydrazine, hydrazine-diethylaniline, hydrazine, hydrazine, hydrazine-diisopropylethylamine and the like can be used. As the solvent, dioxane, 1,2-dichloroethane or the like can be used. The reaction temperature is preferably from 0 to 150 ° C, more preferably from 80 to 120 ° C. The reaction time is preferably 100134953 35 201217385 10 minutes to 48 hours, more preferably 3 to 6 hours. (B-2) The step B-2 is a step of producing a compound represented by the formula (?) by reacting the compound (5) with the compound (4) by an amination reaction using a metal catalyst. The metal catalyst, the ligand, the base, and the reaction conditions are not particularly limited as long as they are reagents and conditions used in the usual amination reaction, and for example, AR Muci, SL Buchwald, Top. Curr. Chem., 219, 131-209, (2002) 荨 § Included in the method. In the step B-2, a method of amination reaction in the presence or absence of a metal catalyst in the presence or absence of a solvent may be suitably employed. At this time, microwave irradiation can also be performed. The metal catalyst is not particularly limited, and for example, palladium acetate (π), palladium (0) dibenzylideneacetone, tris(dibenzylideneacetone)dipalladium (ruthenium), or bis (three third) can be used alone. Base shame) (0), bis(dibenzylideneacetone) (chloroform) two (〇), [I", - bis (diphenyl aryl ferrocene) di-palladium (9), tetra-p-phenyl Palladium complex such as phosphine)palladium or copper arsenide 5 cuprous copper, cuprous cyanate, etc., may also be used in combination (2-biphenyl) bistriphenylphosphine, (2_biphenyl) Dicyclohexylphosphine, tricyclohexylphosphine, 1,3-bis(phenylphosphino)propyl, 2,2,_bis(diphenyllinylnaphthalene, 2·(dicyclohexylphosphinofluorenyl) Biphenyl, 2-dicyclohexyl phenyl-2, _(N,N_:methylamino) phenyl, tetradecylethylenediamine, N,N, dimethylethylenediamine, glycine > A ligand such as N,N-methylglycine or N-methylglycine. There is no particular limitation on the base. For example, hydrogen can be used: hydrogen, hydrogen, potassium hydride, etc. = 'metal clock, metal Nano, metal potassium and other metal tests; hydroxide I oxide, potassium hydroxide and other alkali metals; carbonic acid clock, carbonic acid 1001349 53

36 201217385 Alkali metal carbonates such as sodium, potassium carbonate and carbonic acid planing; lithium diisopropylamide, sodium diisopropylamide, potassium diisopropyl decylamine, lithium hexamethyldidecylamine, Hexamethyl diazepine amine steel, hexamethylene bisphosphonyl quinone, sodium third butoxide, potassium third potassium hydride, n-butyl lithium, second butyl lithium, third butyl Lithium and so on. The solvent is not particularly limited, and for example, tetrahydrofuran, toluene, dioxane, anthracene, fluorenyl-dimercaptocarboxamide, N-decylpyrrolidone, dimethyl azine, water, etc. may be used singly or in combination. . The reaction temperature is preferably from 0 to 200 ° C, more preferably from 100 ° C to 150 ° C. The reaction time is preferably from 1 minute to 5 days, more preferably from 30 minutes to 6 hours. (Manufacturing method of the piperidine derivative represented by the formula (2)) Next, in the compound represented by the formula (2) used in the above reaction, the compound (2a-d) in which both A and B are nitrogen atoms may be used. It is produced by the method described in the following reaction route diagram 3. [Reaction Path Figure 3] [Chem. 14]

Y = 0, Z = N: 2a Y = S, Z = N: 2b Y = N, Z = 0: 2c Y = N, Z = S: 2d (where 丫, 2, 114, 115, 116, 117 has the same meaning as in the above formula (1), R24 represents Cw alkyl or C6-1()aryl Cw alkyl) 100134953 37 201217385 (Cl)Cl step is a step of making compound (6) and anthracene derivative (7) Or a salt thereof to produce a compound (2). The solvent is not particularly limited, and for example, methanol, ethanol, ether, tetrahydrofuran, L4-dioxane, benzene, toluene or the like can be used. Preferred is ethanol. The reaction temperature is preferably from 40 to 120. (:, more preferably 80 ° C to 100 ° C. The reaction time is preferably from 1 hour to 5 days, more preferably from 12 hours to 2 days. Further, the compound (2a-d) can also be referred to Bioorg· Med. Chem. Lett., 2005, 15, 3900., Booklet W02001/047934, Liebigs Ann Chem., 1979, 10, 1534., Indian J. Chem, Sec B., 1994, 33B, 436., W02006/047516 The compound (7) used in the above reaction can be used as it is, or can be suitably produced by a known method, but is not limited thereto. (Big bite derivative represented by the formula (2) (Manufacturing Method) Next, the compound (2e-j) in which any one of A or B in the compound represented by the formula (2) used in the above reaction is a nitrogen atom can be represented by the following reaction scheme in FIG. Manufactured by the method. [Reaction Path Figure 4] [Chem. 15] 100134953 38 201217385

R4

(wherein, Y, Z, R4, R5, R6, and R7 have the same meanings as in the above formula (1), R24 represents a Cw alkyl group or a C6_1Q aryl Ci-6 alkyl group, and w3 represents a halogen atom, a hydroxyl group or an amine group) (D) -1) The compound (2e-h) shown above can be synthesized by referring to the booklet of US2001/0007867. Further, the starting material (6) can be produced by referring to WO2006/047516 Booklet, Bioorg, Med. Chem. Lett., 2004, 14, 5543. 'Liebigs Ann. Chem., 1979, 10, 1534. Further, the compounds (2e, f) and (2i, j) can also be produced by the methods of WO2005/007658 (E-1) and EP0778277 (F-1), respectively. The compounds (6), (7), and (8) used in the above reaction may be used as they are, or may be suitably used by a known method.

S 100134953 39 201217385 It is advisable to manufacture, but is not limited to this. The intermediates and targets obtained by the above respective reactions can be used in purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, various chromatography methods, etc., and can be separated and refined as needed. . Further, the intermediate can be supplied to the next reaction without particular purification. Further, various isomers can be appropriately isolated by a usual method using a difference in physicochemical properties between the isomers. The racemic mixture can be, for example, by conventional derotation by derivatization with a non-Spiegelmer salt of a usual optically active acid such as tartaric acid and by optical detachment or by an optically active column chromatography method. The process is derived as an optically pure isomer. Further, the mixture of the non-image isomers can be isolated by, for example, fractional crystallization or various kinds of chromatography. Further, optically active compounds can also be produced by using suitable optically active starting materials. The compound (1) obtained can be produced into a salt by a usual method. Further, a solvate or a hydrate of a solvent such as a reaction solvent or a recrystallization solvent can be produced. The pharmaceutical composition containing the compound represented by the formula (1) of the present invention or a salt thereof, or a solvate thereof as an active ingredient can be used alone, but usually it is a carrier or an additive which is pharmaceutically acceptable. It is used in the form of a pharmaceutical composition. The form of administration of the pharmaceutical composition is not particularly limited and may be appropriately selected depending on the purpose of the treatment. For example, it may be any of an oral preparation, an injection, a suppository, an ointment, an inhalant, an eye drop, a nasal drop, a patch, and the like. Pharmaceutical compositions suitable for such administration forms can be produced by known formulation methods. 100134953 40 (8) 201217385 In the case of preparing a solid preparation for oral use, an excipient may be added to the compound represented by the formula (1), and if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a bridge flavor may be added. After the agent, the bridge odor, and the like, a key agent, a coated tablet, a granule, a powder, an expectorant, and the like are produced by a usual method. Additives are generally available to the user in the field. For example, as excipients, lactose, self-sugar, gasification, glucose, women, carbon called kaolin, microcrystalline cellulose, and the like are mentioned. = mixture 'explosion · water, ethanol, propanol, monosaccharide poly, glucose solution, v: broad night, carboxymethyl cellulose, hydroxypropyl cellulose, propyl shock, quasi-sugar, contact, calcium phosphate , Polyethylene 吼 Γ Γ t t t = = = = 崩 崩 崩 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼 吼: Refined talc, acid, tartaric acid, etc. In the case of preparing a liquid preparation for oral use, a whitening agent, a leather, or a lemon may be added to the compound, and a humectant, a buffering agent, and an enumeration may be added to the compound; as a buffering agent, it may be a lemon 'two== The second one can be listed as xanthan gum, gum arabic, gelatin and the like.乍 is a female sputum agent, in the preparation of an injection, you can add a pH adjuster, a buffer, a compound in the form of a drunken agent, etc., by the usual method of making a skin A 4, isotonic agent, Local hemp 100134953 Subcutaneous, intramuscular and intravenous injections. Examples of the 201217385 pH adjuster and buffer include sodium citrate, sodium acetate, and sodium phosphate. Examples of the stabilizer include sodium metabisulfite, Ethylene Diamine Tetraacetic Acid (EDTA), thioglycolic acid, and thiolactic acid. Examples of the local anesthetic include pr〇Caine hydrochloride and lidocaine hydrochloride. Examples of the isotonic agent include sodium carbonate, glucose, and the like. In the case of preparing a suppository, a known carrier for a suppository, such as polyethylene glycol, lanolin, cocoa butter, glutaric acid diglyceride, etc., may be added to the compound represented by the formula (1). After adding a surfactant such as Tween (registered trademark), etc., it is manufactured by a conventional method. In the case of the preparation of the ointment, the base, the stabilizer, the wetting agent, the preservative Q agent and the like which are usually used may be blended in the compound represented by the formula (1), and mixed and formulated by a usual method. As the substrate, there may be mentioned: "4 L stone insects, white petrolatum, white material, octyl dodecanol, money, etc. As a preservative, for example, a benzoic acid, a benzoic acid In addition to the above-mentioned forms, the compound represented by the general formula (1) is prepared by the conventional method, and is made into an inhalant, an eye drop, and a nasal drop. As shown in the examples, the compound represented by the formula (1) has a function of promoting the insulin in the hamster pancreas/3 cell line HIT_T15 cells. Therefore, the compound represented by the formula (1), or '咏X Dan驮Additional salt or solvate of this temple is used as a blood sugar lowering agent, and is also used as a disease caused by hyperglycemia of a mammal such as humans including 100134953 42 201217385, such as a preventive and/or therapeutic agent for diabetes. Here, as the diabetes, more specifically, insulin-independent diabetes mellitus (NIDDM) can be cited. The compound represented by the formula (1) of the present invention can be administered by oral administration or parenteral administration. The dosage of the invention's medicine is rooted The patient's body weight, age, sex, symptoms, etc. are different, usually in the case of an adult. 'For the compound represented by the formula (1), it is preferably one to three times a day to give 0.01 to 1000 mg. Preferably, it is 〇"~3〇〇mg. [Examples] Next, the present invention will be further described by way of examples, but the present invention is not limited to the examples. Further, the abbreviations used in the following examples represent the following meanings. s : single peak (singlet) d : doublet (doublet) t : triplet (triplet) q : quartet (quartet) quint: quintet m (multiplet) br: broad peak (broad) J : coupling constant (coupling constant)

