WO2012043505A1 - Novel piperidine derivative and pharmaceutical containing same - Google Patents

Novel piperidine derivative and pharmaceutical containing same Download PDF

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Publication number
WO2012043505A1
WO2012043505A1 PCT/JP2011/071949 JP2011071949W WO2012043505A1 WO 2012043505 A1 WO2012043505 A1 WO 2012043505A1 JP 2011071949 W JP2011071949 W JP 2011071949W WO 2012043505 A1 WO2012043505 A1 WO 2012043505A1
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group
isoxazolo
methylsulfonyl
pyrimidin
carboxylate
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PCT/JP2011/071949
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French (fr)
Japanese (ja)
Inventor
俊晴 森元
智章 越澤
玄 渡部
友昭 福田
忠明 扇谷
奈穂 山崎
訓之 井上
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興和株式会社
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Publication of WO2012043505A1 publication Critical patent/WO2012043505A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to a drug having an action of promoting insulin secretion from pancreatic ⁇ cells and preventing and / or treating diseases caused by hyperglycemia such as diabetes.
  • pancreas is an endocrine / exocrine gland tissue derived from the endoderm, and is composed of endocrine cells, acinar cells, and duct cells.
  • Pancreatic Langerhans Islet pancreatic La Islet
  • pancreatic La Islet which is an endocrine cell, constitutes 1% of the entire pancreas and is mainly classified into four cells. That is, ⁇ cells that secrete glucagon, ⁇ cells that secrete insulin, ⁇ cells that synthesize and secrete somatostatin, and F cells that synthesize and secrete pancreatic polypeptides.
  • insulin secreted from ⁇ cells has the effect of lowering blood sugar as a main physiological function, and is the only hormone that exhibits a hypoglycemic action.
  • Insulin is secreted by sensing an increase in blood glucose in the pancreatic ⁇ cells and released into the portal vein. The released insulin suppresses gluconeogenesis and sugar release in the liver, and promotes glucose uptake in fat and muscle tissues, which are peripheral tissues, thereby maintaining the blood sugar level of the living body.
  • Diabetes is a persistent hyperglycemia caused by insulin deficiency or lack of action. Diabetes mainly causes insulin-dependent diabetes mellitus (IDDM) caused by abnormal pancreatic insulin secretion due to autoimmune diseases, etc., and insulin secretion ability due to pancreatic exhaustion resulting from persistent high insulin state due to insufficient insulin action (insulin resistance) It is divided into two types of non-insulin dependent diabetes mellitus (NIDDM) caused by a decrease.
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non-insulin dependent diabetes mellitus
  • Persistent hyperglycemia due to diabetes causes vascular damage and complications in multiple organs. Typical complications include diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, etc., and problems such as decreased quality of life (QOL), increased medical costs, decreased survival rate, etc. Yes.
  • ⁇ Exercise therapy, diet therapy, and drug therapy are used to treat diabetes.
  • the drug used for drug therapy include a drug that promotes insulin secretion from pancreatic ⁇ cells, a drug that improves insulin resistance, a drug that suppresses sugar absorption, and a drug that promotes the use of sugar.
  • an insulin secretagogue is expected to increase blood insulin concentration and lower blood sugar, and is therefore expected to suppress hyperglycemia and improve diabetes.
  • a sulfonylurea preparation (SU drug), Rapid insulin secretion promoters, DPPIV inhibitors (see Non-Patent Document 1), GLP-1 analogs (see Non-Patent Document 2), etc. are actually used in the field of diabetes treatment.
  • Non-Patent Document 3 the most commonly used SU drug in Japan stimulates pancreatic ⁇ -cells and promotes endogenous insulin secretion (see Non-Patent Document 3), but may exhibit hypoglycemia as a side effect, particularly in the elderly, Care should be taken when using this product if the patient has impaired renal function or if the diet is irregular. Also, side effects such as weight gain have been reported. Furthermore, there may be a primary ineffectiveness in which no effect is seen from the initial administration, or a secondary ineffectiveness in which clinical effects are lost during the administration period (see Non-Patent Document 4), and these side effects are reduced, and the insulin secretion ability Development of an insulin secretagogue that reduces the burden on pancreatic ⁇ cells is desired.
  • piperidine derivatives having a condensed heterocyclic ring at the 4-position include compounds having an adrenocorticotropic hormone releasing factor antagonistic action (Patent Documents 1, 2, 3, 4, 5), compounds having cell growth inhibitory activity, etc. (Patent Documents) 6) etc. have been reported. Moreover, although condensed ring compounds (Patent Documents 7 and 8) related to GPR119 have been reported, the structure is different from the compounds of the present invention.
  • Patent Document 9 a compound having an FXR (Farneoside X receptor) inhibitory action
  • Patent Documents 10 and 11 a compound having an FXR (Farneoside X receptor) inhibitory action
  • Patent Document 12 and 13 a compound having an FXR (Farneoside X receptor) inhibitory action
  • Patent Document 14 a compound having an FXR (Farneoside X receptor) inhibitory action
  • An object of the present invention is to provide a compound having an action of promoting insulin secretion from pancreatic ⁇ cells and useful as a prophylactic or therapeutic drug for diseases caused by hyperglycemia such as diabetes.
  • the present inventors searched for a compound that promotes insulin secretion using a hamster pancreatic ⁇ cell line HIT-T15 cell.
  • the piperidine derivative represented by (1) was found to have an excellent effect of promoting insulin secretion from pancreatic ⁇ cells, and was useful as a therapeutic agent for diabetes, and the present invention was completed.
  • a and B each represents a nitrogen atom, and the other is a nitrogen atom or CR 8 (where R 8 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, an amino group, or Nitro group)
  • D represents a nitrogen atom or CR 9 (wherein R 9 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, an amino group or a nitro group);
  • E represents a nitrogen atom or CR 10 (wherein R 10 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, an amino group or a nitro group);
  • X is an oxygen atom, a sulfur atom, — (CH 2 ) n—N (R 11 ) — or — (CH 2 ) n—CH (R 12 ) — (where R 11
  • R 15 represents a C 1-6 alkyl group
  • R 16 and R 17 are each independently A hydrogen atom or a C 1-6 alkyl group which may have a substituent
  • R 4 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group or an amino group
  • R 5 and R 6 each independently represents a hydrogen atom or a C 1-6 alkyl group
  • R 7 is a C 1-6 alkyl group, —C (O) R 18 , —C (S) R 19 , —S (O) 2 R 20 , an optionally substituted C 6-10 aryl group Or a 5- to 10-membered heteroaryl group which may have a substituent (wherein R 18 is a C 1-6 alkyl group which may have a substituent, a C 1 -1 which may be
  • a heterocycle formed by combining R 1 and R 11 or R 1 and R 12 together has the following formula:
  • R 21 represents a hydrogen atom, a C 1-6 alkyl group, —C (O) R 22 or —S (O) 2 R 23 (where R 22 and R 23 represent a C 1-6 alkyl group, C 3-6 8 represents a cycloalkyl group, and the wavy line represents an aromatic ring constituted by D and E]
  • R 21 represents a hydrogen atom, a C 1-6 alkyl group, —C (O) R 22 or —S (O) 2 R 23 (where R 22 and R 23 represent a C 1-6 alkyl group, C 3-6 8 represents a cycloalkyl group, and the wavy line represents an aromatic ring constituted by D and E]
  • a heterocycle formed by combining R 1 and R 11 or R 1 and R 12 together has the following formula:
  • R 1 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, an amino group, or a nitro group, or a solvate thereof object.
  • R 1 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, an amino group or a nitro group, and R 2 to R 7 are the same as above)
  • a pharmaceutical composition comprising the compound according to any one of [1] to [7] or a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.
  • An insulin secretion promoter comprising the compound or salt thereof according to any one of [1] to [7] or a solvate thereof as an active ingredient.
  • a hypoglycemic agent comprising the compound or salt thereof according to any one of [1] to [7] or a solvate thereof as an active ingredient.
  • a prophylactic and / or therapeutic agent for diabetes comprising the compound according to any one of [1] to [7] or a salt thereof, or a solvate thereof as an active ingredient.
  • a method for promoting insulin secretion comprising administering an effective amount of the compound according to any one of [1] to [7] or a salt thereof, or a solvate thereof.
  • a method for lowering blood glucose comprising administering an effective amount of the compound according to any one of [1] to [7] or a salt thereof, or a solvate thereof.
  • a method for the prophylaxis and / or treatment of diabetes comprising administering an effective amount of the compound according to any one of [1] to [7] or a salt thereof, or a solvate thereof.
  • the piperidine derivative of the present invention or a salt thereof, or a solvate thereof is an orally administrable low-molecular compound having an action of strongly promoting insulin secretion from pancreatic ⁇ cells, and is caused by hyperglycemia in mammals including humans. It is useful as a preventive and / or therapeutic agent for a disease that occurs, such as diabetes.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, Examples thereof include n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, 2-methylbutyl group, 2,2-dimethylpropyl group, n-hexyl group and the like.
  • halo C 1-6 alkyl group a C 1-6 alkyl group substituted by the same or different 1 to replaceable maximum halogen atoms, for example, monofluoromethyl
  • monofluoromethyl examples include a methyl group, a difluoromethyl group, a trifluoromethyl group, a monochloromethyl group, a dichloromethyl group, a trichloromethyl group, a monobromomethyl group, a monoiodomethyl group, or a 2,2,2-trifluoroethyl group.
  • examples of the “C 3-8 cycloalkyl group” include monocyclic, polycyclic or condensed cyclic cycloalkyl groups having 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms.
  • examples of such a cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like.
  • examples of the “C 2-6 alkenyl group” include a vinyl group, a prop-1-en-1-yl group (propenyl group), and a prop-2-en-1-yl group (allyl group).
  • examples of the “C 2-6 alkynyl group” include ethynyl group, prop-1-in-1-yl group, prop-2-yn-1-yl group (propargyl group), but-1 -In-1-yl group, but-3-yn-1-yl group, 1-methylprop-2-in-1-yl group, penta-1-in-1-yl group, penta-4-in-1 -Yl group, hexa-1-in-1-yl group, hexa-5-in-1-yl group and the like.
  • examples of the “C 1-6 alkoxy group” include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group.
  • examples of the “C 3-8 cycloalkyloxy group” include a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, and a cyclooctyloxy group.
  • examples of the “C 2-6 alkenyloxy group” include a vinyloxy group, a prop-1-en-1-yloxy group (propenyloxy group), a prop-2-en-1-yloxy group (allyloxy group).
  • examples of the “C 1-6 alkylthio group” include a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, an isobutylthio group, a sec-butylthio group, and a tert-butylthio group.
  • the “mono (C 1-6 alkyl) amino group” means a group in which the alkyl group is bonded to a nitrogen atom, for example, a methylamino group, an ethylamino group, a propylamino group, Examples include isopropylamino group, butylamino group, sec-butylamino group, tert-butylamino group, n-pentylamino group, isopentylamino group, neopentylamino group, n-hexylamino group, and isohexylamino group. .
  • the “di (C 1-6 alkyl) amino group” means the same or different groups in which two alkyl groups are bonded to a nitrogen atom.
  • a dimethylamino group a methylethylamino group , Diethylamino group, methylpropylamino group, ethylpropylamino group, dipropylamino group, diisopropylamino group, dibutylamino group and the like.
  • examples of the “C 6-10 aryl group” include a phenyl group, a naphthyl group, an azulenyl group, and the like.
  • substituted sulfonyl group refers to a “C 1-6 alkylsulfonyl group” in which an alkyl group is bonded via sulfonyl (—SO 2 —), and a “halo group in which a haloalkyl group is bonded via a sulfonyl group”.
  • examples of the “C 1-6 alkylsulfonyl group” include, for example, methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-butylsulfonyl group, isobutylsulfonyl group, sec-butyl Sulfonyl group, tert-butylsulfonyl group, n-pentylsulfonyl group, isopentylsulfonyl group, neopentylsulfonyl group, 2-methylbutylsulfonyl group, 1-methylbutylsulfonyl group, 1-ethylpropylsulfonyl group, 2,2- Dimethylpropylsulfonyl group, n-hexylsulfonyl group, 4-methylpentyls
  • examples of the “halo C 1-6 alkylsulfonyl group” include a fluoromethylsulfonyl group, a difluoromethylsulfonyl group, a trifluoromethylsulfonyl group, a chloromethylsulfonyl group, a bromomethylsulfonyl group, and an iodomethylsulfonyl group. 2,2,2-trifluoroethylsulfonyl group and the like.
  • examples of the “C 3-8 cycloalkylsulfonyl group” include a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a cyclopentylsulfonyl group, a cyclohexylsulfonyl group, a cycloheptylsulfonyl group, a cyclooctylsulfonyl group, and the like. Can be mentioned.
  • examples of the “C 2-6 alkenylsulfonyl group” include a vinylsulfonyl group, a propenylsulfonyl group, an allylsulfonyl group, a crotylsulfonyl group, and the like.
  • examples of the “C 2-6 alkynylsulfonyl group” include ethynylsulfonyl group, propargylsulfonyl group and the like.
  • examples of the “mono (C 1-6 alkyl) sulfamoyl group” include a methylsulfamoyl group, an ethylsulfamoyl group, a propylsulfamoyl group, an isopropylsulfamoyl group, and a butylsulfamoyl group.
  • examples of the “di (C 1-6 alkyl) sulfamoyl group” include a dimethylsulfamoyl group, a methylethylsulfamoyl group, a diethylsulfamoyl group, a dipropylsulfamoyl group, and a diisopropylsulfamoyl group.
  • a moyl group, a dibutylsulfamoyl group, etc. are mentioned.
  • examples of the “C 6-10 arylsulfonyl group” include a phenylsulfonyl group, a toluenesulfonyl group, a naphthylsulfonyl group, an azulenylsulfonyl group, and the like.
  • the “heterocycle” means a 4- to 10-membered saturated or unsaturated heterocycle which may have at least one nitrogen atom, oxygen atom or sulfur atom, for example, , Pyrrolidine, pyrroline, pyrrole, pyrrolidinone, pyrrolinone, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, indole, indoline, piperidine, piperidinone, dihydropyridine, dihydropyridinone, pyridine Morpholine, pyrimidine, thiophene, furan, benzofuran, benzothiophene, tetrahydropyran, tetrahydrofuran, oxetane and the like.
  • the “5- to 10-membered heteroaryl group” means a 5- to 10-membered monocyclic, polycyclic, or 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom.
  • Fused cyclic aromatic heterocyclic group means, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl , Tetrazolyl group, pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, benzofuranyl group, isobenzofuranyl group, benzothienyl group, indolyl group, isoindolyl group, indazolyl group, benzoimidazolyl group, benzoxazolyl group,
  • the “saturated heterocyclic group” means a 4- to 6-membered saturated heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, for example, Examples include pyrrolidyl group, pyrrolinyl group, imidazolidinyl group, imidazolinyl group, pyrazolidinyl group, pyrazolinyl group, piperidyl group, piperazinyl group, indolinyl group, isoindolinyl group, morpholinyl group, tetrahydropyranyl group, tetrahydrofuryl group, oxetanyl group and the like.
  • the “C 6-10 aryl C 1-6 alkoxy group” means a group in which the C 1-6 alkoxy group is bonded to a phenyl group, a naphthyl group, an azulenyl group or the like. Examples thereof include a phenyl-C 1-6 alkoxy group, a naphthyl-C 1-6 alkoxy group, and an azulenyl-C 1-6 alkoxy group. More specifically, a benzyloxy group, a phenethyloxy group, a naphthylmethyl group, and the like can be given.
  • examples of the “substituent” in the C 1-6 alkyl group which may have a substituent include a halogen atom, a C 3-8 cycloalkyl group, a C 1-6 alkoxy group, a mono ( C 1-6 alkyl) amino group, di (C 1-6 alkyl) amino group, di (C 2-6 alkenyl) amino group, mono (C 3-8 cycloalkyl) amino group, C 2-7 alkoxycarbonyl group Amino group, carboxyl group, cyano group, carbamoyl group, sulfamoyl group, hydroxyl group, nitro group, 5-10 membered heteroaryl group, saturated heterocyclic group and the like. These substituents may have 1 to 4 substituents.
  • the carbon number (C 2-7 ) of the alkoxycarbonyl group indicates a number including the carbonyl carbon.
  • a C 1-6 alkoxy group which may have a substituent a C 2-6 alkenyloxy group which may have a substituent, and a C 3-6 which may have a substituent
  • the “substituent” in the 8 cycloalkyloxy group include a halogen atom, a C 3-8 cycloalkyl group, a C 1-6 alkoxy group, a mono (C 1-6 alkyl) amino group, and di (C 1- 1).
  • alkyl amino group, di (C 2-6 alkenyl) amino group, mono (C 3-8 cycloalkyl) amino group, C 2-7 alkoxycarbonyl group, amino group, carboxyl group, cyano group, carbamoyl group, sulfamoyl Group, hydroxyl group, nitro group, 5-10 membered heteroaryl group, aliphatic heterocyclic group and the like.
  • substituents may have 1 to 4 substituents.
  • the carbon number (C 2-7 ) of the alkoxycarbonyl group indicates a number including the carbonyl carbon.
  • a C 6-10 aryl group which may have a substituent a 5-10 membered heteroaryl group which may have a substituent, and a C 6-10 aryloxy which may have a substituent
  • the “substituent” in the group, C 6-10 aryl C 1-6 alkoxy group which may have a substituent and heterocyclic oxy group which may have a substituent include, for example, a halogen atom, C 1-6 alkyl group, C 3-8 cycloalkyl group, halo C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkoxy group, mono (C 1-6 alkyl) ) Amino group, di (C 1-6 alkyl) amino group, di (C 2-6 alkenyl) amino group, mono (C 3-8 cycloalkyl) amino group, dioxaboranyl group, morpholino group, piperidino group, o
  • R 1 and R 3 are preferably a hydrogen atom, a halogen atom or a C 1-6 alkyl group, particularly preferably a hydrogen atom, a halogen atom or a C 1-4 alkyl group. Among these, R 1 is more preferably a halogen atom or a C 1-6 alkyl group, and R 3 is more preferably a hydrogen atom.
  • the halogen atom in R 1 and R 3 is preferably a fluorine atom.
  • the C 1-6 alkyl group in R 1 and R 3 is preferably a C 1-4 alkyl group, and more preferably a methyl group.
  • R 2 is preferably a hydrogen atom, —S (O) R 13 , —S (O) 2 R 14 , —CO 2 R 15, or —CONR 16 R 17 , preferably a hydrogen atom, — S (O) R 13 and —S (O) 2 R 14 are more preferred.
  • R 4 , R 5 and R 6 are preferably hydrogen atoms.
  • R 7 includes —C (O) R 18 , —C (S) R 19 , —S (O) 2 R 20 , and optionally substituted C 6-10 aryl.
  • a 5- to 10-membered heteroaryl group which may have a group or a substituent is preferable, and —C (O) R 18 , —S (O) 2 R 20 or a 5- to 10-membered heteroaryl which may have a substituent
  • An aryl group is more preferred.
  • R 18 in -C (O) R 18 in R 7 which may have a substituent C 1-6 alkoxy group, an optionally substituted C 2-6
  • a C 1-6 alkoxy group, an optionally substituted heterocyclic oxy group, an optionally substituted 5-10 membered heteroaryl group or mono (C 1-6 alkyl) amino group is preferred.
  • a C 1-6 alkoxy group which may have a group is more preferable.
  • R 19 in -C (S) R 19 in R 7 C 1-6 alkoxy, halo C 1-6 alkoxy group, C 6-10 aryl C 1-6 alkoxy group or A mono (C 1-6 alkyl) amino group is preferred, and a mono (C 1-6 alkyl) amino group is more preferred.
  • R 20 in -S (O) 2 R 20 in R 7 C 1-6 alkyl, halo C 1-6 alkyl group, C 3-8 cycloalkyl group, a substituent
  • a C 6-10 aryl group which may have or a 5-10 membered heteroaryl group which may have a substituent is preferable.
  • the 5-10 membered heteroaryl group in the 5-10 membered heteroaryl group which may have a substituent for R 7 is preferably a pyridyl group, a pyrimidinyl group, or an oxadiazole group.
  • the substituent moiety is preferably a halogen atom, a C 1-6 alkyl group, or a halo C 1-6 alkyl group, more preferably a chlorine atom, an ethyl group, an isopropyl group, or a trifluoromethyl group, and a chlorine atom, an ethyl group Is more preferable.
  • the heterocyclic ring formed by combining R 1 and R 11 or R 1 and R 12 is represented by the following formula:
  • R 21 represents a hydrogen atom, a C 1-6 alkyl group, —C (O) R 22 or —S (O) 2 R 23 (wherein R 22 and R 23 are a C 1-6 alkyl group or C 3- 8 represents an cycloalkyl group, and the wavy line represents an aromatic ring containing D and E].
  • Preferred is a heterocycle selected from
  • R 11 or R 12 is preferably a hydrogen atom.
  • the C 1-6 alkyl group in R 13 or R 14 is preferably a C 1-4 alkyl group, and more preferably a methyl group.
  • the C 6-10 aryl group which may have a substituent for R 13 or R 14 is preferably a phenyl group or a toluyl group, and more preferably a p-toluyl group.
  • the C 1-6 alkoxy group which may have a substituent for R 18 includes a methoxy group, an ethoxy group, an isopropoxy group, a tert-butoxy group, a 2-fluoroethoxy group, 2- Methoxyethoxy group, (3-methyloxetane-3-yl) methoxy group, 1,1,1-trifluoro-2-methylpropan-2-yloxy group, 2,2,2-trifluoroethoxy group, 2,2, A 2-trichloroethoxy group is preferred.
  • the C 3-8 cycloalkyloxy group which may have a substituent for R 18 is C 3-6 cycloalkyloxy optionally substituted with 1 to 3 halogen atoms.
  • Group is preferable, and 4-fluorocyclohexyloxy group and 4,4-difluorocyclohexyloxy group are more preferable.
  • the C 2-6 alkenyloxy group which may have a substituent for R 18 is preferably a C 2-4 alkenyloxy group, and a prop-2-en-1-yloxy group (allyloxy). Group) is more preferred.
  • the C 6-10 aryloxy group for R 18 is preferably a phenyloxy group or a p-nitrophenyloxy group.
  • the C 6-10 aryl C 1-6 alkoxy group in R 18 is preferably a phenyl C 1-6 alkoxy group, more preferably a benzyloxy group.
  • the 5-10 membered heteroaryl group which may have a substituent for R 18 is preferably a pyridyl group.
  • the mono (C 1-6 alkyl) amino group in R 18 is preferably a mono (C 1-4 alkyl) amino group, and more preferably a tert-butylamino group.
  • the mono (C 1-6 alkyl) amino group in R 19 is preferably a mono (C 1-4 alkyl) amino group, and more preferably a tert-butylamino group.
  • the C 1-6 alkyl group in R 20 is preferably a C 1-4 alkyl group, and more preferably an n-butyl group.
  • the halo C 1-6 alkyl group for R 20 is preferably a halo C 1-4 alkyl group, more preferably a trichloromethyl group.
  • the C 3-8 cycloalkyl group in R 20 is preferably a C 3-6 cycloalkyl group, more preferably a cyclopropyl group or a cyclohexyl group.
  • the C 6-10 aryl group which may have a substituent in R 20 is preferably a phenyl group which may have a substituent.
  • a halo C 1-6 alkyl group such as a trifluoromethyl group
  • a C 1-6 alkoxy group such as a methoxy group
  • the C 6-10 heteroaryl group which may have a substituent for R 20 is preferably a thienyl group.
  • a and B when A and B are nitrogen atoms, when A is a nitrogen atom and B is CH, the case where A is CH and B is a nitrogen atom is more preferable, More preferably, A and B are nitrogen atoms.
  • D is preferably a nitrogen atom, CH or C-halogen, and more preferably CH.
  • E is preferably a nitrogen atom, CH or C-halogen, and more preferably CH.
  • X is preferably a nitrogen atom or an oxygen atom, and more preferably a nitrogen atom.
  • Y is preferably an oxygen atom, a sulfur atom, or a nitrogen atom, more preferably an oxygen atom or a nitrogen atom, and even more preferably an oxygen atom.
  • Z is preferably an oxygen atom, a sulfur atom, or a nitrogen atom, more preferably an oxygen atom or a nitrogen atom, and even more preferably a nitrogen atom.
  • the ring structure including D and E is more preferably a benzene ring (both D and E are CH).
  • the ring structure containing A, B, Y and Z includes the following structures:
  • the compounds represented by the following (1a) or (1b) are particularly preferable.
  • R 1 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, an amino group or a nitro group, and R 2 to R 7 are the same as above)
  • tert-butyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-4-yl) piperidine-1-carboxylate (Example 1), 3- (1- (5-Chloropyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine (Example 2) ), 3- (1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine (Example 3) ), 3- (1- (5-Bromopyrimidin-2-yl) piperidin-4-yl) -7- (5- (
  • the salt of the compound represented by the general formula (1) is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • alkali metal salt or alkaline earth metal salt such as sodium, potassium, magnesium, calcium
  • acid addition salts of mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate; benzoate
  • examples include acid addition salts of organic acids such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, maleate, fumarate, tartrate, citrate, and acetate. It is done.
  • Examples of the solvate of the compound represented by the general formula (1) or a salt thereof include, but are not limited to, hydrates and the like.
  • prodrugs are also included in the present invention.
  • examples of the group that forms a prodrug of the compound of the present invention include the groups described in “Progress in Medicine”, Life Science Medica, 1985, Vol. 5, pages 2157-2161. Examples include the groups described in Yodogawa Shoten, 1990, “Development of Drugs”, Vol.
  • the compound represented by the above general formula (1), a salt thereof, or a solvate thereof can be produced by various known methods, and is not particularly limited.
  • the reaction described below It can be manufactured according to the process.
  • functional groups other than the reaction site may be protected in advance as necessary, and may be deprotected at an appropriate stage.
  • a commonly used method for example, a method described in Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc., 1999) can be used.
  • reaction may be carried out by a commonly performed method (for example, the method described in Comprehensive Organic Transformation Second Edition, John Wiley & Sons, Inc; 1999), and isolation and purification are crystallized and recrystallized. Ordinary methods such as chromatography may be appropriately selected or combined.
  • Method for producing the compound represented by the general formula (1) The compound represented by the general formula (1) of the present invention can be produced by the method shown in the following reaction pathway diagram 1. [Reaction Path Diagram 1]
  • Step A-1 is a step in which compound (2) is mixed with a dehydrating condensing agent such as hexafluorophosphoric acid (benzotriazol-1-yloxy) tripyrrolidinophosphonium (PyBOP) in a solvent in the presence of a base.
  • a dehydrating condensing agent such as hexafluorophosphoric acid (benzotriazol-1-yloxy) tripyrrolidinophosphonium (PyBOP) in a solvent in the presence of a base.
  • This is a step for producing a compound (3) by reacting with a sulfonylating agent such as methanesulfonyl chloride.
  • the base is not particularly limited.
  • alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate
  • 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) 1,5-diazabicyclo [4.3.0] non-5-ene (DBN)
  • 1,4-diazabicyclo [2,2,2] octane (DABCO) triethylamine, N, N-diisopropylethylamine, N, N -Organic bases such as diisopropylpentylamine and trimethylamine
  • DBU 1,8-diazabicyclo [5.4.0] undec-7-ene
  • the solvent is not particularly limited, and examples thereof include N, N-dimethylformamide, dioxane, tetrahydrofuran, acetonitrile, propionitrile, chloroform, methylene chloride and the like, and these can be used alone or in combination.
  • Preferred is tetrahydrofuran alone or a mixed solvent of tetrahydrofuran and methylene chloride.
  • the reaction temperature is preferably 0 to 150 ° C., more preferably 10 to 30 ° C.
  • the reaction time is preferably 5 minutes to 48 hours, more preferably 10 minutes to 2 hours.
  • Step A-2 is a step for producing compound (1) by reacting compound (3) with compound (4) in the presence of a base in a solvent.
  • a base for example, Alkali metal hydrides, such as lithium hydride, sodium hydride, potassium hydride; Alkali metals, such as metallic lithium, metallic sodium, metallic potassium; Lithium hydroxide, Hydroxide Alkali metal hydroxides such as sodium and potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, Sodium hexamethyldisilazide, potassium hexamethyldisilazide, tert-butoxy sodium, tert-butoxy potassium, n-butyllithium, sec-butyllithium, tert-butyllith
  • the reaction temperature is preferably 0 to 150 ° C, more preferably 50 to 100 ° C.
  • the reaction time is preferably 5 minutes to 48 hours, more preferably 10 minutes to 4 hours.
  • reaction Path Diagram 2 [Reaction Path Diagram 2]
  • Step B-1 comprises reacting compound (2) with a halogenating agent such as phosphorus oxychloride (POCl 3 ) in the presence or absence of a solvent, in the presence or absence of a base.
  • a halogenating agent such as phosphorus oxychloride (POCl 3 )
  • POCl 3 phosphorus oxychloride
  • compound (5) is produced.
  • the halogenating agent to be used is not particularly limited, and for example, phosphorus oxychloride, phosphorus oxychloride / phosphorus pentachloride, N, N-dimethylformamide / oxalyl chloride and the like can be used.
  • Preferred is phosphorus oxychloride.
  • N N-dimethylaniline, N, N-diethylaniline, N, N, N-diisopropylethylamine or the like can be used.
  • solvent dioxane, 1,2-dichloroethane and the like can be used.
  • the reaction temperature is preferably 0 to 150 ° C, more preferably 80 to 120 ° C.
  • the reaction time is preferably 10 minutes to 48 hours, more preferably 3 to 6 hours.
  • Step B-2 is a step of producing a compound represented by the general formula (1) by reacting compound (5) with 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 that are usually used in an amination reaction. R. Muci, S .; L. Buchwald, Top. Curr. Chem. , 219, 131-209, (2002), etc. can be used.
  • a method of an amination reaction performed in the presence or absence of a base and in the presence of a metal catalyst in a solvent or without a solvent can be applied. In that case, microwave irradiation may be performed.
  • the metal catalyst is not particularly limited.
  • Alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; Alkali metals, such as metallic lithium, metallic sodium, metallic potassium; Lithium hydroxide, Hydroxide Alkali metal hydroxides such as sodium and potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, Sodium hexamethyldisilazide, potassium hexamethyldisilazide, tert-butoxy sodium, tert-butoxy potassium, n-butyllithium, sec-butyllithium, tert-butyllithium, etc.
  • the solvent is not particularly limited, and for example, tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water and the like can be used alone or in combination.
  • the reaction temperature is preferably 0 to 200 ° C, more preferably 100 ° C to 150 ° C.
  • the reaction time is preferably 1 minute to 5 days, more preferably 30 minutes to 6 hours.
  • R 24 is a C 1-6 alkyl group or C 6-10. Represents an aryl C 1-6 alkyl group.
  • Step C-1 is a step for producing compound (2) by reacting compound (6) with amidine derivative (7) or a salt thereof.
  • the solvent is not particularly limited, and for example, methanol, ethanol, ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene and the like can be used. Ethanol is preferable.
  • the reaction temperature is preferably 40 to 120 ° C, more preferably 80 to 100 ° C.
  • the reaction time is preferably 1 hour to 5 days, more preferably 12 hours to 2 days.
  • Compound (2a-d) was also prepared according to Bioorg. Med. Chem. Lett. 2005, 15, 3900. , WO2001 / 047934 pamphlet, Liebigs Ann.
  • R 24 is a C 1-6 alkyl group or C 6-10.
  • Aryl C 1-6 alkyl group, W 3 represents a halogen atom, a hydroxyl group or an amino group.
  • various isomers can be isolated by applying a conventional method using the difference in physicochemical properties between isomers.
  • the racemic mixture is optically purified by a general racemic resolution method such as a method of optical resolution by introducing a diastereomeric salt with a general optically active acid such as tartaric acid or a method using optically active column chromatography. Can lead to isomers.
  • a diastereomeric mixture can be divided
  • An optically active compound can also be produced by using an appropriate optically active raw material.
  • the obtained compound (1) can be converted into a salt by an ordinary method. Moreover, it can also be set as the solvate and hydrate of solvents, such as a reaction solvent and a recrystallization solvent.
  • this active ingredient may be used alone, but it is usually pharmaceutically acceptable. It is used in the form of a pharmaceutical composition by blending carriers, additives and the like.
  • the administration form of the pharmaceutical composition is not particularly limited and can be appropriately selected depending on the purpose of treatment. For example, any of oral preparations, injections, suppositories, ointments, inhalants, eye drops, nasal drops, patches and the like may be used. Pharmaceutical compositions suitable for these dosage forms can be produced by known formulation methods.
  • the compound represented by the general formula (1) is mixed with an excipient, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a corrigent, a corrigent and the like.
  • an excipient e.g., lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid and the like.
  • binder examples include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone and the like.
  • disintegrant examples include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose.
  • lubricant examples include purified talc, stearate, borax, and polyethylene glycol.
  • corrigent examples include sucrose, orange peel, citric acid, and tartaric acid.
  • a corrigent When preparing an oral liquid preparation, add a corrigent, a buffer, a stabilizer, a corrigent, etc. to the compound represented by the general formula (1), and add an oral solution, syrup, elixir, etc. Can be manufactured.
  • the corrigent those mentioned above may be used.
  • the buffer include sodium citrate
  • examples of the stabilizer include tragacanth, gum arabic, and gelatin.
  • a pH regulator, a buffer, a stabilizer, a tonicity agent, a local anesthetic, etc. are added to the compound represented by the general formula (1), and subcutaneous, muscle and Intravenous injections can be manufactured.
