WO2010082601A1 - Nouveau dérivé de pyrrole 2,5-disubstitué - Google Patents

Nouveau dérivé de pyrrole 2,5-disubstitué Download PDF

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WO2010082601A1
WO2010082601A1 PCT/JP2010/050339 JP2010050339W WO2010082601A1 WO 2010082601 A1 WO2010082601 A1 WO 2010082601A1 JP 2010050339 W JP2010050339 W JP 2010050339W WO 2010082601 A1 WO2010082601 A1 WO 2010082601A1
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詔大 古川
剛広 福崎
由香利 大西
英樹 小林
哲義 松藤
雄 本田
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第一三共株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a 2,5-disubstituted pyrrole derivative or a pharmacologically acceptable salt thereof that has an excellent glucokinase activating action and is useful as a therapeutic agent for diabetes and the like.
  • Gluconase (glucokinase, which may be abbreviated as GK in the present specification; EC2.7.1.1) is one of four types of hexokinase (hexokinase IV) found in mammals.
  • Hexokinase is an enzyme that catalyzes the conversion of glucose to glucose-6-phosphate at the initial stage of glycolysis in the cell.
  • GK is expressed mainly in the liver and pancreatic beta cells. ing. In pancreatic beta cells, it functions as a sensing mechanism of extracellular glucose concentration that regulates glucose-stimulated insulin secretion. In the liver, the GK enzyme reaction becomes the rate-limiting step, and the following reactions such as glycolysis and glycogen synthesis are regulated.
  • GK of liver and pancreatic beta cells differ in the sequence of 15 amino acids on the N-terminal side due to differences in splicing, but have the same enzymatic properties.
  • Three hexokinases (I, II, III) other than GK saturate the enzyme activity at a glucose concentration of 1 mM or less, whereas GK has a low affinity for glucose, and its Km value is 8-15 mM, which is a physiological blood glucose level. Close to value. Therefore, the increase in intracellular glucose metabolism via GK occurs in response to changes in blood glucose from normal blood glucose level (around 5 mM) to postprandial hyperglycemia (10-15 mM).
  • Non-Patent Documents 1 to 3 Since ancient times, the hypothesis that GK functions as a glucose sensor in the liver and pancreatic beta cells has been proposed (Non-Patent Documents 1 to 3). Recent research results have demonstrated that GK actually plays an important role in maintaining systemic glucose homeostasis, demonstrating the hypothesis. For example, a mouse with a disrupted glucokinase gene died of severe hyperglycemia soon after birth, and a GK hetero-deficient mouse had poor glucose tolerance and impaired insulin secretion due to sugar stimulation (Non-Patent Document) 4). On the other hand, in normal mice overexpressing GK, a decrease in blood glucose level and an increase in glycogen content in the liver were observed, and the same phenomenon was observed in mice that artificially developed diabetes (Non-patent Document 5). ).
  • GK functions as a glucose sensor and plays an important role in maintaining glucose homeostasis.
  • a GK gene abnormality was found in a family with early-onset adult type diabetes called MODY2 (Maturity Onset Diabetes of the Young), and the relationship between this case and GK activity was clarified (Non-patent Document 6).
  • families with mutations that increase GK activity have also been found, and in these families, fasting hypoglycemia symptoms accompanied by an increase in plasma insulin concentration are observed (Non-patent Document 7). From the above reports, GK functions as a glucose sensor in mammals including humans and plays an important role in blood glucose regulation.
  • GK activator can be expected to have the effect of promoting glucose uptake and release of glucose to the liver and insulin secretion of pancreatic beta cells at the same time. is expected.
  • pancreatic beta cell type GK is expressed exclusively in the feeding center (Ventromedial hypothalamus, VMH) of rat brain. It has been known that VMH has neurons that respond to glucose concentration. When glucose is administered into the rat ventricle, the amount of food intake decreases, whereas when glucose analog glucosamine is administered to inhibit glucose metabolism, food intake increases (Non-patent Document 8). From electrophysiological experiments, it is known that glucose-responsive neurons are activated in response to physiological glucose concentration changes (5-20 mM). At this time, glucokinase acts as a glucose sensor as in peripheral tissues. It was clarified that it was functioning (Non-Patent Document 9). Therefore, not only the liver and pancreatic beta cells but also substances that bring about activation of VMH glucokinase can be expected not only to lower blood glucose but also to correct obesity, which is a problem associated with many patients with type II diabetes.
  • a substance having a GK activation action is used as a therapeutic and prophylactic agent for diabetes or for the treatment of chronic complications of diabetes such as retinopathy, nephropathy, neurosis, ischemic heart disease, arteriosclerosis and the like. It is useful as a preventive drug.