Hz: Hertz CDC13: Deuterated chloroform

100134953 43 S 201217385 d6-DMSO : deuterated dimethyl acetal CD3OD : hydrazine methanol H-NMR · proton nuclear magnetic resonance IR : infrared absorption spectroscopy [Example 1] 4-(7-(5-(methylsulfonyl) Preparation of porphyrin _ 丨 _ yl) isoxazolo[4,5-d]pyrimidin-4-yl)piperidine-1 -decanoic acid tert-butyl ester Step 1: 4-thiol-based Bite _ι_ 酸酸三丁g的制制 The 4-0 bottom sterol (4.6 g, 40 mmol) was dissolved in tetrahydroethane (40 mL) and water (40 mL), and dicarbonate was added. The third butyl group (9 6 g, 44 mmol) and sodium carbonate (5.1 g '48 mmol) were stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. Step 2: Preparation of 3-Methylmercaptopiperidine-1-carboxylic acid tert-butyl ester The third butyl-4-carboxyl group (1〇.〇g, 46.4 mmol) and 2,2,6 , 6-Tetramethyl slightly bite 1-oxyl radical (360 mg, 2.32 mmol) dissolved in chloroform (230 mL). Intravenous sodium/saturated hydrogen carbonate was added dropwise for 1 hour at an internal temperature not exceeding rC. Sodium aqueous solution (1 / 1, 94 mL). After the completion of the dropwise addition, sodium thiosulfate was added to the reaction mixture to terminate the reaction, and extraction was carried out by gas chromatography. The organic layer was dried over anhydrous sodium sulfate (MgSO4). W-NMR (CDC13) (5: 1.46 (9H, s), 1.83-1.94 (2H, m), 2.36-2.45 (1H, m), 2.87-2.98 (2H, m), 3.93-4.03 (2H, m ), 9.66 100134953 44 201217385 (1H, s). Step 3: 4-(1-Phenyl-2-nitroethyl) Ninjabita-1-Weicarboxylic acid tert-butyl ester The third butyl pyridine-1-carboxylate (11.1 g, crude product) and fluorinated (540 mg, 9.28 mmol) were dissolved in isopropanol (50 mL) and nitro decane (14.2 g, 232). The mixture was stirred overnight at room temperature. Water was added to the mixture and the mixture was evaporated. 'The title compound was obtained as a white powder (7.70 g, 61%, 3 steps). 'H-NMR (CDC13) 5 : 1.24-1.39 (2H, m), 1.46 (9H, s), 1.58-1.65 (2H, m)5 1.77-1.84 (1H, m), 2.57-2.62 (1H, m), 2.62-2.74 (2H, m), 4.09-4.24 (3H, m), 4.44 (1H, dd, J=8.5, 13.4 Hz), 4.50 (2H, dd, J=2.9, 13.2 Hz). Step 4 · 4-(2-Nitroethyl) π bottom n _i_ tacrotic third vinegar is manufactured 4-( 1-hydroxy-2-nitroethyl) piperidine -1·carboxylic acid tert-butyl ester (7.70 g, 28.1 mmol) was dissolved in dichloromethane (HOmL), and Dess-Martin peri〇dinane (14.3 g, 33.7 mmol) was added to the chamber. The mixture was stirred for 40 minutes. Aqueous sodium thiosulfate solution and a saturated aqueous solution of sodium hydrogencarbonate were added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. =4 : 1 - 2 : 1) The residue obtained was purified to give the title compound (yield: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; -1.64 (2H, m), 100134953 45 201217385 1.84-1.87 (2H, m), 2.61-2.67 (1H, m), 2.80-2.83 (2H, m), 4.07-4.30 (2H, m), 5.36 (2H , s). Step 5. 4-(1-(Transimino)-2-nitroethyl) π σ 定 小 小 第三 之 之 之 之 之 之 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- The -1-butyric acid tributyl ketone (2.00 g, 7.34 mmol) and hydroxylamine sulfate (1.81 g '11.0 mm 〇l) were dissolved in ethanol/toluene = 1/1 (36 mL) and heated to reflux for 4.5 hours. Concentration under reduced pressure, water was added, and ethyl acetate was evaporated. After drying over anhydrous sodium sulfate, the title compound ( 945 mg, 45%)辰乙-4-基)-4-石肖基异^ et al. _5_ Ethyl carboxylate is produced in an argon atmosphere, 4-(1-(hydroxyimino)_2-nitroethyl) mother bites - Butyric acid tert-butyl ester (100 mg, 0.348 mmol) was dissolved in anhydrous tetrahydrofuran (3.5 mL), and ethyl chloroacetate (95 mg &lt;RTI ID=0.0&gt; Cool to 0 ° C and slowly add triethylamine (o.i mL). Water and saturated brine were added, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the title compound was obtained (jjjjjjjjj %). !H-NMR (CDCI3) ^: 1.43 (3H, t, J = 7.1 Hz), 1.47 (9H, s), 1.76 (1H, dd, J=4.1, 12.0 Hz), 1.82 (1H, dd, J= 4.4, 11.7 Hz), 100134953 46 201217385 1.96-2.03 (2H, m), 2.82-2.96 (2H, m), 3.27 (1H, dddd, J=4.0, 4.0, 11.6, 11.6 Hz), 4.14-4.26 (2H ,m),4 52 (2H,q, J= 7.2

Hz). Step 7: 4-Amino-3-(1-(t-butoxy)-based). No. 55······························ Sodium _5-decanoic acid B (78.8 mg, 0.213 mmol) was dissolved in ethanol/water = i/i (2 mL). Add zinc (140 mg, 2.13 mmol) and ammonium chloride at 0 °C. 280 mg, 5.33 mmol), stirred at room temperature for 4 hours. After concentrating under reduced pressure and dried over anhydrous sodium sulfate, EtOAc (EtOAc) ^H-NMR (CDC13), 5:1.40 (3H, t, 1=7.! Hz), 1.47 (9H, s), 1.74-1.87 (2H, m), 1.90-1.98 (2H, m), 2.79 (1H, dddd, J=4.0, 4.0, 11.6, 11.6 Hz), 2.84-2.96 (2H, m), 4.11-4.24 (4H, m), 4.41 (2H, q, J=7.2 Hz). Step 8: Preparation of 4-(7-hydroxyisoxazolo[4,5-d]pyrimidin-3-yl)piperidine-indole-carboxylic acid tert-butyl ester 4-amino-3-(1-(di) Dibutoxymethyl)0 □0 _4_yl)isosodium·5_ethyl decanoate (32.5 mg, 0.081 mmol) and formazan acetate (26 〇mg, 〇243 mmol) dissolved in ethanol Heated to reflux for 24 hours. The organic layer was concentrated under reduced pressure. After drying over anhydrous sodium sulfate, the residue was concentrated under reduced pressure and purified using silica gel column chromatography (hexane: ethyl acetate: 100134953. The title compound was obtained as a yellow solid (17.9 mg, 69%). 'H-NMR (CDC13) (5:1.48 (9H, s), 1.94 (1H, dd, J=3.9, 12.2 Hz), 2.00 (1H, dd, J=4.1, 12.2 Hz), 2.07-2.16 (2H , m), 2.88-3.03 (2H, m), 3.28 (1H, J=4.0, 4.0, 11.6, 11.6 Hz, dddd), 4.11-4.29 (2H,m), 8.07 (1H, s), 8.24 (1H , d, J=14.i Hz). Step 9. 4-(7-((lH-benzoquinone[(1][1,2,3]三11坐-〖-yl)oxy)) Production of 11th and [4,5-d]pyrimidin-3-yl)piperidine-1-carboxylic acid tert-butyl ester 4-(7-trans-iso-sigma-salt [4,5-d]°密乙-3-基)α辰u定_ι_supplenic acid tert-butyl ester (14.1 mg, 0.044 mmol) and 1Η-benzotriazol-1-yloxytripiride town hexafluorophosphate ( 27.0 mg, 0.053 mmol) was suspended in anhydrous tetrahydrotetramine (0.5 mL), triethylamine (1 〇eL) was added and stirred at room temperature for 1 hour. Water was added and extracted with ethyl acetate. After the sodium was dried, the title compound (71 mg, 37%) was obtained as a white oily oil. H-NMR (CDCI3) δ : 1.49 (9H, s), 1.98-2.12 (2H, m), 2.15-2.24 (2H, m), 2.91-3.08 (2H, m) , 3.44 (1H, dddd, J=4.0, 4.0, 11.2, 11.2 Hz), 4.14-4.33 (2H, m), 7.48-7.53 (2H, m), 7.57-7.62 (1H, m), 8.17 (1H, Dd, J=1.2, 8.0 Hz), 8.64 (1H, s) 0 Step 10: 4-(7-(5-(methylsulfonyl)porphyrin-丨-yl)isoxazolo[4,5_d Manufacture of pyridyl-4-yl)nidanyl-1-carboxylic acid tert-butyl ester 100134953 48 8 201217385 5-(indolylsulfonyl) pi-pyroline (2.5 mg, 〇· under argon atmosphere 〇13 mmol) and 4-(7·((1Η- 笨和[d][1,2 3]三哇小基)oxy) iso-sit and [4,5-(1&gt; dense bite_3- Base) 唆 唆 carboxylic acid tert-butyl ester (7 mg, 〇〇 16 mmol) bath solution in anhydrous N, N-dimercaptocaramine (1) 3 mL), add sodium hydride 〇〇 mg, 0.020 mm 〇 l), stir at 7 〇 for 1 。. Water was added and extraction was carried out with chloroform. After drying over anhydrous sodium sulfate, the residue was evaporated to dryness crystals crystals crystals 25〇/(〇. [Example 2] 3-(1-(5-apyrimidin-2-yl)piperidin-4-yl)-7-(5-(indolylsulfonyl) is called 1 ϋ琳-1 -基)异. No. S. and [4,5-d] β-bite manufacturing step 1: 7-(5-(indolylsulfonyl), porphyrin small group)_3_(α-endidine _4_基) Manufacture of [4,5-d]pyrimidine hydrochloride with 4-(7-(5-(methylsulfonyl)c-pyroline-indolyl)isoxazole And [4,5-d] bite-4-yl) "Butyl-i-carboxylic acid tert-butyl ester (5.8 mg '0.012 mmol) was dissolved in ethyl acetate (0.5 mL) and cooled in an ice bath The title compound (5.8 mg, crude product) was obtained as an orange solid. Step 2: 3-(1-(5············· Pyrimidine·2-yl)pyrazine_4_yl)-7-(5-(indolylsulfonyl)-indolyl-1-yl)iso. The production of 7-(5_(methylsulfonate) Mercapto) is called porphyrin·1-yl)-3-(piperidin-4-yl)iso. Isozo[4,5-d]pyrimidine hydrochloride (5.3 mg in bold) and 2,5-dichloropyrimidine (2.7 mg, 0.018 mmol) dissolved in anhydrous N,N-didecylamine (〇3) mL)