  • the pH adjusting agent and buffer include sodium citrate, sodium acetate, sodium phosphate and the like.
  • the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like.
  • local anesthetics include procaine hydrochloride and lidocaine hydrochloride.
  • isotonic agents include sodium chloride and glucose.
  • a carrier for a suppository known to the compound represented by the general formula (1), such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride and the like, and Tween (registered trademark) as necessary. After adding a surfactant, etc., it can be produced by a conventional method.
  • bases, stabilizers, wetting agents, preservatives, etc. which are usually used for the compound represented by the general formula (1) are blended as necessary, and mixed and formulated by conventional methods. It becomes.
  • the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like.
  • the preservative include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate and the like.
  • the compound represented by the general formula (1) can be converted into an inhalant, an eye drop, or a nasal drop by a conventional method.
  • the compound represented by the general formula (1) has an action of significantly promoting insulin secretion in hamster pancreatic ⁇ cell line HIT-T15 cells. Therefore, the compound represented by the general formula (1), or an acid addition salt thereof, or a solvate thereof is used as a hypoglycemic agent and for prevention of diseases caused by hyperglycemia in mammals including humans such as diabetes. Or it is useful as a therapeutic agent.
  • diabetes non-insulin dependent diabetes mellitus (NIDDM) is mentioned in more detail.
  • the compound represented by the general formula (1) of the present invention is administered by oral administration or parenteral administration.
  • the dose of the medicament of the present invention varies depending on the patient's body weight, age, sex, symptoms, etc., but in the case of a normal adult, it is usually 0.01 to 1000 mg, preferably 0, as the compound represented by the general formula (1). It is preferable to administer 1 to 300 mg in 1 to 3 divided doses.
  • Step 2 Preparation of tert-butyl 4-formylpiperidine-1-carboxylate tert-butyl-4-hydroxymethylpiperidine (10.0 g, 46.4 mmol) and 2,2,6,6-tetramethylpiperidine 1-oxyl Free radicals (360 mg, 2.32 mmol) were dissolved in chloroform (230 mL), and sodium hypochlorite / saturated aqueous sodium hydrogen carbonate solution (1/1, 94 mL) was added over 1 hour so that the internal temperature did not exceed 1 ° C. And dripped. After completion of the dropwise addition, sodium thiosulfate was added to the reaction solution to stop the reaction, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (11.1 g, crude product) as a brown oily product.
  • Step 3 Preparation of tert-butyl 4- (1-hydroxy-2-nitroethyl) piperidine-1-carboxylate tert-butyl 4-formylpiperidine-1-carboxylate (11.1 g, crude product) and potassium fluoride (540 mg, 9.28 mmol) was dissolved in isopropanol (50 mL), nitromethane (14.2 g, 232 mmol) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate and concentration under reduced pressure, diethyl ether was added to the resulting residue, and the suspension solution was filtered to obtain the title compound (7.70 g, 61%, 3 steps) as a white powder.
  • Step 4 Preparation of tert-butyl 4- (2-nitroacetyl) piperidine-1-carboxylate tert-butyl 4- (1-hydroxy-2-nitroethyl) piperidine-1-carboxylate (7.70 g, 28.1 mmol) ) was dissolved in methylene chloride (140 mL), Dess-Martin periodinane (14.3 g, 33.7 mmol) was added, and the mixture was stirred at room temperature for 40 minutes. A sodium thiosulfate aqueous solution and a saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with ethyl acetate.
  • Step 6 Preparation of ethyl 3- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4-nitroisoxazole-5-carboxylate tert-butyl 4- (1- (hydroxyimino) under argon atmosphere -2-Nitroethyl) piperidine-1-carboxylate (100 mg, 0.348 mmol) was dissolved in anhydrous tetrahydrofuran (3.5 mL), ethyl chloroglyoxylate (95 mg, 0.696 mmol) was added, and the mixture was heated at 60 ° C. for 6 hours. did. Cool to 0 ° C. and slowly add triethylamine (0.1 mL).
  • Step 7 Preparation of ethyl 4-amino-3- (1- (tert-butoxycarbonyl) piperidin-4-yl) isoxazole-5-carboxylate
  • zinc (140 mg, 2.13 mmol) and ammonium chloride (280 mg) , 5.33 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 4 hours.
  • concentration under reduced pressure and drying over anhydrous sodium sulfate the resulting residue was purified using silica gel column chromatography (ethyl acetate) to obtain the title compound (64.5 mg, 89%) as a yellow oil.
  • Step 8 Preparation of tert-butyl 4- (7-hydroxyisoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate
  • Ethyl 4-amino-3- (1- (tert-butoxy) Carbonyl) piperidin-4-yl) isoxazole-5-carboxylate (32.5 mg, 0.081 mmol) and formamidine acetate (26.0 mg, 0.243 mmol) are dissolved in ethanol and heated under reflux for 24 hours. It was. The mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform.
  • Step 9 tert-Butyl 4- (7-((1H-benzo [d] [1,2,3] triazol-1-yl) oxy) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine- Preparation of 1-carboxylate tert-Butyl 4- (7-hydroxyisoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate (14.1 mg.0.044 mmol) and 1H-benzo Triazol-1-yloxytripyrrolidinephosphonium hexafluorophosphate (27.0 mg, 0.053 mmol) was suspended in anhydrous tetrahydrofuran (0.5 mL), triethylamine (10 ⁇ L) was added, and the mixture was stirred at room temperature for 1 hour.
  • Step 10 Preparation of tert-butyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-4-yl) piperidine-1-carboxylate under argon atmosphere 5- (Methylsulfonyl) indoline (2.5 mg, 0.013 mmol) and tert-butyl 4- (7-((1H-benzo [d] [1,2,3] triazol-1-yl) oxy) isoxazolo [ 4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate (7.1 mg, 0.016 mmol) was dissolved in anhydrous N, N-dimethylformamide (0.3 mL) and sodium hydride (1.
  • Example 2 3- (1- (5-chloropyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine
  • Production step 1 Production of 7- (5- (methylsulfonyl) indoline-1-yl) -3- (piperidin-4-yl) isoxazolo [4,5-d] pyrimidine hydrochloride tert-butyl 4- (7- (5- (Methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-4-yl) piperidine-1-carboxylate (5.8 mg, 0.012 mmol) in ethyl acetate (0.5 mL) Then, 4N hydrochloric acid ethyl acetate (1.3 mL) was added under ice-cooling, and the mixture was stirred at room
  • Step 2 3- (1- (5-Chloropyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine
  • Preparation 7- (5- (Methylsulfonyl) indoline-1-yl) -3- (piperidin-4-yl) isoxazolo [4,5-d] pyrimidine hydrochloride (5.3 mg, crude) and 2,5- Dichloropyrimidine (2.7 mg, 0.018 mmol) is dissolved in anhydrous N, N-dimethylformamide (0.3 mL), N, N-diisopropylethylamine (7 ⁇ L, 0.036 mmol) is added, and the mixture is stirred at 80 ° C.
  • Example 3 (1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine Preparation The reaction and treatment were conducted in a similar manner to Example 2 using 2-chloro-5-ethylpyrimidine instead of 2,5-dichloropyrimidine, and the title compound was obtained as an orange oil.
  • Example 4 (1- (5-Bromopyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine Production
  • the reaction and treatment were conducted in a similar manner to process 2 of example 2 using 5-bromo-2-chloropyrimidine in place of 2,5-dichloropyrimidine, and the title compound was obtained as a white solid.
  • Example 5 3- (1- (5-Fluoropyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine Production
  • the reaction and treatment were conducted in a similar manner to process 2 of example 2 using 2-chloro-5-fluoropyrimidine in place of 2,5-dichloropyrimidine, and the title compound was obtained as a white solid.
  • Example 6 Ethyl 2- (4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidine-5-carboxy Production of rate Using ethyl 2- (methylsulfinyl) pyrimidine-5-carboxylate instead of 2,5-dichloropyrimidine, the reaction and treatment were carried out in the same manner as in Step 2 of Example 2 to obtain the title compound as a pale yellow solid. It was.
  • Example 8 7- (5- (Methylsulfonyl) indoline-1-yl) -3- (1- (5- (trifluoromethyl) pyrimidin-2-yl) piperidin-4-yl) isoxazolo [4,5- d] Production of pyrimidine The reaction and treatment were conducted in the same manner as in Step 2 of Example 2 using 2- (methylsulfinyl) -5- (trifluoromethyl) pyrimidine in place of 2,5-dichloropyrimidine, and the title compound was palely prepared. Obtained as a yellow solid.
  • 2-chloro-5- (4,4,5,5-tetra instead of 2,5-dichloropyrimidine Methyl-1,3,2-dioxaborolan-2-yl) pyrimidine was used for the reaction and treatment in the same manner as in Step 2 of Example 2 to obtain the title compound as a yellow solid.
  • Step 2 2- (4- (7- (5- (Methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidin-5-ol
  • Preparation 7- (5- (Methylsulfonyl) indoline-1-yl) -3- (1- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine -2-yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidine (13.4 mg, 0.023 mmol) was dissolved in THF (1 mL), 30% aqueous hydrogen peroxide (50 ⁇ L) was added, After stirring at room temperature for 4 hours, an aqueous sodium thiosulfate solution was added, and the mixture was extracted with chloroform.
  • Example 10 3- (1- (5-methoxypyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine
  • Preparation 2- (4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidin-5-ol (10.
  • Example 11 7- (5- (Methylsulfonyl) indoline-1-yl) -3- (1- (5-phenylpyrimidin-2-yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidine
  • Preparation 7- (5- (Methylsulfonyl) indoline-1-yl) -3- (1- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) under argon atmosphere -Yl) pyrimidin-2-yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidine (14.7 mg, 0.024 mmol), iodobenzene (7.5 mg, 0.036 mmol), tetrakistriphenylphosphine Palladium (2.8 mg, 0.0024 mmol) is dissolved in N, N-dimethylformamide (0.4 mL) and water (0.1 mL
  • Preparation of pyrimidine The reaction and treatment were conducted in the same manner as in Step 2 of Example 2 using 2-chloro-5- (trifluoromethyl) pyridine in place of 2,5-dichloropyrimidine, and the title compound was converted to a pale yellow solid. Obtained.
  • Example 14 Preparation of ethyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate Chlorogy instead of isopropyl chloroformate Reaction and treatment were conducted in the same manner as in Example 13 using ethyl acid to obtain the title compound as a pale yellow solid.
  • Example 15 Preparation of 2-fluoroethyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate Instead, the reaction and treatment were conducted in the same manner as in Example 13 using 2-fluoroethyl chloroformate to obtain the title compound as a pale yellow solid.
  • Example 17 Tetrahydro-2H-pyran-4-yl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate
  • the reaction and treatment were conducted in the same manner as in Example 13 using 4-nitrophenyl (tetrahydro-2H-pyran-4-yl) carbonate instead of isopropyl chloroformate, and the title compound was obtained as a pale-yellow solid.
  • Example 19 Preparation of tert-butyl 4- (7- (5 (methylsulfinyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate 5- (Methylsulfonyl) )
  • the reaction and treatment were conducted in the same manner as in step 10 of Example 1 using 5- (methylsulfinyl) indoline instead of indoline to obtain the title compound as a yellow solid.
  • Step 1 Preparation of 7- (5- (methylsulfinyl) indoline-1-yl) -3- (piperidin-4-yl) isoxazolo [4,5-d] pyrimidine hydrochloride tert-butyl 4- (7- ( 5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-4-yl) piperidine-1-carboxylate instead of tert-butyl 4- (7- (5 (methylsulfinyl) indoline) -1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate was reacted and treated in the same manner as in Step 1 of Example 2 to obtain the title compound as a yellow solid. .
  • Step 2 7- (5- (Methylsulfinyl) indoline-1-yl) -3- (1- (5- (trifluoromethyl) pyridin-2-yl) piperidin-4-yl) isoxazolo [4,5- d]
  • pyrimidine 2-chloro-5- (trifluoromethyl) pyridine instead of 2,5-dichloropyrimidine
  • 7- (5- (methylsulfinyl) indoline-1-yl) -3 obtained in Step 1
  • the reaction and treatment were conducted in a similar manner to process 2 of example 2 using-(piperidin-4-yl) isoxazolo [4,5-d] pyrimidine hydrochloride to obtain the title compound as a yellow solid.
  • Example 21 2,2-Dimethyl-1- (4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) Production of propan-1-one
  • the reaction and treatment were conducted in the same manner as in Example 13 using pivaloyl chloride in place of isopropyl chloroformate, and the title compound was obtained as a pale-yellow solid.
  • Example 22 Preparation of tert-butyl 4- (7-((2-fluoro-4- (methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate 5
  • the reaction and treatment were conducted in a similar manner to process 10 of example 1 using 2-fluoro-4- (methylsulfonyl) aniline in place of-(methylsulfonyl) indoline, and the title compound was obtained as a pale-yellow solid.
  • Step 2 N- (2-Fluoro-4- (methylsulfonyl) phenyl) -3- (1- (5- (trifluoromethyl) pyrimidin-2-yl) piperidin-4-yl) isoxazolo [4,5- d]
  • pyrimidine-7-amine 2- (methylsulfinyl) -5- (trifluoromethyl) pyrimidine instead of 2,5-dichloropyrimidine and N- (2-fluoro-4- ( Methylsulfonyl) phenyl) -3- (piperidin-4-yl) isoxazolo [4,5-d] pyrimidin-7-amine hydrochloride was reacted and treated in the same manner as in Step 2 of Example 2 to obtain the title compound. Obtained as a pale yellow solid.
  • Example 26 2,2,2-trifluoroethyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1- Preparation of carboxylate 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate instead of 1,2,1-trifluoroethyl 1H-imidazole-1-carboxylate The reaction and treatment were conducted in the same manner as in Example 25 to obtain the title compound as a pale yellow amorphous.
  • Example 27 2,2,2-Trichloroethyl 4- (7-((2-Fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxy Production of rate The reaction and treatment were conducted in the same manner as in Example 13 using 2,2,2-trichloroethyl chloroformate instead of isopropyl chloroformate to obtain the title compound as a pale yellow solid.
  • Example 28 Preparation of neopentyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate Instead, the reaction and treatment were conducted in the same manner as in Example 13 using neopentyl chloroformate to obtain the title compound as a pale yellow solid.
  • Example 29 4,4-Difluorocyclohexyl 4- (7-((2-Fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate
  • Example 25 using 4,4-difluorocyclohexyl 1H-imidazole-1-carboxylate instead of 1H-imidazole-1-carboxylate The title compound was obtained as a yellow amorphous product.
  • Example 30 Preparation of Oxetan-3-yl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate
  • the reaction and treatment were conducted in a similar manner to Example 13 using 4-nitrophenyl oxetane-3-yl carbonate in place of isopropyl chloroformate, and the title compound was obtained as a pale-yellow solid.
  • Example 31 (3-Methyloxetane-3-yl) methyl 4- (7-((2-fluoro-4- (methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine Preparation of -1-carboxylate The reaction and treatment were conducted in the same manner as in Example 13 using (3-methyloxetane-3-yl) methyl (4-nitrophenyl) carbonate instead of isopropyl chloroformate, and the title compound was pale yellow. Obtained as a solid.
  • Example 32 Preparation of phenyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate Instead, phenyl chloroformate was used and reacted and treated in the same manner as in Example 13 to obtain the title compound as a pale yellow solid.
  • Example 33 Preparation of 4-nitrophenyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate The reaction and treatment were conducted in a similar manner to Example 13 using 4-nitrophenyl chloroformate instead of isopropyl acid, and the title compound was obtained as a pale-yellow solid.
  • Example 35 Preparation of tert-butyl 4- (7- (4- (methylsulfonyl) phenoxy) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate of 5- (methylsulfonyl) indoline Instead, 4- (methylsulfonyl) phenol was used for the reaction and treatment in the same manner as in Step 10 of Example 1 to obtain the title compound as a pale yellow oil.
  • Example 36 Preparation of tert-butyl 4- (7- (2-fluoro-4- (methylsulfonyl) phenoxy) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate 5- (Methyl).
  • the reaction and treatment were conducted in a similar manner to process 10 of example 1 using 2-fluoro-4- (methylsulfonyl) phenol in place of sulfonyl) indoline, and the title compound was obtained as a pale-yellow oil.
  • Example 37 Preparation of tert-butyl 4- (7- (4- (1H-tetrazol-1-yl) phenoxy) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate 5- ( The reaction and treatment were conducted in a similar manner to process 10 of example 1 using 4- (1H-tetrazol-1-yl) phenol in place of methylsulfonyl) indoline, and the title compound was obtained as a white solid.
  • Example 38 tert-butyl 4- (1-methyl-7- (5- (methylsulfonyl) indoline-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-3-yl) piperidine-1-carvone Production process of xylate 1: Production of tert-butyl 4- (methoxy (methyl) carbamoyl) piperidine-1-carboxylate 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (15.0 g, 65.4 mmol) N, O-dimethylhydroxylamine hydrochloride (8.3 g, 85.0 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (16.3 g, 85.0 mmol) in dichloromethane (400 mL) And triethylamine (13.7 mL, 98.1 mmol) and N, N- Dimethylaminopyridine (0.80 g, 6.
  • Step 2 Preparation of tert-butyl 4-acetylpiperidine-1-carboxylate tert-butyl 4- ⁇ methoxy (methyl) carbamoyl ⁇ piperidine-1-carboxylate (17.7 g, 65.0 mmol) under an argon atmosphere. It melt
  • Step 3 Preparation of tert-butyl 4- (4-ethoxy-3,4-dioxobutanoyl) piperidine-1-carboxylate tert-butyl 4-acetylpiperidine-1-carboxylate (1.20 g, 4.40 mmol) ) was dissolved in tetrahydrofuran (20 mL) under argon atmosphere, hexamethyldisilazane lithium (7.27 mL, 1.09 mol / L hexane solution) was added dropwise at -78 ° C, and the mixture was stirred at 0 ° C for 1 hour.
  • Step 4 Preparation of tert-butyl 4- (1-methyl-7-oxo-6,7-dihydro-1H-pyrazo [4,3-d] pyrimidin-3-yl) piperidine-1-carboxylate
  • tert-butyl (4-Ethoxy-3,4-dioxobutanoyl) piperidine-1-carboxylate 100 mg, 0.305 mmol
  • acetic acid 1 mL
  • sodium nitrite 23.2 mg, 0.336 mmol
  • Step 5 tert-Butyl 4- (7-((1H-benzo [d] [1,2,3] triazo-1-yl) oxy) -1-methyl-1H-pyrazolo [4,3-d] pyrimidine
  • -3-yl piperidin-1-carboxylate
  • tert-butyl 4- (1-methyl-7-oxo-6,7-dihydro-1H-pyrazo [4,3-d] pyrimidin-3-yl) piperidine 1-carboxylate (9.7 mg, 0.029 mmol) and 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (16.6 mg, 0.032 mmol) were dissolved in tetrahydrofuran (1 mL).
  • 1,8-diazabicyclo [5,4,0] -7-undecene (5.2 ⁇ L, 0.035 mmol) was added, and the mixture was stirred at room temperature for 1 hour. .
  • Step 6 tert-Butyl 4- (1-methyl-7- (5- (methylsulfonyl) indoline-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-3-yl) piperidine-1-carvone
  • xylate tert-butyl 4- (7-((1H-benzo [d] [1,2,3] triazo-1-yl) oxy) -1-methyl-1H-pyrazolo [4,3-d] Pyrimidin-3-yl) piperidine-1-carboxylate (7.6 mg, 0.017 mmol) and 5- (methylsulfonyl) indoline (4.5 mg, 0.023 mmol) in N, N-dimethylformamide (1 mL).
  • Test Example 1 Insulin Secretion Promoting Action Hamster pancreatic ⁇ cell line HIT-T15 cells are passaged using Ham's F-12K medium containing penicillin (100 units / mL), streptomycin (100 ⁇ g / mL) and 10% fetal bovine serum. Subcultured. Cells were seeded in a 24-well culture plate, cultured for 48 hours at 37 ° C., and then washed with a KRBH buffer containing 0.1% albumin. Subsequently, it left still at 37 degreeC with the same buffer for 1 hour.
  • Glucose was added to this to a final concentration of 2 mM, and the compound of the present invention dissolved in dimethyl sulfoxide at a concentration 1000 times the concentration (from 0.0001 ⁇ M to 10 ⁇ M at a common ratio of 10) was added to the buffer. It was added under the condition of 0.1% by volume. After adding the compound of the present invention, the mixture was allowed to stand at 37 ° C. for 1 hour, and then the insulin concentration contained in the supernatant was measured with an insulin kit (Setty Medical Co., Ltd.). As the standard solution, a hamster insulin standard solution (Shiba Goat Co., Ltd.) was used. A control to which only dimethyl sulfoxide was added was used. The results are shown in Table 2 as 50% effective concentration (EC 50 value, 50% effect concentration) of each test compound. The EC 50 value was calculated using a statistical analysis program, SAS preclinical package Ver 5.0 (SAS Institute Japan Co., Tokyo).
  • the compound of the present invention has a strong insulin secretion promoting effect.
  • the piperidine derivative represented by the general formula (1) of the present invention or a salt thereof, or a solvate thereof has an excellent insulin secretion promoting action and is useful for the prevention and / or treatment of diabetes, Has industrial applicability.

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Abstract

A novel compound that has the effect of promoting insulin secretion from pancreatic β 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

新規なピペリジン誘導体及びこれを含有する医薬Novel piperidine derivatives and medicaments containing the same
　本発明は、膵臓β細胞からのインスリン分泌を促進する作用を有し、高血糖に起因する疾患、例えば糖尿病を予防及び／又は治療する薬剤に関する。 The present invention relates to a drug having an action of promoting insulin secretion from pancreatic β cells and preventing and / or treating diseases caused by hyperglycemia such as diabetes.
　膵臓は内胚葉由来の内分泌・外分泌腺組織で、内分泌細胞・腺房細胞・導管細胞から構成される。内分泌細胞である膵ランゲルハンス氏島（膵ラ氏島）は膵臓全体の１％を構成し、主に４つの細胞に分類される。即ち、グルカゴンを分泌するα細胞、インスリンを分泌するβ細胞、ソマトスタチンを合成・分泌するδ細胞、膵性ポリペプチドを合成・分泌するＦ細胞である。このうち、β細胞から分泌されるインスリンは主な生理機能として血糖を低下させる作用を有し、血糖降下作用を示す唯一のホルモンでもある。インスリンは、膵臓β細胞において血糖の上昇を感知することにより分泌され、門脈内に放出される。放出されたインスリンは、肝臓においては糖新生や糖放出を抑制し、末梢組織である脂肪・筋肉組織では糖取り込みを促進することにより生体の血糖レベルを保つ作用をする。 The pancreas is an endocrine / exocrine gland tissue derived from the endoderm, and is composed of endocrine cells, acinar cells, and duct cells. Pancreatic Langerhans Islet (pancreatic La Islet), which is an endocrine cell, constitutes 1% of the entire pancreas and is mainly classified into four cells. That is, α cells that secrete glucagon, β cells that secrete insulin, δ cells that synthesize and secrete somatostatin, and F cells that synthesize and secrete pancreatic polypeptides. Of these, insulin secreted from β cells has the effect of lowering blood sugar as a main physiological function, and is the only hormone that exhibits a hypoglycemic action. Insulin is secreted by sensing an increase in blood glucose in the pancreatic β cells and released into the portal vein. The released insulin suppresses gluconeogenesis and sugar release in the liver, and promotes glucose uptake in fat and muscle tissues, which are peripheral tissues, thereby maintaining the blood sugar level of the living body.
　糖尿病は、インスリン欠乏、あるいは、その作用不足により引き起こされる持続的高血糖状態である。糖尿病は主に、自己免疫疾患などにより膵インスリン分泌異常によって生じるインスリン依存型糖尿病（ＩＤＤＭ）と、インスリン作用不足（インスリン抵抗性）により持続的高インスリン状態を招き、それに伴う膵疲弊によるインスリン分泌能低下が原因となるインスリン非依存型糖尿病（ＮＩＤＤＭ）の二つの種類に分けられる。糖尿病による持続的高血糖は、血管障害を引き起こし、多臓器に合併症を引き起こす。代表的な合併症として、糖尿病性腎症、糖尿病性網膜症、糖尿病性神経症などがあげられ、生活の質（ＱＯＬ）の低下、医療費の増大、生存率の低下などが問題視されている。 Diabetes is a persistent hyperglycemia caused by insulin deficiency or lack of action. Diabetes mainly causes insulin-dependent diabetes mellitus (IDDM) caused by abnormal pancreatic insulin secretion due to autoimmune diseases, etc., and insulin secretion ability due to pancreatic exhaustion resulting from persistent high insulin state due to insufficient insulin action (insulin resistance) It is divided into two types of non-insulin dependent diabetes mellitus (NIDDM) caused by a decrease. Persistent hyperglycemia due to diabetes causes vascular damage and complications in multiple organs. Typical complications include diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, etc., and problems such as decreased quality of life (QOL), increased medical costs, decreased survival rate, etc. Yes.
　糖尿病の治療には、運動療法、食事療法、薬物療法が行われる。薬物療法に用いられる薬剤としては、例えば、膵臓β細胞からのインスリン分泌を促進する薬剤、インスリン抵抗性を改善する薬剤、糖の吸収を抑制する薬剤、糖の利用を促進する薬剤などがある。中でもインスリン分泌促進剤は、血中インスリン濃度を上昇させ、血糖を低下させる効果が期待出来ることから、高血糖を抑制し、糖尿病を改善させることが期待されており、スルホニルウレア製剤（ＳＵ薬）、速攻型インスリン分泌促進薬、ＤＰＰＩＶ阻害薬（非特許文献１参照）、ＧＬＰ－１アナログ（非特許文献２参照）などが糖尿病治療の現場で実際に用いられている。しかしながら、日本において最も繁用されているＳＵ薬は、膵臓β細胞を刺激し内因性インスリン分泌を促進するが（非特許文献３参照）、副作用として低血糖を呈する場合があり、特に高齢者、腎機能低下者や食事が不規則な場合の使用においては注意が必要となる。また、体重増加等の副作用も報告されている。さらに、初期投与時から効果が見られない一次無効や、投与期間中に臨床効果がなくなる二次無効が起こることがあり（非特許文献４参照）、これらの副作用を軽減し、またインスリン分泌能力を損なわないよう膵臓β細胞に対する負担の少ないインスリン分泌促進剤の開発が望まれている。 運動 Exercise therapy, diet therapy, and drug therapy are used to treat diabetes. Examples of the drug used for drug therapy include a drug that promotes insulin secretion from pancreatic β cells, a drug that improves insulin resistance, a drug that suppresses sugar absorption, and a drug that promotes the use of sugar. Among them, an insulin secretagogue is expected to increase blood insulin concentration and lower blood sugar, and is therefore expected to suppress hyperglycemia and improve diabetes. A sulfonylurea preparation (SU drug), Rapid insulin secretion promoters, DPPIV inhibitors (see Non-Patent Document 1), GLP-1 analogs (see Non-Patent Document 2), etc. are actually used in the field of diabetes treatment. However, the most commonly used SU drug in Japan stimulates pancreatic β-cells and promotes endogenous insulin secretion (see Non-Patent Document 3), but may exhibit hypoglycemia as a side effect, particularly in the elderly, Care should be taken when using this product if the patient has impaired renal function or if the diet is irregular. Also, side effects such as weight gain have been reported. Furthermore, there may be a primary ineffectiveness in which no effect is seen from the initial administration, or a secondary ineffectiveness in which clinical effects are lost during the administration period (see Non-Patent Document 4), and these side effects are reduced, and the insulin secretion ability Development of an insulin secretagogue that reduces the burden on pancreatic β cells is desired.
　縮合型複素環を４位に有するピペリジン誘導体としては、副腎皮質刺激ホルモン放出因子拮抗作用を有する化合物（特許文献１、２、３、４、５）、細胞増殖抑制活性等を有する化合物（特許文献６）等が報告されている。また、ＧＰＲ１１９に関与する縮合環化合物（特許文献７、８）が報告されているが、本発明化合物とは構造が異なる。一方、縮合ピリジン又は縮合ピリミジン骨格を有する化合物としては、ＦＸＲ（Ｆａｒｎｅｓｏｉｄ　Ｘ　ｒｅｃｅｐｔｏｒ）阻害作用を有する化合物（特許文献９）、代謝性疾患の治療剤として有用な化合物（特許文献１０及び１１）、プロテインキナーゼ阻害剤として有用な化合物（特許文献１２及び１３）、薬物耐性の治療剤として有用な化合物（特許文献１４）が報告されている。 Examples of piperidine derivatives having a condensed heterocyclic ring at the 4-position include compounds having an adrenocorticotropic hormone releasing factor antagonistic action (Patent Documents 1, 2, 3, 4, 5), compounds having cell growth inhibitory activity, etc. (Patent Documents) 6) etc. have been reported. Moreover, although condensed ring compounds (Patent Documents 7 and 8) related to GPR119 have been reported, the structure is different from the compounds of the present invention. On the other hand, as a compound having a condensed pyridine or condensed pyrimidine skeleton, a compound having an FXR (Farneoside X receptor) inhibitory action (Patent Document 9), a compound useful as a therapeutic agent for metabolic diseases (Patent Documents 10 and 11), a protein Compounds useful as kinase inhibitors (patent documents 12 and 13) and compounds useful as drug resistance therapeutic agents (patent document 14) have been reported.
ＥＰ１１４９５８３公報EP 1149583 ＷＯ２０１０／０５８４８９号パンフレットWO2010 / 058489 pamphlet ＥＰ１０９７７０９公報EP1097709 特開２００１－５１４２６０号公報JP 2001-514260 A 特開２０００－１０９４３１号公報JP 2000-109431 A ＷＯ２０００／０４３３９４号パンフレットWO2000 / 043394 pamphlet ＷＯ２０１０／０８８５１８号パンフレットWO2010 / 088518 pamphlet ＷＯ２０１０／０９５６６３号パンフレットWO2010 / 095663 pamphlet ＷＯ２００９／１２７３２１号パンフレットWO2009 / 127321 pamphlet ＷＯ２００７／１１５８２２号パンフレットWO2007 / 115822 pamphlet ＷＯ２００６／０７７４０１号パンフレットWO2006 / 077401 pamphlet ＷＯ２００５／１１３５６０号パンフレットWO2005 / 113560 pamphlet ＷＯ２００９／０７０５２４号パンフレットWO2009 / 070524 pamphlet ＷＯ２００４／０６５３８９号パンフレットWO2004 / 065389 pamphlet
　本発明の課題は、膵臓β細胞からのインスリン分泌を促進する作用を有し、高血糖に起因する疾患、例えば糖尿病の予防治療薬として有用な化合物を提供することにある。 An object of the present invention is to provide a compound having an action of promoting insulin secretion from pancreatic β cells and useful as a prophylactic or therapeutic drug for diseases caused by hyperglycemia such as diabetes.
　本発明者らは、インスリン分泌促進活性を有する化合物を見出す研究の一環として、ハムスター膵臓β細胞株ＨＩＴ－Ｔ１５細胞を用いて、インスリン分泌を促進する化合物の探索を行ったところ、一般式（１）で示されるピペリジン誘導体が、優れた膵臓β細胞からのインスリン分泌を促進する作用を有し、糖尿病予防治療薬として有用であることを見出し、本発明を完成した。 As part of research to find a compound having insulin secretion promoting activity, the present inventors searched for a compound that promotes insulin secretion using a hamster pancreatic β cell line HIT-T15 cell. The piperidine derivative represented by (1) was found to have an excellent effect of promoting insulin secretion from pancreatic β cells, and was useful as a therapeutic agent for diabetes, and the present invention was completed.
　即ち、本発明は、以下に示す発明に関する。
［１］次の一般式（１）： That is, this invention relates to the invention shown below.