100134953 49 S 201217385 N,N-Diisopropylethylamine (7 //L, 0.036 mmol) was added and stirred at 80 ° C for 4 hours. Water was added and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the title compound was obtained (yield: 2.8 mg, 46%) ). [Example 3] 3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-7-(5-(methylsulfonyl)porphyrin-1 -yl) The production of oxazolo[4,5-d]pyrimidine was carried out in the same manner as in Example 2 except that 2-chloro-5-ethylpyrimidine was used instead of 2,5-dichloropyrimidine, and an orange oil was obtained. Title compound. [Example 4] 3-(1-(5-Bromopyrimidin-2-yl)piperidin-4-yl)-7-(5-(methylsulfonyl)porphyrin-1 -yl)isoindole Production of oxazo[4,5-d]pyrimidine Using 5-bromo-2-chloropyrimidine instead of 2,5-dichloropyrimidine, the reaction was carried out in the same manner as in the second step of Example 2 to obtain a title as a white solid. Compound. [Example 5] 3-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)-7-(5-(methylsulfonyl)porphyrin-1-yl)isoxazole The production of [4,5-d]pyrimidine was carried out in the same manner as in Step 2 of Example 2, using 2-chloro-5-fluoropyrimidine instead of 2,5-di-pyrimidine. . [Example 6] 2-(4-(7-(5-(methylsulfonyl) porphyrin-1-yl)isoxazo[4,5-d]pyrimidin-3-yl)piperidine Manufacture of ethyl 1-yl)pyrimidine-5-carboxylate using ethyl 2-(decylsulfinyl)pyrimidine-5-carboxylate instead of 2,5-dichloropyrimidine, and step 2 of Example 2 The title compound was obtained as a pale yellow solid. 100134953 50

201217385 [Example 7] 2-(4-(7-(5-(methylsulfonyl) porphyrin-1-yl)isoxazo[4,5-d]pyrimidin-3-yl)piperidin Preparation of pyridin-1-yl)pyrimidine-5-carboxylic acid under argon, 2-(4-(5-(5-(indolylsulfonyl)) porphyrin-1-yl)isoxazole And [4,5-d]pyrimidin-3-yl)piperidin-1-yl)pyrimidine-5-carboxylic acid allyl ester (7 mg, 0.012 mmol). More than a bite (1 mg, 0.013 mmol) and tetrakis(triphenylphosphine)palladium (6 mg, 0.005 mmol) were dissolved in anhydrous N,N-didecylfurfural (0.5 mL) and stirred at room temperature for 2 hours. . Ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added, the organic layer was separated, and acetic acid was added to the aqueous layer to adjust the pH to 6. The title compound (2 mg, 32%) was obtained. [Example 8] 7-(5-(indolylsulfonyl)-pyroline-1-yl)-3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidine- Preparation of 4-yl)isoxazolo[4,5-d]pyrimidine using 2-(methylsulfinyl)-5-(trifluoromethyl)pyrimidine instead of 2,5-dichloropyrimidine The title compound was obtained as a pale yellow solid. [Example 9] 2-(4-(7-(5-(indolylsulfonyl)porphyrin-1-yl)isoxazo[4,5-d]pyrimidin-3-yl)piperidine Manufacture of -1-yl)pyrimidin-5-ol Step 1 : 7-(5-(indolylsulfonyl)porphyrin-1-yl)-3-(1-(5-(4,4,5) ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperidin-4-yl)isoxazo[4,5-d]pyrimidine Manufactured using 2-chloro-5-(4,4,5,5-tetradecyldioxaborolan-2-yl)pyrimidine instead of 2,5-dichloropyrimidine, and step 2 of Example 2 In the same way

S 100134953 51 201217385 The title compound was obtained as a yellow solid. Step 2: 2-(4-(7-(5-(methylsulfonyl)porphyrin·1-yl)iso 11 oxazolo[4 $pyrimidin-3-yl)piperidin-1-yl) The production of pyrimidine-5-ol will be 7-(5-(曱- 续 续 弓 朵 — — - tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2- )) piperidine _4_ yl) isopazole ^ [4,5-d] pyrimidine (13.4 mg, 0.023 mmol) dissolved in tetrahydrofuran mL), added 30% hydrogen peroxide water (50 call, at room temperature After collecting 4 small ^, adding sodium thiosulfate aqueous solution, extracting the organic layer with sodium chloride and extracting the organic layer, and then concentrating under reduced pressure, by (4) (4) Qing ^ layer ^ ^ imitation: methanol = 20: 1) The compound of the formula (2.6 mg, 23%) was obtained from the milky product. τ [Example 10] 3-(1-(5-Methoxypyrimidin-2-yl)piperidin-1)-pyridin-4-yl)-7-(5·(methyl sulphate)° α Doolin-1-based). Wait. Sit and [4,5-d]e dense η 定制制,生生2·(4_(Η5_(methyl continuation) t 七 七 七 七)) sit and sit [C bit-3-yl) bite · i-based) shot · 54 (1 〇. 〇 mg, 〇〇 17 mm 〇 i) dissolved in two anhydrous N, N-dimercaptocaramine (1 mL), deuterated carbonic acid unloading (5, 〇 〇36 mmol) and moth? Lang mg, 0,036 mmol), % min was given at room temperature. Adding water 'extracted with chloroform', anhydrous, sodium and drying the organic layer, and then reducing the concentration, and obtaining the residue obtained by the preparation of the thin layer chromatography (formation of methanol-%. 1) The title compound (28 mg, 31%) was obtained from white solid. [Example 11] </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; Pyrimidine was produced under the argon atmosphere, 7-(5-(methylsulfonyl) porphyrin-1-yl)-3-(1-(5-(4,4,5,5-four) Mercapto-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperidin-4-yl)isoxazo[4,5-d]pyrimidine (14.7 mg, 0.024 mmol), benzene (7.5 mg, 0.036 mmol), tetrakis(triphenylphosphine)! Bar (2.8 mg, 0.0024 mmol) dissolved in hydrazine, hydrazine-dimethyl decylamine (0.4 mL) and water (0.1 In the mL), sodium carbonate (5.1 mg, 0.048 mmol) was added and heated at 80 ° C for 2 hours. Water was added and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjjjjj ) is porphyrin-1-yl)-3-(1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)isoxazo[4,5-d]pyrimidine Made using 2-chloro-5-(trifluoromethyl) acridine 2,5-Dichloropyrimidine was reacted and treated in the same manner as in Step 2 of Example 2 to give the title compound as a pale yellow solid. [Example 13] 4-(7-(5-(nonylsulfonyl) Manufacture of porphyrin-1-yl)isoxazo[4,5-d]pyrimidin-3-yl)pyridin-1-carboxylic acid isopropyl ester 7-(5-(indolylsulfonyl) ) porphyrin-1-yl)-3-(piperidin-4-yl)iso. Isozo[4,5-d]flfn hydrochloride (4 mg, 0.011 mmol) dissolved in anhydrous dichloromethane Add chloropyridinium isopropylate (2 mg, 0.017 mmol) to the mixture (0.2 mL). After stirring for 20 minutes, add water and extract with chloroform. Dry with anhydrous sulphuric acid steel 100134953 53 201217385 After drying the organic layer, reduce (4) Reducing the residue obtained by (4) gel thin layer chromatography to obtain the title compound (3 mg, 64%) [yield 14] 4_(7-(5-(methylsulfonate) ) 哚 哚 哚 哚 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) In the same manner as in Example 13, the title compound was obtained as a pale yellow solid. [Example 15] 4-( 7-(5-(indolylsulfonyl)porphyrin-丨-yl)isoxazo[4,5-d]pyrimidin-3-yl)piperidine-1·carboxylic acid 2-fluoroethyl ester In the same manner as in Example 13, the title compound was obtained as a pale yellow solid. [Scheme 16] 4-(7-(5-(indolyl), hydrazine-hydrazino)iso-azolo[4,5-d]pyrimidin-3-yl)piperidine-1 - Preparation of 2-methoxyethyl carboxylate The title compound was obtained as a pale yellow solid. [Example 17] 4-(7-(5-(methyl-Rheinyl). 哚哚琳_ι_基)iso. No. Sit and [4,5-d]pyrimidin-3-yl) Preparation of pyridine--1-carboxylic acid tetrahydro-2H-pyran-4-yl vinegar using 4-nitrophenyl carbonate (tetrahydro-2H-pyran-4-yl ester) instead of isopropyl chloroformate The reaction was carried out in the same manner as in Example 13 to give the title compound. [Example 18] 2-(4-(7-(5-(indolylsulfonyl). porphyrin-丨-yl)isoxazolo[4,5-d]pyrimidin-3-yl)piperidin Manufacture of pyridine-1-yl)pyrimidine-5-carboxylic acid allyl g 100134953 54 201217385 Replacement of 2,5-dichloropyrimidine with allyl 2-(decylsulfinyl)pyrimidine-5-carboxylate The reaction was carried out in the same manner as in the step 2 of Example 2 to give the title compound. [Example 19] 4-(7-(5(methylsulfinyl)carinoxalin-1-yl)isoxazo[4,5-d]pyrimidin-3-yl)piperidin-1- The production of the third butyl carboxylate uses 5-(mercaptosulfinyl). In the same manner as in the step 10 of Example 1, the title compound was obtained as a yellow solid. [Example 20] 7-(5-(methylsulfinyl) porphyrin-1-yl)-3-(1-(5-(trifluoromethyl)acridin-2-yl)piperidin Preparation of pyridin-4-yl)isoxazo[4,5-d]pyrimidine Step 1: 7-(5-(indolylsulfinyl) porphyrin-1-yl)-3-(piperidine) -4-yl)isoxazolo[4,5-d]pyrimidine hydrochloride was prepared using 4-(7-(5(indolylsulfinyl)-pyridin-1-ylisoxazole [4,5-d]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester instead of 4-(7-(5-(indolylsulfonyl)porphyrin-1-yl)isoindole The butyl benzo[4,5-d]pyrimidin-4-yl)piperidine-1-carboxylic acid tert-butyl ester was reacted and treated in the same manner as in the step 1 of Example 2 to give the title compound as a yellow solid. 2 : 7-(5-(indolylsulfinyl) porphyrin-1-yl)-3-(1 -(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl The production of isoxazo[4,5-d]pyrimidine is carried out using 2-chloro-5-(trifluoromethyl)-pyridyl and 7-(5-(indenylsulfinyl) obtained in step 1. The porphyrin-1 -yl)-3-(piperidin-4-yl)isoxazo[4,5-d]pyrimidine hydrochloride replaces 2,5-dichloropyrimidine, and the procedure of Example 2 2 similarly carried out 100134953 55 201217385 reaction, The title compound was obtained as a yellow solid. [Example 21] 2,2-dimethyl-1-(4-(7-(5-(indolylsulfonyl))pyridin-1-yl) Production of oxazolo[4,5-d]pyrimidin-3-yl)piperidin-1-yl)propan-1-one was carried out in the same manner as in Example 13 except that pentyl chloride was used instead of isopropyl chloroformate. The title compound was obtained as a pale yellow solid. [Example 22] 4-(7-((2-fluoro-4-(methylsulfonyl)phenyl)amino)isoxazo[4] , 5-D-pyrimidin-3-yl)piperidine-1-carboxylic acid tert-butyl ester was produced by using 2-fluoro-4-(fluorenylsulfonyl)aniline instead of 5-(methylsulfonyl)anthracene The porphyrin was reacted and treated in the same manner as in the step 10 of Example 1 to give the title compound as a pale yellow solid. [Example 23] N-(2-fluoro-4-(methylsulfonyl)phenyl) Process for the preparation of 3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)isoxazo[4,5-d]pyrimidin-7-amine Step 1: N -(2-Fluoro-4-(methylsulfonyl)phenyl)-3-(piperidin-4-yl)isoxazo[4,5-d]pyrimidin-7-amine hydrochloride 4-(7-((2-Fluoro-4-(indolylsulfonyl)phenyl)amino)isoxazo[4,5-d]pyrimidin-3-yl) Instead of 4-(7-(5-(indolylxanthyl)porphyrin-1-yl)isoxazo[4,5-d]pyrimidin-4-yl)peridine, pyridine-1 -carboxylic acid tert-butyl ester The title compound was obtained as a yellow solid. The title compound was obtained as a yellow solid. Step 2: N-(2-Fluoro-4-(methylsulfonyl)phenyl)-3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl) The production of isoxazo[4,5-d]pyrimidin-7-amine using 2-(mercaptosulfinyl)-5-(trifluoromethyl)pyrimidine and the N-100100953 56 201217385 obtained in step 1 (2-fluoro-4-(fluorenylsulfonyl)phenyl)-3-(piperidin-4-yl)isoxazo[4,5-d]pyrimidin-7-amine hydrochloride instead of 2, 5-dichloropyrimidine was reacted and treated in the same manner as in the step 2 of Example 2 to give the title compound as a pale yellow solid. [Example 24] N-(2-Fluoro-4-(methylsulfonyl)phenyl)-3-(1-(5-(trifluoromethyl)pyridin-2-yl)acridin-4- Preparation of isoxazo[4,5-d]-7-amine using N-(2-fluoro-4-(methylsulfonyl)phenyl)-3-(piperidin-4-yl) Isoxazo[4,5-d]pyrimidin-7-amine hydrochloride replaces 7-(5-(indolylsulfonyl)porphyrin-1 -yl)-3-(piperidin-4-yl) Isoxazolo[4,5-d]pyrimidine hydrochloride, using 2-chloro-5-(trifluoromethyl)pyridine instead of 2,5-dichloropyrimidine, in the same manner as in step 2 of Example 2. The title compound was obtained as a yellow solid. [Example 25] 4-(7-((2-Fluoro-4-methylsulfonyl)phenyl)amino)isoxazo[4,5-d]pyrimidin-3-yl)piperidine- Preparation of 1-carboxylic acid 1,1,1-trifluoro-2-mercaptopropan-2-yl ester N-(2-fluoro-4-(methylsulfonyl)phenyl)-3-(piperidin Pyridin-4-yl)isoxazo[4,5-(1]'1 dimethylidene-7-amine hydrochloride (1〇111 吕,0.024 111111〇1) and 111-°米11 sit-1 - 1,1,1-trifluoro-2-mercaptopropan-2-yl carboxylate (10 mg, 0.048 mmol) was dissolved in anhydrous hydrazine, hydrazine-dimercaptofuraldehyde (0.2 mL), and N was added. N-diisopropylethylamine (10 mg, 0.072 mmol) was stirred at 80 ° C for 3 hours. The solvent was removed under reduced pressure and purified by preparative silica gel chromatography (chloroform: decyl alcohol = 20: 1) The title compound (7 mg, 53%) was obtained as a pale yellow amorphous material. [Example 26] 4-(7-((2-fluoro-4-indolylsulfonyl)phenyl)amino) Isocarbazole

S 100134953 57 201217385 [4,5-d]pyrimidin-3-yl)piperidine-1-carboxylic acid 2,2,2-trifluoroethyl ester Manufactured using 111-imidazole-1-carboxylic acid 2,2,2 -Trifluoroethyl ester was used in place of 111-imidazole-1-carboxylic acid 1,1,1-trifluoro-2-mercaptopropan-2-yl ester, and reacted and treated in the same manner as in Example 25 to obtain a pale yellow color. The title compound of the crystalline substance. [Example 27] 4-(7-((2-Fluoro-4-methylsulfonyl)phenyl)amino)isoxazo[4,5-d]pyrimidin-3-yl)piperidine- Preparation of 2-carboxylic acid 2,2,2-tri-ethane ethyl ester The use of 2,2,2-trichloroethyl chloroformate in place of isopropyl chloroformate was carried out in the same manner as in Example 13 to obtain a The title compound is a pale yellow solid. [Example 28] 4-(7-((2-Fluoro-4-methylsulfonyl)phenyl)amino)isoxazo[4,5-d]pyrimidin-3-yl)piperidine- The production of 1-carboxylic acid neopentyl ester was carried out by using the neopentyl chloroantimonate instead of isopropyl chloroformate, and the reaction was carried out in the same manner as in Example 13 to give the title compound. [Example 29] 4-(7-((2-Fluoro-4-methylsulfonyl)phenyl)amino)isoxazo[4,5-d]pyrimidin-3-yl)piperidine- Preparation of 1-carboxylic acid 4,4-difluorocyclohexyl ester using 1H-imidazole-1 -carboxylic acid 4,4-difluorocyclohexyl ester instead of 1H-imidazole-1 -carboxylic acid 1,1,1-trifluoro 2-methylpropan-2-yl ester was reacted and treated in the same manner as in Example 25 to give the title compound as yellow amorphous. [Example 30] 4-(7-((2-Fluoro-4-indolylsulfonyl)phenyl)amino)iso). Preparation of oxazolo[4,5-d]pyrimidin-3-yl)piperidine-1-carboxylic acid oxetane-3-yl ester using 4-nitrophenyl carbonate-oxetane- The 3-formyl ester was replaced with isopropyl chloroformate, and the reaction was carried out in the same manner as in Example 13 to give the title compound as a pale yellow solid 100134953 58 201217385. [Example 31] 4-(7-((2-fluoro-4-(indolylsulfonyl)phenyl)amino)isoxazo[4,5-d]pyrimidin-3-yl)piperidine Preparation of 1-carboxylic acid (3-mercapto oxetane-3-yl) decyl ester using (3-mercapto oxetane-3-yl) decyl carbonate (4-nitrophenyl ester) In the same manner as in Example 13, the title compound was obtained as a pale yellow solid. [Example 32] 4-(7-((2-Fluoro-4-methylsulfonyl)phenyl)amino)isoxazo[4,5-d]pyrimidin-3-yl)piperidine- The phenyl carboxylic acid phenyl ester was used to give the title compound as a pale yellow solid. [Example 33] 4-(7-((2-Fluoro-4-indolylsulfonyl)phenyl)amino)isoxazolo[4,5-d]pyrimidin-3-yl)piperidine- The production of 4-nitrophenyl carboxylic acid was carried out by using 4-nitrophenyl chloroformate instead of isopropyl chloroformate, and the title compound was obtained as a pale yellow solid. [Example 34] (4-(7-((2-fluoro-4-(fluorenylsulfonyl)phenyl)amino)isoxazolo[4,5-d]pyrimidin-3-yl)piperidin Preparation of pyridin-1-yl)(pyridin-2-yl)anthone by N-(2-fluoro-4-(indolylsulfonyl)phenyl)-3-(piperidin-4) under argon -yl)isoxazolo[4,5-d]pyrimidin-7-amine hydrochloride (11 mg, 0.027 mmol), 2-0 ratio of decanoic acid (4 mg, 0.032 mmol), 1-ethyl -3-(3-Diamylaminopropyl)carbodiimide hydrochloride (8 mg, 0.041 mmol) and hydrazine, hydrazine-dimercapto-4-amine group (1 mg) dissolved in anhydrous To dichlorohydrazine (0.6 mL), 100134953 59 201217385 triethylamine (12 // L, 0.081 mmol) was added and stirred overnight at room temperature. After adding water and extracting with chloroform, the organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the residue obtained was purified by preparative silica gel chromatography (chloroform: decyl alcohol = 20:1) to obtain a yellow solid. The title compound (2 mg, 14%). [Example 35] 4-(7-(4-(methylsulfonyl)phenoxy)iso-isoazolo[4,5-d]pyrimidin-3-yl)piperidine-1-carboxylic acid The production of tributyl ester was carried out by using 4-(methylsulfonyl) phenol instead of 5-(methylsulfonyl) η porphyrin, and reacting and treating in the same manner as in the step 10 of Example 1, to obtain a pale yellow oil. The title compound. [Example 36] 4-(7-(2-Fluoro-4-(indolylsulfonyl)phenoxy)isoxazo[4,5-d]pyrimidin-3-yl)piperidin-1- The production of the third butyl carboxylic acid was carried out in the same manner as in the step 1 of Example 1, except that 2-fluoro-4-(fluorenylsulfonyl) phenol was used instead of 5-(fluorenylsulfonyl)porphyrin. The title compound was obtained as a pale yellow oil. [Example 37] 4-(7-(4-(1Η-tetrazol-1-yl)phenoxy)isoxazo[4,5-d]pyrimidin-3-yl)piperidine-1-carboxylate The production of the acid tert-butyl ester was carried out by using 4-(1Η-tetrazol-1-yl)phenol instead of 5-(methylsulfonyl)porphyrin, and reacting and treating in the same manner as in the step 10 of Example 1. The title compound is a white solid. [Example 38] 4-(1-methyl-7-(5-(methylsulfonyl)porphyrin-1-yl)-1Η-pyrazolo[4,3-d]pyrimidine-3- Manufacture of tert-butyl piperidine-1-carboxylic acid tert-butyl ester Step 1: 4-(methoxy(indenyl)aminomethane) piperidine-1-carboxylic acid tert-butyl ester 100134953 60 201217385 1-(Tertibutoxycarbonyl)piperidine-4-furic acid (15 〇g, 65 4 mm〇1), N,0-dimethyl-transamine hydrochloride (8.3 g, 85.〇_ 〇1), ^ethyl_3_(3-diamidinopropyl)carbodiimide hydrochloride (16·3 g, 85.0 mmol) was dissolved in dichlorosilane (400 mL) in an ice bath Triethylamine (13.7 mL·, 98,1 mmol) and N,N-dimethylamine-based bite (〇8〇g, 6 54 leg 〇1) were added under cooling, at room temperature (iv). Water was added to the reverse slit, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified using a silica gel chromatography ( chloroform:methanol = 20:1) to give the title compound (17.7 g, 99% &gt; H-NMR (CDC13) δ: 1.46 ( 9H, s), 1.60-1.77 (4H, m), 2.77-2.89 (3H? m), 3.19 (3H, s), 3.72 (3H, s), 4.00-4.29 (2H, brs). Step 2 · 4 - acetamidylpiperidine·ι_carboxylic acid tert-butyl ester was produced under the argon atmosphere of '{4-methoxy(indenyl)amine sulfhydryl}piperidine-hydrazine-carboxylic acid second Butyl ester (17.7 g, 65.0 mmol) was dissolved in tetrahydrofuran (230 mL), and methylmagnesium bromide (87.1 mL, 112 m〇l/L of tetrahydrogen) was added to the ice bath. The mixture was stirred at room temperature for 4 hours, and the reaction mixture was quenched with a 30% aqueous solution of sodium potassium tartrate tetrahydrate, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained was purified using a silica gel chromatography (hexane: ethyl acetate = 5:1 - 3:1) to give 4-ethylmercaptopiperidin-1-carboxylate as a pale yellow oil.