[1] The following general formula (1):
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
［式中、
Ａ及びＢは、一方が窒素原子を示し、他方が窒素原子又はＣＲ８（ここで、Ｒ８は、水素原子、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、アミノ基又はニトロ基を示す）を示し；
Ｄは、窒素原子又はＣＲ９（ここで、Ｒ９は、水素原子、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、アミノ基又はニトロ基を示す）を示し；
Ｅは、窒素原子又はＣＲ１０（ここで、Ｒ１０は、水素原子、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、アミノ基又はニトロ基を示す）を示し；
Ｘは、酸素原子、硫黄原子、－（ＣＨ２）ｎ－Ｎ（Ｒ１１）－又は－（ＣＨ２）ｎ－ＣＨ（Ｒ１２）－（ここで、Ｒ１１及びＲ１２は、それぞれ水素原子又はＣ１－６アルキル基を示し、ｎは、０又は１を示す）を示し；
Ｙは酸素原子、硫黄原子又は窒素原子を示し；
Ｚは酸素原子、硫黄原子又は窒素原子を示し；
Ｒ１及びＲ３は、それぞれ独立して、水素原子、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、アミノ基又はニトロ基を示すか、
あるいは、Ｒ１とＲ１１又はＲ１とＲ１２が一緒になって、
ヘテロ環を形成してもよく；
Ｒ２は、水素原子、－Ｓ（Ｏ）Ｒ１３、－Ｓ（Ｏ）２Ｒ１４、－ＣＯ２Ｒ１５　又は－ＣＯＮＲ１６Ｒ１７、アリール基、ヘテロアリール基（ここで、Ｒ１３及びＲ１４は、それぞれＣ１－６アルキル基、Ｃ３－８シクロアルキル基、Ｃ２－６アルケニル基、Ｃ２－６アルキニル基、置換基を有してもよいＣ６－１０アリール基、アミノ基、モノ（Ｃ１－６アルキル）アミノ基又はジ（Ｃ１－６アルキル）アミノ基を示し、Ｒ１５は、Ｃ１－６アルキル基を示し、Ｒ１６及びＲ１７は、それぞれ独立して、水素原子又は置換基を有してもよいＣ１－６アルキル基を示す）を示し；
Ｒ４は、水素原子、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、Ｃ１－６アルキルチオ基又はアミノ基を示し；
Ｒ５及びＲ６は、それぞれ独立して、水素原子又はＣ１－６アルキル基を示し；
Ｒ７は、Ｃ１－６アルキル基、－Ｃ（Ｏ）Ｒ１８、－Ｃ（Ｓ）Ｒ１９、－Ｓ（Ｏ）２Ｒ２０、置換基を有してもよいＣ６－１０アリール基又は置換基を有してもよい５－１０員ヘテロアリール基（ここで、Ｒ１８は、置換基を有してもよいＣ１－６アルキル基、置換基を有してもよいＣ１－６アルコキシ基、置換基を有していてもよいＣ２－６アルケニルオキシ基、置換基を有していてもよいＣ６－１０アリールオキシ基、置換基を有していてもよいＣ６－１０アリールＣ１－６アルコキシ基、置換基を有してもよいＣ３－８シクロアルキルオキシ基、置換基を有していてもよいヘテロ環オキシ基、置換基を有してもよい５－１０員ヘテロアリール基又はモノ（Ｃ１－６アルキル）アミノ基を示し、Ｒ１９及びＲ２０は、それぞれＣ１－６アルキル基、ハロＣ１－６アルキル基、Ｃ３－８シクロアルキル基、モノ（Ｃ１－６アルキル）アミノ基、置換基を有してもよいＣ６－１０アリール基又は置換基を有してもよい５－１０員ヘテロアリール基を示す）を示す］
で表される化合物若しくはその塩、又はそれらの溶媒和物。 [Where:
A and B each represents a nitrogen atom, and the other is a nitrogen atom or CR 8 (where R 8 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, an amino group, or Nitro group)
D represents a nitrogen atom or CR 9 (wherein R 9 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, an amino group or a nitro group);
E represents a nitrogen atom or CR 10 (wherein R 10 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, an amino group or a nitro group);
X is an oxygen atom, a sulfur atom, — (CH 2 ) n—N (R 11 ) — or — (CH 2 ) n—CH (R 12 ) — (where R 11 and R 12 are each a hydrogen atom, Or a C 1-6 alkyl group, and n represents 0 or 1);
Y represents an oxygen atom, a sulfur atom or a nitrogen atom;
Z represents an oxygen atom, a sulfur atom or a nitrogen atom;
R 1 and R 3 each independently represent a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, an amino group or a nitro group,
Or R 1 and R 11 or R 1 and R 12 together
May form a heterocycle;
R 2 represents a hydrogen atom, —S (O) R 13 , —S (O) 2 R 14 , —CO 2 R 15 or —CONR 16 R 17 , an aryl group, a heteroaryl group (where R 13 and R 14 represents a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, an optionally substituted C 6-10 aryl group, an amino group, respectively. A mono (C 1-6 alkyl) amino group or a di (C 1-6 alkyl) amino group, R 15 represents a C 1-6 alkyl group, and R 16 and R 17 are each independently A hydrogen atom or a C 1-6 alkyl group which may have a substituent);
R 4 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group or an amino group;
R 5 and R 6 each independently represents a hydrogen atom or a C 1-6 alkyl group;
R 7 is a C 1-6 alkyl group, —C (O) R 18 , —C (S) R 19 , —S (O) 2 R 20 , an optionally substituted C 6-10 aryl group Or a 5- to 10-membered heteroaryl group which may have a substituent (wherein R 18 is a C 1-6 alkyl group which may have a substituent, a C 1 -1 which may have a substituent) 6 an alkoxy group, an optionally substituted C 2-6 alkenyloxy group, an optionally substituted C 6-10 aryloxy group, an optionally substituted C 6- 10 aryl C 1-6 alkoxy group, optionally substituted C 3-8 cycloalkyloxy group, optionally substituted heterocyclic oxy group, optionally substituted 5- Represents a 10-membered heteroaryl group or a mono (C 1-6 alkyl) amino group, R 19 and R 20 represent C 1-6 alkyl group, halo C 1-6 alkyl group, C 3-8 cycloalkyl group, mono (C 1-6 alkyl) amino group, optionally substituted C 6-10 aryl group Or a 5- to 10-membered heteroaryl group which may have a substituent)
Or a salt thereof, or a solvate thereof.
［２］Ｒ１とＲ１１又はＲ１とＲ１２が一緒になって形成されるヘテロ環が、次式： [2] A heterocycle formed by combining R 1 and R 11 or R 1 and R 12 together has the following formula:
Figure JPOXMLDOC01-appb-C000007
 ［式中、
Ｒ２１は水素原子、Ｃ１－６アルキル基、－Ｃ（Ｏ）Ｒ２２又は－Ｓ（Ｏ）２Ｒ２３（ここで、Ｒ２２及びＲ２３はそれぞれＣ１－６アルキル基、Ｃ３－８シクロアルキル基を示す）を示し、波線部はＤ及びＥによって構成されている芳香環を示す］
から選ばれる、前記［１］に記載の化合物若しくはその塩、又はそれらの溶媒和物。
Figure JPOXMLDOC01-appb-C000007
 [Where:
R 21 represents a hydrogen atom, a C 1-6 alkyl group, —C (O) R 22 or —S (O) 2 R 23 (where R 22 and R 23 represent a C 1-6 alkyl group, C 3-6 8 represents a cycloalkyl group, and the wavy line represents an aromatic ring constituted by D and E]
The compound according to [1] or a salt thereof, or a solvate thereof, selected from the group consisting of:
［３］Ｒ１とＲ１１又はＲ１とＲ１２が一緒になって形成されるヘテロ環が、次式： [3] A heterocycle formed by combining R 1 and R 11 or R 1 and R 12 together has the following formula:
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
から選ばれる、［１］に記載の化合物若しくはその塩、又はそれらの溶媒和物。 The compound or a salt thereof according to [1], or a solvate thereof, selected from
［４］次式（１ａ）： [4] Formula (1a):
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
（式中、Ｒ２～Ｒ７は前記と同じ）
で表される、［１］に記載の化合物、若しくはその塩、又はそれらの溶媒和物。 (Wherein R 2 to R 7 are the same as above)
Or a salt thereof, or a solvate thereof according to [1].
［５］Ｒ１が、水素原子、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、アミノ基又はニトロ基である［１］に記載の化合物若しくはその塩、又はそれらの溶媒和物。 [5] The compound or salt thereof according to [1], wherein R 1 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, an amino group, or a nitro group, or a solvate thereof object.
［６］次式（１ｂ）： [6] The following formula (1b):
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
（式中、Ｒ１は水素原子、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、アミノ基又はニトロ基を示し、Ｒ２～Ｒ７は前記と同じ） (Wherein R 1 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, an amino group or a nitro group, and R 2 to R 7 are the same as above)
で表される［１］に記載の化合物若しくはその塩、又はそれらの溶媒和物。 Or a salt thereof, or a solvate thereof according to [1].
［７］下記の化合物群：
　ｔｅｒｔ－ブチル　４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－４－イル）ピペリジン－１－カルボキシレート、３－（１－（５－クロロピリミジン－２－イル）ピペリジン－４－イル）－７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン、３－（１－（５－エチルピリミジン－２－イル）ピペリジン－４－イル）－７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン、３－（１－（５－ブロモピリミジン－２－イル）ピペリジン－４－イル）－７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン、３－（１－（５－フロロピリミジン－２－イル）ピペリジン－４－イル）－７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン、エチル　２－（４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）ピリミジン－５－カルボキシレート、２－（４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）ピリミジン－５－カルボン酸、７－（５－（メチルスルホニル）インドリン－１－イル）－３－（１－（５－（トリフロロメチル）ピリミジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン、２－（４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）ピリミジン－５－オール、３－（１－（５－メトキシピリミジン－２－イル）ピペリジン－４－イル）－７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン、７－（５－（メチルスルホニル）インドリン－１－イル）－３－（１－（５－フェニルピリミジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン、７－（５－（メチルスルホニル）インドリン－１－イル）－３－（１－（５－（トリフロロメチル）ピリジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン、イソプロピル　４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、エチル　４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、２－フロロエチル　４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、２－メトキシエチル　４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、テトラヒドロ－２Ｈ－ピラン－４－イル　４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、アリル　２－（４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）ピリミジン－５－カルボキシレート、ｔｅｒｔ－ブチル　４－（７－（５（メチルスルフィニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、７－（５－（メチルスルフィニル）インドリン－１－イル）－３－（１－（５－（トリフロロメチル）ピリジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン、２，２－ジメチル－１－（４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）プロパン－１－オン、ｔｅｒｔ－ブチル　４－（７－（（２－フロロ－４－（メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、Ｎ－（２－フロロ－４－（メチルスルホニル）フェニル）－３－（１－（５－（トリフロロメチル）ピリミジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－７－アミン、Ｎ－（２－フロロ－４－（メチルスルホニル）フェニル）３－（１－（５－（トリフロロメチル）ピリジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］－７－アミン、１，１，１－トリフロロ－２－メチルプロパン－２－イル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、２，２，２－トリフロロエチル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、２，２，２－トリクロロエチル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、ネオペンチル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、４，４－ジフロロシクロヘキシル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、オキセタン－３－イル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、（３－メチルオキセタン－３－イル）メチル　４－（７－（（２－フロロ－４－（メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、フェニル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、４－ニトロフェニル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、（４－（７－（（２－フロロ－４－（メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）（ピリジン－２－イル）メタノン、ｔｅｒｔ－ブチル　４－（７－（４－（メチルスルホニル）フェノキシ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、ｔｅｒｔ－ブチル　４－（７－（２－フロロ－４－（メチルスルホニル）フェノキシ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、ｔｅｒｔ－ブチル　４－（７－（４－（１Ｈ－テトラゾル－１－イル）フェノキシ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、及びｔｅｒｔ－ブチル　４－（１－メチル－７－（５－（メチルスルホニル）インドリン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートから選ばれる［１］～［６］のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物。 [7] The following compound group:
tert-Butyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-4-yl) piperidine-1-carboxylate, 3- (1- (5- Chloropyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine, 3- (1- (5-ethylpyrimidine- 2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine, 3- (1- (5-bromopyrimidin-2-yl) ) Piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine, 3- (1- (5-fluoropyrimidine) Gin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine, ethyl 2- (4- (7- (5- (Methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidine-5-carboxylate, 2- (4- (7- (5- (methyl Sulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidine-5-carboxylic acid, 7- (5- (methylsulfonyl) indoline-1-yl) -3- (1- (5- (trifluoromethyl) pyrimidin-2-yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidine, 2- (4- (7- (5 -(Methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidin-5-ol, 3- (1- (5-methoxypyrimidine-2-) Yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine, 7- (5- (methylsulfonyl) indoline-1-yl)- 3- (1- (5-phenylpyrimidin-2-yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidine, 7- (5- (methylsulfonyl) indoline-1-yl) -3- ( 1- (5- (trifluoromethyl) pyridin-2-yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidine, isopropyl 4- (7- (5- ( Methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-carboxylate, ethyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate, 2-fluoroethyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine -3-yl) piperidine-1-carboxylate, 2-methoxyethyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine- 1-carboxylate, tetrahydro-2H-pyran-4-yl 4- (7- (5- (methylsulfonyl) i Ndolin-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate, allyl 2- (4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidin-5-carboxylate, tert-butyl 4- (7- (5 (methylsulfinyl) indoline-1-yl) isoxazolo [4 5-d] pyrimidin-3-yl) piperidine-1-carboxylate, 7- (5- (methylsulfinyl) indoline-1-yl) -3- (1- (5- (trifluoromethyl) pyridine-2- Yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidine, 2,2-dimethyl-1- (4- (7- (5- (methylsulf Nyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) propan-1-one, tert-butyl 4- (7-((2-fluoro-4- (Methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate, N- (2-fluoro-4- (methylsulfonyl) phenyl) -3- (1- (5- (trifluoromethyl) pyrimidin-2-yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidin-7-amine, N- (2-fluoro-4- (methylsulfonyl) phenyl) 3 -(1- (5- (trifluoromethyl) pyridin-2-yl) piperidin-4-yl) isoxazolo [4,5-d] -7-amine, 1,1,1-trif Ro-2-methylpropan-2-yl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate 2,2,2-trifluoroethyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate 2,2,2-trichloroethyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate, Neopentyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidine-3-i ) Piperidine-1-carboxylate, 4,4-difluorocyclohexyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine -1-carboxylate, oxetan-3-yl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxyl , (3-Methyloxetane-3-yl) methyl 4- (7-((2-Fluoro-4- (methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine- 1-carboxylate, phenyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxa B [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate, 4-nitrophenyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5 -D] pyrimidin-3-yl) piperidine-1-carboxylate, (4- (7-((2-fluoro-4- (methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidine-3- Yl) piperidin-1-yl) (pyridin-2-yl) methanone, tert-butyl 4- (7- (4- (methylsulfonyl) phenoxy) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine- 1-carboxylate, tert-butyl 4- (7- (2-fluoro-4- (methylsulfonyl) phenoxy) isoxazolo [4,5-d ] Pyrimidin-3-yl) piperidine-1-carboxylate, tert-butyl 4- (7- (4- (1H-tetrazol-1-yl) phenoxy) isoxazolo [4,5-d] pyrimidin-3-yl) Piperidine-1-carboxylate and tert-butyl 4- (1-methyl-7- (5- (methylsulfonyl) indoline-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-3-yl) The compound according to any one of [1] to [6] selected from piperidine-1-carboxylate, a salt thereof, or a solvate thereof.
［８］前記［１］～［７］のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物、及び医薬として許容される担体を含有する医薬組成物。 [8] A pharmaceutical composition comprising the compound according to any one of [1] to [7] or a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.
［９］前記［１］～［７］のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物を有効成分とする、インスリン分泌促進剤。 [9] An insulin secretion promoter comprising the compound or salt thereof according to any one of [1] to [7] or a solvate thereof as an active ingredient.
［１０］前記［１］～［７］のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物を有効成分とする、血糖低下剤。 [10] A hypoglycemic agent comprising the compound or salt thereof according to any one of [1] to [7] or a solvate thereof as an active ingredient.
［１１］前記［１］～［７］のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物を有効成分とする、糖尿病の予防及び／又は治療剤。 [11] A prophylactic and / or therapeutic agent for diabetes comprising the compound according to any one of [1] to [7] or a salt thereof, or a solvate thereof as an active ingredient.
［１２］前記［１］～［７］のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物の有効量を投与することを特徴とするインスリン分泌促進方法。 [12] A method for promoting insulin secretion, comprising administering an effective amount of the compound according to any one of [1] to [7] or a salt thereof, or a solvate thereof.
［１３］前記［１］～［７］のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物の有効量を投与することを特徴とする血糖低下方法。 [13] A method for lowering blood glucose, comprising administering an effective amount of the compound according to any one of [1] to [7] or a salt thereof, or a solvate thereof.
［１４］前記［１］～［７］のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物の有効量を投与することを特徴とする、糖尿病の予防及び／又は治療方法。 [14] A method for the prophylaxis and / or treatment of diabetes, comprising administering an effective amount of the compound according to any one of [1] to [7] or a salt thereof, or a solvate thereof.
［１５］インスリンを分泌促進するための、前記［１］～［７］のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物。 [15] The compound according to any one of the above [1] to [7] or a salt thereof, or a solvate thereof, for promoting secretion of insulin.
［１６］血糖を低下するための、前記［１］～［７］のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物。 [16] The compound according to any one of the above [1] to [7] or a salt thereof, or a solvate thereof for reducing blood glucose.
［１７］糖尿病を予防及び／又は治療するための、前記［１］～［７］のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物。 [17] The compound according to any one of the above [1] to [7] or a salt thereof, or a solvate thereof for preventing and / or treating diabetes.
［１８］インスリン分泌促進剤、血糖低下剤又は糖尿病予防及び／又は治療剤製造のための、前記［１］～［７］のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物の使用。 [18] A compound or a salt thereof according to any one of [1] to [7] above, or a solvate thereof, for producing an insulin secretion promoter, a hypoglycemic agent, or a preventive and / or therapeutic agent for diabetes. use.
　本発明のピペリジン誘導体若しくはその塩、又はそれらの溶媒和物は、膵臓β細胞からインスリン分泌を強力に促進する作用を有する経口投与可能な低分子化合物であり、ヒトを含む哺乳類の高血糖に起因する疾患、例えば糖尿病の予防及び／又は治療剤として有用である。 The piperidine derivative of the present invention or a salt thereof, or a solvate thereof is an orally administrable low-molecular compound having an action of strongly promoting insulin secretion from pancreatic β cells, and is caused by hyperglycemia in mammals including humans. It is useful as a preventive and / or therapeutic agent for a disease that occurs, such as diabetes.
　本明細書において、「ハロゲン原子」としては、例えば、フッ素原子、塩素原子、臭素原子又はヨウ素原子等が挙げられる。 In the present specification, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
　本明細書において、「Ｃ１－６アルキル基」とは、直鎖又は分岐鎖の炭素数１～６のアルキル基を意味し、例えば、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｔｅｒｔ－ブチル基、ｎ－ペンチル基、２－メチルブチル基、２，２－ジメチルプロピル基、ｎ－ヘキシル基等が挙げられる。 In the present specification, the “C 1-6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, Examples thereof include n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, 2-methylbutyl group, 2,2-dimethylpropyl group, n-hexyl group and the like.
　本明細書において、「ハロＣ１－６アルキル基」とは、同一若しくは異なった１個～置換可能な最大数のハロゲン原子で置換されているＣ１－６アルキル基であり、例えば、モノフルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、モノクロロメチル基、ジクロロメチル基、トリクロロメチル基、モノブロモメチル基、モノヨードメチル基又は２，２，２－トリフルオロエチル基等が挙げられる。 In the present specification, "halo C 1-6 alkyl group", a C 1-6 alkyl group substituted by the same or different 1 to replaceable maximum halogen atoms, for example, monofluoromethyl Examples include a methyl group, a difluoromethyl group, a trifluoromethyl group, a monochloromethyl group, a dichloromethyl group, a trichloromethyl group, a monobromomethyl group, a monoiodomethyl group, or a 2,2,2-trifluoroethyl group.
　本明細書において、「Ｃ３－８シクロアルキル基」としては、炭素数３～８、好ましくは炭素数３～６の単環式、多環式又は縮合環式のシクロアルキル基が挙げられる。このようなシクロアルキル基としては、例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基、シクロオクチル基等が挙げられる。 In the present specification, examples of the “C 3-8 cycloalkyl group” include monocyclic, polycyclic or condensed cyclic cycloalkyl groups having 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Examples of such a cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like.
　本明細書において、「Ｃ２－６アルケニル基」としては、例えば、ビニル基、プロパ－１－エン－１－イル基（プロペニル基）、プロパ－２－エン－１－イル基（アリル基）、イソプロペニル基、ブタ－１－エン－１－イル基、ブタ－２－エン－１－イル基（クロチル基）、ブタ－３－エン－１－イル基、２－メチルプロパ－２－エン－１－イル基、１－メチルプロパ－２－エン－１－イル基、ペンタ－１－エン－１－イル基、ペンタ－２－エン－１－イル基、ペンタ－３－エン－１－イル基、ペンタ－４－エン－１－イル基、３－メチルブタ－２－エン－１－イル基、３－メチルブタ－３－エン－１－イル基、ヘキサ－１－エン－１－イル基、ヘキサ－２－エン－１－イル基、ヘキサ－３－エン－１－イル基、ヘキサ－４－エン－１－イル基、ヘキサ－５－エン－１－イル基、４－メチルペンタ－３－エン－１－イル基等が挙げられる。 In the present specification, examples of the “C 2-6 alkenyl group” include a vinyl group, a prop-1-en-1-yl group (propenyl group), and a prop-2-en-1-yl group (allyl group). , Isopropenyl group, but-1-en-1-yl group, but-2-en-1-yl group (crotyl group), but-3-en-1-yl group, 2-methylprop-2-ene- 1-yl group, 1-methylprop-2-en-1-yl group, penta-1-en-1-yl group, penta-2-en-1-yl group, penta-3-en-1-yl group Penta-4-en-1-yl group, 3-methylbut-2-en-1-yl group, 3-methylbut-3-en-1-yl group, hexa-1-en-1-yl group, hexa -2-en-1-yl group, hexa-3-en-1-yl group, hexa-4-en-1-yl Group, hexa-5-en-1-yl group, 4-methylpent-3-en-1-yl group and the like.
　本明細書において、「Ｃ２－６アルキニル基」としては、例えば、エチニル基、プロパ－１－イン－１－イル基、プロパ－２－イン－１－イル基（プロパルギル基）、ブタ－１－イン－１－イル基、ブタ－３－イン－１－イル基、１－メチルプロパ－２－イン－１－イル基、ペンタ－１－イン－１－イル基、ペンタ－４－イン－１－イル基、ヘキサ－１－イン－１－イル基、ヘキサ－５－イン－１－イル基等が挙げられる。 In the present specification, examples of the “C 2-6 alkynyl group” include ethynyl group, prop-1-in-1-yl group, prop-2-yn-1-yl group (propargyl group), but-1 -In-1-yl group, but-3-yn-1-yl group, 1-methylprop-2-in-1-yl group, penta-1-in-1-yl group, penta-4-in-1 -Yl group, hexa-1-in-1-yl group, hexa-5-in-1-yl group and the like.
　本明細書において、「Ｃ１－６アルコキシ基」としては、例えば、メトキシ基、エトキシ基、ｎ－プロポキシ基、イソプロポキシ基、ｎ－ブトキシ基、イソブトキシ基、ｓｅｃ－ブトキシ基、ｔｅｒｔ－ブトキシ基、ｎ－ペントキシ基、イソペントキシ基、ネオペントキシ基、ｎ－ヘキシルオキシ基、イソヘキシルオキシ基等が挙げられる。 In the present specification, examples of the “C 1-6 alkoxy group” include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group. N-pentoxy group, isopentoxy group, neopentoxy group, n-hexyloxy group, isohexyloxy group and the like.
　本明細書において、「Ｃ３－８シクロアルキルオキシ基」としては、例えばシクロプロピルオキシ基、シクロブチルオキシ基、シクロペンチルオキシ基、シクロヘキシルオキシ基、シクロヘプチルオキシ基、シクロオクチルオキシ基が挙げられる。 In the present specification, examples of the “C 3-8 cycloalkyloxy group” include a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, and a cyclooctyloxy group.
　本明細書において、「Ｃ２－６アルケニルオキシ基」としては、例えば、ビニルオキシ基、プロパ－１－エン－１－イルオキシ基（プロペニルオキシ基）、プロパ－２－エン－１－イルオキシ基（アリルオキシ基）、イソプロペニルオキシ基、ブタ－１－エン－１－イルオキシ基、ブタ－２－エン－１－イルオキシ基（クロチルオキシ基）、ブタ－３－エン－１－イルオキシ基、２－メチルプロパ－２－エン－１－イルオキシ基、１－メチルプロパ－２－エン－１－イルオキシ基、ペンタ－１－エン－１－イルオキシ基、ペンタ－２－エン－１－イルオキシ基、ペンタ－３－エン－１－イルオキシ基、ペンタ－４－エン－１－イルオキシ基、３－メチルブタ－２－エン－１－イルオキシ基、３－メチルブタ－３－エン－１－イルオキシ基、ヘキサ－１－エン－１－イルオキシ基、ヘキサ－２－エン－１－イルオキシ基、ヘキサ－３－エン－１－イルオキシ基、ヘキサ－４－エン－１－イルオキシ基、ヘキサ－５－エン－１－イルオキシ基、４－メチルペンタ－３－エン－１－イルオキシ基等が挙げられる。 In the present specification, examples of the “C 2-6 alkenyloxy group” include a vinyloxy group, a prop-1-en-1-yloxy group (propenyloxy group), a prop-2-en-1-yloxy group (allyloxy group). Group), isopropenyloxy group, but-1-en-1-yloxy group, but-2-en-1-yloxy group (crotyloxy group), but-3-en-1-yloxy group, 2-methylprop-2 -En-1-yloxy group, 1-methylprop-2-en-1-yloxy group, penta-1-en-1-yloxy group, penta-2-en-1-yloxy group, penta-3-ene-1 -Yloxy group, penta-4-en-1-yloxy group, 3-methylbut-2-en-1-yloxy group, 3-methylbut-3-en-1-yloxy group, Oxa-1-en-1-yloxy group, hexa-2-en-1-yloxy group, hexa-3-en-1-yloxy group, hexa-4-en-1-yloxy group, hexa-5-ene- Examples thereof include a 1-yloxy group and a 4-methylpent-3-en-1-yloxy group.
　本明細書において、「Ｃ１－６アルキルチオ基」としては、例えば、メチルチオ基、エチルチオ基、ｎ－プロピルチオ基、イソプロピルチオ基、ｎ－ブチルチオ基、イソブチルチオ基、ｓｅｃ－ブチルチオ基、ｔｅｒｔ－ブチルチオ基、ｎ－ペンチルチオ基、イソペンチルチオ基、ネオペンチルチオ基、ｎ－ヘキシルチオ基、イソヘキシルチオ基等が挙げられる。 In this specification, examples of the “C 1-6 alkylthio group” include a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, an isobutylthio group, a sec-butylthio group, and a tert-butylthio group. Group, n-pentylthio group, isopentylthio group, neopentylthio group, n-hexylthio group, isohexylthio group and the like.
　本明細書において、「モノ（Ｃ１－６アルキル）アミノ基」とは、前記アルキル基が窒素原子に１つ結合した基を意味し、例えば、メチルアミノ基、エチルアミノ基、プロピルアミノ基、イソプロピルアミノ基、ブチルアミノ基、ｓｅｃ－ブチルアミノ基、ｔｅｒｔ－ブチルアミノ基、ｎ－ペンチルアミノ基、イソペンチルアミノ基、ネオペンチルアミノ基、ｎ－ヘキシルアミノ基、イソヘキシルアミノ基等が挙げられる。 In the present specification, the “mono (C 1-6 alkyl) amino group” means a group in which the alkyl group is bonded to a nitrogen atom, for example, a methylamino group, an ethylamino group, a propylamino group, Examples include isopropylamino group, butylamino group, sec-butylamino group, tert-butylamino group, n-pentylamino group, isopentylamino group, neopentylamino group, n-hexylamino group, and isohexylamino group. .
　本明細書において、「ジ（Ｃ１－６アルキル）アミノ基」とは、同一又は異なって前記アルキル基が窒素原子に２つ結合した基を意味し、例えば、ジメチルアミノ基、メチルエチルアミノ基、ジエチルアミノ基、メチルプロピルアミノ基、エチルプロピルアミノ基、ジプロピルアミノ基、ジイソプロピルアミノ基、ジブチルアミノ基等が挙げられる。 In the present specification, the “di (C 1-6 alkyl) amino group” means the same or different groups in which two alkyl groups are bonded to a nitrogen atom. For example, a dimethylamino group, a methylethylamino group , Diethylamino group, methylpropylamino group, ethylpropylamino group, dipropylamino group, diisopropylamino group, dibutylamino group and the like.
　本明細書において、「Ｃ６－１０アリール基」としては、例えば、フェニル基、ナフチル基、アズレニル基等が挙げられる。 In the present specification, examples of the “C 6-10 aryl group” include a phenyl group, a naphthyl group, an azulenyl group, and the like.
　本明細書において、「置換スルホニル基」とは、アルキル基がスルホニル（－ＳＯ２－）を介して結合した「Ｃ１－６アルキルスルホニル基」、ハロアルキル基がスルホニル基を介して結合した「ハロＣ１－６アルキルスルホニル基」、Ｃ３－８シクロアルキル基がスルホニルを介して結合した「Ｃ３－８シクロアルキルスルホニル基」、Ｃ２－６アルケニル基がスルホニルを介して結合した「Ｃ２－６アルケニルスルホニル基」、Ｃ２－６アルキニル基がスルホニルを介して結合した「Ｃ２－６アルキニルスルホニル基」、アミノ基がスルホニルを介して結合した「スルファモイル基」、モノ（Ｃ１－６アルキル）アミノ基又はジ（Ｃ１－６アルキル）アミノ基がスルホニルを介して結合した「モノ（Ｃ１－６アルキル）スルファモイル基」又は「ジ（Ｃ１－６アルキル）スルファモイル基」、アリール基がスルホニルを介して結合した「Ｃ６－１０アリールスルホニル基」等を意味する。 In this specification, the “substituted sulfonyl group” refers to a “C 1-6 alkylsulfonyl group” in which an alkyl group is bonded via sulfonyl (—SO 2 —), and a “halo group in which a haloalkyl group is bonded via a sulfonyl group”. C 1-6 alkylsulfonyl group ", a C 3-8 cycloalkyl group" C 3-8 cycloalkyl sulfonyl group attached through a sulfonyl ", C 2-6 alkenyl group bonded through a sulfonyl" C 2 -6 alkenylsulfonyl group ", C 2-6 alkynyl group bonded through a sulfonyl" C 2-6 alkynylsulfonyl group ", an amino group is bonded through a sulfonyl" sulfamoyl group ", mono (C 1-6 alkyl) amino group or a di (C 1-6 alkyl) amino group is bonded through a sulfonyl "mono (C 1-6 alkyl) sulfa A “moyl group” or “di (C 1-6 alkyl) sulfamoyl group”, a “C 6-10 arylsulfonyl group” in which an aryl group is bonded via a sulfonyl, and the like are meant.
　本明細書において、「Ｃ１－６アルキルスルホニル基」としては、例えば、メチルスルホニル基、エチルスルホニル基、ｎ－プロピルスルホニル基、イソプロピルスルホニル基、ｎ－ブチルスルホニル基、イソブチルスルホニル基、ｓｅｃ－ブチルスルホニル基、ｔｅｒｔ－ブチルスルホニル基、ｎ－ペンチルスルホニル基、イソペンチルスルホニル基、ネオペンチルスルホニル基、２－メチルブチルスルホニル基、１－メチルブチルスルホニル基、１－エチルプロピルスルホニル基、２，２－ジメチルプロピルスルホニル基、ｎ－ヘキシルスルホニル基、４－メチルペンチルスルホニル基、３－メチルペンチルスルホニル基、２－メチルペンチルスルホニル基、１－メチルペンチルスルホニル基、３，３－ジメチルブチルスルホニル基、２，２－ジメチルブチルスルホニル基、１，１－ジメチルブチルスルホニル基、１，２－ジメチルブチルスルホニル基、１，３－ジメチルブチルスルホニル基、２，３－ジメチルブチルスルホニル基、１－エチルブチルスルホニル基、２－エチルブチルスルホニル基等が挙げられる。 In the present specification, examples of the “C 1-6 alkylsulfonyl group” include, for example, methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-butylsulfonyl group, isobutylsulfonyl group, sec-butyl Sulfonyl group, tert-butylsulfonyl group, n-pentylsulfonyl group, isopentylsulfonyl group, neopentylsulfonyl group, 2-methylbutylsulfonyl group, 1-methylbutylsulfonyl group, 1-ethylpropylsulfonyl group, 2,2- Dimethylpropylsulfonyl group, n-hexylsulfonyl group, 4-methylpentylsulfonyl group, 3-methylpentylsulfonyl group, 2-methylpentylsulfonyl group, 1-methylpentylsulfonyl group, 3,3-dimethylbutylsulfonyl group, 2 , 2-dimethylbutylsulfonyl group, 1,1-dimethylbutylsulfonyl group, 1,2-dimethylbutylsulfonyl group, 1,3-dimethylbutylsulfonyl group, 2,3-dimethylbutylsulfonyl group, 1-ethylbutylsulfonyl group And 2-ethylbutylsulfonyl group.
　本明細書において、「ハロＣ１－６アルキルスルホニル基」としては、例えば、フルオロメチルスルホニル基、ジフルオロメチルスルホニル基、トリフルオロメチルスルホニル基、クロロメチルスルホニル基、ブロモメチルスルホニル基、ヨードメチルスルホニル基、２，２，２－トリフルオロエチルスルホニル基等が挙げられる。 In the present specification, examples of the “halo C 1-6 alkylsulfonyl group” include a fluoromethylsulfonyl group, a difluoromethylsulfonyl group, a trifluoromethylsulfonyl group, a chloromethylsulfonyl group, a bromomethylsulfonyl group, and an iodomethylsulfonyl group. 2,2,2-trifluoroethylsulfonyl group and the like.
　本明細書において、「Ｃ３－８シクロアルキルスルホニル基」としては、例えば、シクロプロピルスルホニル基、シクロブチルスルホニル基、シクロペンチルスルホニル基、シクロヘキシルスルホニル基、シクロへプチルスルホニル基、シクロオクチルスルホニル基等が挙げられる。 In the present specification, examples of the “C 3-8 cycloalkylsulfonyl group” include a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a cyclopentylsulfonyl group, a cyclohexylsulfonyl group, a cycloheptylsulfonyl group, a cyclooctylsulfonyl group, and the like. Can be mentioned.