S 100134953 61 201217385 Tert-butyl acid ester (14.23 g, 96%). 'H-NMR (CDC13) (5: 1.46 (9H, s), 1.49-1.58 (2H, m), 1.87-1.91 (2H, m), 2.17 (3H, s), 2.41-2.51 (1H, tt, J=3.7, 11.3 Hz), 2·79 (2H, t, J = 12.1 Hz), 3.98-4.22 (2H, m) Step 3: 4-(4-Ethoxy-3,4-di-side oxygen Preparation of tert-butyl hydrazide-l-carboxylic acid tert-butyl ester. Dissolving tert-butyl 4-ethenylpiperidine-1-carboxylic acid (1.2 〇g, 4.40 mmol) in tetrahydrofuran under argon atmosphere. (20 mL), add hexamethyldiazepine nitrogen-burning chain (7.27 mL ' 1.09 mol/L of hexane solution) at -78 °C, stir at 〇 °C for 1 day. In the reaction solution The mixture was stirred for 5 hours at room temperature, and the mixture was diluted with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried. After drying over sodium sulfate, the residue was evaporated. mjjjjjjjjjjjjj , 49%) H-NMR (CDC13) ^: 1.38 (3H, t, J = 7.2 Hz), 1.46 (9H, s), 1.52-1.68 (2H, m), 1.76-1.93 (2 H, m), 2.53 (1H, tt, J=3.7, 11.5 Hz), 2.79 (2H, t, J=12A Hz), 4.06-4.24 (2H, m), 4.36 (2H, q, J=7.2 Hz ), 6.41 (1H, s). Step 4 · 4-(1-methyl-7. oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-3-yl)piperidin Preparation of tert-butyl-1-carboxylic acid tert-butyl ester. (4-Ethoxy-3,4-dioxaoxybutanyl)piperidinecarboxylic acid tert-butyl ester 100134953 62 201217385 (100 mg '0.305 mmol) was dissolved in In acetic acid (1 mL), an aqueous solution (〇.5 1111^) of sodium nitrite (23.2 11^, 0.336 111111 〇1) was added dropwise at 10 〇. (;: 30 minutes of mixing. The reaction mixture was diluted and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4-(4-ethoxy-2-(hydroxyiamine). The crude form of the tert-butyl ester of piperidine-1-carboxylic acid. The obtained crude substance was dissolved in ethanol (1 mL), and methyl hydrazine (0.2 mL) was added to 〇〇c, and stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium disulfoxide was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue obtained was purified using a silica gel chromatograph (hexane: propyl g = 2: 1) to give 4-(4-amino-5-(ethoxymethyl hydrazino).仏 比 比 坐 基 基 基 a a a -1- -1- carboxylic acid tert-butyl ester and its isomer (26,8 mg). The obtained mixture (26.8 mg, 0.082 mmol) was dissolved in ethanol ( 2 mL) was added with A-methyl acetate (51.2 mg, 0.492 mmol) and heated to recover for 24 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel chromatography (hexane: hexane = 2.1). Residual, / check 'obtained a pale yellow amorphous 4_( 1 _ methyl-yl-7-sideoxy-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidine-3 -Based on the small carboxylic acid tert-butyl ester (9.7 mg, 10%). Further, the isomer 4-(2-mercapto-7-sideoxy-6) was obtained as a pale yellow amorphous substance. , 7-Dihydro-2H- ° ratio. Sodium [4,3-d]pyrimidin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (6.4 mg, 6%). [Product] ^- NMR (CDC13) δ : 1.47 (9H, s), 1.84-2.04 (4H, m)} 100134953 63 201217385 2.81-3.00 (2H, m), 3.19 (1H? tt, 1=3.8, 11.3 Hz), 4.21 ( 2H, brs), 4.26(3H, s), 7.78 (lH, d, Jr2.7Hz), l〇 .17(lH,brs). [isomer] ^-NMR (CDC13) δ : 1.49 (9H, s), 1.76-1.93 (2H, m)5 2.11-2.39 (2H, m), 2.79-2.92 ( 2H, 3.01-3.12 (1H, m), 4.12 (3H, s), 4.32 (2H, brs), 7.77 (1H, d, J=3.2 Hz), 10.88 (1H, brs) 0 Step 5: 4-( 7-((lH-Benzo[d][l,2,3]triazolyl)oxyl·1-methyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl)piperidin Manufacture of pyridine-1 -carboxylic acid tert-butyl ester 4-(1-methyl-7-sideoxy·6,7-dihydro_1Η_σ-pyrazolo[.-U.S. Decidine-1-deoxy acid tert-butyl ester (9.7 mg ' 〇.029 mmo1) and 1 Η benzotriazol-1-yloxy triparthrinyl hexafluorophosphate (16.6 mg, 0.032 mmol) Dissolved in tetrahydrofuran (丨mL), added 1,8-diazabicyclo[5,4,0]-7-e11 (5.2 //L, 0.03 5 mmol), taxed at room temperature for 1 day Inch. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The title compound (7.6 mg, 58%) obtained as a pale yellow amorphous material was obtained by chromatography (yield: methanol = 10 ··1). ^-NMR (CDCI3) δ : 1.49 (9H, s), 1.92-2.06 (2H, m), 2.06-2.16 (2H, m), 2.86-3.07 (2H, m), 3.38 (1H, tt, J= 3.8, 11.5 Hz), 4.25 (2H, brs), 4.46 (3H, s), 7.46-7.53 (2H, m), 7,56-7,62 (1H,m), 8.12 (1H, d,J= 8.3 Hz), 8.36 (1H, s). 100134953 64 201217385 Step 6 : 4-(1-Methyl-7-(5-(methylsulfonyl) porphyrin-1-yl)-1Η-pyrazino[4,3-(1]'5密定-3-基)Brigade bite_1_Manufacture of tartary acid tert-butyl ester 4-(7-((1Η-benzo[d][1,2,3]triazol-1-yl)) Oxy)-1-indolyl-indole_%. Sodium(4,3-d)pyrimidin-3-yl)piperidine-1-furic acid tert-butyl ester (7.6 mg, 〇·〇 17 mmol) and 5 -(Methylsulfonyl) π porphyrin (4 5 , 0.023 mmol) dissolved in N,N-dimethylformamide (1 mL) 'Add sodium hydride (5 〇〇 / 〇 in oil) 2,5 mg, 0.058 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained was purified using a silica gel layer (hexane: acetone = 3: 2) to give the title compound (7.3 mg, 84%) as pale yellow amorphous. The compound obtained by the above examples is shown in Tables 1 to 8. 100134953 65 201217385 [Table 1] Example Structural Properties 1 Ή-NMR (CDCI3) 5: 1.49 (9H, s), 1.98 (1H. dd, J = 3.9, 12.2 Hz), 2.04 ( 1H, dd, J = 3.9, 11.7 Hz), 2.13-2.23 (2H, m), 2.97-3.12 (2H, m), 3.07 (3H, s), 3.33-3.49 (1H, m), 3.45 (2H, t, J = 8.5 Hz), 4.16-4.31 (2H, m), 4.83 (2H, t, J = 8.8 Hz), 7.83 (1H, s), 7.88 (1H, d, J = 8.8 Hz), 8.78 (1H. s) , 8.82 (1H. d, J = 8.8 Hz). 2 Ή-NMR (CDCI3) δ: 2.04-2.13 (2H, m), 2.23-2.31 (2H, m), 3.07 (3H, s). 3.16-3.23 (2H, m), 3.42-3.53 (1H, m), 3.44 (2H, t. J = 8.5 Hz), 4.79-4.86 (4H, m), 7.83 (1H, s), 7.88 (1H, dd, J = 2.0, 8.8 Hz), 8.24 (2H, s), 8.78 (1H. s), 8.82 (1H, d, J = 8.8 Hz). 3 'H-NMR (CDCI3) 5: 1.20 (3H, t, J = 7.6 Hz). 2.06-2.12 (2H, m), 2.27-2.30 (2H, m), 2.48 (2H, q, J =7.5 Hz), 3.07 (3H, s), 3.15-3.18 (2H, m) 3.40-3.53 (2H, m), 4.77-4.89 (2H.m), 4.82 (2H, t, J = 8.8 Hz), 7.82 (1H, s), 7.88 (1H, d, J = 8.8 Hz), 8.20 (2H, s), 8.78 (1H, s), 8.82 (1H, d, J = 8.8 Hz). 4 Ή-NMR (CDCI3) δ : 2.05 (1H, dd, J = 3.4, 12.2 Hz), 2.11 (1H. dd, J = 3.9. 11.7 Hz). 2.24-2.32 (2H, m). 3.07 (3H, s), 3.13-3.24 (2H, m), 3.44 (2H, t, J = 8.8 Hz), 3.47-3.57 (1H, m), 4.77-4.87 (4H , m), 7.83 (1H, s), 7.88 (1H, dd, J = 2.0, 8.8 Hz), 8.31 (2H. s), 8.78 (1H, s). 8.82 (1H, d, J = 8.3 Hz) 5 Meo^^A?vc^N&gt;F Ή-NMR (CDC!3) 6: 2.06 (1H, dd, J = 3.4, 12.7 Hz), 2.12 (1H, dd, J = 4.4, 11.7 Hz), 2.23-2.32 (2H. m), 3.07 (3H, s), 3.13-3.23 (2H. m). 3.41-3.55 (3H, m), 4.76-4.87 (4H, m). 7.83 (1H, s), 7.88 (1H, dd, J = 2.0, 8.8 Hz), 8.22 (2H, s), 8.78 (1H, s), 8.82 (1H, d, J = 8.8 Hz). 66 100134953 201217385 [Table 2] Example construction Physical property values 6 Ή-NMR (CDCI3) δ: 1.39 (3Η, q, J = 7.6 Hz), 2.02-2.19 (2H, m), 2.27-2.39 (2H, m), 3.07 (3H, s), 3.27 -3.31 (2H, m). 3.44 (2H, t J = 8.5 Hz), 3.51-3.61 (1H, m), 4.35 (2Ht q, J = 7.2 Hz), 4.83 (2H, t, J = 8.5 Hz) , 4.94-5.07 (2H, m), 7.83 (1H, s), 7.88 (1H, d, J = 8.3 Hz), 8.78 (1H, s), 8.82 (tH, d, J = 8.8 Hz). 8.86 ( 2H, s). 7 M&quot;^^rCN^&gt;c〇2H Ή-NMR (DMSO-D6) δ\ 1.89-2.02 (2H, m), 2.19-2.27 (2H, m). 3.19 (3H. s 3.28-3.43 (4H, m), 3.57-3.66 (1H, m), 4.77 (2H, t, J = 8.5 Hz), 4.80-4.89 (2H, m). 7.83-7.86 (2H, m), 8.72 (1H, d, J = 8.8 Hz), 8.78 (1H, s), 8.79 (2H, s). 8 Ή-NMR (CDC!3) &lt;5: 2.07 (1H, dd, J = 3.9, 11.7 Hz). 2.13 (1H, dd, J = 3.9, 11.7 Hz), 2.26-2.36 (2H, m), 3.07 (3H, s), 3.23-3.32 (2H, m). 3.45 (2H, t, J = 8.5 Hz), 3.50-3.61 (1H, m), 4.83 (2H, t, J = 8.8 Hz), 4.91-5.00 (2H. m), 7.83 (1H, s). 7.88 (1H, dd, J = 2.0, 8.8 Hz) , 8.51 (2H, s), 8.79 (1H, s), 8.82 (1H. d, J = 8.8 Hz). 9 Ή-NMR (CDCI3) &lt;5: 1.99-2.16 (2H, m), 2.22-2.34 (2H, m), 3.07 (3H, s), 3.09-3.22 (3H, m), 3.38-3.57 (5H, m), 4.66-4.79 (2H, m), 4.83 (2H, t, J = 8.5 Hz ), 7.82 (1H. s), 7.88 (1H, d, J = 9.3 Hz), 8.10 (2H. s). 8.78 (1H, s). 8.82 (1H, d, J = 8.8 Hz). 10 ΜΘ° ^^^ν〇ΝΛ&gt;〇Μβ Ή-NMR (CDCI3) δ: 2.06 (1H, dd, J = 4.4, 12.2 Hz), 2.12 (1H, dd, J = 4.4, 12.2 Hz), 2.24-2.33 (2H , m), 3.07 (3H, $), 3.11-3.20 (2H, m), 3.44 (3H, t, J = 8.5 Hz), 3.45-3.55 (1H, m), 3.82 (3H, s), 4.70- 4.80 (2H, m), 4.83 (2H, t, J = 8.5 Hz), 7.82 (1H, s), 7.88 (1H, d, J = 10.2 Hz), 8.12 (2H, s), 8.78 (1H, s ), 8.82 (1H, d, J = 8.8 Hz) 67 100134953 201217385 [Table 3] Example Structural property value 11 Ή-NMR (CDCg &lt;5: 2.10 (1H, dd, J = 3.9, 12.2 Hz). 2.16 (1H, dd. J = 12.2. 3.9 Hz ), 2.28-2.37 (2H.m), 3.07 (3H, s), 3.20-3.32 (2H, m), 3.44 (2H, t, J = 8.8 Hz), 3.55 (1H, m), 4.83 (2H, t, J = 8.8 Hz), 4.90-4.99 (2H, m), 7.35 (1H, t J = 7.1 Hz), 7.42-7.52 (5H, m), 7.83 (1H, s), 7.88 (1H, dd, J = 1.2, 8.5 Hz), 8.58 (2H. s), 8.79 (1H, s), 8.83 (1H, d, J = 8.8 Hz). 12 Ή-NMR (CDCI3) &lt;5: 2.05-2.20 (2H , m), 2.24-2.37 (2H, m), 3.07 (3H, s), 3.17-3.28 (2H, m), 3.45 (2H, t J = 8.5 Hz), 3.48-3.59 (1H, m), 4.48 -4.58 (2H, m), 4.83 (2H, t. J = 8.5 Hz), 6.72 (1H. d, J = 9.3 Hz), 7.64 (1H, dd, J = 2.4, 9.3 Hz), 7.82 (1H, s). 7.88 (1H, d, J = 8.3 Hz), 8.41 (1H, s), 8.78 (1H, s), 8.82 (1H, d, J = 8.8 Hz). 13 μΆνΧ^〇疋乂Ή-NMR (CDCI3) δ : 1.27 (6H, d. J = 6.3 Hz), 1.99 (1H, dd, J = 4.1. 12.0 Hz), 2.06 (1H, dd, J = 4.1, 12.0 Hz), 2.13-2.27 (2H m), 2.93-3.07 (2H, m), 3.07 (3H, s), 3.35-3.42 (1H, m), 3.45 (2Ht t, J = 8.8 Hz), 4.20-4.38 (2H, m), 4.83 (2H, t, J = 8.5 Hz), 4.90-4.99 (1H, m). 7.83 (1H. s). 7.88 (1H, d, J = 8.8 Hz ), 8.78 (1H, s), 8.82 (1H, d, J = 8.3 Hz). 14 乂' Ή-NMR (CDCI3) &lt;5: 1.29 (3H, t. J = 7.1 Hz), 2.01 (1H, Dd, J = 4.1, 12.4 Hz), 2.07 (1H, dd, J = 4.1, 12.4 Hz), 2.15-2.25 (2H, m), 2.97-3.10 (3H, m), 3.07 (3H, s), 3.34 -3.43 (3H, m), 3.45 (3H, t, J = 8.5 Hz), 4.17 (2H, q, J = 7.2 Hz), 4.22-4.39 (2H, m), 4.83 (2H, t. J = 8.5 Hz), 7.83 (1H, s), 7.88 (1H, d. J = 8.8 Hz), 8.78 (1H, d, J = 1.0 Hz), 8.82 (1H, d, J = 8.8 Hz). 15 Ή-NMR (CDCIj) «5: 2.00-2.13 (2H. m), 2.16-2.28 (2H, m), 3.03-3.16 (2H, m), 3.07 (3H, s), 3.36-3.49 (5H, m), 4.43 -4.25 (3H, m), 4.41 (1H. s), 4.57 (1H, t, J = 4.1 Hz), 4.69 (1H, t, J = 4.1 Hz), 4.83 (2H, t, J = 8.5 Hz) , 7.83 (1H, s), 7.88 (1H, dd, J = 8.3, 2.0 Hz), 8.78 (1H, s), 8.82 (1H, d, J = 8.8 Hz). 68 100134953 201217385 [Table 4] Example Structural property values 16 Ή-NMR (CDCI3) δ: 1.95-2.11 (2Η, m), 2.15-2.25 (2H, m), 3.00-3.14 (2H, m), 3.07 (3H, s), 3.36-3.43 (1H. m). 3.41 (3H, s). 3.45 (2H, t, J = 8.5 Hz), 3.63 (2H, t J = 4.6 Hz), 4.21-4.38 (4H, m), 4.83 ( 2H, t, J = 8.5 Hz), 7.83 (1H, d, J = 1.5 Hz), 7.88 (1H, dd, J = 8.8, 2.0 Hz), 8.77 (1H. s), 8.82 (1H. d. J = 8.8 Hz). 17 &gt;H-NMR (CDCI3) &lt;5: 1.65-1.76 (2H, m), 1.93-2.10 (4H, m), 2.16-2.26 (2H, m), 3.00-3.16 (2H , m), 3.07 (3H, s), 3.35-3.49 (3H, m), 3.53-3.64 (2H, m), 3.87-3.96 (2H, m), 4.21-4.36 (2H. m). 4.83 (2H , t, J = 8.8 Hz), 4.87-4.95 (1H, m), 7.83 (1H, d, J = 1.5 Hz). 7.88 (1H, dd, J = 2.0, 8.8 Hz), 8.78 (1H, s) , 8.82 (1H, d. J = 8.8 Hz). 18 Ή-NMR (CDCI3) d: 2.05-2.20 (2H, m), 2.27-2.36 (2H, m), 3.07 (3H, s), 3.25-3.34 (2H, m). 3.44 (2H, t, J = 8.8 Hz), 3.52-3.61 (1H, m), 4.76-4.88 (4H, m), 4.97-5.06 (2H, m), 5.25-5.45 (2H , m), 5.95-6.09 (1H, m), 7.82 (1H, s)t 7.88 (1H, dd, J = 2.0, 8.8 Hz), 8.78 (1H, s), 8.82 (1H, d, J = 8.8 Hz), 8.88 (2H, s). 19 Ή-NMR (CDCI3) ά: 1.48 (9H, s), 1.97 (1H, dd, J = 4,1, 12.0 Hz), 2.03 (1H, dd. J = 4.1, 12.0 Hz), 2.13-2.22 (2H, m ), 2.50 (3H, s), 2.92-3.07 (2H, m), 3.28-3.40 (3H, m), 4.14-4.29 (2H, m), 4.71 (2H, t, J = 8.5 Hz), 7.20- 7.22 (2H, m), 8.58 (1H, d, J = 9.3 Hz), 8.66 (1H, s). 20 Ή-NMR (CDCI3) 6: 2.06-2.18 (2H, m), 2.28-2.38 (2H, m), 2.50 (3H, s), 3.22 (2H, t J = 11.7 Hz), 3.34 (2H, t, J = 8.3 Hz), 3.46-3.55 (1H, m), 4.49-4.57 (2H, m) , 4.72 (2H, t, J = 8.3 Hz), 6,71 (1H, d, J = 8.8 Hz), 7.17-7.25 (2H, m), 7.64 (1H, d, J = 8.8 Hz), 8.41 ( 1H, s). 8.59 (1H, d, J = 8.3 Hz), 8.68 (1H, s). 100134953 69 s 201217385 [Table 5] Example Structural property value 21 'H-NMR (CDCIj) δ: 1.33 ( 9H, s), 1.97-2.09 (2H, m), 2.21-2.29 (2H, m). 3.04-3.19 (2H, m), 3.07 (3H, s), 3.39-3.53 (3H, m), 4.57- 4.47 (2H, m), 4.82 (2H, t, J = 8.5 Hz), 7.83 (1H, dr J = 1.5 Hz), 7.88 (1H. dd. J = 2.0, 8.8 Hz). 8.77 (1H, s) , 8.82 (1H, d. J = 8.3 Hz). 22 F Π 0, Ν Ή-NMR (CDCI3) 6 : 1.49 (9H, s), 2.00 (1H, dd, J = 3.9, 12.2 Hz), 2.06 ( 1H, dd, J = 3.9, 12.2 Hz), 2.14 - 2.21 (2H, m), 2.94-3.09 (3H, m). 3.10 (3H. s), 3.35-3.44 (1H, m), 4.08-4 .40 (2H, m). 7.59-7.66 (1H, m), 7.80 (1H, dd, J = 2.0, 10.2 Hz), 7.84 (1H, d, J = 8.8 Hz), 8.81 (1H, s), 9.05 (1H, t, J = 8.3 Hz). 23 F 〇, N Ή-NMR (CDCIa) &lt;5: 2.05-2.17 (3H. m), 2.27-2.35 (2H, m), 3.10 (3H. s ), 3.22-3.32 (2H, m). 3.52-3.63 (1H, m), 4.93-5.01 (2H, m), 7.61 (1H, br s), 7.80 (1H, dd, J = 2.2, 10.2 Hz) , 7.84 (1H, d, J = 8.8 Hz), 8.51 (2H, s), 8.82 (1H, s). 9.05 (1H. t, J = 8.3 Hz). 24 Ή-NMR (CDCI3) 5: 2.12 ( 1H, dd, J = 3.2, 12.0 Hz), 2.18 (1H, dd, J = 3.2, 12.0 Hz), 2.25-2.42 (2H, m), 3.10 (3H, s), 3.22 (2H. t, J = 11.5 Hz), 3.51-3.58 (1H, m), 4.50-4.59 (2H, m), 6.72 (1H, d, J = 9.3 Hz), 7.57-7.69 (2H, m). 7.80 (1H, d, J = 10.2 Hz), 7.84 (1H, d, J = 8.8 Hz), 8.41 (1H, s), 8.82 (1H, s), 9.05 (1H, t, J = 8.0 Hz). 25 'H-NMR (CDCI3 6: 1.72 (6H, s). 1.99-2.14 (2H, m), 2.16-2.30 (2H, m), 3.03-3.10 (2H, m), 3.10 (3H, s), 3.38-3.45 (1H, m), 4.09-4.30 (2H, m), 7.62 (1H, br s), 7.80 (1H, d. J = 10.2 Hz), 7'84 (1H, d, J 9.3 Hz), 8.81 (1H, s), 9.04 (1H, t, J = 8.0 Hz). 70 100134953 201217385 [Table 6] Example Structural property value 26 Ή-NMR (CDCI3) δ: 2.04-2.15 (2H, m), 2.19-2.28 (2H, m), 3.10 (3H, s), 3.11-3.24 (2H, m). 3.40-3.49 (1H, m). 4.17-4.37 (2H. m), 4.45-4.58 (2H, m), 7.64 (1H, br s), 7.80 (1H, dd. J = 1.7, 10.0 Hz), 7.84 (1H, d, J = 8.8 Hz), 8.81 (1H, s), 9.04 (1H, t, J = 8.0 Hz). 27 Me〇2Sv^ N^N 〇F ° 'N c / Ή-NMR (CDCI3) δ: 2.06-2.19 (2H, m), 2.21-2.30 (2H. m), 3.06-3.26 (2H, m), 3.10 (3H, s), 3.42-3.51 ( (2H, m, 3.4 Hz) 2H. d, J = 9.3 Hz). 8.81 (1H, s). 9.05 (1H, t, J = 8.0 Hz). 28 F Π 0, N / Ή-NMR (CDCI3) 6: 0.97 (9H, s) , 1.98-2.12 (2H, m). 2.16-2.26 (2H. m). 3.02-3.09 (2H. m). 3.10 (3H, s), 3.40-3.45 (1H. m), 3.82 (2H, s) , 4.25-4.34 (2H, m), 7.61 (1H, br s), 7.80 (1H, dd, J = 2.0, 9.8 Hz), 7.82-7.87 (1H. m), 8.81 (1H, s), 9.05 ( 1H, t, J = 8.3 Hz). 29 Ή-NMR (CDCIj) 6: 1.89-2.13 (11H, m), 2.17-2.26 (2H, m). 3.01-3.08 (2H, m), 3.10 (3H, 5), 3.38-3.47 (1H, m), 4.15-4.39 (2H, m), 4.86-4.97 (1H, m), 7.80 (1H, dd, J = 2.2, 10.0 Hz), 7.84 (1H , d, J = 8.8 Hz), 8.81 (1H, s), 9.04 (1H, t, J = 8.0 Hz). 30 FM 〇, N Ή-NMR (CDCI3) δ: 1.95-2.16 (2H, m), 2.19-2.27 (2H, m), 3.06-3.20 (5H.m), 3.40-3.48 (1H, m), 4.24-4.33 (2H, m), 4.65-4.73 (2H. m), 4.92 (2H, t , J = 7.1 Hz), 5.39-5.48 (1H, m), 6.90 (1H, d, J = 9.3 Hz), 7.65 (1H, br s), 7.80 (1H, dd, J = 2.2, 10.0 Hz), 7.84 (1H, d. J = 9.3 Hz), 8.16 (1H. d, J = 9.3 Hz), 8.82 (1H, s), 9.04 (1H, t, J = 8.0 Hz).

S 100134953 71 201217385 [Table 7] Example Structural property value 31 匕0 Ή-NMR (CDC!3) δ: 1.36 (3H, s), 2.00-2.14 (2H, m), 2.16-2.28 (2H, m ), 2.97-3.20 (4H, m), 3.38-3.49 (1H. m), 4.19 (2H, s), 4.30 (2H, br s). 4.41 (2H, d, J = 5.9 Hz), 4.55-4.64 (2H, m), 7.72 (1H, br s), 7.79 (2H, dd, J = 1.7, 10.0 Hz), 7.84 (3H, d, J = 8.8 Hz), 8.81 (1H, s), 9.02 (1H , t, J = 8.0 Hz). 32 _W〇切Ή-NMR (CDCI3) δ: 2.10-2.33 (4H, m), 3.10 (3H, s). 3.12-3.36 (2H, m), 3.43-3.55 ( 1H, m), 4.34-4.51 (2H, m), 7.12-7.16 (2H, m), 7.18-7.24 (1H. m), 7.34-7.41 (2H, m), 7.66 (1H, br s), 7.80 (1H, dd, J = 10.0, 2.2 Hz), 7.82-7.87 (1H, m). 8.83 (1H, s), 9.03 (1H, t, J = 8.0 Hz). 33 1H~NMR (CDC13) 5: 2.12-2.35 (4H, m), 3.11 (3H, s), 3.20 (1H, t J = 12.0 Hz), 3.34 (1H, t, J = 12.0 Hz), 3.48-3.55 (1H, m), 4.35- 4.44 (2H, m), 7.33 (2H, d, J = 9.3 Hz), 7.67 (1H. br s), 7.80 (1H, d, J = 10.2 Hz), 7.85 (1H, d, J = 8.8 Hz) , 8.27 (2H, d. J = 7.8 Hz), 8.83 (1H, s), 9.04 (1H, t, J = 8.0 Hz). 34 Me02S^^ N^N q Ή-NMR (CDCI3) 6: 2.14-2.26 (3H. m), 2.34-2.42 (1H, m), 3.10 (3H, s), 3.13-3.24 (1H. m), 3.30-3.42 (1H, m), 3.45-3.62 (1H , m), 4.10-4.20 (1H, m), 4.77-4.87 (1H, m). 7.30-7.38 (1H, m), 7.62 (1H, br s), 7.68 (1H, dd, J = 1.0, 7.8 Hz), 7.77-7.87 (3H, m), 8.61 (1H, dd, J = 1.0, 4.9 Hz), 8.81 (1H, s). 9.05 (1H. t, J = 8.0 Hz). 35 ON Ή-NMR (CDCI3) δ: 1.49 (9H, s), 1.98-2.11 (2H, m), 2.13-2.25 (2H, m), 2.92-3.04 (2H, m), 3.12 (3H, s), 3.36-3.48 ( 1H, m). 4.18-4.33 (2H, m), 7.53 (2H, d, J = 8.8 Hz), 8.09 (2H,d, J = 8.8 Hz), 8.69 (1H, s). 72 100134953 201217385 [Table 8] Example Structural property value 36 Ή-NMR (CDCI3) &lt;5: 1-48 (9H. s), 1.63-1.76 (2H, m). 2.14-2.17 (2H.m). 2.84-2.99 ( 2H, m). 3.01-3.12 (1H, m), 3.08 (3H, s), 4.12-4.37 (2H, m). 7.41 (1H, d, J = 3.4 Hz), 7.64 (1H, s), 7.75 (1H, dd. J = 2.2. 10.0 Hz), 7.81 (1H, d, J = 7.8 Hz), 8.75 (1H, s), 9.08 (1H. t, J = 8.0 Hz). 37 Ή-NMR (CDCI3 δ: 2.06-2.20 (2H. m), 2.26-2.37 (2H, m). 2.50 (3H. s), 3.17-3.28 (2H, m), 3.34 (2H, t, J = 8.3 Hz), 3.46 -3.58 (tH, m), 4.48-4.57 (2H, m), 4.72 (2H, t, J = 8.3 Hz). 6.71 (1H. d. J = 8.8 Hz), 7.21-7.23 (2H, m), 7.64 (1H, d, J = 8.8 Hz), 8.41 (1H, s), 8.59 (1H, d, J = 8.3 Hz), 8.68 (1H, s). 38 Ή-NMR (CDCI,) δ: 1.49 ( 9H. s), 1.93-2.06 (2H, m), 2.08-2.17 (2H, m), 2.93-3.04 (2H, m), 3.05 (3H, s), 3.31 (2H, t, J — 8.0 Hz) , 3.34~3.43 (1H, m). 3.92 (3H. s), 4.25 (2H. brs), 4.38 (3H. t, J = 8.0 Hz), 6.78 (1H, d. J = 8.5 Hz), 7.70 ( 1H, d, J = 8.5 Hz), 7.82 (1H, s), 8.73 (1H, s).