　本明細書において、「Ｃ２－６アルケニルスルホニル基」としては、例えば、ビニルスルホニル基、プロペニルスルホニル基、アリルスルホニル基、クロチルスルホニル基等が挙げられる。 In the present specification, examples of the “C 2-6 alkenylsulfonyl group” include a vinylsulfonyl group, a propenylsulfonyl group, an allylsulfonyl group, a crotylsulfonyl group, and the like.
　本明細書において、「Ｃ２－６アルキニルスルホニル基」としては、例えば、エチニルスルホニル基、プロパルギルスルホニル基等が挙げられる。 In the present specification, examples of the “C 2-6 alkynylsulfonyl group” include ethynylsulfonyl group, propargylsulfonyl group and the like.
　本明細書において、「モノ（Ｃ１－６アルキル）スルファモイル基」としては、例えば、メチルスルファモイル基、エチルスルファモイル基、プロピルスルファモイル基、イソプロピルスルファモイル基、ブチルスルファモイル基、ｓｅｃ－ブチルスルファモイル基、ｔｅｒｔ－ブチルスルファモイル基、ペンチルスルファモイル基、ヘキシルスルファモイル基等が挙げられる。 In the present specification, examples of the “mono (C 1-6 alkyl) sulfamoyl group” include a methylsulfamoyl group, an ethylsulfamoyl group, a propylsulfamoyl group, an isopropylsulfamoyl group, and a butylsulfamoyl group. Group, sec-butylsulfamoyl group, tert-butylsulfamoyl group, pentylsulfamoyl group, hexylsulfamoyl group and the like.
　本明細書において、「ジ（Ｃ１－６アルキル）スルファモイル基」としては、例えば、ジメチルスルファモイル基、メチルエチルスルファモイル基、ジエチルスルファモイル基、ジプロピルスルファモイル基、ジイソプロピルスルファモイル基、ジブチルスルファモイル基等が挙げられる。 In the present specification, examples of the “di (C 1-6 alkyl) sulfamoyl group” include a dimethylsulfamoyl group, a methylethylsulfamoyl group, a diethylsulfamoyl group, a dipropylsulfamoyl group, and a diisopropylsulfamoyl group. A moyl group, a dibutylsulfamoyl group, etc. are mentioned.
　本明細書において、「Ｃ６－１０アリールスルホニル基」としては、例えば、フェニルスルホニル基、トルエンスルホニル基、ナフチルスルホニル基、アズレニルスルホニル基等が挙げられる。 In the present specification, examples of the “C 6-10 arylsulfonyl group” include a phenylsulfonyl group, a toluenesulfonyl group, a naphthylsulfonyl group, an azulenylsulfonyl group, and the like.
　本明細書において、「ヘテロ環」とは、少なくとも１個の窒素原子、酸素原子又はイオウ原子を有していてもよい、４員ないし１０員の飽和又は不飽和のヘテロ環を意味し、例えば、ピロリジン、ピロリン、ピロール、ピロリジノン、ピロリノン、オキサゾール、イソオキサゾール、チアゾール、イソチアゾール、イミダゾール、ピラゾール、キノリン、イソキノリン、テトラヒドロキノリン、テトラヒドロイソキノリン、インドール、インドリン、ピペリジン、ピペリジノン、ジヒドロピリジン、ジヒドロピリジノン、ピリジン、モルホリン、ピリミジン、チオフェン、フラン、ベンゾフラン、ベンゾチオフェン、テトラヒドロピラン、テトラヒドロフラン、オキセタン等が挙げられる。 In the present specification, the “heterocycle” means a 4- to 10-membered saturated or unsaturated heterocycle which may have at least one nitrogen atom, oxygen atom or sulfur atom, for example, , Pyrrolidine, pyrroline, pyrrole, pyrrolidinone, pyrrolinone, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, indole, indoline, piperidine, piperidinone, dihydropyridine, dihydropyridinone, pyridine Morpholine, pyrimidine, thiophene, furan, benzofuran, benzothiophene, tetrahydropyran, tetrahydrofuran, oxetane and the like.
　本明細書において、「５－１０員ヘテロアリール基」とは、酸素原子、イオウ原子及び窒素原子から選ばれるヘテロ原子を１から４個含有する５～１０員の単環式、多環式又は縮合環式の芳香族ヘテロ環基を意味し、例えば、フリル基、チエニル基、ピロリル基、オキサゾリル基、イソオキサゾリル基、チアゾリル基、イソチアゾリル基、イミダゾリル基、ピラゾリル基、オキサジアゾリル基、チアジアゾリル基、トリアゾリル基、テトラゾリル基、ピリジル基、ピリミジル基、ピラジニル基、ピリダジニル基、ベンゾフラニル基、イソベンゾフラニル基、ベンゾチエニル基、インドリル基、イソインドリル基、インダゾリル基、ベンゾイミダゾリル基、ベンゾオキサゾリル基、ベンゾイソオキサゾリル基、ベンゾチアゾリル基、ベンゾイソチアゾリル基、ベンゾオキサジアゾリル基、ベンゾチアジアゾリル基、ベンゾトリアゾリル基、キノリル基、イソキノリル基、シンノリニル基、キナゾリニル基、キノキサリニル基、フタラジニル基、ナフチリジニル基、プリニル基、プテリジニル基、フロピリジル基、チエノピリジル基、ピロロピリジル基、オキサゾロピリジル基、チアゾロピリジル基、イミダゾピリジル基等が挙げられる。 In the present specification, the “5- to 10-membered heteroaryl group” means a 5- to 10-membered monocyclic, polycyclic, or 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. Fused cyclic aromatic heterocyclic group means, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl , Tetrazolyl group, pyridyl group, pyrimidyl group, pyrazinyl group, pyridazinyl group, benzofuranyl group, isobenzofuranyl group, benzothienyl group, indolyl group, isoindolyl group, indazolyl group, benzoimidazolyl group, benzoxazolyl group, benzoisoxa Zolyl group, benzothiazolyl group, benzoy Thiazolyl group, benzooxadiazolyl group, benzothiadiazolyl group, benzotriazolyl group, quinolyl group, isoquinolyl group, cinnolinyl group, quinazolinyl group, quinoxalinyl group, phthalazinyl group, naphthyridinyl group, purinyl group, pteridinyl group, phlopyridyl group , Thienopyridyl group, pyrrolopyridyl group, oxazolopyridyl group, thiazolopyridyl group, imidazopyridyl group and the like.
　本明細書において、「飽和ヘテロ環基」とは、酸素原子、イオウ原子及び窒素原子から選ばれるヘテロ原子を１から４個含有する４員ないし６員の飽和ヘテロ環基を意味し、例えば、ピロリジル基、ピロリニル基、イミダゾリジニル基、イミダゾリニル基、ピラゾリジニル基、ピラゾリニル基、ピペリジル基、ピペラジニル基、インドリニル基、イソインドリニル基、モルホリニル基、テトラヒドロピラニル基、テトラヒドロフリル基、オキセタニル基等が挙げられる。 In the present specification, the “saturated heterocyclic group” means a 4- to 6-membered saturated heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, for example, Examples include pyrrolidyl group, pyrrolinyl group, imidazolidinyl group, imidazolinyl group, pyrazolidinyl group, pyrazolinyl group, piperidyl group, piperazinyl group, indolinyl group, isoindolinyl group, morpholinyl group, tetrahydropyranyl group, tetrahydrofuryl group, oxetanyl group and the like.
　本明細書において、「Ｃ６－１０アリールＣ１－６アルコキシ基」としては、フェニル基、ナフチル基、アズレニル基等に前記Ｃ１－６アルコキシ基が結合した基を意味する。例えばフェニル－Ｃ１－６アルコキシ基、ナフチル－Ｃ１－６アルコキシ基、アズレニル－Ｃ１－６アルコキシ基が挙げられる。より具体的にはベンジルオキシ基、フェネチルオキシ基、ナフチルメチル基等が挙げられる。 In the present specification, the “C 6-10 aryl C 1-6 alkoxy group” means a group in which the C 1-6 alkoxy group is bonded to a phenyl group, a naphthyl group, an azulenyl group or the like. Examples thereof include a phenyl-C 1-6 alkoxy group, a naphthyl-C 1-6 alkoxy group, and an azulenyl-C 1-6 alkoxy group. More specifically, a benzyloxy group, a phenethyloxy group, a naphthylmethyl group, and the like can be given.
　本明細書において、置換基を有してもよいＣ１－６アルキル基における、「置換基」としては、例えば、ハロゲン原子、Ｃ３－８シクロアルキル基、Ｃ１－６アルコキシ基、モノ（Ｃ１－６アルキル）アミノ基、ジ（Ｃ１－６アルキル）アミノ基、ジ（Ｃ２－６アルケニル）アミノ基、モノ（Ｃ３－８シクロアルキル）アミノ基、Ｃ２－７アルコキシカルボニル基、アミノ基、カルボキシル基、シアノ基、カルバモイル基、スルファモイル基、水酸基、ニトロ基、５－１０員ヘテロアリール基、飽和ヘテロ環基等が挙げられる。これらの置換基は１～４個有していてもよい。なお、アルコキシカルボニル基の炭素数（Ｃ２－７）は、カルボニル炭素を含んだ数字を示す。 In the present specification, examples of the “substituent” in the C 1-6 alkyl group which may have a substituent include a halogen atom, a C 3-8 cycloalkyl group, a C 1-6 alkoxy group, a mono ( C 1-6 alkyl) amino group, di (C 1-6 alkyl) amino group, di (C 2-6 alkenyl) amino group, mono (C 3-8 cycloalkyl) amino group, C 2-7 alkoxycarbonyl group Amino group, carboxyl group, cyano group, carbamoyl group, sulfamoyl group, hydroxyl group, nitro group, 5-10 membered heteroaryl group, saturated heterocyclic group and the like. These substituents may have 1 to 4 substituents. The carbon number (C 2-7 ) of the alkoxycarbonyl group indicates a number including the carbonyl carbon.
　本明細書において、置換基を有してもよいＣ１－６アルコキシ基、置換基を有していてもよいＣ２－６アルケニルオキシ基、及び置換基を有していてもよいＣ３－８シクロアルキルオキシ基における、「置換基」としては、例えば、ハロゲン原子、Ｃ３－８シクロアルキル基、Ｃ１－６アルコキシ基、モノ（Ｃ１－６アルキル）アミノ基、ジ（Ｃ１－６アルキル）アミノ基、ジ（Ｃ２－６アルケニル）アミノ基、モノ（Ｃ３－８シクロアルキル）アミノ基、Ｃ２－７アルコキシカルボニル基、アミノ基、カルボキシル基、シアノ基、カルバモイル基、スルファモイル基、水酸基、ニトロ基、５－１０員ヘテロアリール基、脂肪族ヘテロ環基等が挙げられる。これらの置換基は１～４個有していてもよい。なお、アルコキシカルボニル基の炭素数（Ｃ２－７）は、カルボニル炭素を含んだ数字を示す。 In the present specification, a C 1-6 alkoxy group which may have a substituent, a C 2-6 alkenyloxy group which may have a substituent, and a C 3-6 which may have a substituent Examples of the “substituent” in the 8 cycloalkyloxy group include a halogen atom, a C 3-8 cycloalkyl group, a C 1-6 alkoxy group, a mono (C 1-6 alkyl) amino group, and di (C 1- 1). 6 alkyl) amino group, di (C 2-6 alkenyl) amino group, mono (C 3-8 cycloalkyl) amino group, C 2-7 alkoxycarbonyl group, amino group, carboxyl group, cyano group, carbamoyl group, sulfamoyl Group, hydroxyl group, nitro group, 5-10 membered heteroaryl group, aliphatic heterocyclic group and the like. These substituents may have 1 to 4 substituents. The carbon number (C 2-7 ) of the alkoxycarbonyl group indicates a number including the carbonyl carbon.
　本明細書において、置換基を有してもよいＣ６－１０アリール基、置換基を有してもよい５－１０員ヘテロアリール基、置換基を有してもよいＣ６－１０アリールオキシ基、置換基を有してもよいＣ６－１０アリールＣ１－６アルコキシ基及び置換基を有していてもよいヘテロ環オキシ基における、「置換基」としては、例えば、ハロゲン原子、Ｃ１－６アルキル基、Ｃ３－８シクロアルキル基、ハロＣ１－６アルキル基、Ｃ２－６アルケニル基、Ｃ２－６アルキニル基、Ｃ１－６アルコキシ基、モノ（Ｃ１－６アルキル）アミノ基、ジ（Ｃ１－６アルキル）アミノ基、ジ（Ｃ２－６アルケニル）アミノ基、モノ（Ｃ３－８シクロアルキル）アミノ基、ジオキサボラニル基、モルホリノ基、ピペリジノ基、オキサジアゾリル基、Ｃ２－７アルコキシカルボニル基、アミノ基、カルボキシル基、シアノ基、カルバモイル基、スルファモイル基、水酸基、ニトロ基等が挙げられる。これらの置換基は１～４個有していてもよい。また、これらの置換基はさらに置換基を有していてもよい。 In the present specification, a C 6-10 aryl group which may have a substituent, a 5-10 membered heteroaryl group which may have a substituent, and a C 6-10 aryloxy which may have a substituent Examples of the “substituent” in the group, C 6-10 aryl C 1-6 alkoxy group which may have a substituent and heterocyclic oxy group which may have a substituent include, for example, a halogen atom, C 1-6 alkyl group, C 3-8 cycloalkyl group, halo C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkoxy group, mono (C 1-6 alkyl) ) Amino group, di (C 1-6 alkyl) amino group, di (C 2-6 alkenyl) amino group, mono (C 3-8 cycloalkyl) amino group, dioxaboranyl group, morpholino group, piperidino group, oxadiazolyl group, C -7 alkoxycarbonyl group, an amino group, a carboxyl group, a cyano group, a carbamoyl group, a sulfamoyl group, a hydroxyl group, and a nitro group. These substituents may have 1 to 4 substituents. Moreover, these substituents may further have a substituent.
　Ｒ１及びＲ３としては、水素原子、ハロゲン原子、Ｃ１－６アルキル基が好ましく、特に水素原子、ハロゲン原子又はＣ１－４アルキル基が好ましい。このうち、Ｒ１はハロゲン原子又はＣ１－６アルキル基がより好ましく、Ｒ３は水素原子がより好ましい。 R 1 and R 3 are preferably a hydrogen atom, a halogen atom or a C 1-6 alkyl group, particularly preferably a hydrogen atom, a halogen atom or a C 1-4 alkyl group. Among these, R 1 is more preferably a halogen atom or a C 1-6 alkyl group, and R 3 is more preferably a hydrogen atom.
　一般式（１）中、Ｒ１、Ｒ３におけるハロゲン原子としては、フッ素原子が好ましい。 In general formula (1), the halogen atom in R 1 and R 3 is preferably a fluorine atom.
　一般式（１）中、Ｒ１、Ｒ３におけるＣ１－６アルキル基としては、Ｃ１－４アルキル基が好ましく、メチル基がより好ましい。 In the general formula (1), the C 1-6 alkyl group in R 1 and R 3 is preferably a C 1-4 alkyl group, and more preferably a methyl group.
　一般式（１）中、Ｒ２としては、水素原子、－Ｓ（Ｏ）Ｒ１３、－Ｓ（Ｏ）２Ｒ１４、－ＣＯ２Ｒ１５又は－ＣＯＮＲ１６Ｒ１７が好ましく、水素原子、－Ｓ（Ｏ）Ｒ１３、－Ｓ（Ｏ）２Ｒ１４がより好ましい。 In general formula (1), R 2 is preferably a hydrogen atom, —S (O) R 13 , —S (O) 2 R 14 , —CO 2 R 15, or —CONR 16 R 17 , preferably a hydrogen atom, — S (O) R 13 and —S (O) 2 R 14 are more preferred.
　一般式（１）中、Ｒ４、Ｒ５及びＲ６としては水素原子が好ましい。 In general formula (1), R 4 , R 5 and R 6 are preferably hydrogen atoms.
　一般式（１）中、Ｒ７としては、－Ｃ（Ｏ）Ｒ１８、－Ｃ（Ｓ）Ｒ１９、－Ｓ（Ｏ）２Ｒ２０、置換基を有してもよいＣ６－１０アリール基又は置換基を有してもよい５－１０員ヘテロアリール基が好ましく、－Ｃ（Ｏ）Ｒ１８、－Ｓ（Ｏ）２Ｒ２０又は置換基を有してもよい５－１０員ヘテロアリール基がより好ましい。 In the general formula (1), R 7 includes —C (O) R 18 , —C (S) R 19 , —S (O) 2 R 20 , and optionally substituted C 6-10 aryl. A 5- to 10-membered heteroaryl group which may have a group or a substituent is preferable, and —C (O) R 18 , —S (O) 2 R 20 or a 5- to 10-membered heteroaryl which may have a substituent An aryl group is more preferred.
　一般式（１）中、Ｒ７における－Ｃ（Ｏ）Ｒ１８におけるＲ１８としては、置換基を有してもよいＣ１－６アルコキシ基、置換基を有してもよいＣ２－６アルケニルオキシ基、置換基を有してもよいＣ６－１０アリールオキシ基、置換基を有してもよいＣ３－８シクロアルキルオキシ基、置換基を有してもよいＣ６－１０アリールＣ１－６アルコキシ基、置換基を有してもよいヘテロ環オキシ基、置換基を有してもよい５－１０員ヘテロアリール基又はモノ（Ｃ１－６アルキル）アミノ基が好ましく、置換基を有してもよいＣ１－６アルコキシ基がより好ましい。 In the general formula (1), as the R 18 in -C (O) R 18 in R 7, which may have a substituent C 1-6 alkoxy group, an optionally substituted C 2-6 An alkenyloxy group, an optionally substituted C 6-10 aryloxy group, an optionally substituted C 3-8 cycloalkyloxy group, an optionally substituted C 6-10 aryl A C 1-6 alkoxy group, an optionally substituted heterocyclic oxy group, an optionally substituted 5-10 membered heteroaryl group or mono (C 1-6 alkyl) amino group is preferred. A C 1-6 alkoxy group which may have a group is more preferable.
　一般式（１）中、Ｒ７における－Ｃ（Ｓ）Ｒ１９におけるＲ１９としては、Ｃ１－６アルコキシ基、ハロＣ１－６アルコキシ基、Ｃ６－１０アリールＣ１－６アルコキシ基又はモノ（Ｃ１－６アルキル）アミノ基が好ましく、モノ（Ｃ１－６アルキル）アミノ基がより好ましい。 In the general formula (1), as the R 19 in -C (S) R 19 in R 7, C 1-6 alkoxy, halo C 1-6 alkoxy group, C 6-10 aryl C 1-6 alkoxy group or A mono (C 1-6 alkyl) amino group is preferred, and a mono (C 1-6 alkyl) amino group is more preferred.
　一般式（１）中、Ｒ７における－Ｓ（Ｏ）２Ｒ２０におけるＲ２０としては、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、Ｃ３－８シクロアルキル基、置換基を有してもよいＣ６－１０アリール基又は置換基を有してもよい５－１０員ヘテロアリール基が好ましい。 In the general formula (1), as the R 20 in -S (O) 2 R 20 in R 7, C 1-6 alkyl, halo C 1-6 alkyl group, C 3-8 cycloalkyl group, a substituent A C 6-10 aryl group which may have or a 5-10 membered heteroaryl group which may have a substituent is preferable.
　一般式（１）中、Ｒ７における置換基を有してもよい５－１０員ヘテロアリール基における５－１０員ヘテロアリール基としては、ピリジル基、ピリミジニル基、オキサジアゾール基が好ましい。また、置換基部分としては、ハロゲン原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基が好ましく、塩素原子、エチル基、イソプロピル基、トリフルオロメチル基がより好ましく、塩素原子、エチル基がさらに好ましい。 In the general formula (1), the 5-10 membered heteroaryl group in the 5-10 membered heteroaryl group which may have a substituent for R 7 is preferably a pyridyl group, a pyrimidinyl group, or an oxadiazole group. The substituent moiety is preferably a halogen atom, a C 1-6 alkyl group, or a halo C 1-6 alkyl group, more preferably a chlorine atom, an ethyl group, an isopropyl group, or a trifluoromethyl group, and a chlorine atom, an ethyl group Is more preferable.
　一般式（１）中、Ｒ１とＲ１１又はＲ１とＲ１２が一緒になって形成されるヘテロ環としては、次式： In the general formula (1), the heterocyclic ring formed by combining R 1 and R 11 or R 1 and R 12 is represented by the following formula:
Figure JPOXMLDOC01-appb-C000011
 ［式中、
Ｒ２１は水素原子、Ｃ１－６アルキル基、－Ｃ（Ｏ）Ｒ２２又は－Ｓ（Ｏ）２Ｒ２３（ここで、Ｒ２２及びＲ２３はそれぞれＣ１－６アルキル基又はＣ３－８シクロアルキル基を示す）を示し、波線部はＤ及びＥを含む芳香環を示す］
Figure JPOXMLDOC01-appb-C000011
 [Where:
R 21 represents a hydrogen atom, a C 1-6 alkyl group, —C (O) R 22 or —S (O) 2 R 23 (wherein R 22 and R 23 are a C 1-6 alkyl group or C 3- 8 represents an cycloalkyl group, and the wavy line represents an aromatic ring containing D and E].
から選択されるヘテロ環が好ましく、 Preferred is a heterocycle selected from
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
がより好ましく、 Is more preferred,
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
がさらに好ましい。 Is more preferable.
　一般式（１）中、Ｒ１１又はＲ１２としては、水素原子が好ましい。 In general formula (1), R 11 or R 12 is preferably a hydrogen atom.
　一般式（１）中、Ｒ１３又はＲ１４におけるＣ１－６アルキル基としては、Ｃ１－４アルキル基が好ましく、メチル基がより好ましい。 In general formula (1), the C 1-6 alkyl group in R 13 or R 14 is preferably a C 1-4 alkyl group, and more preferably a methyl group.
　一般式（１）中、Ｒ１３又はＲ１４における置換基を有してもよいＣ６－１０アリール基としては、フェニル基又はトルイル基が好ましく、ｐ－トルイル基がより好ましい。 In the general formula (1), the C 6-10 aryl group which may have a substituent for R 13 or R 14 is preferably a phenyl group or a toluyl group, and more preferably a p-toluyl group.
　一般式（１）中、Ｒ１８における置換基を有してもよいＣ１－６アルコキシ基としては、メトキシ基、エトキシ基、イソプロポキシ基、ｔｅｒｔ－ブトキシ基、２－フロロエトキシ基、２－メトキシエトキシ基、（３－メチルオキセタン－３－イル）メトキシ基、１，１，１－トリフロロ－２－メチルプロパン－２－イルオキシ基、２，２，２－トリフロロエトキシ基、２，２，２－トリクロロエトキシ基が好ましい。 In the general formula (1), the C 1-6 alkoxy group which may have a substituent for R 18 includes a methoxy group, an ethoxy group, an isopropoxy group, a tert-butoxy group, a 2-fluoroethoxy group, 2- Methoxyethoxy group, (3-methyloxetane-3-yl) methoxy group, 1,1,1-trifluoro-2-methylpropan-2-yloxy group, 2,2,2-trifluoroethoxy group, 2,2, A 2-trichloroethoxy group is preferred.
　一般式（１）中、Ｒ１８における置換基を有してもよいＣ３－８シクロアルキルオキシ基としては、１～３個のハロゲン原子が置換していてもよいＣ３－６シクロアルキルオキシ基が好ましく、４－フルオロシクロヘキシルオキシ基、４，４－ジフルオロシクロヘキシルオキシ基がより好ましい。 In the general formula (1), the C 3-8 cycloalkyloxy group which may have a substituent for R 18 is C 3-6 cycloalkyloxy optionally substituted with 1 to 3 halogen atoms. Group is preferable, and 4-fluorocyclohexyloxy group and 4,4-difluorocyclohexyloxy group are more preferable.
　一般式（１）中、Ｒ１８における置換基を有してもよいＣ２－６アルケニルオキシ基としては、Ｃ２－４アルケニルオキシ基が好ましく、プロパ－２－エン－１－イルオキシ基（アリルオキシ基）がより好ましい。 In the general formula (1), the C 2-6 alkenyloxy group which may have a substituent for R 18 is preferably a C 2-4 alkenyloxy group, and a prop-2-en-1-yloxy group (allyloxy). Group) is more preferred.
　一般式（１）中、Ｒ１８におけるＣ６－１０アリールオキシ基としては、フェニルオキシ基、ｐ－ニトロフェニルオキシ基が好ましい。 In general formula (1), the C 6-10 aryloxy group for R 18 is preferably a phenyloxy group or a p-nitrophenyloxy group.
　一般式（１）中、Ｒ１８におけるＣ６－１０アリールＣ１－６アルコキシ基としては、フェニルＣ１－６アルコキシ基が好ましく、ベンジルオキシ基がより好ましい。 In the general formula (1), the C 6-10 aryl C 1-6 alkoxy group in R 18 is preferably a phenyl C 1-6 alkoxy group, more preferably a benzyloxy group.
　一般式（１）中、Ｒ１８における置換基を有してもよい５－１０員ヘテロアリール基としては、ピリジル基が好ましい。 In the general formula (1), the 5-10 membered heteroaryl group which may have a substituent for R 18 is preferably a pyridyl group.
　一般式（１）中、Ｒ１８におけるモノ（Ｃ１－６アルキル）アミノ基としては、モノ（Ｃ１－４アルキル）アミノ基が好ましく、ｔｅｒｔ－ブチルアミノ基がより好ましい。 In the general formula (1), the mono (C 1-6 alkyl) amino group in R 18 is preferably a mono (C 1-4 alkyl) amino group, and more preferably a tert-butylamino group.
　一般式（１）中、Ｒ１９におけるモノ（Ｃ１－６アルキル）アミノ基としては、モノ（Ｃ１－４アルキル）アミノ基が好ましく、ｔｅｒｔ－ブチルアミノ基がより好ましい。 In general formula (1), the mono (C 1-6 alkyl) amino group in R 19 is preferably a mono (C 1-4 alkyl) amino group, and more preferably a tert-butylamino group.
　一般式（１）中、Ｒ２０におけるＣ１－６アルキル基としては、Ｃ１－４アルキル基が好ましく、ｎ－ブチル基がより好ましい。 In the general formula (1), the C 1-6 alkyl group in R 20 is preferably a C 1-4 alkyl group, and more preferably an n-butyl group.
　一般式（１）中、Ｒ２０におけるハロＣ１－６アルキル基としては、ハロＣ１－４アルキル基が好ましく、トリクロロメチル基がより好ましい。 In the general formula (1), the halo C 1-6 alkyl group for R 20 is preferably a halo C 1-4 alkyl group, more preferably a trichloromethyl group.
　一般式（１）中、Ｒ２０におけるＣ３－８シクロアルキル基としては、Ｃ３－６シクロアルキル基が好ましく、シクロプロピル基、シクロヘキシル基が好ましい。 In the general formula (1), the C 3-8 cycloalkyl group in R 20 is preferably a C 3-6 cycloalkyl group, more preferably a cyclopropyl group or a cyclohexyl group.
　一般式（１）中、Ｒ２０における置換基を有してもよいＣ６－１０アリール基としては、置換基を有してもよいフェニル基が好ましい。置換基部分としては、ハロＣ１－６アルキル基（トリフルオロメチル基等）、Ｃ１－６アルコキシ基（メトキシ基等）が好ましい。 In the general formula (1), the C 6-10 aryl group which may have a substituent in R 20 is preferably a phenyl group which may have a substituent. As the substituent portion, a halo C 1-6 alkyl group (such as a trifluoromethyl group) or a C 1-6 alkoxy group (such as a methoxy group) is preferable.
　一般式（１）中、Ｒ２０における置換基を有してもよいＣ６－１０ヘテロアリール基としては、チエニル基が好ましい。 In general formula (1), the C 6-10 heteroaryl group which may have a substituent for R 20 is preferably a thienyl group.
　一般式（１）中、Ａ及びＢとしては、Ａ及びＢが窒素原子である場合、Ａが窒素原子でＢがＣＨである場合、ＡがＣＨでＢが窒素原子である場合がより好ましく、Ａ及びＢが窒素原子であるのがさらに好ましい。 In general formula (1), as A and B, when A and B are nitrogen atoms, when A is a nitrogen atom and B is CH, the case where A is CH and B is a nitrogen atom is more preferable, More preferably, A and B are nitrogen atoms.
　一般式（１）中、Ｄとしては、窒素原子、ＣＨ又はＣ－ハロゲンが好ましく、ＣＨがより好ましい。 In general formula (1), D is preferably a nitrogen atom, CH or C-halogen, and more preferably CH.
　一般式（１）中、Ｅとしては、窒素原子、ＣＨ又はＣ－ハロゲンが好ましく、ＣＨがより好ましい。 In general formula (1), E is preferably a nitrogen atom, CH or C-halogen, and more preferably CH.
　一般式（１）中、Ｘとしては、窒素原子又は酸素原子が好ましく、窒素原子がより好ましい。 In general formula (1), X is preferably a nitrogen atom or an oxygen atom, and more preferably a nitrogen atom.
　一般式（１）中、Ｙとしては、酸素原子、硫黄原子、窒素原子が好ましく、酸素原子又は窒素原子がより好ましく、酸素原子がさらに好ましい。 In general formula (1), Y is preferably an oxygen atom, a sulfur atom, or a nitrogen atom, more preferably an oxygen atom or a nitrogen atom, and even more preferably an oxygen atom.
　一般式（１）中、Ｚとしては、酸素原子、硫黄原子、窒素原子が好ましく、酸素原子又は窒素原子がより好ましく、窒素原子がさらに好ましい。 In general formula (1), Z is preferably an oxygen atom, a sulfur atom, or a nitrogen atom, more preferably an oxygen atom or a nitrogen atom, and even more preferably a nitrogen atom.
　一般式（１）中、Ｄ及びＥを含む環構造としては、ベンゼン環（Ｄ及びＥがともにＣＨ）がより好ましい。また、一般式（１）中、Ａ、Ｂ、Ｙ及びＺを含む環構造としては、下記の構造 In general formula (1), the ring structure including D and E is more preferably a benzene ring (both D and E are CH). In the general formula (1), the ring structure containing A, B, Y and Z includes the following structures:
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
がより好ましく、下記の構造 Is more preferable, the following structure
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
（式中、Ｒ４は前記と同じ）
がさらに好ましい。 (Wherein R 4 is the same as above)
Is more preferable.
　一般式（１）で表されるピペリジン誘導体のうち、下記の（１ａ）又は（１ｂ）で表される化合物が特に好ましい。 Among the piperidine derivatives represented by the general formula (1), the compounds represented by the following (1a) or (1b) are particularly preferable.