[Test Example 1] Insulin-promoting effect Hamster pancreatic cell line HIT-T15 cells were subcultured using Ham, s F_12K medium containing penicillin (100 units/mL) and streptomycin (100 and 10% fetal bovine serum). The cells were seeded on a 24-well culture dish, and after 48 hours of culture, the cells were washed with KRBH buffer containing 1% albumin, and then allowed to stand at 37 ° C for 1 hour in the same buffer. Glucose is added in a manner of 2 mM, and further added at a concentration of 0.1% by volume in the buffer to each concentration (in terms of a ratio of 10, from 〇 = 〇 1 to 1 〇 / / 财) The compound of the present invention is dissolved in a concentration by using dimethyl hydrazine. After the compound of the present invention is added, it is allowed to stand in Pi for 1 day, and then the insulin solution kit (SCET Medical Co., Ltd.) is used to measure 2 100134953 73 201217385. The insulin concentration was measured using a hamster insulin standard solution (SHIBAYAGI Co., Ltd.) in the standard solution, and only dimethyl hydrazine was added to the control group. The result was 50% effect concentration (EC5. value, of each test compound). 50% e The form of the ffect concentration is shown in Table 2. Further, the EC50 value was calculated using a statistical analysis program and SAS Preclinical Package Ver 5.0 (SAS institute Japan Co., Tokyo). [Table 9] Example No. ECSft (nM) 1 16. 0 2 58. 5 3 20. 5 8 13. 0 10 12. 1 11 27. 7 13 65. 8 14 54. 7 22 18. 1 23 13. 2 24 6. 5 25 31. 0 27 17 8 28 73. 9 35 89. 7 36 5. 0 It is known from the above that the compound of the present invention has a strong insulin-promoting effect. (Industrial Applicability) The formula (1) of the present invention The travel bite derivative or a salt thereof, or a solvate thereof, has industrial applicability because it has an excellent insulin-promoting action and is used for prevention and/or treatment of diabetes in the pre-treatment of 100134953 74 vS 201217385.