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
（式中、Ｒ１は水素原子、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、アミノ基又はニトロ基を示し、Ｒ２～Ｒ７は前記と同じ） (Wherein R 1 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, an amino group or a nitro group, and R 2 to R 7 are the same as above)
　一般式（１）で表されるピペリジン誘導体のより好ましい化合物としては、
ｔｅｒｔ－ブチル　４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－４－イル）ピペリジン－１－カルボキシレート（実施例１）、
３－（１－（５－クロロピリミジン－２－イル）ピペリジン－４－イル）－７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン（実施例２）、
３－（１－（５－エチルピリミジン－２－イル）ピペリジン－４－イル）－７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン（実施例３）、
３－（１－（５－ブロモピリミジン－２－イル）ピペリジン－４－イル）－７－（５－（メチルスルホニル）インドリン－1－イル）イソオキサゾロ［４，５－ｄ］ピリミジン（実施例４）、
３－（１－（５－フロロピリミジン－２－イル）ピペリジン－４－イル）－７－（５－（メチルスルホニル）インドリン－1－イル）イソオキサゾロ［４，５－ｄ］ピリミジン（実施例５）、
エチル　２－（４－（７－（５－（メチルスルホニル）インドリン－1－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）ピリミジン－５－カルボキシレート（実施例６）、
２－（４－（７－（５－（メチルスルホニル）インドリン－1－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）ピリミジン－５－カルボン酸（実施例７）、
７－（５－（メチルスルホニル）インドリン－1－イル）－３－（１－（５－（トリフロロメチル）ピリミジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン（実施例８）、
２－（４－（７－（５－（メチルスルホニル）インドリン－1－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）ピリミジン－５－オール（実施例９）、
３－（１－（５－メトキシピリミジン－２－イル）ピペリジン－４－イル）－７－（５－（メチルスルホニル）インドリン－1－イル）イソオキサゾロ［４，５－ｄ］ピリミジン（実施例１０）、
７－（５－（メチルスルホニル）インドリン－1－イル）－３－（１－（５－フェニルピリミジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン（実施例１１）、
７－（５－（メチルスルホニル）インドリン－1－イル）－３－（１－（５－（トリフロロメチル）ピリジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン（実施例１２）、
イソプロピル　４－（７－（５－（メチルスルホニル）インドリン－1－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（実施例１３）、
エチル　４－（７－（５－（メチルスルホニル）インドリン－1－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（実施例１４）、
２－フロロエチル　４－（７－（５－（メチルスルホニル）インドリン－1－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（実施例１５）、
２－メトキシエチル　４－（７－（５－（メチルスルホニル）インドリン－1－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（実施例１６）、
テトラヒドロ－２Ｈ－ピラン－４－イル　４－（７－（５－（メチルスルホニル）インドリン－1－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（実施例１７）、
アリル　２－（４－（７－（５－（メチルスルホニル）インドリン－1－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）ピリミジン－５－カルボキシレート（実施例１８）、
ｔｅｒｔ－ブチル　４－（７－（5（メチルスルフィニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（実施例１９）、
７－（５－（メチルスルフィニル）インドリン－１－イル）－３－（１－（５－（トリフロロメチル）ピリジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン（実施例２０）、
２，２－ジメチル－１－（４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）プロパン－１－オン（実施例２１）、
ｔｅｒｔ－ブチル　４－（７－（（２－フロロ－４－（メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（実施例２２）、
Ｎ－（２－フロロ－４－（メチルスルホニル）フェニル）－３－（１－（５－（トリフロロメチル）ピリミジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－７－アミン（実施例２３）、
Ｎ－（２－フロロ－４－（メチルスルホニル）フェニル）３－（１－（５－（トリフロロメチル）ピリジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］－７－アミン（実施例２４）、
１，１，１－トリフロロ－２－メチルプロパン－２－イル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（実施例２５）、
２，２，２－トリフロロエチル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（実施例２６）、
２，２，２－トリクロロエチル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（実施例２７）、
ネオペンチル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（実施例２８）、
４，４－ジフロロシクロヘキシル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（実施例２９）、
オキセタン－３－イル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（実施例３０）、
（３－メチルオキセタン－３－イル）メチル　４－（７－（（２－フロロ－４－（メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（実施例３１）、
フェニル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（実施例３２）、
４－ニトロフェニル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（実施例３３）、
（４－（７－（（２－フロロ－４－（メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）（ピリジン－２－イル）メタノン（実施例３４）、
ｔｅｒｔ－ブチル　４－（７－（４－（メチルスルホニル）フェノキシ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（実施例３５）、
ｔｅｒｔ－ブチル　４－（７－（２－フロロ－４－（メチルスルホニル）フェノキシ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（実施例３６）、
ｔｅｒｔ－ブチル　４－（７－（４－（1Ｈ－テトラゾル－１－イル）フェノキシ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（実施例３７）、及び
ｔｅｒｔ－ブチル　４－（１－メチル－７－（５－（メチルスルホニル）インドリン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（実施例３８）
からなる群から選ばれる化合物を挙げることができる。 As a more preferable compound of the piperidine derivative represented by the general formula (1),
tert-butyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-4-yl) piperidine-1-carboxylate (Example 1),
3- (1- (5-Chloropyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine (Example 2) ),
3- (1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine (Example 3) ),
3- (1- (5-Bromopyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine (Example 4) ),
3- (1- (5-Fluoropyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine (Example 5) ),
Ethyl 2- (4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidine-5-carboxylate Example 6),
2- (4- (7- (5- (Methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidine-5-carboxylic acid (Examples) 7),
7- (5- (Methylsulfonyl) indoline-1-yl) -3- (1- (5- (trifluoromethyl) pyrimidin-2-yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidine (Example 8),
2- (4- (7- (5- (Methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidin-5-ol (Example 9) ),
3- (1- (5-methoxypyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine (Example 10) ),
7- (5- (Methylsulfonyl) indoline-1-yl) -3- (1- (5-phenylpyrimidin-2-yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidine (Example 11) ),
7- (5- (Methylsulfonyl) indoline-1-yl) -3- (1- (5- (trifluoromethyl) pyridin-2-yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidine (Example 12),
Isopropyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate (Example 13),
Ethyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate (Example 14),
2-Fluoroethyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate (Example 15),
2-methoxyethyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate (Example 16),
Tetrahydro-2H-pyran-4-yl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate (Examples) 17),
Allyl 2- (4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidine-5-carboxylate Example 18),
tert-butyl 4- (7- (5 (methylsulfinyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate (Example 19),
7- (5- (Methylsulfinyl) indoline-1-yl) -3- (1- (5- (trifluoromethyl) pyridin-2-yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidine (Example 20),
2,2-Dimethyl-1- (4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) propane-1 -ON (Example 21),
tert-butyl 4- (7-((2-fluoro-4- (methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate (Example 22),
N- (2-Fluoro-4- (methylsulfonyl) phenyl) -3- (1- (5- (trifluoromethyl) pyrimidin-2-yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidine -7-amine (Example 23),
N- (2-Fluoro-4- (methylsulfonyl) phenyl) 3- (1- (5- (trifluoromethyl) pyridin-2-yl) piperidin-4-yl) isoxazolo [4,5-d] -7 An amine (Example 24),
1,1,1-trifluoro-2-methylpropan-2-yl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) Piperidine-1-carboxylate (Example 25),
2,2,2-trifluoroethyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate ( Example 26),
2,2,2-trichloroethyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate Example 27),
Neopentyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate (Example 28),
4,4-Difluorocyclohexyl 4- (7-((2-Fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate (Examples) 29),
Oxetan-3-yl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate (Example 30) ,
(3-Methyloxetane-3-yl) methyl 4- (7-((2-fluoro-4- (methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1- Carboxylate (Example 31),
Phenyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate (Example 32),
4-nitrophenyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate (Example 33),
(4- (7-((2-Fluoro-4- (methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) (pyridin-2-yl) methanone (Example 34),
tert-butyl 4- (7- (4- (methylsulfonyl) phenoxy) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate (Example 35),
tert-butyl 4- (7- (2-fluoro-4- (methylsulfonyl) phenoxy) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate (Example 36),
tert-butyl 4- (7- (4- (1H-tetrazol-1-yl) phenoxy) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate (Example 37), and tert -Butyl 4- (1-methyl-7- (5- (methylsulfonyl) indoline-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-3-yl) piperidine-1-carboxylate (Examples) 38)
A compound selected from the group consisting of:
　本発明の化合物に幾何異性体又は光学異性体が存在する場合は、それらの異性体も本発明の範囲に含まれる。これらの異性体の分離は常法により行われる。 When a geometric isomer or optical isomer exists in the compound of the present invention, these isomers are also included in the scope of the present invention. These isomers are separated by a conventional method.
　一般式（１）で表される化合物の塩としては、医薬として許容される塩であれば特に制限されない。化合物を酸性化合物として扱う場合は、例えば、ナトリウム、カリウム、マグネシウム、カルシウム等のアルカリ金属塩又はアルカリ土類金属塩；トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、Ｎ－メチルピロリジン、Ｎ－メチルピペリジン、Ｎ－メチルモルホリン等の有機塩基との塩等が挙げられる。化合物を塩基性化合物として扱う場合には、例えば、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硫酸塩、硝酸塩、リン酸塩のような鉱酸の酸付加塩；安息香酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩、マレイン酸塩、フマル酸塩、酒石酸塩、クエン酸塩、酢酸塩等の有機酸の酸付加塩等が挙げられる。 The salt of the compound represented by the general formula (1) is not particularly limited as long as it is a pharmaceutically acceptable salt. When the compound is treated as an acidic compound, for example, alkali metal salt or alkaline earth metal salt such as sodium, potassium, magnesium, calcium; trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylpiperidine, N- And salts with organic bases such as methylmorpholine. When treating a compound as a basic compound, for example, acid addition salts of mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate; benzoate, Examples include acid addition salts of organic acids such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, maleate, fumarate, tartrate, citrate, and acetate. It is done.
　一般式（１）で表される化合物、又はその塩の溶媒和物としては、例えば、水和物等が挙げられるが、これに限定されるものではない。 Examples of the solvate of the compound represented by the general formula (1) or a salt thereof include, but are not limited to, hydrates and the like.
　なお、生体内において代謝されて一般式（１）で表される化合物に変換される化合物、いわゆるプロドラッグもすべて本発明に包含される。本発明の化合物のプロドラッグを形成する基としては、「プログレス・イン・メディシン（Ｐｒｏｇｒｅｓｓ　ｉｎ　Ｍｅｄｉｃｉｎｅ）」、ライフサイエンス・メディカ社、１９８５年、５巻、２１５７－２１６１ページに記載されている基や、廣川書店１９９０年刊「医薬品の開発」第７巻 分子設計１６３－１９８ページに記載されている基が挙げられる。 It should be noted that all compounds that are metabolized in vivo and converted to the compound represented by the general formula (1), so-called prodrugs, are also included in the present invention. Examples of the group that forms a prodrug of the compound of the present invention include the groups described in “Progress in Medicine”, Life Science Medica, 1985, Vol. 5, pages 2157-2161. Examples include the groups described in Yodogawa Shoten, 1990, “Development of Drugs”, Vol.
　上記一般式（１）で表される化合物、若しくはその塩、又はそれらの溶媒和物は種々の公知の方法で製造することができ、特に制限されるものではなく、例えば、次に説明する反応工程に従い製造することができる。また、下記反応を行う際において、反応部位以外の官能基については必要に応じて予め保護しておき、適当な段階においてこれを脱保護してもよい。保護、脱保護条件としては一般に用いられる方法（例えば、Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ　Ｔｈｉｒｄ　Ｅｄｉｔｉｏｎ，Ｊｏｈｎ　Ｗｉｌｅｙ　＆　Ｓｏｎｓ，Ｉｎｃ．，１９９９に記載された方法）を参考にして行うことができる。さらに、各工程において、反応は通常行われる方法（例えば、Ｃｏｍｐｒｅｈｅｎｓｉｖｅ　Ｏｒｇａｎｉｃ　Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ　Ｓｅｃｏｎｄ　Ｅｄｉｔｉｏｎ，Ｊｏｈｎ　Ｗｉｌｅｙ　＆　Ｓｏｎｓ，Ｉｎｃ；１９９９に記載された方法）で行えばよく、単離精製は結晶化、再結晶化、クロマトグラフィー等の通常の方法を適宜選択し、又は組み合わせて行えばよい。
（一般式（１）で表される化合物の製造方法）
　本発明の一般式（１）で表される化合物は、下記反応経路図１に記載の方法により製造することができる。
［反応経路図１］ The compound represented by the above general formula (1), a salt thereof, or a solvate thereof can be produced by various known methods, and is not particularly limited. For example, the reaction described below It can be manufactured according to the process. Moreover, when performing the following reaction, functional groups other than the reaction site may be protected in advance as necessary, and may be deprotected at an appropriate stage. As the protection and deprotection conditions, a commonly used method (for example, a method described in Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc., 1999) can be used. Further, in each step, the reaction may be carried out by a commonly performed method (for example, the method described in Comprehensive Organic Transformation Second Edition, John Wiley & Sons, Inc; 1999), and isolation and purification are crystallized and recrystallized. Ordinary methods such as chromatography may be appropriately selected or combined.
(Method for producing the compound represented by the general formula (1))
The compound represented by the general formula (1) of the present invention can be produced by the method shown in the following reaction pathway diagram 1.
[Reaction Path Diagram 1]
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
（式中、Ａ、Ｂ、Ｄ、Ｅ、Ｘ、Ｙ、Ｚ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６、Ｒ７は、前記の一般式（１）におけるものと同義であり、Ｗ１は脱離基を示す。） (In the formula, A, B, D, E, X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are the same as those in the general formula (1). And W 1 represents a leaving group.)
（Ａ－１）Ａ－１工程は、化合物（２）を、溶媒中、塩基存在下にヘキサフルオロリン酸（ベンゾトリアゾール－１－イルオキシ）トリピロリジノホスホニウム（ＰｙＢＯＰ）のような脱水縮合剤や塩化メタンスルホニルのようなスルホニル化剤と反応させて化合物（３）を製造する工程である。塩基としては特に制限は無いが、例えば、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の炭酸アルカリ金属類；１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）、１，５－ジアザビシクロ［４．３．０］ノナ－５－エン（ＤＢＮ）、１，４－ジアザビシクロ［２，２，２］オクタン（ＤＡＢＣＯ）、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ，Ｎ－ジイソプロピルペンチルアミン、トリメチルアミン等の有機塩基等を使用することができる。好ましくは、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）である。溶媒としては特に制限は無いが、例えば、Ｎ，Ｎ－ジメチルホルムアミド、ジオキサン、テトラヒドロフラン、アセトニトリル、プロピオニトリル、クロロホルム、塩化メチレン等であり、これらを単独又は組み合わせて使用することができる。好ましくはテトラヒドロフラン単独か又はテトラヒドロフランと塩化メチレンの混合溶媒である。反応温度は０～１５０℃が好ましく、より好ましくは１０～３０℃である。反応時間は５分～４８時間が好ましく、より好ましくは１０分～２時間である。 (A-1) Step A-1 is a step in which compound (2) is mixed with a dehydrating condensing agent such as hexafluorophosphoric acid (benzotriazol-1-yloxy) tripyrrolidinophosphonium (PyBOP) in a solvent in the presence of a base. This is a step for producing a compound (3) by reacting with a sulfonylating agent such as methanesulfonyl chloride. The base is not particularly limited. For example, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate; 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2,2,2] octane (DABCO), triethylamine, N, N-diisopropylethylamine, N, N -Organic bases such as diisopropylpentylamine and trimethylamine can be used. 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) is preferred. The solvent is not particularly limited, and examples thereof include N, N-dimethylformamide, dioxane, tetrahydrofuran, acetonitrile, propionitrile, chloroform, methylene chloride and the like, and these can be used alone or in combination. Preferred is tetrahydrofuran alone or a mixed solvent of tetrahydrofuran and methylene chloride. The reaction temperature is preferably 0 to 150 ° C., more preferably 10 to 30 ° C. The reaction time is preferably 5 minutes to 48 hours, more preferably 10 minutes to 2 hours.
（Ａ－２）Ａ－２工程は、化合物（３）を、溶媒中、塩基存在下に化合物（４）と反応させて化合物（１）を製造する工程である。塩基としては特に制限は無いが、例えば、水素化リチウム、水素化ナトリウム、水素化カリウム等の水素化アルカリ金属類；金属リチウム、金属ナトリウム、金属カリウム等のアルカリ金属類；水酸化リチウム、水酸化ナトリウム、水酸化カリウム等の水酸化アルカリ金属類；炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の炭酸アルカリ金属類；リチウムジイソプロピルアミド、ナトリウムジイソプロピルアミド、カリウムジイソプロピルアミド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ｔｅｒｔ－ブトキシナトリウム、ｔｅｒｔ－ブトキシカリウム、ｎ－ブチルリチウム、ｓｅｃ－ブチルリチウム、ｔｅｒｔ－ブチルリチウム等を使用することができる。好ましくは、水素化ナトリウムである。溶媒としては特に制限は無いが、例えば、Ｎ，Ｎ－ジメチルホルムアミド、ジオキサン、テトラヒドロフラン、アセトニトリル、プロピオニトリル等であり、これらを単独又は組み合わせて使用することができる。好ましくはＮ，Ｎ－ジメチルホルムアミドである。反応温度は０～１５０℃が好ましく、より好ましくは５０～１００℃である。反応時間は５分～４８時間が好ましく、より好ましくは１０分～４時間である。 (A-2) Step A-2 is a step for producing compound (1) by reacting compound (3) with compound (4) in the presence of a base in a solvent. Although there is no restriction | limiting in particular as a base, For example, Alkali metal hydrides, such as lithium hydride, sodium hydride, potassium hydride; Alkali metals, such as metallic lithium, metallic sodium, metallic potassium; Lithium hydroxide, Hydroxide Alkali metal hydroxides such as sodium and potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, Sodium hexamethyldisilazide, potassium hexamethyldisilazide, tert-butoxy sodium, tert-butoxy potassium, n-butyllithium, sec-butyllithium, tert-butyllithium, etc. can be used. . Sodium hydride is preferable. The solvent is not particularly limited, and examples thereof include N, N-dimethylformamide, dioxane, tetrahydrofuran, acetonitrile, propionitrile and the like, and these can be used alone or in combination. N, N-dimethylformamide is preferred. The reaction temperature is preferably 0 to 150 ° C, more preferably 50 to 100 ° C. The reaction time is preferably 5 minutes to 48 hours, more preferably 10 minutes to 4 hours.
　上記した方法とは別に、本発明の一般式（１）で表される化合物は、下記反応経路図２に記載の方法によっても製造することができる。
［反応経路図２］ Apart from the method described above, the compound represented by the general formula (1) of the present invention can also be produced by the method described in the following reaction pathway diagram 2.
[Reaction Path Diagram 2]
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
（式中、Ａ、Ｂ、Ｄ、Ｅ、Ｘ、Ｙ、Ｚ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６、Ｒ７は、前記の一般式（１）におけるものと同義であり、Ｗ２は脱離基を示す。） (In the formula, A, B, D, E, X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are the same as those in the general formula (1). And is synonymous and W 2 represents a leaving group.)
（Ｂ－１）Ｂ－１工程は、化合物（２）を溶媒存在下、又は非存在下、塩基存在下、又は非存在下にオキシ塩化リン（ＰＯＣｌ３）のようなハロゲン化剤と反応させて化合物（５）を製造する工程である。使用されるハロゲン化剤としては特に制限は無いが、例えば、オキシ塩化リン、オキシ塩化リン／五塩化リン、Ｎ，Ｎ－ジメチルホルムアミド／塩化オギザリル等を使用することができる。好ましくはオキシ塩化リンである。塩基としては、Ｎ，Ｎ－ジメチルアニリン、Ｎ，Ｎ－ジエチルアニリン、Ｎ，Ｎ，Ｎ－ジイソプロピルエチルアミン等を使用することができる。溶媒としては、ジオキサン、１，２－ジクロロエタン等を使用することができる。反応温度は０～１５０℃が好ましく、より好ましくは８０～１２０℃である。反応時間は１０分間～４８時間が好ましく、より好ましくは３～６時間である。 (B-1) Step B-1 comprises reacting compound (2) with a halogenating agent such as phosphorus oxychloride (POCl 3 ) in the presence or absence of a solvent, in the presence or absence of a base. In this step, compound (5) is produced. The halogenating agent to be used is not particularly limited, and for example, phosphorus oxychloride, phosphorus oxychloride / phosphorus pentachloride, N, N-dimethylformamide / oxalyl chloride and the like can be used. Preferred is phosphorus oxychloride. As the base, N, N-dimethylaniline, N, N-diethylaniline, N, N, N-diisopropylethylamine or the like can be used. As the solvent, dioxane, 1,2-dichloroethane and the like can be used. The reaction temperature is preferably 0 to 150 ° C, more preferably 80 to 120 ° C. The reaction time is preferably 10 minutes to 48 hours, more preferably 3 to 6 hours.
（Ｂ－２）Ｂ－２工程は、化合物（５）を、金属触媒を用いたアミノ化反応により化合物（４）と反応させて一般式（１）で表される化合物を製造する工程である。金属触媒、配位子、塩基ならびに反応条件は、通常アミノ化反応に使用される試薬及び条件であれば特に限定されないが、例えばＡ．Ｒ．Ｍｕｃｉ，Ｓ．Ｌ．Ｂｕｃｈｗａｌｄ，Ｔｏｐ．Ｃｕｒｒ．Ｃｈｅｍ．，２１９，１３１－２０９，（２００２）などに記載されている方法を用いることができる。Ｂ－２工程においては、溶媒中又は無溶媒にて、塩基の存在下又は非存在下、金属触媒存在下にて行われるアミノ化反応の手法を適用することもできる。その際には、マイクロウェーブ照射を行ってもよい。金属触媒としては特に制限は無いが、例えば、酢酸パラジウム（ＩＩ）、パラジウム（０）ジベンジリデンアセトン、トリス（ジベンジリデンアセトン）ジパラジウム（０）、ビス（トリ－ｔｅｒｔ－ブチルホスフィン）パラジウム（０）、トリス（ジベンジリデンアセトン）（クロロホルム）ジパラジウム（０）、［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）、テトラキス（トリフェニルホスフィン）パラジウム等のパラジウム錯体、又はヨウ化第一銅、臭化第一銅、青酸第一銅等の一価銅試薬を単独として用いてもよいが、（２－ビフェニル）ジ－ｔｅｒｔ－ブチルホスフィン、（２－ビフェニル）ジシクロヘキシルホスフィン、トリシクロヘキシルホスフィン、１，３－ビス（フェニルホスホノ）プロパン、２，２’－ビス（ジフェニルホスファニル）－１，１’－ビナフチル、２－（ジシクロヘキシルホスホノ）ビフェニル、２－ジシクロヘキシルホスフィノ－２’－（Ｎ，Ｎ－ジメチルアミノ）ビフェニル、テトラメチルエチレンジアミン、Ｎ，Ｎ’－ジメチルエチレンジアミン、グリシン、Ｎ，Ｎ－ジメチルグリシン、Ｎ－メチルグリシン等の配位子を組み合わせて使用することもできる。塩基としては特に制限は無いが、例えば、水素化リチウム、水素化ナトリウム、水素化カリウム等の水素化アルカリ金属類；金属リチウム、金属ナトリウム、金属カリウム等のアルカリ金属類；水酸化リチウム、水酸化ナトリウム、水酸化カリウム等の水酸化アルカリ金属類；炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の炭酸アルカリ金属類；リチウムジイソプロピルアミド、ナトリウムジイソプロピルアミド、カリウムジイソプロピルアミド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ｔｅｒｔ－ブトキシナトリウム、ｔｅｒｔ－ブトキシカリウム、ｎ－ブチルリチウム、ｓｅｃ－ブチルリチウム、ｔｅｒｔ－ブチルリチウム等を使用することができる。溶媒としては特に制限はないが、例えば、テトラヒドロフラン、トルエン、ジオキサン、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチルピロリドン、ジメチルスルホキシド、水等を単独又は組み合わせて使用することができる。反応温度は、０～２００℃が好ましく、より好ましくは１００℃～１５０℃である。反応時間は、１分～５日間が好ましく、より好ましくは３０分間～６時間である。 (B-2) Step B-2 is a step of producing a compound represented by the general formula (1) by reacting compound (5) with 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 that are usually used in an amination reaction. R. Muci, S .; L. Buchwald, Top. Curr. Chem. , 219, 131-209, (2002), etc. can be used. In the step B-2, a method of an amination reaction performed in the presence or absence of a base and in the presence of a metal catalyst in a solvent or without a solvent can be applied. In that case, microwave irradiation may be performed. The metal catalyst is not particularly limited. For example, palladium (II) acetate, palladium (0) dibenzylideneacetone, tris (dibenzylideneacetone) dipalladium (0), bis (tri-tert-butylphosphine) palladium (0 ), Tris (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), palladium complexes such as tetrakis (triphenylphosphine) palladium, or Monovalent copper reagents such as cuprous iodide, cuprous bromide, and cuprous cyanide may be used alone, but (2-biphenyl) di-tert-butylphosphine, (2-biphenyl) dicyclohexylphosphine , Tricyclohexylphosphine, 1,3-bis (phenylphospho ) Propane, 2,2′-bis (diphenylphosphanyl) -1,1′-binaphthyl, 2- (dicyclohexylphosphono) biphenyl, 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl, A combination of ligands such as tetramethylethylenediamine, N, N′-dimethylethylenediamine, glycine, N, N-dimethylglycine, and N-methylglycine can also be used. Although there is no restriction | limiting in particular as a base, For example, Alkali metal hydrides, such as lithium hydride, sodium hydride, potassium hydride; Alkali metals, such as metallic lithium, metallic sodium, metallic potassium; Lithium hydroxide, Hydroxide Alkali metal hydroxides such as sodium and potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, Sodium hexamethyldisilazide, potassium hexamethyldisilazide, tert-butoxy sodium, tert-butoxy potassium, n-butyllithium, sec-butyllithium, tert-butyllithium, etc. can be used. . The solvent is not particularly limited, and for example, tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water and the like can be used alone or in combination. The reaction temperature is preferably 0 to 200 ° C, more preferably 100 ° C to 150 ° C. The reaction time is preferably 1 minute to 5 days, more preferably 30 minutes to 6 hours.
（一般式（２）で表されるピペリジン誘導体の製造方法）
　次に、上記反応で用いる一般式（２）で表される化合物のうちＡ及びＢが共に窒素原子である化合物（２ａ－ｄ）は、下記反応経路図３に記載の方法により製造することができる。
［反応経路図３］ (Method for producing piperidine derivative represented by general formula (2))
Next, among the compounds represented by the general formula (2) used in the above reaction, the compounds (2a-d) in which A and B are both nitrogen atoms can be produced by the method shown in the following reaction route diagram 3. it can.
[Reaction route diagram 3]
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
（式中、Ｙ、Ｚ、Ｒ４、Ｒ５、Ｒ６、Ｒ７は、前記の一般式（１）におけるものと同義であり、Ｒ２４は、Ｃ１－６アルキル基又はＣ６－１０アリールＣ１－６アルキル基を示す。） (In the formula, Y, Z, R 4 , R 5 , R 6 , and R 7 are as defined in the general formula (1), and R 24 is a C 1-6 alkyl group or C 6-10. Represents an aryl C 1-6 alkyl group.)
（Ｃ－１）Ｃ－１工程は、化合物（６）をアミジン誘導体（７）又はその塩と反応させて化合物（２）を製造する工程である。溶媒としては特に制限はないが、例えば、メタノール、エタノール、エーテル、テトラヒドロフラン、１，４－ジオキサン、ベンゼン、トルエン等を使用することができる。好ましくは、エタノールである。反応温度は、４０～１２０℃が好ましく、より好ましくは８０℃～１００℃である。反応時間は、１時間～５日間が好ましく、より好ましくは１２時間～２日間である。また、化合物（２ａ－ｄ）は、Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．Ｌｅｔｔ．，２００５，１５，３９００．、ＷＯ２００１／０４７９３４号パンフレット、Ｌｉｅｂｉｇｓ　Ａｎｎ．Ｃｈｅｍ．，１９７９，１０，１５３４．、Ｉｎｄｉａｎ　Ｊ．Ｃｈｅｍ，Ｓｅｃ　Ｂ．，１９９４，３３Ｂ，４３６．、ＷＯ２００６／０４７５１６パンフレットを参照にしても製造することができる。上記反応で用いる化合物（７）は、入手可能なものをそのまま使用するか、あるいは、公知の方法により適宜製造できるが、これに限定されるものではない。 (C-1) Step C-1 is a step for producing compound (2) by reacting compound (6) with amidine derivative (7) or a salt thereof. The solvent is not particularly limited, and for example, methanol, ethanol, ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene and the like can be used. Ethanol is preferable. The reaction temperature is preferably 40 to 120 ° C, more preferably 80 to 100 ° C. The reaction time is preferably 1 hour to 5 days, more preferably 12 hours to 2 days. Compound (2a-d) was also prepared according to Bioorg. Med. Chem. Lett. 2005, 15, 3900. , WO2001 / 047934 pamphlet, Liebigs Ann. Chem. 1979, 10, 1534. , Indian J. Chem, Sec B. 1994, 33B, 436. It can also be produced by referring to the WO2006 / 047516 pamphlet. As the compound (7) used in the above reaction, an available compound can be used as it is, or it can be appropriately produced by a known method, but it is not limited thereto.
（一般式（２）で表されるピペリジン誘導体の製造方法）
　次に、上記反応で用いる一般式（２）で表される化合物のうちＡ又はＢどちらか一方が窒素原子である化合物（２ｅ－ｊ）は、下記反応経路図４に記載の方法により製造することができる。
［反応経路図４］ (Method for producing piperidine derivative represented by general formula (2))
Next, among the compounds represented by the general formula (2) used in the above reaction, a compound (2e-j) in which either A or B is a nitrogen atom is produced by the method shown in the following reaction route diagram 4. be able to.
[Reaction route diagram 4]
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
（式中、Ｙ、Ｚ、Ｒ４、Ｒ５、Ｒ６、Ｒ７は、前記の一般式（１）におけるものと同義であり、Ｒ２４は、Ｃ１－６アルキル基又はＣ６－１０アリールＣ１－６アルキル基、Ｗ３は、ハロゲン原子、水酸基又はアミノ基を示す。） (In the formula, Y, Z, R 4 , R 5 , R 6 , and R 7 are as defined in the general formula (1), and R 24 is a C 1-6 alkyl group or C 6-10. Aryl C 1-6 alkyl group, W 3 represents a halogen atom, a hydroxyl group or an amino group.
（Ｄ－１）上記に示す化合物（２ｅ－ｈ）はＵＳ２００１／０００７８６７パンフレットを参考に合成できる。また、原料（６）はＷＯ２００６／０４７５１６パンフレット、Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．Ｌｅｔｔ．，２００４，１４，５５４３．、Ｌｉｅｂｉｇｓ　Ａｎｎ．Ｃｈｅｍ．，１９７９，１０，１５３４．を参照にして製造することができる。
　また、化合物（２ｅ，ｆ）と（２ｉ，ｊ）はそれぞれＷＯ２００５／００７６５８（Ｅ－１）、ＥＰ０７７８２７７（Ｆ－１）の方法によっても製造することができる。上記反応で用いる化合物（６）、（７）、（８）は、入手可能なものをそのまま使用するか、あるいは、公知の方法により適宜製造できるが、これに限定されるものではない。 (D-1) The compound (2e-h) shown above can be synthesized with reference to US2001 / 0007867 pamphlet. The raw material (6) is disclosed in WO 2006/047516 pamphlet, Bioorg. Med. Chem. Lett. 2004, 14, 5543. Liebigs Ann. Chem. 1979, 10, 1534. It can manufacture with reference to.
Compounds (2e, f) and (2i, j) can also be produced by the methods of WO2005 / 007658 (E-1) and EP0778277 (F-1), respectively. As the compounds (6), (7), and (8) used in the above reaction, those that are available can be used as they are, or can be appropriately produced by known methods, but are not limited thereto.
　前記の各反応で得られた中間体及び目的物は、有機合成化学で常用されている精製法、例えば、ろ過、抽出、洗浄、乾燥、濃縮、再結晶、各種クロマトグラフィー等に付して必要に応じて単離、精製することができる。また、中間体においては、特に精製することなく次反応に供することもできる。 Intermediates and target products obtained in the above reactions are necessary for purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc. Can be isolated and purified. In addition, the intermediate can be subjected to the next reaction without any particular purification.
　さらに、各種の異性体は異性体間の物理化学的性質の差を利用した常法を適用して単離できる。ラセミ混合物は、例えば酒石酸等の一般的な光学活性酸とのジアステレオマー塩に導き光学分割する方法又は光学活性カラムクロマトグラフィーを用いた方法等の一般的ラセミ分割法により、光学的に純粋な異性体に導くことができる。また、ジアステレオマー混合物は、例えば分別結晶化又は各種クロマトグラフィー等により分割できる。また、光学活性な化合物は適当な光学活性な原料を用いることにより製造することもできる。 Furthermore, various isomers can be isolated by applying a conventional method using the difference in physicochemical properties between isomers. The racemic mixture is optically purified by a general racemic resolution method such as a method of optical resolution by introducing a diastereomeric salt with a general optically active acid such as tartaric acid or a method using optically active column chromatography. Can lead to isomers. Moreover, a diastereomeric mixture can be divided | segmented by fractional crystallization or various chromatography, for example. An optically active compound can also be produced by using an appropriate optically active raw material.
　得られた化合物（１）は通常の方法で塩にすることができる。また、反応溶媒、再結晶溶媒等の溶媒の溶媒和物や水和物とすることもできる。 The obtained compound (1) can be converted into a salt by an ordinary method. Moreover, it can also be set as the solvate and hydrate of solvents, such as a reaction solvent and a recrystallization solvent.
　本発明の一般式（１）で表される化合物若しくはその塩、又はそれらの溶媒和物を有効成分として含有する医薬としては、この有効成分を単独で用いてよいが、通常は医薬として許容される担体、添加物等を配合して医薬組成物の形態で使用される。医薬組成物の投与形態は、特に限定されず、治療目的に応じて適宜選択できる。例えば、経口剤、注射剤、坐剤、軟膏剤、吸入剤、点眼剤、点鼻剤、貼付剤等のいずれでもよい。これらの投与形態に適した医薬組成物は、公知の製剤方法により製造できる。 As a medicament containing the compound represented by the general formula (1) of the present invention or a salt thereof, or a solvate thereof as an active ingredient, this active ingredient may be used alone, but it is usually pharmaceutically acceptable. It is used in the form of a pharmaceutical composition by blending carriers, additives and the like. The administration form of the pharmaceutical composition is not particularly limited and can be appropriately selected depending on the purpose of treatment. For example, any of oral preparations, injections, suppositories, ointments, inhalants, eye drops, nasal drops, patches and the like may be used. Pharmaceutical compositions suitable for these dosage forms can be produced by known formulation methods.
　経口用固形製剤を調製する場合は、一般式（１）で表される化合物に賦形剤、さらに必要に応じて結合剤、崩壊剤、滑沢剤、着色剤、矯味剤、矯臭剤等を加えた後、常法により錠剤、被覆錠剤、顆粒剤、散剤、カプセル剤等を製造することができる。添加剤は、当該分野で一般的に使用されているものでよい。例えば、賦形剤としては、乳糖、白糖、塩化ナトリウム、ブドウ糖、デンプン、炭酸カルシウム、カオリン、微結晶セルロース、珪酸等が挙げられる。結合剤としては水、エタノール、プロパノール、単シロップ、ブドウ糖液、デンプン液、ゼラチン液、カルボキシメチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルスターチ、メチルセルロース、エチルセルロース、シェラック、リン酸カルシウム、ポリビニルピロリドン等が挙げられる。崩壊剤としては乾燥デンプン、アルギン酸ナトリウム、カンテン末、炭酸水素ナトリウム、炭酸カルシウム、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、乳糖等が挙げられる。滑沢剤としては精製タルク、ステアリン酸塩、ホウ砂、ポリエチレングリコール等が挙げられる。矯味剤としては白糖、橙皮、クエン酸、酒石酸等が挙げられる。 When preparing an oral solid preparation, the compound represented by the general formula (1) is mixed with an excipient, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a corrigent, a corrigent and the like. After the addition, tablets, coated tablets, granules, powders, capsules and the like can be produced by conventional methods. The additive may be one commonly used in the art. Examples of excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid and the like. Examples of the binder include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone and the like. Examples of the disintegrant include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose. Examples of the lubricant include purified talc, stearate, borax, and polyethylene glycol. Examples of the corrigent include sucrose, orange peel, citric acid, and tartaric acid.
　経口用液体製剤を調製する場合は、一般式（１）で表される化合物に矯味剤、緩衝剤、安定化剤、矯臭剤等を加えて常法により内服液剤、シロップ剤、エリキシル剤等を製造することができる。矯味剤としては上記に挙げられたものでよく、緩衝剤としてはクエン酸ナトリウム等が、安定化剤としてはトラガント、アラビアゴム、ゼラチン等が挙げられる。 When preparing an oral liquid preparation, add a corrigent, a buffer, a stabilizer, a corrigent, etc. to the compound represented by the general formula (1), and add an oral solution, syrup, elixir, etc. Can be manufactured. As the corrigent, those mentioned above may be used. Examples of the buffer include sodium citrate, and examples of the stabilizer include tragacanth, gum arabic, and gelatin.
　注射剤を調製する場合は、一般式（１）で表される化合物にｐＨ調節剤、緩衝剤、安定化剤、等張化剤、局所麻酔剤等を添加し、常法により皮下、筋肉及び静脈内注射剤を製造することができる。ｐＨ調製剤及び緩衝剤としてはクエン酸ナトリウム、酢酸ナトリウム、リン酸ナトリウム等が挙げられる。安定化剤としてはピロ亜硫酸ナトリウム、ＥＤＴＡ、チオグリコール酸、チオ乳酸等が挙げられる。局所麻酔剤としては塩酸プロカイン、塩酸リドカイン等が挙げられる。等張化剤としては、塩化ナトリウム、ブドウ糖等が挙げられる。 When preparing an injection, a pH regulator, a buffer, a stabilizer, a tonicity agent, a local anesthetic, etc. are added to the compound represented by the general formula (1), and subcutaneous, muscle and Intravenous injections can be manufactured. Examples of the pH adjusting agent and buffer include sodium citrate, sodium acetate, sodium phosphate and the like. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like. Examples of local anesthetics include procaine hydrochloride and lidocaine hydrochloride. Examples of isotonic agents include sodium chloride and glucose.
　坐剤を調製する場合は、一般式（１）で表される化合物に公知の坐剤用担体、例えば、ポリエチレングリコール、ラノリン、カカオ脂、脂肪酸トリグリセライド等、さらに必要に応じてツイーン（登録商標）等の界面活性剤等を加えた後、常法により製造することができる。 When preparing a suppository, a carrier for a suppository known to the compound represented by the general formula (1), such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride and the like, and Tween (registered trademark) as necessary. After adding a surfactant, etc., it can be produced by a conventional method.
　軟膏剤を調製する場合は、一般式（１）で表される化合物に通常使用される基剤、安定化剤、湿潤剤、保存剤等が必要に応じて配合され、常法により混合、製剤化される。基剤としては、流動パラフィン、白色ワセリン、サラシミツロウ、オクチルドデシルアルコール、パラフィン等が挙げられる。保存剤としては、ｐ－ヒドロキシ安息香酸メチル、ｐ－ヒドロキシ安息香酸エチル、ｐ－ヒドロキシ安息香酸プロピル等が挙げられる。 When preparing an ointment, bases, stabilizers, wetting agents, preservatives, etc., which are usually used for the compound represented by the general formula (1) are blended as necessary, and mixed and formulated by conventional methods. It becomes. Examples of the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like. Examples of the preservative include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate and the like.
　一般式（１）で表される化合物は、上記以外に、常法により吸入剤、点眼剤、点鼻剤とすることもできる。 In addition to the above, the compound represented by the general formula (1) can be converted into an inhalant, an eye drop, or a nasal drop by a conventional method.
　後記実施例に示すとおり、一般式（１）で表わされる化合物は、ハムスター膵臓β細胞株ＨＩＴ－Ｔ１５細胞におけるインスリン分泌を有意に促進する作用を有する。従って、一般式（１）で表わされる化合物、若しくはその酸付加塩又はこれらの溶媒和物は、血糖低下剤として、また、ヒトを含む哺乳類の高血糖に起因する疾患、例えば糖尿病の予防及び／又は治療剤として有用である。ここで、糖尿病としては、より詳細にはインスリン非依存型糖尿病（ＮＩＤＤＭ）が挙げられる。 As shown in Examples below, the compound represented by the general formula (1) has an action of significantly promoting insulin secretion in hamster pancreatic β cell line HIT-T15 cells. Therefore, the compound represented by the general formula (1), or an acid addition salt thereof, or a solvate thereof is used as a hypoglycemic agent and for prevention of diseases caused by hyperglycemia in mammals including humans such as diabetes. Or it is useful as a therapeutic agent. Here, as diabetes, non-insulin dependent diabetes mellitus (NIDDM) is mentioned in more detail.
　本発明の一般式（１）で表わされる化合物は、経口投与又は非経口投与により投与される。本発明の医薬の投与量は、患者の体重、年齢、性別、症状等によって異なるが、通常成人の場合、一般式（１）で表される化合物として一日０．０１～１０００ｍｇ、好ましくは０．１～３００ｍｇを１～３回に分けて投与するのが好ましい。 The compound represented by the general formula (1) of the present invention is administered by oral administration or parenteral administration. The dose of the medicament of the present invention varies depending on the patient's body weight, age, sex, symptoms, etc., but in the case of a normal adult, it is usually 0.01 to 1000 mg, preferably 0, as the compound represented by the general formula (1). It is preferable to administer 1 to 300 mg in 1 to 3 divided doses.
　次に、実施例を挙げて本発明をさらに説明するが、本発明はこれら実施例に限定されるものではない。なお、下記実施例中で用いられている略号は下記の意味を示す。
ｓ：シングレット（ｓｉｎｇｌｅｔ）
ｄ：ダブレット（ｄｏｕｂｌｅｔ）
ｔ：トリプレット（ｔｒｉｐｌｅｔ）
ｑ：クアルテット（ｑｕａｒｔｅｔ）
ｑｕｉｎｔ：クインテット（ｑｕｉｎｔｅｔ）
ｍ：マルチプレット（ｍｕｌｔｉｐｌｅｔ）
ｂｒ：ブロード（ｂｒｏａｄ）
Ｊ：カップリング定数（ｃｏｕｐｌｉｎｇ ｃｏｎｓｔａｎｔ）
Ｈｚ：ヘルツ（Ｈｅｒｔｚ）
ＣＤＣｌ３：重クロロホルム
ｄ６－ＤＭＳＯ：重ジメチルスルホキシド
ＣＤ３ＯＤ：重メタノール
１Ｈ-ＮＭＲ：プロトン核磁気共鳴
ＩＲ：赤外線吸収スペクトル EXAMPLES Next, although an Example is given and this invention is further demonstrated, this invention is not limited to these Examples. In addition, the symbol used in the following Example shows the following meaning.
s: singlet
d: doublet
t: triplet
q: quartet
quintet: quintet
m: multiplet
br: broad
J: Coupling constant
Hz: Hertz
CDCl 3 : deuterated chloroform d 6 -DMSO: deuterated dimethyl sulfoxide CD 3 OD: deuterated methanol
1 H-NMR: proton nuclear magnetic resonance IR: infrared absorption spectrum
実施例１　ｔｅｒｔ－ブチル　４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－４－イル）ピペリジン－１－カルボキシレートの製造
工程１：ｔｅｒｔ－ブチル　４－ヒドロキシメチルピペリジン－１－カルボキシレートの製造
　４－ピペリジンメタノール（４．６ｇ，４０ｍｍｏｌ）をテトラヒドロフラン（４０ｍＬ）及び水（４０ｍＬ）に溶解させ、ジ－ｔｅｒｔ－ブチルジカーボネート（９．６ｇ，４４ｍｍｏｌ）及び炭酸ナトリウム（５．１ｇ，４８ｍｍｏｌ）を加え、室温にて終夜攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムにて乾燥後、減圧濃縮し表題化合物（１２．９ｇ）を粗生成物として得た。 Example 1 Production of tert-butyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-4-yl) piperidine-1-carboxylate Step 1: tert Preparation of 4-butyl 4-hydroxymethylpiperidine-1-carboxylate 4-piperidinemethanol (4.6 g, 40 mmol) was dissolved in tetrahydrofuran (40 mL) and water (40 mL), and di-tert-butyl dicarbonate (9.6 g) was dissolved. , 44 mmol) and sodium carbonate (5.1 g, 48 mmol) were added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (12.9 g) as a crude product.
工程２：ｔｅｒｔ－ブチル　４－ホルミルピペリジン－１－カルボキシレートの製造
　ｔｅｒｔ－ブチル－４－ヒドロキシメチルピペリジン（１０．０ｇ，４６．４ｍｍｏｌ）及び２，２，６，６－テトラメチルピペリジン１－オキシル　フリーラジカル（３６０ｍｇ，２．３２ｍｍｏｌ）をクロロホルム（２３０ｍＬ）に溶解させ、次亜塩素酸ナトリウム／飽和炭酸水素ナトリウム水溶液（１／１，９４ｍＬ）を内温が１℃を越えないように１時間かけて滴下した。滴下終了後、反応液にチオ硫酸ナトリウムを加え、反応を停止し、クロロホルムで抽出した。有機層を無水硫酸ナトリウムにて乾燥後、減圧濃縮をし、表題化合物（１１．１ｇ，粗生成物）を褐色油成物として得た。 Step 2: Preparation of tert-butyl 4-formylpiperidine-1-carboxylate tert-butyl-4-hydroxymethylpiperidine (10.0 g, 46.4 mmol) and 2,2,6,6-tetramethylpiperidine 1-oxyl Free radicals (360 mg, 2.32 mmol) were dissolved in chloroform (230 mL), and sodium hypochlorite / saturated aqueous sodium hydrogen carbonate solution (1/1, 94 mL) was added over 1 hour so that the internal temperature did not exceed 1 ° C. And dripped. After completion of the dropwise addition, sodium thiosulfate was added to the reaction solution to stop the reaction, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (11.1 g, crude product) as a brown oily product.
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：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（１Ｈ，ｓ）． 1 H-NMR (CDCl 3 ) δ: 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 (1H, s).
工程３：ｔｅｒｔ－ブチル　４－（１－ヒドロキシ－２－ニトロエチル）ピペリジン－１－カルボキシレートの製造
　ｔｅｒｔ－ブチル　４－ホルミルピペリジン－１－カルボキシレート（１１．１ｇ，粗生成物）及びフッ化カリウム（５４０ｍｇ，９．２８ｍｍｏｌ）をイソプロパノール（５０ｍＬ）に溶解させ、ニトロメタン（１４．２ｇ，２３２ｍｍｏｌ）を加え、室温で終夜攪拌した。反応液に水を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにて乾燥後、減圧濃縮をし、得られた残渣にジエチルエーテルを加え、懸濁溶液をろ過し、表題化合物（７．７０ｇ，６１％　３工程）を白色粉末として得た。 Step 3: Preparation of tert-butyl 4- (1-hydroxy-2-nitroethyl) piperidine-1-carboxylate tert-butyl 4-formylpiperidine-1-carboxylate (11.1 g, crude product) and potassium fluoride (540 mg, 9.28 mmol) was dissolved in isopropanol (50 mL), nitromethane (14.2 g, 232 mmol) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate and concentration under reduced pressure, diethyl ether was added to the resulting residue, and the suspension solution was filtered to obtain the title compound (7.70 g, 61%, 3 steps) as a white powder.
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．２４－１．３９（２Ｈ，ｍ），１．４６（９Ｈ，ｓ），１．５８－１．６５（２Ｈ，ｍ），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＝８．５，１３．４Ｈｚ），４．５０（２Ｈ，ｄｄ，Ｊ＝２．９，１３．２Ｈｚ）． 1 H-NMR (CDCl 3 ) δ: 1.24 to 1.39 (2H, m), 1.46 (9H, s), 1.58 to 1.65 (2H, m), 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).
工程４：ｔｅｒｔ－ブチル　４－（２－ニトロアセチル）ピペリジン－１－カルボキシレートの製造
　ｔｅｒｔ－ブチル　４－（１－ヒドロキシ－２－ニトロエチル）ピペリジン－１－カルボキシレート（７．７０ｇ，２８．１ｍｍｏｌ）を塩化メチレン（１４０ｍＬ）に溶解させ、デス－マーチンペルヨージナン（１４．３ｇ，３３．７ｍｍｏｌ）を加え、室温で４０分攪拌した。チオ硫酸ナトリウム水溶液及び飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムで乾燥後、減圧濃縮をし、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝４：１→２：１）を用いて精製し、表題化合物（６．８３ｇ，８９％）を黄色固体として得た。 Step 4: Preparation of tert-butyl 4- (2-nitroacetyl) piperidine-1-carboxylate tert-butyl 4- (1-hydroxy-2-nitroethyl) piperidine-1-carboxylate (7.70 g, 28.1 mmol) ) Was dissolved in methylene chloride (140 mL), Dess-Martin periodinane (14.3 g, 33.7 mmol) was added, and the mixture was stirred at room temperature for 40 minutes. A sodium thiosulfate aqueous solution and a saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 2: 1) to give the title compound (6.83 g, 89% ) Was obtained as a yellow solid.
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．４６（９Ｈ，ｓ），１．６０－１．６４（２Ｈ，ｍ），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）． 1 H-NMR (CDCl 3 ) δ: 1.46 (9H, s), 1.60-1.64 (2H, m), 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).
工程５：ｔｅｒｔ－ブチル　４－（１－（ヒドロキシイミノ）－２－ニトロエチル）ピペリジン－１－カルボキシレートの製造
　ｔｅｒｔ－ブチル　４－（２－ニトロアセチル）ピペリジン－１－カルボキシレート（２．００ｇ，７．３４ｍｍｏｌ）及び硫酸ヒドロキシアミン（１．８１ｇ，１１．０ｍｍｏｌ）をエタノール／トルエン＝１／１（３６ｍＬ）に溶解させ、４時間半加熱還流を行った。減圧濃縮をし、水を加え、酢酸エチルで抽出した。無水硫酸ナトリウムで乾燥後、減圧濃縮し、Ｅ／Ｚ混合物の表題化合物（９４５ｍｇ，４５％）を黄色固体として得た。 Step 5: Preparation of tert-butyl 4- (1- (hydroxyimino) -2-nitroethyl) piperidine-1-carboxylate tert-butyl 4- (2-nitroacetyl) piperidine-1-carboxylate (2.00 g, 7.34 mmol) and hydroxyamine sulfate (1.81 g, 11.0 mmol) were dissolved in ethanol / toluene = 1/1 (36 mL) and refluxed for 4 and a half hours. The mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate and concentration under reduced pressure, the title compound (945 mg, 45%) as an E / Z mixture was obtained as a yellow solid.
工程６：エチル　３－（１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル）－４－ニトロイソオキサゾール－５－カルボキシレートの製造
　アルゴン雰囲気下、ｔｅｒｔ－ブチル　４－（１－（ヒドロキシイミノ）－２－ニトロエチル）ピペリジン－１－カルボキシレート（１００ｍｇ，０．３４８ｍｍｏｌ）を無水テトラヒドロフラン（３．５ｍＬ）に溶解させ、クロログリオキシル酸エチル（９５ｍｇ，０．６９６ｍｍｏｌ）を加え、６０℃で６時間加熱した。０℃に冷却し、トリエチルアミン（０．１ｍＬ）をゆっくり加えた。水及び飽和食塩水を加え、酢酸エチルで抽出した。無水硫酸ナトリウムで乾燥後、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１）を用いて精製し、表題化合物（３８．６ｍｇ，３０％）を無色油状物として得た。 Step 6: Preparation of ethyl 3- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4-nitroisoxazole-5-carboxylate tert-butyl 4- (1- (hydroxyimino) under argon atmosphere -2-Nitroethyl) piperidine-1-carboxylate (100 mg, 0.348 mmol) was dissolved in anhydrous tetrahydrofuran (3.5 mL), ethyl chloroglyoxylate (95 mg, 0.696 mmol) was added, and the mixture was heated at 60 ° C. for 6 hours. did. Cool to 0 ° C. and slowly add triethylamine (0.1 mL). Water and saturated brine were added, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give the title compound (38.6 mg, 30%) as a colorless oil. Got as.
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．４３（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），１．４７（９Ｈ，ｓ），１．７６（１Ｈ，ｄｄ，Ｊ＝４．１，１２．０Ｈｚ），１．８２（１Ｈ，ｄｄ，Ｊ＝４．４，１１．７Ｈｚ），１．９６－２．０３（２Ｈ，ｍ），２．８２－２．９６（２Ｈ，ｍ），３．２７（１Ｈ，ｄｄｄｄ，Ｊ＝４．０，４．０，１１．６，１１．６Ｈｚ），４．１４－４．２６（２Ｈ，ｍ），４．５２（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ）． 1 H-NMR (CDCl 3 ) δ: 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), 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).
工程７：エチル　４－アミノ－３－（１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル）イソオキサゾール－５－カルボキシレートの製造
　エチル　３－（１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル）－４－ニトロイソオキサゾール－５－カルボキシレート（７８．８ｍｇ，０．２１３ｍｍｏｌ）をエタノール／水＝１／１（２ｍＬ）に溶解させ、亜鉛（１４０ｍｇ，２．１３ｍｍｏｌ）及び塩化アンモニウム（２８０ｍｇ，５．３３ｍｍｏｌ）を０℃で加え、４時間室温で攪拌した。減圧濃縮し、無水硫酸ナトリウムで乾燥後、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）を用いて精製し、表題化合物（６４．５ｍｇ，８９％）を黄色油状物として得た。 Step 7: Preparation of ethyl 4-amino-3- (1- (tert-butoxycarbonyl) piperidin-4-yl) isoxazole-5-carboxylate Ethyl 3- (1- (tert-butoxycarbonyl) piperidine-4- Yl) -4-nitroisoxazole-5-carboxylate (78.8 mg, 0.213 mmol) dissolved in ethanol / water = 1/1 (2 mL), zinc (140 mg, 2.13 mmol) and ammonium chloride (280 mg) , 5.33 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 4 hours. After concentration under reduced pressure and drying over anhydrous sodium sulfate, the resulting residue was purified using silica gel column chromatography (ethyl acetate) to obtain the title compound (64.5 mg, 89%) as a yellow oil.
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．４０（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），１．４７（９Ｈ，ｓ），１．７４－１．８７（２Ｈ，ｍ），１．９０－１．９８（２Ｈ，ｍ），２．７９（１Ｈ，ｄｄｄｄ，Ｊ＝４．０，４．０，１１．６，１１．６Ｈｚ），２．８４－２．９６（２Ｈ，ｍ），４．１１－４．２４（４Ｈ，ｍ），４．４１（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ）． 1 H-NMR (CDCl 3 ) δ: 1.40 (3H, t, J = 7.1 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).
工程８：ｔｅｒｔ－ブチル　４－（７－ヒドロキシイソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートの製造
　エチル　４－アミノ－３－（１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル）イソオキサゾール－５－カルボキシレート（３２．５ｍｇ，０．０８１ｍｍｏｌ）及びホルムアミジン酢酸塩（２６．０ｍｇ，０．２４３ｍｍｏｌ）をエタノールに溶解させ、２４時間加熱還流を行った。減圧濃縮し、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムで乾燥後、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１→クロロホルム：メタノール＝９：１）を用いて精製し、表題化合物（１７．９ｍｇ，６９％）を黄色固体として得た。 Step 8: Preparation of tert-butyl 4- (7-hydroxyisoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate Ethyl 4-amino-3- (1- (tert-butoxy) Carbonyl) piperidin-4-yl) isoxazole-5-carboxylate (32.5 mg, 0.081 mmol) and formamidine acetate (26.0 mg, 0.243 mmol) are dissolved in ethanol and heated under reflux for 24 hours. It was. The mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 2: 1 → chloroform: methanol = 9: 1) to give the title compound (17.9 mg). 69%) as a yellow solid.
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．４８（９Ｈ，ｓ），１．９４（１Ｈ，ｄｄ，Ｊ＝３．９，１２．２Ｈｚ），２．００（１Ｈ，ｄｄ，Ｊ＝４．１，１２．２Ｈｚ），２．０７－２．１６（２Ｈ，ｍ），２．８８－３．０３（２Ｈ，ｍ），３．２８（１Ｈ，Ｊ＝４．０，４．０，１１．６，１１．６Ｈｚ，ｄｄｄｄ），４．１１－４．２９（２Ｈ，ｍ），８．０７（１Ｈ，ｓ），８．２４（１Ｈ，ｄ，Ｊ＝１４．１Ｈｚ）． 1 H-NMR (CDCl 3 ) δ: 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 (1 H, J = 4.0, 4.0, 11 .6, 11.6 Hz, dddd), 4.11-4.29 (2H, m), 8.07 (1H, s), 8.24 (1 H, d, J = 14.1 Hz).
工程９：ｔｅｒｔ－ブチル４－（７－（（１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾール－１－イル）オキシ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートの製造
　ｔｅｒｔ－ブチル　４－（７－ヒドロキシイソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（１４．１ｍｇ．０．０４４ｍｍｏｌ）及び１Ｈ－ベンゾトリアゾール－１－イルオキシトリピロリジンホスホニウムヘキサフルオロホスファート（２７．０ｍｇ，０．０５３ｍｍｏｌ）を無水テトラヒドロフラン（０．５ｍＬ）に懸濁させ、トリエチルアミン（１０μＬ）を加え、室温で１時間攪拌した。水を加え、酢酸エチルで抽出した。無水硫酸ナトリウムで乾燥後、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１）を用いて精製し、表題化合物（７．１ｍｇ，３７％）を白濁油状物として得た。 Step 9: tert-Butyl 4- (7-((1H-benzo [d] [1,2,3] triazol-1-yl) oxy) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine- Preparation of 1-carboxylate tert-Butyl 4- (7-hydroxyisoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate (14.1 mg.0.044 mmol) and 1H-benzo Triazol-1-yloxytripyrrolidinephosphonium hexafluorophosphate (27.0 mg, 0.053 mmol) was suspended in anhydrous tetrahydrofuran (0.5 mL), triethylamine (10 μL) was added, and the mixture was stirred at room temperature for 1 hour. Water was added and extracted with ethyl acetate. After drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound (7.1 mg, 37%) as a cloudy oil. Got as.
１Ｈ－ＮＭＲ（ＣＤＣｌ３）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＝４．０，４．０，１１．２，１１．２Ｈｚ），４．１４－４．３３（２Ｈ，ｍ），７．４８－７．５３（２Ｈ，ｍ），７．５７－７．６２（１Ｈ，ｍ），８．１７（１Ｈ，ｄｄ，Ｊ＝１．２，８．０Ｈｚ），８．６４（１Ｈ，ｓ）． 1 H-NMR (CDCl 3 ) 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 (1 H, m), 8.17 (1 H, dd, J = 1.2, 8.0 Hz), 8.64 (1 H, s ).
工程１０：ｔｅｒｔ－ブチル　４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－４－イル）ピペリジン－１－カルボキシレートの製造
　アルゴン雰囲気下、５－（メチルスルホニル）インドリン（２．５ｍｇ，０．０１３ｍｍｏｌ）及びｔｅｒｔ－ブチル４－（７－（（１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾール－１－イル）オキシ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（７．１ｍｇ，０．０１６ｍｍｏｌ）を無水Ｎ，Ｎ－ジメチルホルムアミド（０．３ｍＬ）に溶解させ、水素化ナトリウム（１．０ｍｇ，０．０２０ｍｍｏｌ）を加え、７０℃で１０分攪拌した。水を加え、クロロホルムで抽出した。無水硫酸ナトリウムで乾燥後、減圧濃縮し、得られた残渣をシリカゲル分取薄層クロマトグラフィー（クロロホルム：メタノール＝５０：１）にて精製し、表題化合物（１．６ｍｇ，２５％）を褐色固体として得た。 Step 10: Preparation of tert-butyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-4-yl) piperidine-1-carboxylate under argon atmosphere 5- (Methylsulfonyl) indoline (2.5 mg, 0.013 mmol) and tert-butyl 4- (7-((1H-benzo [d] [1,2,3] triazol-1-yl) oxy) isoxazolo [ 4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate (7.1 mg, 0.016 mmol) was dissolved in anhydrous N, N-dimethylformamide (0.3 mL) and sodium hydride (1. 0 mg, 0.020 mmol) was added, and the mixture was stirred at 70 ° C. for 10 minutes. Water was added and extracted with chloroform. After drying over anhydrous sodium sulfate and concentrating under reduced pressure, the resulting residue was purified by silica gel preparative thin layer chromatography (chloroform: methanol = 50: 1) to give the title compound (1.6 mg, 25%) as a brown solid Got as.
実施例２　３－（１－（５－クロロピリミジン－２－イル）ピペリジン－４－イル）－７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジンの製造
工程１：７－（５－（メチルスルホニル）インドリン－１－イル）－３－（ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン塩酸塩の製造
　ｔｅｒｔ－ブチル　４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－４－イル）ピペリジン－１－カルボキシレート（５．８ｍｇ，０．０１２ｍｍｏｌ）を酢酸エチル（０．５ｍＬ）に溶解させ、氷冷下、４規定塩酸酢酸エチル（１．３ｍＬ）を加え、室温で２時間半攪拌した。減圧濃縮し、表題化合物（５．８ｍｇ，粗生成物）を橙色固体として得た。 Example 2 3- (1- (5-chloropyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine Production step 1: Production of 7- (5- (methylsulfonyl) indoline-1-yl) -3- (piperidin-4-yl) isoxazolo [4,5-d] pyrimidine hydrochloride tert-butyl 4- (7- (5- (Methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-4-yl) piperidine-1-carboxylate (5.8 mg, 0.012 mmol) in ethyl acetate (0.5 mL) Then, 4N hydrochloric acid ethyl acetate (1.3 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 2.5 hours. Concentration under reduced pressure gave the title compound (5.8 mg, crude product) as an orange solid.
工程２：３－（１－（５－クロロピリミジン－２－イル）ピペリジン－４－イル）－７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジンの製造
　７－（５－（メチルスルホニル）インドリン－１－イル）－３－（ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン塩酸塩（５．３ｍｇ，粗体）及び２，５－ジクロロピリミジン（２．７ｍｇ，０．０１８ｍｍｏｌ）を無水Ｎ，Ｎ－ジメチルホルムアミド（０．３ｍＬ）に溶解させ、Ｎ，Ｎ－ジイソプロピルエチルアミン（７μＬ，０．０３６ｍｍｏｌ）を加え、８０℃で４時間攪拌した。水を加え、酢酸エチルで抽出した。無水硫酸ナトリウムで乾燥後、減圧濃縮し、得られた残渣をシリカゲル分取薄層クロマトグラフィー（クロロホルム：メタノール＝８０：１）にて精製し、表題化合物（２．８ｍｇ，４６％）を黄色固体として得た。 Step 2: 3- (1- (5-Chloropyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine Preparation 7- (5- (Methylsulfonyl) indoline-1-yl) -3- (piperidin-4-yl) isoxazolo [4,5-d] pyrimidine hydrochloride (5.3 mg, crude) and 2,5- Dichloropyrimidine (2.7 mg, 0.018 mmol) is dissolved in anhydrous N, N-dimethylformamide (0.3 mL), N, N-diisopropylethylamine (7 μL, 0.036 mmol) is added, and the mixture is stirred at 80 ° C. for 4 hours. did. Water was added and extracted with ethyl acetate. After drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified by silica gel preparative thin layer chromatography (chloroform: methanol = 80: 1) to give the title compound (2.8 mg, 46%) as a yellow solid. Got as.
実施例３　３－（１－（５－エチルピリミジン－２－イル）ピペリジン－４－イル）－７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジンの製造
　２，５－ジクロロピリミジンの代わりに２－クロロ－５－エチルピリミジンを用いて実施例２と同様に反応・処理し、表題化合物を橙色油状物として得た。 Example 3 3- (1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine Preparation The reaction and treatment were conducted in a similar manner to Example 2 using 2-chloro-5-ethylpyrimidine instead of 2,5-dichloropyrimidine, and the title compound was obtained as an orange oil.
実施例４　３－（１－（５－ブロモピリミジン－２－イル）ピペリジン－４－イル）－７－（５－（メチルスルホニル）インドリン－1－イル）イソオキサゾロ［４，５－ｄ］ピリミジンの製造
　２，５－ジクロロピリミジンの代わりに５－ブロモ－２－クロロピリミジンを用いて実施例２の工程２と同様に反応・処理し、表題化合物を白色固体として得た。 Example 4 3- (1- (5-Bromopyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine Production The reaction and treatment were conducted in a similar manner to process 2 of example 2 using 5-bromo-2-chloropyrimidine in place of 2,5-dichloropyrimidine, and the title compound was obtained as a white solid.
実施例５　３－（１－（５－フロロピリミジン－２－イル）ピペリジン－４－イル）－７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジンの製造
　２，５－ジクロロピリミジンの代わりに２－クロロ－５－フロロピリミジンを用いて実施例２の工程２と同様に反応・処理し、表題化合物を白色固体として得た。 Example 5 3- (1- (5-Fluoropyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine Production The reaction and treatment were conducted in a similar manner to process 2 of example 2 using 2-chloro-5-fluoropyrimidine in place of 2,5-dichloropyrimidine, and the title compound was obtained as a white solid.
実施例６　エチル　２－（４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）ピリミジン－５－カルボキシレートの製造
　２，５－ジクロロピリミジンの代わりにエチル　２－（メチルスルフィニル）ピリミジン－５－カルボキシレートを用いて実施例２の工程２と同様に反応・処理し、表題化合物を淡黄色固体として得た。 Example 6 Ethyl 2- (4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidine-5-carboxy Production of rate Using ethyl 2- (methylsulfinyl) pyrimidine-5-carboxylate instead of 2,5-dichloropyrimidine, the reaction and treatment were carried out in the same manner as in Step 2 of Example 2 to obtain the title compound as a pale yellow solid. It was.
実施例７　２－（４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）ピリミジン－５－カルボン酸の製造
　アルゴン雰囲気下、アリル　２－（４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）ピリミジン－５－カルボキシレート（７ｍｇ，０．０１２ｍｍｏｌ）、ピロリジン（１ｍｇ，０．０１３ｍｍｏｌ）およびテトラキストリフェニルホスフィンパラジウム（６ｍｇ，０．００５ｍｍｏｌ）を無水Ｎ，Ｎ－ジメチルホルムアルデヒド（０．５ｍＬ）に溶解し、室温で２時間撹拌した。酢酸エチルと飽和炭酸水素ナトリウム水溶液を加え、有機層を分離し、水層に酢酸を加えｐＨ６とした。クロロホルムで抽出し、有機層を無水硫酸ナトリウムで乾燥した後、減圧濃縮し、表題化合物（２ｍｇ，３２％）をオレンジ色固体として得た。 Example 7 2- (4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidine-5-carboxylic acid Preparation of allyl 2- (4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidine- under argon atmosphere 5-carboxylate (7 mg, 0.012 mmol), pyrrolidine (1 mg, 0.013 mmol) and tetrakistriphenylphosphine palladium (6 mg, 0.005 mmol) are dissolved in anhydrous N, N-dimethylformaldehyde (0.5 mL), Stir at room temperature for 2 hours. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, the organic layer was separated, and acetic acid was added to the aqueous layer to adjust to pH 6. After extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound (2 mg, 32%) as an orange solid.
実施例８　７－（５－（メチルスルホニル）インドリン－１－イル）－３－（１－（５－（トリフロロメチル）ピリミジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジンの製造
　２，５－ジクロロピリミジンの代わりに２－（メチルスルフィニル）－５－（トリフロロメチル）ピリミジンを用いて実施例２の工程２と同様に反応・処理し、表題化合物を淡黄色固体として得た。 Example 8 7- (5- (Methylsulfonyl) indoline-1-yl) -3- (1- (5- (trifluoromethyl) pyrimidin-2-yl) piperidin-4-yl) isoxazolo [4,5- d] Production of pyrimidine The reaction and treatment were conducted in the same manner as in Step 2 of Example 2 using 2- (methylsulfinyl) -5- (trifluoromethyl) pyrimidine in place of 2,5-dichloropyrimidine, and the title compound was palely prepared. Obtained as a yellow solid.
実施例９　２－（４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）ピリミジン－５－オールの製造
工程１：７－（５－（メチルスルホニル）インドリン－１－イル）－３－（１－（５－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）ピリミジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジンの製造
　２，５－ジクロロピリミジンの代わりに２－クロロ－５－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）ピリミジンを用いて実施例２の工程２と同様に反応・処理し、表題化合物を黄色固体として得た。 Example 9 of 2- (4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidin-5-ol Production step 1: 7- (5- (methylsulfonyl) indoline-1-yl) -3- (1- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-) Preparation of yl) pyrimidin-2-yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidine 2-chloro-5- (4,4,5,5-tetra instead of 2,5-dichloropyrimidine Methyl-1,3,2-dioxaborolan-2-yl) pyrimidine was used for the reaction and treatment in the same manner as in Step 2 of Example 2 to obtain the title compound as a yellow solid.