S 100134953 75

Claims (1)

201217385 VII. Patent Application Range: 1. A compound or a salt thereof, or a solvate thereof, which is represented by the following formula (1): [Chemical Formula 1] (1) [wherein A and B represent a nitrogen atom, and the other represents a nitrogen atom or a position where R 8 represents a hydrogen atom, a halogen sulfonium group, a genus, a C6 alkyl group, a C 6 alkoxy group, a group Or a nitro); , a halogen atom, a halogen atom, D represents a nitrogen atom or CR9 (wherein R9 represents a hydrogen atom Cl_6 alkyl group, an alkoxy group, an amine group or a nitro group); and E represents a nitrogen atom or CR10 ( Here, 'rI〇 denotes a hydrogen atom Cl_6 alkyl group, a Cl.6 alkoxy group, an amine group or a nitro group); a sulfur atom 'R}1 and R12 X represents an oxygen atom -(CH2)n-CH(R12)· (wherein the base 'η denotes 〇 or j); , -(CHJn-iv^R11)- or respectively denote a hydrogen atom or q_6 Y denotes an oxygen atom, a spar atom or a nitrogen atom; Ζ denotes an oxygen atom, a sulfur atom or a nitrogen Atom; Ck6 alkyl, Cl_6 R1 and R3 divided into a hydrogen atom, dentate atom 100134953 76 201217385 alkoxy, amine or nitro* or R1 and R11 or R1 and R12 may also form a heterocyclic ring; R2 Represents a hydrogen atom, -S(0)R13, -S(0)2R14, -C02R15 or -CONR16R17, an aryl group, a heteroaryl group (here, R13 and R14 are separately |J represents a Cm alkyl group, a C3_8 cycloalkyl group , C2_6 alkenyl group, C2_6 alkynyl group, C6_1Q aryl group which may have a substituent, an amine group, a mono((6-alkyl)amino group or a di(CV6 alkyl)amino group, R15 represents a Cu alkyl group, and R16 and R17 respectively Independently represents a hydrogen atom or a Ci_6 alkyl group which may have a substituent; R4 represents a hydrogen atom, a halogen atom, a Cu alkyl group, a Cu alkoxy group, a (^_6 fluorenyl fluorenyl group or an amine group; and R5 and R6 each independently represent hydrogen Atom or CV6 alkyl; R7 represents Ck alkyl, -C(0)R18, -C(S)R19, -S(0)2R2G, C6_1G aryl which may have a substituent or 5-10 which may have a substituent a heteroaryl group (herein, R18 represents a Cu alkyl group which may have a substituent, a Cm alkoxy group which may have a substituent, a C2_6 alkenyloxy group which may have a substituent, and a C6_1() aryl group which may have a substituent An oxy group, a C6_1Q aryl C1-6 alkoxy group which may have a substituent, a C3_8 cycloalkyloxy group which may have a substituent, a heterocyclic oxy group which may have a substituent, and 5-10 members which may have a substituent An aryl or a mono(Ci_6 alkyl)amino group, and R19 and R2G each represent a Cu alkyl group, a halogenated CK6 alkyl group, a C3-8 cycloalkyl group, a mono(Cy alkyl)amino group, a C6_1G aryl group which may have a substituent or Have a substitution 5-10 member heteroaryl)] 2. A compound according to claim 1 or a salt thereof, or a solvent thereof, 100134953 77 201217385, wherein R1 and R11 or R1 and R12 form a heterocyclic ring Is selected from the following formula: [Chemical 2] [wherein R21 represents a hydrogen atom, &lt;^_6 alkyl, -C(0)R22 or -S(0)2R23 (wherein R22 and R23 represent a CV6 alkyl group, a C3_8 cycloalkyl group, respectively), a wavy line Partially denotes an aromatic ring composed of D and E]. 3. The compound of claim 1 or a salt thereof, or a solvate thereof, wherein R1 and R11 or R1 and R12 are formed together with a heterocyclic ring selected from the group consisting of: 0. The compound of claim 1 or a salt thereof, or a solvent thereof, 100134953 78 201217385, which is represented by the following formula (la): [Chemical 4] (la) 5. The scope of the patent application, wherein 'R1 is a hydrogen atom amine group or &gt; 6 Schottky group. A compound or a salt thereof, or a solvate thereof, an alkyl group, a Ci6 alkoxy group, or a compound of the formula or a salt thereof, or a solvate thereof, which is represented by the following formula ( Lb) means: mouth [5] In the formula, R1 represents a hydrogen atom, a dentate atom, a Cl-6 alkyl group, a fluorene16 alkoxy group, an amine group or a nitro group, and r2 to r7 are the same as defined above. 7. A compound according to claim 1 or a salt thereof, or a solvate thereof, which is selected from the group consisting of 4-(7-(5-(indolylsulfonyl)).啉 丨 丨 基 基 。 4 4 [4,5_d]pyrimidinyl) piperidine carboxylic acid tert-butyl, 3-(1-(5-amphetyl-2-yl)piperidine 100134953 79 S 201217385 -7-(5-(methylsulfonyl)porphyrin_丨_yl)iso-sigma-azolo[4,5-pyrimidine, 3-(1-(5-ethylpyridine)_2 _yl)pyridinium I))_7_(5_(methylsulfonylpyridin-1-yl)iso-azolo[4,5-d]pyrimidine, 3-(1-(5-bromopyrimidine) 2-yl) piperidine_4_yl)-7-(5-(methylsulfonyl)porphyrin_丨_yl)isos and the like oxazo[4,5-d]pyrimidine, 3-(1_(5- Fluoropyrimidin-2-yl)piperidinyl)_7_(5-(methylsulfonyl)porphyrin-1-yl)iso-sand[4,5-d] shot, 2_(4_(7_(5_( Methyl continuation of the base of the singularity of the base of the sylvestre and the [4,5-d] pyridinium -3 base) brigade. Ding + base) _5_ acid-lowering ethyl ester, 2_(4_(7· (5-(Methylsulfonyl) porphyrin-1-yl)isoxazo[4,5-d]pyrimidin-3-yl) Brigade. Ding Xiaoji) Mouth „定_5_竣酸, 7_(5_(methylstone-yl)dodoline 1yl)3 (1-(5-( Fluoromethyl), bite, _2, yl), genus, ketone, ketone, ketone, ketone, ketone, ketone, ketone Porphyrin_丨_yl)isoxazolo[4,5-(1] kiss^疋-3-yl)-l-yl-1-yl)pyrimidine _5-alcohol, 3_(1_(5_methoxy Azoxypyrimidin-2-yl)piperidin-4-yl)-7-(5-(methylsulfonyl)porphyrin-丨-yl)isoxazo[4,5-d]pyrimidine, 7-(5-(methylsulfonyl)porphyrinphenylpyrimidin-2-yl)piperidin-4-yl)isoxazo[4,5-d]pyrimidine, 7-(5-(fluorenyl) Sulfhydryl)porphyrin-1-yl)-3-(1-(5-(trifluoromethyl)pyridine-2-yl)piperidine-4-yl)isoxazo[4,5-d Pyrimidine, 4-(7-(5-(methylsulfonyl)porphyrin-yl)isoxazo[4,5-d]pyrimidin-3-yl)piperidine-1-carboxylic acid Isopropyl ester, 4_(7_(5-(methylsulfonyl)), oxalin-1-yl)isoxazolo[4,5-d]pyrimidin-3-yl)piperidine-indole-carboxylic acid Ester, 2-(7-(5-(methylsulfonyl) porphyrinyl)isoxazolo[4,5-pyrimidin-3-yl)piperidine-1-carboxylic acid 2-fluoroethyl ester 4-(7_(5_(methylsulfonyl)α-inducing porphyrin&lt;_ base) iso- 0-salt[4,5-d]B^n--3-yl)-determinin-1-竣Acid 2-meroxyoxyethylene, 4-(7-(5-(methylsulfonyl)) Porphyrinyl)isoxazo[4,5d]pyrimidin-3-yl) 100134953 80 201217385 Piperidine-1-carboxylic acid tetrahydro-2H-pyran-4-yl ester, 2-(4-(7- (5-(indolylsulfonyl)-indolyl-1-yl)iso-azolo[4,5-d]pyrimidin-3-yl)-endridin-1-yl)-metididine-5 - Physic acid allyl ester, 4-(7-(5(decylsulfinyl)) porphyrin-1-yl). T-butyl benzo[4,5-d]pyrimidin-3-yl)piperidine-1-carboxylate, 7-(5-(methylsulfinyl) porphyrin-1-yl)- 3-(1-(5-(Trifluoromethyl)pyridin-2-yl)piperidin-4-yl)isoxazolo[4,5-d]pyrimidine, 2,2-dimercapto-1- (4-(7-(5-(indolylsulfonyl). 哚 -1- -1 -yl) is iso-iso[[,5-(1]°密密定-3-基)派σ Di-1-yl) propyl-1-one, 4-(7-((2-fluoro-4-(methylsulfonyl)phenyl)amino)isoxazo[4,5-(1 ] pyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester, n-(2-fluoro-4-(fluorenylsulfonyl)phenyl)-3_(1-(5-(trifluoromethyl) (1,5-d)pyrimidin-7-amine, N-(2-fluoro-4-(methylsulfonyl)phenyl)_3_(1_ (5-(Trifluoromethyl)pyridin-2-yl)piperidin-4-yl)isoxazo[4,5-d]-7-amine, 4-(7-((2-fluoro-4_ 曱)基))))))))))))))]][4,5_d] -3-yl)pyridine-i-acid 1,1,1-trifluoro-2-mercaptopropane-2 -yl ester, 4-(7-((2-fluoro-4-indolylsulfonyl)phenyl)amino)isoxazo[4,5-d]pyrimidin-3-yl)piperidine-1 - 2,2,2-trifluoroethyl carboxylate, 4-(7-((2-fluoro-4-indolylsulfonyl)phenyl)amine 2,2,2_tris, ethyl 4-(2,5-d)pyrimidin-3-yl)piperidinecarboxylic acid, 4_(7_((2_fluoro_4_ decylsulfonyl)) Phenyl)amino)isoxazo[4,5-d]pyrimidin-3-yl)piperidine oxime carboxylic acid neopentyl ester, 4-(7-((2-fluoro-4-indolyl)sulfonyl) ) alkyl)amino)isoxazo[4,5-d]pyrimidinyl)piperidine _:[_carboxylic acid 4,4-difluorocyclohexyl ester, 4·(7_((2-fluoro_4) ·Methyl such as 4 yl) phenyl) Amino) 十 坐 Μ Μ 密 密 密 密 密 密 密 密 密 密 密 密 叛 叛 叛 叛 叛 叛 叛 叛 叛 叛 叛 叛 叛 3 3 4 4 4 4 4 4 4 4 4 4 4 (methyl hydrazino) alkyl) isoxazolo[4,5-d]pyrimidin-3-yl)piperidine _ 丨-decanoic acid (3_methyloxocyclohexane 100134953 S 201217385 butane-3 -yl) decyl ester, 4-(7-(2-fluoro-4-indolylsulfonyl)phenyl)amino)isoindole[4,5-(1]Feed_3_ base ) Bite bit _1_ phenyl acid ester, 4_(7-((2_fluoro_4_methyl)) phenyl)amino) iso-sit and [4,5-d] mouth bite-3 -Based on the bite of small tremolite 4 · nitrophenyl ester, (4-(7_((2_fluoro_4_(methylsulfonyl)phenyl))amino)isoxazo[4,5-d ] 鸣 -3- -3- ) 派 派 派 派 -3- -3- _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 And [Ο♦ dense bite I base) brigade bite-dic acid tert-butyl ester, heart (7-(2_fluoro-4-(fluorenyl) phenoxy) isotope, 5· ^ Bite winter base) Pie bite-i-remediate third butyl ester, 4 servant (4_〇h order sitting _Buji) phenoxy) sit and sit [4,5♦ dense bite each base] • (iv) third vinegar, and called methyl-H5-(methyl continuation) „弓卜朵琳小基) Qin^ sit and [4,3 flavon-3-yl)piperidine-i_ Tert-butyl carboxylate. A pharmaceutical composition comprising a compound according to any one of the items of the invention, or a salt thereof, or a solvate thereof, and a carrier acceptable for the drug. 9. An insulin secretion promoter, which will apply for the patent scope! The compound of any one of the items 7 or a salt thereof or a solvate thereof is used as an active ingredient. A blood sugar lowering agent which comprises, as an active ingredient, a compound of the above-mentioned claim or a salt thereof or a solvate thereof. , the prevention of the species _, and / or _, which will apply for the patent range of the first, the middle - the compound or its salt, or its dissolved matter as effective 100134953 82 201217385 IV. Designated representative map (1) The representative picture is: None (2) Simple description of the symbol of the representative figure: No. 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: [Chemical 1] 100134953 2 ©