工程２：２－（４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）ピリミジン－５－オールの製造
　７－（５－（メチルスルホニル）インドリン－１－イル）－３－（１－（５－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）ピリミジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン（１３．４ｍｇ，０．０２３ｍｍｏｌ）をＴＨＦ（１ｍＬ）に溶解し、３０％過酸化水素水（５０μＬ）を加え、室温で４時間撹拌した後、チオ硫酸ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧濃縮し得られた残渣をシリカゲル分取薄層クロマトグラフィー（クロロホルム：メタノール＝２０：１）にて精製し、表題化合物（２．６ｍｇ，２３％）を黄色固体として得た。 Step 2: 2- (4- (7- (5- (Methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidin-5-ol Preparation 7- (5- (Methylsulfonyl) indoline-1-yl) -3- (1- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine -2-yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidine (13.4 mg, 0.023 mmol) was dissolved in THF (1 mL), 30% aqueous hydrogen peroxide (50 μL) was added, After stirring at room temperature for 4 hours, an aqueous sodium thiosulfate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel preparative thin layer chromatography (chloroform: methanol = 20: 1) to give the title compound (2.6 mg, 23%). Was obtained as a yellow solid.
実施例１０　３－（１－（５－メトキシピリミジン－２－イル）ピペリジン－４－イル）－７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジンの製造
　２－（４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）ピリミジン－５－オール（１０．０ｍｇ，０．０１７ｍｍｏｌ）を無水Ｎ，Ｎ－ジメチルホルムアミド（１ｍＬ）に溶解し、炭酸カリウム（５ｍｇ，０．０３６ｍｍｏｌ）およびヨードメタン（５ｍｇ，０．０３６ｍｍｏｌ）を加え、室温で５０分間撹拌した。水を加え、クロロホルムで抽出し、有機層を無水硫酸ナトリウムで乾燥した後、減圧濃縮し得られた残渣をシリカゲル分取薄層クロマトグラフィー（クロロホルム：メタノール＝５０：１）にて精製し、表題化合物（２．８ｍｇ，３１％）を白色固体として得た。 Example 10 3- (1- (5-methoxypyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine Preparation 2- (4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidin-5-ol (10. 0 mg, 0.017 mmol) was dissolved in anhydrous N, N-dimethylformamide (1 mL), potassium carbonate (5 mg, 0.036 mmol) and iodomethane (5 mg, 0.036 mmol) were added, and the mixture was stirred at room temperature for 50 minutes. Water was added and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel preparative thin layer chromatography (chloroform: methanol = 50: 1) to give the title The compound (2.8 mg, 31%) was obtained as a white solid.
実施例１１　７－（５－（メチルスルホニル）インドリン－１－イル）－３－（１－（５－フェニルピリミジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジンの製造
　アルゴン雰囲気下、７－（５－（メチルスルホニル）インドリン－１－イル）－３－（１－（５－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）ピリミジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン（１４．７ｍｇ，０．０２４ｍｍｏｌ）、ヨードベンゼン（７．５ｍｇ，０．０３６ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（２．８ｍｇ，０．００２４ｍｍｏｌ）をＮ，Ｎ－ジメチルホルムアミド（０．４ｍＬ）および水（０．１ｍＬ）に溶解し、炭酸ナトリウム（５．１ｍｇ，０．０４８ｍｍｏｌ）を加え、８０℃で２時間加熱した。水を加え、クロロホルムで抽出し、有機層を無水硫酸ナトリウムで乾燥した後、減圧濃縮し得られた残渣をシリカゲル分取薄層クロマトグラフィー（クロロホルム：メタノール＝８０：１）にて精製し、表題化合物（６．５ｍｇ，４９％）を褐色固体として得た。 Example 11 7- (5- (Methylsulfonyl) indoline-1-yl) -3- (1- (5-phenylpyrimidin-2-yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidine Preparation 7- (5- (Methylsulfonyl) indoline-1-yl) -3- (1- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) under argon atmosphere -Yl) pyrimidin-2-yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidine (14.7 mg, 0.024 mmol), iodobenzene (7.5 mg, 0.036 mmol), tetrakistriphenylphosphine Palladium (2.8 mg, 0.0024 mmol) is dissolved in N, N-dimethylformamide (0.4 mL) and water (0.1 mL), and carbonated. Thorium (5.1 mg, 0.048 mmol) was added and heated for 2 hours at 80 ° C.. Water was added and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel preparative thin layer chromatography (chloroform: methanol = 80: 1) to give the title The compound (6.5 mg, 49%) was obtained as a brown solid.
実施例１２　７－（５－（メチルスルホニル）インドリン－１－イル）－３－（１－（５－（トリフロロメチル）ピリジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジンの製造
　２，５－ジクロロピリミジンの代わりに２－クロロ－５－（トリフロロメチル）ピリジンを用いて実施例２の工程２と同様に反応・処理し、表題化合物を淡黄色固体として得た。 Example 12 7- (5- (Methylsulfonyl) indoline-1-yl) -3- (1- (5- (trifluoromethyl) pyridin-2-yl) piperidin-4-yl) isoxazolo [4,5- d] Preparation of pyrimidine The reaction and treatment were conducted in the same manner as in Step 2 of Example 2 using 2-chloro-5- (trifluoromethyl) pyridine in place of 2,5-dichloropyrimidine, and the title compound was converted to a pale yellow solid. Obtained.
実施例１３　イソプロピル　４－（７－（５－（メチルスルホニル）インドリン－1－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートの製造
　７－（５－（メチルスルホニル）インドリン－１－イル）－３－（ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン塩酸塩（４ｍｇ，０．０１１ｍｍｏｌ）を無水ジクロロメタン（０．２ｍＬ）に溶解し、クロロギ酸イソプロピル（２ｍｇ，０．０１７ｍｍｏｌ）を加えた。２０分間攪拌した後、水を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮し得られた残渣をシリカゲル分取薄層クロマトグラフィーにて精製し、表題化合物（３ｍｇ，６４％）を淡黄色固体として得た。 Example 13 Preparation of Isopropyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate 7- (5- ( Methylsulfonyl) indoline-1-yl) -3- (piperidin-4-yl) isoxazolo [4,5-d] pyrimidine hydrochloride (4 mg, 0.011 mmol) was dissolved in anhydrous dichloromethane (0.2 mL) Isopropyl acid (2 mg, 0.017 mmol) was added. After stirring for 20 minutes, water was added and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by silica gel preparative thin layer chromatography to obtain the title compound (3 mg, 64%) as a pale yellow solid.
実施例１４　エチル　４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートの製造
　クロロギ酸イソプロピルの代わりクロロギ酸エチルを用いて実施例１３と同様に反応・処理し、表題化合物を淡黄色固体として得た。 Example 14 Preparation of ethyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate Chlorogy instead of isopropyl chloroformate Reaction and treatment were conducted in the same manner as in Example 13 using ethyl acid to obtain the title compound as a pale yellow solid.
実施例１５　２－フロロエチル　４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートの製造
　クロロギ酸イソプロピルの代わりクロロギ酸２－フロロエチルを用いて実施例１３と同様に反応・処理し、表題化合物を淡黄色固体として得た。 Example 15 Preparation of 2-fluoroethyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate Instead, the reaction and treatment were conducted in the same manner as in Example 13 using 2-fluoroethyl chloroformate to obtain the title compound as a pale yellow solid.
実施例１６　２－メトキシエチル　４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートの製造
　クロロギ酸イソプロピルの代わりクロロギ酸２－メトキシエチルを用いて実施例１３と同様に反応・処理し、表題化合物を淡黄色固体として得た。 Example 16 Preparation of 2-methoxyethyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate Isopropyl chloroformate The reaction and treatment were conducted in a similar manner to Example 13 using 2-methoxyethyl chloroformate instead of 1, to give the title compound as a pale yellow solid.
実施例１７　テトラヒドロ－２Ｈ－ピラン－４－イル　４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートの製造
　クロロギ酸イソプロピルの代わりに４－ニトロフェニル（テトラヒドロ－２Ｈ－ピラン－４－イル）カーボネートを用いて実施例１３と同様に反応・処理し、表題化合物を淡黄色固体として得た。 Example 17 Tetrahydro-2H-pyran-4-yl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate The reaction and treatment were conducted in the same manner as in Example 13 using 4-nitrophenyl (tetrahydro-2H-pyran-4-yl) carbonate instead of isopropyl chloroformate, and the title compound was obtained as a pale-yellow solid.
実施例１８　アリル　２－（４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）ピリミジン－５－カルボキシレートの製造
　２，５－ジクロロピリミジンの代わりにアリル　２－（メチルスルフィニル）ピリミジン－５－カルボキシレートを用いて実施例２の工程２と同様に反応・処理し、表題化合物を淡黄色固体として得た。 Example 18 Allyl 2- (4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidine-5-carboxy Production of rate Using allyl 2- (methylsulfinyl) pyrimidine-5-carboxylate instead of 2,5-dichloropyrimidine, the reaction and treatment were carried out in the same manner as in Step 2 of Example 2 to obtain the title compound as a pale yellow solid. It was.
実施例１９　ｔｅｒｔ－ブチル　４－（７－（５（メチルスルフィニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートの製造
　５－（メチルスルホニル）インドリンの代わりに５－（メチルスルフィニル）インドリンを用いて実施例１の工程１０と同様に反応・処理し、表題化合物を黄色固体として得た。 Example 19 Preparation of tert-butyl 4- (7- (5 (methylsulfinyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate 5- (Methylsulfonyl) ) The reaction and treatment were conducted in the same manner as in step 10 of Example 1 using 5- (methylsulfinyl) indoline instead of indoline to obtain the title compound as a yellow solid.
実施例２０　７－（５－（メチルスルフィニル）インドリン－１－イル）－３－（１－（５－（トリフロロメチル）ピリジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジンの製造 Example 20 7- (5- (methylsulfinyl) indoline-1-yl) -3- (1- (5- (trifluoromethyl) pyridin-2-yl) piperidin-4-yl) isoxazolo [4,5- d] Production of pyrimidine
工程１：７－（５－（メチルスルフィニル）インドリン－１－イル）－３－（ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン塩酸塩の製造
　ｔｅｒｔ－ブチル　４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－４－イル）ピペリジン－１－カルボキシレートの代わりにｔｅｒｔ－ブチル　４－（７－（５（メチルスルフィニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートを用いて実施例２の工程１と同様に反応・処理し、表題化合物を黄色固体として得た。 Step 1: Preparation of 7- (5- (methylsulfinyl) indoline-1-yl) -3- (piperidin-4-yl) isoxazolo [4,5-d] pyrimidine hydrochloride tert-butyl 4- (7- ( 5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-4-yl) piperidine-1-carboxylate instead of tert-butyl 4- (7- (5 (methylsulfinyl) indoline) -1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate was reacted and treated in the same manner as in Step 1 of Example 2 to obtain the title compound as a yellow solid. .
工程２：７－（５－（メチルスルフィニル）インドリン－１－イル）－３－（１－（５－（トリフロロメチル）ピリジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジンの製造
　２，５－ジクロロピリミジンの代わりに２－クロロ－５－（トリフロロメチル）ピリジンと工程１で得られた７－（５－（メチルスルフィニル）インドリン－１－イル）－３－（ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン塩酸塩を用いて実施例２の工程２と同様に反応・処理し、表題化合物を黄色固体として得た。 Step 2: 7- (5- (Methylsulfinyl) indoline-1-yl) -3- (1- (5- (trifluoromethyl) pyridin-2-yl) piperidin-4-yl) isoxazolo [4,5- d] Preparation of pyrimidine 2-chloro-5- (trifluoromethyl) pyridine instead of 2,5-dichloropyrimidine and 7- (5- (methylsulfinyl) indoline-1-yl) -3 obtained in Step 1 The reaction and treatment were conducted in a similar manner to process 2 of example 2 using-(piperidin-4-yl) isoxazolo [4,5-d] pyrimidine hydrochloride to obtain the title compound as a yellow solid.
実施例２１　２，２－ジメチル－１－（４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）プロパン－１－オンの製造
　クロロギ酸イソプロピルの代わりにピバロイルクロリドを用いて実施例１３と同様に反応・処理し、表題化合物を淡黄色固体として得た。 Example 21 2,2-Dimethyl-1- (4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) Production of propan-1-one The reaction and treatment were conducted in the same manner as in Example 13 using pivaloyl chloride in place of isopropyl chloroformate, and the title compound was obtained as a pale-yellow solid.
実施例２２　ｔｅｒｔ－ブチル　４－（７－（（２－フロロ－４－（メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートの製造
　５－（メチルスルホニル）インドリンの代わりに２－フロロ－４－（メチルスルホニル）アニリンを用いて実施例１の工程１０と同様に反応・処理し、表題化合物を淡黄色固体として得た。 Example 22 Preparation of tert-butyl 4- (7-((2-fluoro-4- (methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate 5 The reaction and treatment were conducted in a similar manner to process 10 of example 1 using 2-fluoro-4- (methylsulfonyl) aniline in place of-(methylsulfonyl) indoline, and the title compound was obtained as a pale-yellow solid.
実施例２３　Ｎ－（２－フロロ－４－（メチルスルホニル）フェニル）－３－（１－（５－（トリフロロメチル）ピリミジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－７－アミンの製造
工程１：Ｎ－（２－フロロ－４－（メチルスルホニル）フェニル）－３－（ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－７－アミン塩酸塩の製造
　ｔｅｒｔ－ブチル　４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－４－イル）ピペリジン－１－カルボキシレートの代わりにｔｅｒｔ－ブチル　４－（７－（（２－フロロ－４－（メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートを用いて実施例２の工程１と同様に反応・処理し、表題化合物を黄色固体として得た。 Example 23 N- (2-Fluoro-4- (methylsulfonyl) phenyl) -3- (1- (5- (trifluoromethyl) pyrimidin-2-yl) piperidin-4-yl) isoxazolo [4,5- d] Pyrimidin-7-amine production step 1: N- (2-fluoro-4- (methylsulfonyl) phenyl) -3- (piperidin-4-yl) isoxazolo [4,5-d] pyrimidin-7-amine Preparation of hydrochloride salt tert-butyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-4-yl) piperidine-1-carboxylate instead of tert- Butyl 4- (7-((2-fluoro-4- (methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine- The reaction and treatment were conducted in a similar manner to process 1 of example 2 using 1-carboxylate, and the title compound was obtained as a yellow solid.
工程２：Ｎ－（２－フロロ－４－（メチルスルホニル）フェニル）－３－（１－（５－（トリフロロメチル）ピリミジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－７－アミンの製造
　２，５－ジクロロピリミジンの代わりに２－（メチルスルフィニル）－５－（トリフロロメチル）ピリミジンと工程１で得られたＮ－（２－フロロ－４－（メチルスルホニル）フェニル）－３－（ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－７－アミン塩酸塩を用いて実施例２の工程２と同様に反応・処理し、表題化合物を淡黄色固体として得た。 Step 2: N- (2-Fluoro-4- (methylsulfonyl) phenyl) -3- (1- (5- (trifluoromethyl) pyrimidin-2-yl) piperidin-4-yl) isoxazolo [4,5- d] Preparation of pyrimidine-7-amine 2- (methylsulfinyl) -5- (trifluoromethyl) pyrimidine instead of 2,5-dichloropyrimidine and N- (2-fluoro-4- ( Methylsulfonyl) phenyl) -3- (piperidin-4-yl) isoxazolo [4,5-d] pyrimidin-7-amine hydrochloride was reacted and treated in the same manner as in Step 2 of Example 2 to obtain the title compound. Obtained as a pale yellow solid.
実施例２４　Ｎ－（２－フロロ－４－（メチルスルホニル）フェニル）３－（１－（５－（トリフロロメチル）ピリジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］－７－アミンの製造
　７－（５－（メチルスルホニル）インドリン－１－イル）－３－（ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン塩酸塩の代わりにＮ－（２－フロロ－４－（メチルスルホニル）フェニル）－３－（ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－７－アミン塩酸塩を、２，５－ジクロロピリミジンの代わりに２－クロロ－５－（トリフロロメチル）ピリジンを用いて実施例２の工程２と同様に反応・処理し、表題化合物を黄色固体として得た。 Example 24 N- (2-Fluoro-4- (methylsulfonyl) phenyl) 3- (1- (5- (trifluoromethyl) pyridin-2-yl) piperidin-4-yl) isoxazolo [4,5-d Preparation of 7-amine 7- (5- (methylsulfonyl) indoline-1-yl) -3- (piperidin-4-yl) isoxazolo [4,5-d] pyrimidine hydrochloride instead of N- (2 -Fluoro-4- (methylsulfonyl) phenyl) -3- (piperidin-4-yl) isoxazolo [4,5-d] pyrimidin-7-amine hydrochloride instead of 2,5-dichloropyrimidine The reaction and treatment were conducted in a similar manner to process 2 of example 2 using -5- (trifluoromethyl) pyridine to give the title compound as a yellow solid.
実施例２５　１，１，１－トリフロロ－２－メチルプロパン－２－イル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートの製造
　Ｎ－（２－フロロ－４－（メチルスルホニル）フェニル）－３－（ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－７－アミン塩酸塩（１０ｍｇ，０．０２４ｍｍｏｌ）及び１，１，１－トリフロロ－２－メチルプロパン－２－イル　１Ｈ－イミダゾール－１－カルボキシレート（１０ｍｇ，０．０４８ｍｍｏｌ）を無水Ｎ，Ｎ－ジメチルホルムアルデヒド（０．２ｍＬ）に溶解し、Ｎ，Ｎ－ジイソプロピルエチルアミン（１０ｍｇ，０．０７２ｍｍｏｌ）を加え、８０℃で３時間撹拌した。溶媒を減圧除去し、残渣をシリカゲル分取薄層クロマトグラフィー（クロロホルム：メタノール＝２０：１）にて精製し、表題化合物（７ｍｇ，５３％）を淡黄色アモルファスとして得た。 Example 25 1,1,1-Trifluoro-2-methylpropan-2-yl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidine-3 -Il) Preparation of piperidine-1-carboxylate N- (2-Fluoro-4- (methylsulfonyl) phenyl) -3- (piperidin-4-yl) isoxazolo [4,5-d] pyrimidin-7-amine hydrochloride Salt (10 mg, 0.024 mmol) and 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (10 mg, 0.048 mmol) in anhydrous N, N-dimethylformaldehyde (0 2 mL), N, N-diisopropylethylamine (10 mg, 0.072 mmol) was added, and the mixture was stirred at 80 ° C. for 3 hours. Stir. The solvent was removed under reduced pressure, and the residue was purified by silica gel preparative thin layer chromatography (chloroform: methanol = 20: 1) to obtain the title compound (7 mg, 53%) as a pale yellow amorphous.
実施例２６　２，２，２－トリフロロエチル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートの製造
　１，１，１－トリフロロ－２－メチルプロパン－２－イル　１Ｈ－イミダゾール－１－カルボキシレートの代わりに２，２，２－トリフロロエチル　１Ｈ－イミダゾール－１－カルボキシレートを用いて実施例２５と同様に反応・処理し、表題化合物を淡黄色アモルファスとして得た。 Example 26 2,2,2-trifluoroethyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1- Preparation of carboxylate 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate instead of 1,2,1-trifluoroethyl 1H-imidazole-1-carboxylate The reaction and treatment were conducted in the same manner as in Example 25 to obtain the title compound as a pale yellow amorphous.
実施例２７　２，２，２－トリクロロエチル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートの製造
　クロロギ酸イソプロピルの代わりクロロギ酸２，２，２－トリクロロエチルを用いて実施例１３と同様に反応・処理し、表題化合物を淡黄色固体として得た。 Example 27 2,2,2-Trichloroethyl 4- (7-((2-Fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxy Production of rate The reaction and treatment were conducted in the same manner as in Example 13 using 2,2,2-trichloroethyl chloroformate instead of isopropyl chloroformate to obtain the title compound as a pale yellow solid.
実施例２８　ネオペンチル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートの製造
　クロロギ酸イソプロピルの代わりクロロギ酸ネオペンチルを用いて実施例１３と同様に反応・処理し、表題化合物を淡黄色固体として得た。 Example 28 Preparation of neopentyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate Instead, the reaction and treatment were conducted in the same manner as in Example 13 using neopentyl chloroformate to obtain the title compound as a pale yellow solid.
実施例２９　４，４－ジフロロシクロヘキシル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートの製造
　１，１，１－トリフロロ－２－メチルプロパン－２－イル　１Ｈ－イミダゾール－１－カルボキシレートの代わりに４，４－ジフロロシクロヘキシル　１Ｈ－イミダゾール－１－カルボキシレートを用いて実施例２５と同様に反応・処理し、表題化合物を黄色アモルファスとして得た。 Example 29 4,4-Difluorocyclohexyl 4- (7-((2-Fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate Example 25 using 4,4-difluorocyclohexyl 1H-imidazole-1-carboxylate instead of 1H-imidazole-1-carboxylate The title compound was obtained as a yellow amorphous product.
実施例３０　オキセタン－３－イル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートの製造
　クロロギ酸イソプロピルの代わりに４－ニトロフェニル　オキセタン－３－イル　カーボネートを用いて実施例１３と同様に反応・処理し、表題化合物を淡黄色固体として得た。 Example 30 Preparation of Oxetan-3-yl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate The reaction and treatment were conducted in a similar manner to Example 13 using 4-nitrophenyl oxetane-3-yl carbonate in place of isopropyl chloroformate, and the title compound was obtained as a pale-yellow solid.
実施例３１　（３－メチルオキセタン－３－イル）メチル　４－（７－（（２－フロロ－４－（メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートの製造
　クロロギ酸イソプロピルの代わりに（３－メチルオキセタン－３－イル）メチル　（４－ニトロフェニル）カーボネートを用いて実施例１３と同様に反応・処理し、表題化合物を淡黄色固体として得た。 Example 31 (3-Methyloxetane-3-yl) methyl 4- (7-((2-fluoro-4- (methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine Preparation of -1-carboxylate The reaction and treatment were conducted in the same manner as in Example 13 using (3-methyloxetane-3-yl) methyl (4-nitrophenyl) carbonate instead of isopropyl chloroformate, and the title compound was pale yellow. Obtained as a solid.
実施例３２　フェニル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートの製造
　クロロギ酸イソプロピルの代わりクロロギ酸フェニルを用いて実施例１３と同様に反応・処理し、表題化合物を淡黄色固体として得た。 Example 32 Preparation of phenyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate Instead, phenyl chloroformate was used and reacted and treated in the same manner as in Example 13 to obtain the title compound as a pale yellow solid.
実施例３３　４－ニトロフェニル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートの製造
　クロロギ酸イソプロピルの代わりにクロロギ酸４－ニトロフェニルを用いて実施例１３と同様に反応・処理し、表題化合物を淡黄色固体として得た。 Example 33 Preparation of 4-nitrophenyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate The reaction and treatment were conducted in a similar manner to Example 13 using 4-nitrophenyl chloroformate instead of isopropyl acid, and the title compound was obtained as a pale-yellow solid.
実施例３４　（４－（７－（（２－フロロ－４－（メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）（ピリジン－２－イル）メタノンの製造
　アルゴン雰囲気下、Ｎ－（２－フロロ－４－（メチルスルホニル）フェニル）－３－（ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－７－アミン塩酸塩（１１ｍｇ，０．０２７ｍｍｏｌ）、２－ピコリン酸（４ｍｇ，０．０３２ｍｍｏｌ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（８ｍｇ，０．０４１ｍｍｏｌ）及びＮ，Ｎ－ジメチル－４－アミノピリジン（１ｍｇ）を無水ジクロロメタン（０．６ｍＬ）に溶解し、トリエチルアミン（１２μＬ，０．０８１ｍｍｏｌ）を加え、室温で終夜撹拌した。水を加え、クロロホルムで抽出し、有機層を無水硫酸ナトリウムで乾燥した後、減圧濃縮し得られた残渣をシリカゲル分取薄層クロマトグラフィー（クロロホルム：メタノール＝２０：１）にて精製し、表題化合物（２ｍｇ，１４％）を黄色固体として得た。 Example 34 (4- (7-((2-Fluoro-4- (methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) (pyridine-2- Yl) Preparation of Methanone N- (2-Fluoro-4- (methylsulfonyl) phenyl) -3- (piperidin-4-yl) isoxazolo [4,5-d] pyrimidin-7-amine hydrochloride under argon atmosphere 11 mg, 0.027 mmol), 2-picolinic acid (4 mg, 0.032 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (8 mg, 0.041 mmol) and N, N-dimethyl-4 -Dissolve aminopyridine (1 mg) in anhydrous dichloromethane (0.6 mL) and add triethylamine (12 μL, 0.081 mmol). The mixture was stirred overnight at room temperature. Water was added and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel preparative thin layer chromatography (chloroform: methanol = 20: 1) to give the title The compound (2 mg, 14%) was obtained as a yellow solid.
実施例３５　ｔｅｒｔ－ブチル　４－（７－（４－（メチルスルホニル）フェノキシ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートの製造
　５－（メチルスルホニル）インドリンの代わりに４－（メチルスルホニル）フェノールを用いて実施例１の工程１０と同様に反応・処理し、表題化合物を淡黄色油状物として得た。 Example 35 Preparation of tert-butyl 4- (7- (4- (methylsulfonyl) phenoxy) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate of 5- (methylsulfonyl) indoline Instead, 4- (methylsulfonyl) phenol was used for the reaction and treatment in the same manner as in Step 10 of Example 1 to obtain the title compound as a pale yellow oil.
実施例３６　ｔｅｒｔ－ブチル　４－（７－（２－フロロ－４－（メチルスルホニル）フェノキシ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートの製造
　５－（メチルスルホニル）インドリンの代わりに２－フロロ－４－（メチルスルホニル）フェノールを用いて実施例１の工程１０と同様に反応・処理し、表題化合物を淡黄色油状物として得た。 Example 36 Preparation of tert-butyl 4- (7- (2-fluoro-4- (methylsulfonyl) phenoxy) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate 5- (Methyl The reaction and treatment were conducted in a similar manner to process 10 of example 1 using 2-fluoro-4- (methylsulfonyl) phenol in place of sulfonyl) indoline, and the title compound was obtained as a pale-yellow oil.
実施例３７　ｔｅｒｔ－ブチル　４－（７－（４－（１Ｈ－テトラゾル－１－イル）フェノキシ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートの製造
　５－（メチルスルホニル）インドリンの代わりに４－（１Ｈ－テトラゾル－１－イル）フェノールを用いて実施例１の工程１０と同様に反応・処理し、表題化合物を白色固体として得た。 Example 37 Preparation of tert-butyl 4- (7- (4- (1H-tetrazol-1-yl) phenoxy) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate 5- ( The reaction and treatment were conducted in a similar manner to process 10 of example 1 using 4- (1H-tetrazol-1-yl) phenol in place of methylsulfonyl) indoline, and the title compound was obtained as a white solid.
実施例３８　ｔｅｒｔ－ブチル　４－（１－メチル－７－（５－（メチルスルホニル）インドリン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボンキシレートの製造
工程１：ｔｅｒｔ－ブチル　４－（メトキシ（メチル）カルバモイル）ピペリジン－１－カルボキシレートの製造
　１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－カルボン酸（１５．０ｇ，６５．４ｍｍｏｌ）、Ｎ，Ｏ－ジメチルヒドロキシルアミン塩酸塩（８．３ｇ，８５．０ｍｍｏｌ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（１６．３ｇ，８５．０ｍｍｏｌ）をジクロロメタン（４００ｍＬ）に溶解し、氷冷下トリエチルアミン（１３．７ｍＬ，９８．１ｍｍｏｌ）及び、Ｎ，Ｎ－ジメチルアミノピリジン（０．８０ｇ，６．５４ｍｍｏｌ）を加え、室温で７０時間撹拌した。反応液に水を加え、有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム：メタノール＝２０：１）を用いて精製し、表題化合物（１７．７０ｇ、９９％）を無色透明オイル状物質として得た。 Example 38 tert-butyl 4- (1-methyl-7- (5- (methylsulfonyl) indoline-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-3-yl) piperidine-1-carvone Production process of xylate 1: Production of tert-butyl 4- (methoxy (methyl) carbamoyl) piperidine-1-carboxylate 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (15.0 g, 65.4 mmol) N, O-dimethylhydroxylamine hydrochloride (8.3 g, 85.0 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (16.3 g, 85.0 mmol) in dichloromethane (400 mL) And triethylamine (13.7 mL, 98.1 mmol) and N, N- Dimethylaminopyridine (0.80 g, 6.54 mmol) was added and stirred at room temperature for 70 hours. Water was added to the reaction mixture, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: methanol = 20: 1) to obtain the title compound (17.70 g, 99%) as a colorless transparent oily substance.
１Ｈ－ＮＭＲ（ＣＤＣｌ３）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）． 1 H-NMR (CDCl 3 ) 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).
工程２：ｔｅｒｔ－ブチル　４－アセチルピペリジン－１－カルボキシレートの製造
　アルゴン雰囲気下、ｔｅｒｔ－ブチル　４－｛メトキシ（メチル）カルバモイル｝ピペリジン－１－カルボキシレート（１７．７ｇ，６５．０ｍｍｏｌ）を．テトラヒドロフラン（２３０ｍＬ）に溶解し、氷冷下臭化メチルマグネシウム（８７．１ｍＬ、１．１２ｍｏｌ／Ｌテトラヒドロフラン溶液）を加え、室温で４時間撹拌した。反応液を３０％酒石酸ナトリウムカリウム四水和物水溶液にてクエンチ後、酢酸エチルで抽出した。有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝５：１→３：１）を用いて精製し、ｔｅｒｔ－ブチル　４－アセチルピペリジン－１－カルボキシレート（１４．２３ｇ、９６％）を淡黄色オイル状物質として得た。 Step 2: Preparation of tert-butyl 4-acetylpiperidine-1-carboxylate tert-butyl 4- {methoxy (methyl) carbamoyl} piperidine-1-carboxylate (17.7 g, 65.0 mmol) under an argon atmosphere. It melt | dissolved in tetrahydrofuran (230 mL), methylmagnesium bromide (87.1 mL, 1.12 mol / L tetrahydrofuran solution) was added under ice-cooling, and it stirred at room temperature for 4 hours. The reaction was quenched with 30% aqueous sodium potassium tartrate tetrahydrate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified using silica gel chromatography (hexane: ethyl acetate = 5: 1 → 3: 1) to give tert-butyl 4-acetylpiperidine-1-carboxylate (14.23 g, 96%) Obtained as a yellow oil.
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：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＝３．７，１１．３Ｈｚ），２．７９（２Ｈ，ｔ，Ｊ＝１２．１Ｈｚ），３．９８－４．２２（２Ｈ，ｍ）． 1 H-NMR (CDCl 3 ) δ: 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).
工程３：ｔｅｒｔ－ブチル　４－（４－エトキシ－３，４－ジオキソブタノイル）ピペリジン－１－カルボキシレートの製造
　ｔｅｒｔ－ブチル　４－アセチルピペリジン－１－カルボキシレート（１．２０ｇ，４．４０ｍｍｏｌ）をアルゴン雰囲気下、テトラヒドロフラン（２０ｍＬ）に溶解し、－７８℃でヘキサメチルジシラザンリチウム（７．２７ｍＬ，１．０９ｍｏｌ／Ｌヘキサン溶液）を滴下し、０℃で１時間撹拌した。反応液にジエチルオキサレート（１．４３ｍＬ，８．８０ｍｍｏｌ）を滴下し、室温で５時間撹拌した。反応液を飽和塩化アンモニウム水溶液で希釈し、酢酸エチルで抽出した。有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝７：１→３：１）を用いて精製し、表題化合物（７０８．３ｍｇ、４９％）を淡黄色固体として得た。 Step 3: Preparation of tert-butyl 4- (4-ethoxy-3,4-dioxobutanoyl) piperidine-1-carboxylate tert-butyl 4-acetylpiperidine-1-carboxylate (1.20 g, 4.40 mmol) ) Was dissolved in tetrahydrofuran (20 mL) under argon atmosphere, hexamethyldisilazane lithium (7.27 mL, 1.09 mol / L hexane solution) was added dropwise at -78 ° C, and the mixture was stirred at 0 ° C for 1 hour. Diethyl oxalate (1.43 mL, 8.80 mmol) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 7: 1 → 3: 1) to obtain the title compound (708.3 mg, 49%) as a pale yellow solid.
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．３８（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），１．４６（９Ｈ，ｓ），１．５２－１．６８（２Ｈ，ｍ），１．７６－１．９３（２Ｈ，ｍ），２．５３（１Ｈ，ｔｔ，Ｊ＝３．７，１１．５Ｈｚ），２．７９（２Ｈ，ｔ，Ｊ＝１２．１Ｈｚ），４．０６－４．２４（２Ｈ，ｍ），４．３６（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），６．４１（１Ｈ，ｓ）． 1 H-NMR (CDCl 3 ) δ: 1.38 (3H, t, J = 7.2 Hz), 1.46 (9H, s), 1.52-1.68 (2H, m), 1.76 -1.93 (2H, m), 2.53 (1H, tt, J = 3.7, 11.5 Hz), 2.79 (2H, t, J = 12.1 Hz), 4.06-4. 24 (2H, m), 4.36 (2H, q, J = 7.2 Hz), 6.41 (1H, s).
工程４：ｔｅｒｔ－ブチル　４－（１－メチル－７－オキソ－６，７－ジヒドロ－１Ｈ－ピラゾ［４，３－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートの製造
　ｔｅｒｔ－ブチル（４－エトキシ－３，４－ジオキソブタノイル）ピペリジン－１－カルボキシレート（１００ｍｇ，０．３０５ｍｍｏｌ）を酢酸（１ｍＬ）に溶解し、１０℃で亜硝酸ナトリウム（２３．２ｍｇ，０．３３６ｍｍｏｌ）の水溶液（０．５ｍＬ）を滴下し、１０℃で３０分間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮し、４－ｔｅｒｔ－ブチル（４－エトキシ－２－（ヒドロキシイミノ）－３，４－ジオキソブタノイル）ピペリジン－１－カルボキシレートの粗体を得た。
　得られた粗体をエタノール（１ｍＬ）に溶解し、メチルヒドラジン（０．２ｍＬ）を０℃で加え、室温で３０分間撹拌した。反応液に飽和亜ジチオン酸ナトリウム水溶液を加え室温で３０分間撹拌した。反応溶液を減圧濃縮し、得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：アセトン＝２：１）を用いて精製し、ｔｅｒｔ－ブチル　４－（４－アミノ－５－（エトキシカルボニル－１－メチル－１Ｈ－ピラゾール－３－イル）ピペリジン－１－カルボキシレートとその異性体（２６．８ｍｇ）を得た。
　得られた混合物（２６．８ｍｇ，０．０８２ｍｍｏｌ）をエタノール（２ｍＬ）に溶解し、ホルムアミジン酢酸塩（５１．２ｍｇ，０．４９２ｍｍｏｌ）を加え、２４時間加熱還流した。反応液を減圧濃縮し、得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：アセトン＝２：１）を用いて精製し、ｔｅｒｔ－ブチル　４－（１－メチル－７－オキソ－６，７－ジヒドロ－１Ｈ－ピラゾ［４，３－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（９．７ｍｇ、１０％）を淡黄色アモルファスとして得た。さらに、その異性体ｔｅｒｔ－ブチル　４－（２－メチル－７－オキソ－６，７－ジヒドロ－２Ｈ－ピラゾ［４，３－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（６．４ｍｇ，６％）を淡黄色アモルファスとして得た。 Step 4: Preparation of tert-butyl 4- (1-methyl-7-oxo-6,7-dihydro-1H-pyrazo [4,3-d] pyrimidin-3-yl) piperidine-1-carboxylate tert-butyl (4-Ethoxy-3,4-dioxobutanoyl) piperidine-1-carboxylate (100 mg, 0.305 mmol) was dissolved in acetic acid (1 mL) and sodium nitrite (23.2 mg, 0.336 mmol) at 10 ° C. ) Was added dropwise and stirred at 10 ° C. for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 4-tert-butyl (4-ethoxy-2- (hydroxyimino) -3,4-dioxobutanoyl) piperidine. A crude product of -1-carboxylate was obtained.
The obtained crude product was dissolved in ethanol (1 mL), methylhydrazine (0.2 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium dithionite solution was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified using silica gel chromatography (hexane: acetone = 2: 1) to give tert-butyl 4- (4-amino-5- (ethoxycarbonyl-1-methyl-). 1H-pyrazol-3-yl) piperidine-1-carboxylate and its isomer (26.8 mg) were obtained.
The obtained mixture (26.8 mg, 0.082 mmol) was dissolved in ethanol (2 mL), formamidine acetate (51.2 mg, 0.492 mmol) was added, and the mixture was heated to reflux for 24 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using silica gel chromatography (hexane: acetone = 2: 1) to give tert-butyl 4- (1-methyl-7-oxo-6,7-dihydro- 1H-pyrazo [4,3-d] pyrimidin-3-yl) piperidine-1-carboxylate (9.7 mg, 10%) was obtained as a pale yellow amorphous. In addition, the isomer tert-butyl 4- (2-methyl-7-oxo-6,7-dihydro-2H-pyrazo [4,3-d] pyrimidin-3-yl) piperidine-1-carboxylate (6. 4 mg, 6%) was obtained as a pale yellow amorphous.
［生成物］
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．４７（９Ｈ，ｓ），１．８４－２．０４（４Ｈ，ｍ），２．８１－３．００（２Ｈ，ｍ），３．１９（１Ｈ，ｔｔ，Ｊ＝３．８，１１．３Ｈｚ），４．２１（２Ｈ，ｂｒｓ），４．２６（３Ｈ，ｓ），７．７８（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ），１０．１７（１Ｈ，ｂｒｓ）． [Product]
1 H-NMR (CDCl 3 ) δ: 1.47 (9H, s), 1.84 to 2.04 (4H, m), 2.81 to 3.00 (2H, m), 3.19 (1H , Tt, J = 3.8, 11.3 Hz), 4.21 (2H, brs), 4.26 (3H, s), 7.78 (1H, d, J = 2.7 Hz), 10.17 (1H, brs).
［異性体］
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．４９（９Ｈ，ｓ），１．７６－１．９３（２Ｈ，ｍ），２．１１－２．３９（２Ｈ，ｍ），２．７９－２．９２（２Ｈ，ｍ），３．０１－３．１２（１Ｈ，ｍ），４．１２（３Ｈ，ｓ），４．３２（２Ｈ，ｂｒｓ），７．７７（１Ｈ，ｄ，Ｊ＝３．２Ｈｚ），１０．８８（１Ｈ，ｂｒｓ）． [Isomer]
1 H-NMR (CDCl 3 ) δ: 1.49 (9H, s), 1.76-1.93 (2H, m), 2.11-2.39 (2H, m), 2.79-2 .92 (2H, m), 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).
工程５：ｔｅｒｔ－ブチル　４－（７－（（１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾ－１－イル）オキシ）－１－メチル－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートの製造
　ｔｅｒｔ－ブチル　４－（１－メチル－７－オキソ－６，７－ジヒドロ－１Ｈ－ピラゾ［４，３－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（９．７ｍｇ，０．０２９ｍｍｏｌ）及び、１Ｈ－ベンゾトリアゾール－１－イルオキシトリピロリジノホスホニウム　ヘキサフルオロホスファート（１６．６ｍｇ，０．０３２ｍｍｏｌ）をテトラヒドロフラン（１ｍＬ）に溶解し、１，８－ジアザビシクロ［５，４，０］－７－ウンデセン（５．２μＬ，０．０３５ｍｍｏｌ）を加え、室温で１時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム：メタノール＝１０：１）を用いて精製し、表題化合物（７．６ｍｇ、５８％）を淡黄色アモルファスとして得た。 Step 5: tert-Butyl 4- (7-((1H-benzo [d] [1,2,3] triazo-1-yl) oxy) -1-methyl-1H-pyrazolo [4,3-d] pyrimidine Preparation of -3-yl) piperidin-1-carboxylate tert-butyl 4- (1-methyl-7-oxo-6,7-dihydro-1H-pyrazo [4,3-d] pyrimidin-3-yl) piperidine 1-carboxylate (9.7 mg, 0.029 mmol) and 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (16.6 mg, 0.032 mmol) were dissolved in tetrahydrofuran (1 mL). 1,8-diazabicyclo [5,4,0] -7-undecene (5.2 μL, 0.035 mmol) was added, and the mixture was stirred at room temperature for 1 hour. . The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform: methanol = 10: 1) to obtain the title compound (7.6 mg, 58%) as a pale yellow amorphous.
１Ｈ－ＮＭＲ（ＣＤＣｌ３）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＝３．８，１１．５Ｈｚ），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＝８．３Ｈｚ），８．３６（１Ｈ，ｓ）． 1 H-NMR (CDCl 3 ) 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 (1 H, m), 8.12 (1 H, d, J = 8.3 Hz), 8.36 (1 H, s).
工程６：ｔｅｒｔ－ブチル　４－（１－メチル－７－（５－（メチルスルホニル）インドリン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボンキシレートの製造
　ｔｅｒｔ－ブチル　４－（７－（（１Ｈ－ベンゾ［ｄ］［１，２，３］トリアゾ－１－イル）オキシ）－１－メチル－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート（７．６ｍｇ，０．０１７ｍｍｏｌ）及び、５－（メチルスルホニル）インドリン（４．５ｍｇ，０．０２３ｍｍｏｌ）をＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）に溶解し、水素化ナトリウム（５０％　ｉｎ　ｏｉｌ，２．５ｍｇ，０．０５８ｍｍｏｌ）を加え、室温で２時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：アセトン＝３：２）を用いて精製し、表題化合物（７．３ｍｇ、８４％）を淡黄色アモルファスとして得た。 Step 6: tert-Butyl 4- (1-methyl-7- (5- (methylsulfonyl) indoline-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-3-yl) piperidine-1-carvone Preparation of xylate tert-butyl 4- (7-((1H-benzo [d] [1,2,3] triazo-1-yl) oxy) -1-methyl-1H-pyrazolo [4,3-d] Pyrimidin-3-yl) piperidine-1-carboxylate (7.6 mg, 0.017 mmol) and 5- (methylsulfonyl) indoline (4.5 mg, 0.023 mmol) in N, N-dimethylformamide (1 mL). After dissolution, sodium hydride (50% in oil, 2.5 mg, 0.058 mmol) was added and 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 saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel chromatography (hexane: acetone = 3: 2) to give the title compound (7.3 mg, 84%) as a pale yellow amorphous product.
　上記実施例によって得られた化合物を表１～８に示す。 The compounds obtained in the above examples are shown in Tables 1-8.
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
試験例１　インスリン分泌促進作用
　ハムスター膵臓β細胞株ＨＩＴ－Ｔ１５細胞をペニシリン（１００単位／ｍＬ）、ストレプトマイシン（１００μｇ／ｍＬ）及び１０％胎児ウシ血清を含むＨａｍ’ｓ　Ｆ－１２Ｋ培地を用いて継代培養した。２４穴培養プレートに細胞を播種し、４８時間３７℃で培養後、０．１％アルブミン含有ＫＲＢＨバッファーにて洗浄した。次いで、同バッファーにて１時間、３７℃で静置した。これに、ブドウ糖を最終濃度で２ｍＭになるように添加し、さらに各濃度（０．０００１μＭから公比１０にて１０μＭまで）の１０００倍の濃度でジメチルスルホキシドにて溶解した本発明化合物を、バッファー中０．１体積％含有となる条件で添加した。本発明化合物添加後、１時間、３７℃で静置した後、上清に含まれるインスリン濃度をインスリンキット（セティ・メディカル株式会社）で測定した。標準溶液にはハムスターインスリン標準溶液（株式会社シバヤギ）を使用した。コントロールとしてジメチルスルホキシドのみを添加したものを用いた。結果を各被検化合物の５０％効果濃度（ＥＣ５０値、５０％　ｅｆｆｅｃｔ　ｃｏｎｃｅｎｔｒａｔｉｏｎ））として表２に示す。なお、ＥＣ５０値は、統計解析プログラム、ＳＡＳ前臨床パッケージＶｅｒ５．０（ＳＡＳ　ｉｎｓｔｉｔｕｔｅ　Ｊａｐａｎ　Ｃｏ．，東京）を用いて算出した。 Test Example 1 Insulin Secretion Promoting Action Hamster pancreatic β cell line HIT-T15 cells are passaged using Ham's F-12K medium containing penicillin (100 units / mL), streptomycin (100 μg / mL) and 10% fetal bovine serum. Subcultured. Cells were seeded in a 24-well culture plate, cultured for 48 hours at 37 ° C., and then washed with a KRBH buffer containing 0.1% albumin. Subsequently, it left still at 37 degreeC with the same buffer for 1 hour. Glucose was added to this to a final concentration of 2 mM, and the compound of the present invention dissolved in dimethyl sulfoxide at a concentration 1000 times the concentration (from 0.0001 μM to 10 μM at a common ratio of 10) was added to the buffer. It was added under the condition of 0.1% by volume. After adding the compound of the present invention, the mixture was allowed to stand at 37 ° C. for 1 hour, and then the insulin concentration contained in the supernatant was measured with an insulin kit (Setty Medical Co., Ltd.). As the standard solution, a hamster insulin standard solution (Shiba Goat Co., Ltd.) was used. A control to which only dimethyl sulfoxide was added was used. The results are shown in Table 2 as 50% effective concentration (EC 50 value, 50% effect concentration) of each test compound. The EC 50 value was calculated using a statistical analysis program, SAS preclinical package Ver 5.0 (SAS Institute Japan Co., Tokyo).
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
　以上より、本発明化合物は強いインスリン分泌促進効果を有していることが分かる。 From the above, it can be seen that the compound of the present invention has a strong insulin secretion promoting effect.
　本発明の一般式（１）で表されるピペリジン誘導体若しくはその塩、又はそれらの溶媒和物は、優れたインスリン分泌促進作用を有し、糖尿病の予防及び／又は治療に有用であることから、産業上の利用可能性を有している。 Since the piperidine derivative represented by the general formula (1) of the present invention or a salt thereof, or a solvate thereof has an excellent insulin secretion promoting action and is useful for the prevention and / or treatment of diabetes, Has industrial applicability.

Claims (18)

  1. 　次の一般式（１）：
    Figure JPOXMLDOC01-appb-C000001
     ［式中、
    Ａ及びＢは、一方が窒素原子を示し、他方が窒素原子又はＣＲ８（ここで、Ｒ８は、水素原子、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、アミノ基又はニトロ基を示す）を示し；
    Ｄは、窒素原子又はＣＲ９（ここで、Ｒ９は、水素原子、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、アミノ基又はニトロ基を示す）を示し；
    Ｅは、窒素原子又はＣＲ１０（ここで、Ｒ１０は、水素原子、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、アミノ基又はニトロ基を示す）を示し；
    Ｘは、酸素原子、硫黄原子、－（ＣＨ２）ｎ－Ｎ（Ｒ１１）－又は－（ＣＨ２）ｎ－ＣＨ（Ｒ１２）－（ここで、Ｒ１１及びＲ１２は、それぞれ水素原子又はＣ１－６アルキル基を示し、ｎは、０又は１を示す）を示し；
    Ｙは酸素原子、硫黄原子又は窒素原子を示し；
    Ｚは酸素原子、硫黄原子又は窒素原子を示し；
    Ｒ１及びＲ３は、それぞれ独立して、水素原子、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、アミノ基又はニトロ基を示すか、
    あるいは、Ｒ１とＲ１１又はＲ１とＲ１２が一緒になって、ヘテロ環を形成してもよく；
    Ｒ２は、水素原子、－Ｓ（Ｏ）Ｒ１３、－Ｓ（Ｏ）２Ｒ１４、－ＣＯ２Ｒ１５　又は－ＣＯＮＲ１６Ｒ１７、アリール基、ヘテロアリール基（ここで、Ｒ１３及びＲ１４は、それぞれＣ１－６アルキル基、Ｃ３－８シクロアルキル基、Ｃ２－６アルケニル基、Ｃ２－６アルキニル基、置換基を有してもよいＣ６－１０アリール基、アミノ基、モノ（Ｃ１－６アルキル）アミノ基又はジ（Ｃ１－６アルキル）アミノ基を示し、Ｒ１５は、Ｃ１－６アルキル基を示し、Ｒ１６及びＲ１７は、それぞれ独立して、水素原子又は置換基を有してもよいＣ１－６アルキル基を示す）を示し；
    Ｒ４は、水素原子、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、Ｃ１－６アルキルチオ基又はアミノ基を示し；
    Ｒ５及びＲ６は、それぞれ独立して、水素原子又はＣ１－６アルキル基を示し；
    Ｒ７は、Ｃ１－６アルキル基、－Ｃ（Ｏ）Ｒ１８、－Ｃ（Ｓ）Ｒ１９、－Ｓ（Ｏ）２Ｒ２０、置換基を有してもよいＣ６－１０アリール基又は置換基を有してもよい５－１０員ヘテロアリール基（ここで、Ｒ１８は、置換基を有してもよいＣ１－６アルキル基、置換基を有してもよいＣ１－６アルコキシ基、置換基を有していてもよいＣ２－６アルケニルオキシ基、置換基を有していてもよいＣ６－１０アリールオキシ基、置換基を有していてもよいＣ６－１０アリールＣ１－６アルコキシ基、置換基を有してもよいＣ３－８シクロアルキルオキシ基、置換基を有していてもよいヘテロ環オキシ基、置換基を有してもよい５－１０員ヘテロアリール基又はモノ（Ｃ１－６アルキル）アミノ基を示し、Ｒ１９及びＲ２０は、それぞれＣ１－６アルキル基、ハロＣ１－６アルキル基、Ｃ３－８シクロアルキル基、モノ（Ｃ１－６アルキル）アミノ基、置換基を有してもよいＣ６－１０アリール基又は置換基を有してもよい５－１０員ヘテロアリール基を示す）を示す］
    で表される化合物若しくはその塩、又はそれらの溶媒和物。     The following general formula (1):
    Figure JPOXMLDOC01-appb-C000001
     [Where:
    A and B each represents a nitrogen atom, and the other is a nitrogen atom or CR 8 (where R 8 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, an amino group, or Nitro group)
    D represents a nitrogen atom or CR 9 (wherein R 9 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, an amino group or a nitro group);
    E represents a nitrogen atom or CR 10 (wherein R 10 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, an amino group or a nitro group);
    X is an oxygen atom, a sulfur atom, — (CH 2 ) n—N (R 11 ) — or — (CH 2 ) n—CH (R 12 ) — (where R 11 and R 12 are each a hydrogen atom, Or a C 1-6 alkyl group, and n represents 0 or 1);
    Y represents an oxygen atom, a sulfur atom or a nitrogen atom;
    Z represents an oxygen atom, a sulfur atom or a nitrogen atom;
    R 1 and R 3 each independently represent a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, an amino group or a nitro group,
    Alternatively, R 1 and R 11 or R 1 and R 12 may be combined to form a heterocycle;
    R 2 represents a hydrogen atom, —S (O) R 13 , —S (O) 2 R 14 , —CO 2 R 15 or —CONR 16 R 17 , an aryl group, a heteroaryl group (where R 13 and R 14 represents a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, an optionally substituted C 6-10 aryl group, an amino group, respectively. A mono (C 1-6 alkyl) amino group or a di (C 1-6 alkyl) amino group, R 15 represents a C 1-6 alkyl group, and R 16 and R 17 are each independently A hydrogen atom or a C 1-6 alkyl group which may have a substituent);
    R 4 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group or an amino group;
    R 5 and R 6 each independently represents a hydrogen atom or a C 1-6 alkyl group;
    R 7 is a C 1-6 alkyl group, —C (O) R 18 , —C (S) R 19 , —S (O) 2 R 20 , an optionally substituted C 6-10 aryl group Or a 5- to 10-membered heteroaryl group which may have a substituent (wherein R 18 is a C 1-6 alkyl group which may have a substituent, a C 1 -1 which may have a substituent) 6 an alkoxy group, an optionally substituted C 2-6 alkenyloxy group, an optionally substituted C 6-10 aryloxy group, an optionally substituted C 6- 10 aryl C 1-6 alkoxy group, optionally substituted C 3-8 cycloalkyloxy group, optionally substituted heterocyclic oxy group, optionally substituted 5- Represents a 10-membered heteroaryl group or a mono (C 1-6 alkyl) amino group, R 19 and R 20 represent C 1-6 alkyl group, halo C 1-6 alkyl group, C 3-8 cycloalkyl group, mono (C 1-6 alkyl) amino group, optionally substituted C 6-10 aryl group Or a 5- to 10-membered heteroaryl group which may have a substituent)
    Or a salt thereof, or a solvate thereof.
  2. 　Ｒ１とＲ１１又はＲ１とＲ１２が一緒になって形成されるヘテロ環が、次式：
    Figure JPOXMLDOC01-appb-C000002
     ［式中、
    Ｒ２１は水素原子、Ｃ１－６アルキル基、－Ｃ（Ｏ）Ｒ２２又は－Ｓ（Ｏ）２Ｒ２３（ここで、Ｒ２２及びＲ２３はそれぞれＣ１－６アルキル基、Ｃ３－８シクロアルキル基を示す）を示し、波線部はＤ及びＥによって構成されている芳香環を示す］
    から選ばれる、請求項１に記載の化合物若しくはその塩、又はそれらの溶媒和物。     A heterocycle formed by R 1 and R 11 or R 1 and R 12 taken together has the following formula:
    Figure JPOXMLDOC01-appb-C000002
     [Where:
    R 21 represents a hydrogen atom, a C 1-6 alkyl group, —C (O) R 22 or —S (O) 2 R 23 (where R 22 and R 23 represent a C 1-6 alkyl group, C 3-6 8 represents a cycloalkyl group, and the wavy line represents an aromatic ring constituted by D and E]
    The compound or its salt of Claim 1 selected from these, or those solvates.
  3. 　Ｒ１とＲ１１又はＲ１とＲ１２が一緒になって形成されるヘテロ環が、次式：
    Figure JPOXMLDOC01-appb-C000003
     から選ばれる、請求項１に記載の化合物若しくはその塩、又はそれらの溶媒和物。     A heterocycle formed by R 1 and R 11 or R 1 and R 12 taken together has the following formula:
    Figure JPOXMLDOC01-appb-C000003
     The compound or its salt of Claim 1 selected from these, or those solvates.
  4. 　次式（１ａ）：
    Figure JPOXMLDOC01-appb-C000004
     （式中、Ｒ２～Ｒ７は前記と同じ）
    で表される、請求項１記載の化合物、若しくはその塩、又はそれらの溶媒和物。     The following formula (1a):
    Figure JPOXMLDOC01-appb-C000004
     (Wherein R 2 to R 7 are the same as above)
    The compound of Claim 1 represented by these, its salt, or those solvates.
  5. 　Ｒ１が、水素原子、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、アミノ基又はニトロ基である、請求項１に記載の化合物若しくはその塩、又はそれらの溶媒和物。 The compound or a salt thereof, or a solvate thereof according to claim 1 , wherein R 1 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, an amino group, or a nitro group.
  6. 　次式（１ｂ）：
    Figure JPOXMLDOC01-appb-C000005
     （式中、Ｒ１は水素原子、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、アミノ基又はニトロ基を示し、Ｒ２～Ｒ７は前記と同じ）
    で表される、請求項１に記載の化合物若しくはその塩、又はそれらの溶媒和物。     Formula (1b):
    Figure JPOXMLDOC01-appb-C000005
     (Wherein R 1 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, an amino group or a nitro group, and R 2 to R 7 are the same as above)
    The compound of Claim 1 represented by these, its salt, or those solvates.
  7. 　下記の化合物群：
    　ｔｅｒｔ－ブチル　４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－４－イル）ピペリジン－１－カルボキシレート、３－（１－（５－クロロピリミジン－２－イル）ピペリジン－４－イル）－７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン、３－（１－（５－エチルピリミジン－２－イル）ピペリジン－４－イル）－７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン、３－（１－（５－ブロモピリミジン－２－イル）ピペリジン－４－イル）－７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン、３－（１－（５－フロロピリミジン－２－イル）ピペリジン－４－イル）－７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン、エチル　２－（４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）ピリミジン－５－カルボキシレート、２－（４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）ピリミジン－５－カルボン酸、７－（５－（メチルスルホニル）インドリン－１－イル）－３－（１－（５－（トリフロロメチル）ピリミジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン、２－（４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）ピリミジン－５－オール、３－（１－（５－メトキシピリミジン－２－イル）ピペリジン－４－イル）－７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン、７－（５－（メチルスルホニル）インドリン－１－イル）－３－（１－（５－フェニルピリミジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン、７－（５－（メチルスルホニル）インドリン－１－イル）－３－（１－（５－（トリフロロメチル）ピリジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン、イソプロピル　４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、エチル　４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、２－フロロエチル　４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、２－メトキシエチル　４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、テトラヒドロ－２Ｈ－ピラン－４－イル　４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、アリル　２－（４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）ピリミジン－５－カルボキシレート、ｔｅｒｔ－ブチル　４－（７－（５（メチルスルフィニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、７－（５－（メチルスルフィニル）インドリン－１－イル）－３－（１－（５－（トリフロロメチル）ピリジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン、２，２－ジメチル－１－（４－（７－（５－（メチルスルホニル）インドリン－１－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）プロパン－１－オン、ｔｅｒｔ－ブチル　４－（７－（（２－フロロ－４－（メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、Ｎ－（２－フロロ－４－（メチルスルホニル）フェニル）－３－（１－（５－（トリフロロメチル）ピリミジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］ピリミジン－７－アミン、Ｎ－（２－フロロ－４－（メチルスルホニル）フェニル）３－（１－（５－（トリフロロメチル）ピリジン－２－イル）ピペリジン－４－イル）イソオキサゾロ［４，５－ｄ］－７－アミン、１，１，１－トリフロロ－２－メチルプロパン－２－イル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、２，２，２－トリフロロエチル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、２，２，２－トリクロロエチル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、ネオペンチル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、４，４－ジフロロシクロヘキシル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、オキセタン－３－イル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、（３－メチルオキセタン－３－イル）メチル　４－（７－（（２－フロロ－４－（メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、フェニル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、４－ニトロフェニル　４－（７－（（２－フロロ－４－メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、（４－（７－（（２－フロロ－４－（メチルスルホニル）フェニル）アミノ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－イル）（ピリジン－２－イル）メタノン、ｔｅｒｔ－ブチル　４－（７－（４－（メチルスルホニル）フェノキシ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、ｔｅｒｔ－ブチル　４－（７－（２－フロロ－４－（メチルスルホニル）フェノキシ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、ｔｅｒｔ－ブチル　４－（７－（４－（１Ｈ－テトラゾル－１－イル）フェノキシ）イソオキサゾロ［４，５－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレート、及びｔｅｒｔ－ブチル　４－（１－メチル－７－（５－（メチルスルホニル）インドリン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－３－イル）ピペリジン－１－カルボキシレートから選ばれる請求項１～６のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物。     The following compound groups:
    tert-Butyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-4-yl) piperidine-1-carboxylate, 3- (1- (5- Chloropyrimidin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine, 3- (1- (5-ethylpyrimidine- 2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine, 3- (1- (5-bromopyrimidin-2-yl) ) Piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine, 3- (1- (5-fluoropyrimidine) Gin-2-yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine, ethyl 2- (4- (7- (5- (Methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidine-5-carboxylate, 2- (4- (7- (5- (methyl Sulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidine-5-carboxylic acid, 7- (5- (methylsulfonyl) indoline-1-yl) -3- (1- (5- (trifluoromethyl) pyrimidin-2-yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidine, 2- (4- (7- (5 -(Methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidin-5-ol, 3- (1- (5-methoxypyrimidine-2-) Yl) piperidin-4-yl) -7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine, 7- (5- (methylsulfonyl) indoline-1-yl)- 3- (1- (5-phenylpyrimidin-2-yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidine, 7- (5- (methylsulfonyl) indoline-1-yl) -3- ( 1- (5- (trifluoromethyl) pyridin-2-yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidine, isopropyl 4- (7- (5- ( Methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-carboxylate, ethyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate, 2-fluoroethyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidine -3-yl) piperidine-1-carboxylate, 2-methoxyethyl 4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine- 1-carboxylate, tetrahydro-2H-pyran-4-yl 4- (7- (5- (methylsulfonyl) i Ndolin-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate, allyl 2- (4- (7- (5- (methylsulfonyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) pyrimidin-5-carboxylate, tert-butyl 4- (7- (5 (methylsulfinyl) indoline-1-yl) isoxazolo [4 5-d] pyrimidin-3-yl) piperidine-1-carboxylate, 7- (5- (methylsulfinyl) indoline-1-yl) -3- (1- (5- (trifluoromethyl) pyridine-2- Yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidine, 2,2-dimethyl-1- (4- (7- (5- (methylsulf Nyl) indoline-1-yl) isoxazolo [4,5-d] pyrimidin-3-yl) piperidin-1-yl) propan-1-one, tert-butyl 4- (7-((2-fluoro-4- (Methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate, N- (2-fluoro-4- (methylsulfonyl) phenyl) -3- (1- (5- (trifluoromethyl) pyrimidin-2-yl) piperidin-4-yl) isoxazolo [4,5-d] pyrimidin-7-amine, N- (2-fluoro-4- (methylsulfonyl) phenyl) 3 -(1- (5- (trifluoromethyl) pyridin-2-yl) piperidin-4-yl) isoxazolo [4,5-d] -7-amine, 1,1,1-trif Ro-2-methylpropan-2-yl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate 2,2,2-trifluoroethyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate 2,2,2-trichloroethyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate, Neopentyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidine-3-i ) Piperidine-1-carboxylate, 4,4-difluorocyclohexyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine -1-carboxylate, oxetan-3-yl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine-1-carboxyl , (3-Methyloxetane-3-yl) methyl 4- (7-((2-Fluoro-4- (methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine- 1-carboxylate, phenyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxa B [4,5-d] pyrimidin-3-yl) piperidine-1-carboxylate, 4-nitrophenyl 4- (7-((2-fluoro-4-methylsulfonyl) phenyl) amino) isoxazolo [4,5 -D] pyrimidin-3-yl) piperidine-1-carboxylate, (4- (7-((2-fluoro-4- (methylsulfonyl) phenyl) amino) isoxazolo [4,5-d] pyrimidine-3- Yl) piperidin-1-yl) (pyridin-2-yl) methanone, tert-butyl 4- (7- (4- (methylsulfonyl) phenoxy) isoxazolo [4,5-d] pyrimidin-3-yl) piperidine- 1-carboxylate, tert-butyl 4- (7- (2-fluoro-4- (methylsulfonyl) phenoxy) isoxazolo [4,5-d ] Pyrimidin-3-yl) piperidine-1-carboxylate, tert-butyl 4- (7- (4- (1H-tetrazol-1-yl) phenoxy) isoxazolo [4,5-d] pyrimidin-3-yl) Piperidine-1-carboxylate and tert-butyl 4- (1-methyl-7- (5- (methylsulfonyl) indoline-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-3-yl) The compound according to any one of claims 1 to 6, or a salt thereof, or a solvate thereof, selected from piperidine-1-carboxylate.
  8. 　請求項１～７のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物、及び医薬として許容される担体を含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.
  9. 　請求項１～７のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物を有効成分とするインスリン分泌促進剤。 An insulin secretion promoter comprising the compound according to any one of claims 1 to 7 or a salt thereof, or a solvate thereof as an active ingredient.
  10. 　請求項１～７のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物を有効成分とする血糖低下剤。 A hypoglycemic agent comprising the compound according to any one of claims 1 to 7 or a salt thereof, or a solvate thereof as an active ingredient.
  11. 　請求項１～７のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物を有効成分とする糖尿病の予防及び／又は治療剤。 A prophylactic and / or therapeutic agent for diabetes comprising the compound according to any one of claims 1 to 7 or a salt thereof, or a solvate thereof as an active ingredient.
  12. 　請求項１～７のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物の有効量を投与することを特徴とするインスリン分泌促進方法。 A method for promoting insulin secretion, comprising administering an effective amount of the compound according to any one of claims 1 to 7, or a salt thereof, or a solvate thereof.
  13. 　請求項１～７のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物の有効量を投与することを特徴とする血糖低下方法。 A method for lowering blood glucose, comprising administering an effective amount of the compound according to any one of claims 1 to 7, or a salt thereof, or a solvate thereof.
  14. 　請求項１～７のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物の有効量を投与することを特徴とする糖尿病の予防及び／又は治療方法。 A method for preventing and / or treating diabetes, comprising administering an effective amount of the compound according to any one of claims 1 to 7, or a salt thereof, or a solvate thereof.
  15. 　インスリンを分泌促進するための、請求項１～７のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物。 The compound according to any one of claims 1 to 7, or a salt thereof, or a solvate thereof, for promoting secretion of insulin.
  16. 　血糖を低下するための、請求項１～７のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物。 The compound according to any one of claims 1 to 7, or a salt thereof, or a solvate thereof, for lowering blood glucose.
  17. 　糖尿病を予防及び／又は治療するための、請求項１～７のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物。 The compound according to any one of claims 1 to 7, or a salt thereof, or a solvate thereof, for preventing and / or treating diabetes.
  18. 　インスリン分泌促進剤、血糖低下剤又は糖尿病予防及び／又は治療剤製造のための、請求項１～７のいずれかに記載の化合物若しくはその塩、又はそれらの溶媒和物の使用。 Use of the compound according to any one of claims 1 to 7 or a salt thereof, or a solvate thereof for the manufacture of an insulin secretion promoter, a hypoglycemic agent, or a preventive and / or therapeutic agent for diabetes.
PCT/JP2011/071949 2010-09-28 2011-09-27 Novel piperidine derivative and pharmaceutical containing same WO2012043505A1 (en)

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US9624217B2 (en) 2014-02-03 2017-04-18 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10047085B2 (en) 2014-02-03 2018-08-14 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
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US10399976B2 (en) 2014-02-03 2019-09-03 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US10807980B2 (en) 2014-02-03 2020-10-20 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9796710B2 (en) 2014-10-14 2017-10-24 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
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US11001583B2 (en) 2014-11-05 2021-05-11 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
US10301261B2 (en) 2015-08-05 2019-05-28 Vitae Pharmaceuticals, Llc Substituted indoles as modulators of ROR-gamma
US10829448B2 (en) 2015-08-05 2020-11-10 Vitae Pharmaceuticals, Llc Substituted benzoimidazoles as modulators of ROR-γ
US11008340B2 (en) 2015-11-20 2021-05-18 Vitae Pharmaceuticals, Llc Modulators of ROR-gamma
US10829481B2 (en) 2016-01-29 2020-11-10 Vitae Pharmaceuticals, Llc Benzimidazole derivatives as modulators of ROR-gamma
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10913739B2 (en) 2017-07-24 2021-02-09 Vitae Pharmaceuticals, LLC (121374) Inhibitors of RORγ
US11186573B2 (en) 2017-07-24 2021-11-30 Vitae Pharmaceuticals, Llc Inhibitors of ROR gamma

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