  • Patent Document 1 describes a compound that requires an amide structure, but the compound of the present invention requires pyrrole instead of amide.
  • Patent Document 2 describes a compound having a condensed pyrrole, but the compound of the present invention requires a pyrrole that is not condensed.
  • Patent Document 3 describes a compound having 3,5-disubstituted pyrazole or 1,2,4-triazole, which is different from the 2,5-disubstituted pyrrole structure of the present invention.
  • Patent Documents 4 to 15, Non-Patent Documents 10 and 11 are examples of structures different from the compounds of the present invention.
  • An object of the present invention is to provide a 2,5-disubstituted pyrrole derivative and a GK activator using the derivative, and particularly to provide a therapeutic and prophylactic agent for diabetes and impaired glucose tolerance.
  • a 2,5-disubstituted pyrrole compound having a specific chemical structure has an excellent GK activation action.
  • the compound of the present invention has excellent GK selectivity, low toxicity, and few side effects.
  • this 2,5-disubstituted pyrrole compound is diabetic, impaired glucose tolerance, gestational diabetes, chronic complications of diabetes (diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic major It was found to be useful as an active ingredient of a medicament for the treatment and / or prevention of a disease selected from the group consisting of (including angiopathy) and metabolic syndrome.
  • the present invention has been completed based on the above findings.
  • the present invention comprises (1) general formula (I)
  • R 1 is the same or different and is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted by 1 or 2 hydroxy groups, (C 1 -C 6 alkylthio)-(C 1 -C 6 alkyl) group, carboxyl group, carbamoyl group, mono-C 1 -C 6 alkylaminocarbonyl group or di- (C 1 -C 6 alkyl) aminocarbonyl group
  • R 2 may be independently substituted with 1 to 5 groups independently selected from a group selected from Substituent Group A or 1 to 3 independently substituted with a group selected from Substituent Group A
  • R 3 is a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a (C 1 -C 6 alkyl group) which may be independently substituted with
  • R 4 and R 5 are the same or different and each represents a hydrogen atom, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group, or together with the nitrogen atom to which R 4 and R 5 are bonded, It forms a 4- to 6-membered heterosaturated ring which may be independently substituted by 1 to 3 groups independently of the group consisting of a C 1 -C 6 alkyl group and an oxo group.
  • the 4- to 6-membered heterosaturated ring may further contain one oxygen atom or nitrogen atom.
  • U represents an oxygen atom or a carbonyl group; (However, the 2-hydroxy-1-methylethoxy group is excluded from the group represented by the formula -UR 3. )
  • n represents an integer of 0 to 3
  • Substituent group A includes a halogen atom, C 1 -C 6 alkoxy group, C 2 -C 7 alkylcarbonyl group, C 2 -C 7 halogenated alkylcarbonyl group, C 2 -C 7 alkoxycarbonyl group, C 2 -C 7 halogenated alkoxycarbonyl group, C 1 -C 6 alkylsulfonyl group, C 1 -C 6 halogenated alkylsulfonyl group, C 3 -C 6 cycloalkylsulfonyl group, (C 1 -C 6 alkoxy)-(C 1- C 6 alkylsulfonyl) group, (C 1 -C 6 halogenated alkoxy)-(C 1
  • R 1 is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted with one or two hydroxy groups, or a carbamoyl group, or a pharmacological thereof Top acceptable salt.
  • R 2 is a phenyl group substituted at the 4- or 3-position with a group selected from Substituent Group C, and 1 at the 2-position with a group selected from Substituent Group C 5-
  • Substituent group C includes a C 1 -C 6 alkoxy group, a C 1 -C 6 alkylsulfonyl group and a group represented by the formula —V—NR 6 R 7 (V represents a carbonyl group or a sulfonyl group, R 6 , R 7 is the same or different and represents a hydrogen atom or a C 1 -C 6 alkyl group.
  • R 2 represents 3-methoxyphenyl group, 2-methylaminocarbonyl-5-pyridyl group, 4-methylsulfonylphenyl group, 2-methylsulfonyl-5-pyridyl group, 2-methylaminosulfonyl-5-pyridyl group, 5 A compound which is a methylsulfonyl-2-pyrazinyl group or a 5-methylaminosulfonyl-2-pyrazinyl group or a pharmacologically acceptable salt thereof.
  • R 3 is independently one or two in the group consisting of a C 1 -C 6 alkyl group or a (C 3 -C 6 cycloalkyl group and an oxo group) which may be independently substituted with 1 to 5 halogen atoms.
  • a compound or a pharmacologically acceptable salt thereof which is a 3- to 6-membered saturated ring which may be substituted and may contain one oxygen atom or nitrogen atom, and U is an oxygen atom.
  • R 3 is a C 1 -C 6 alkyl group or a group represented by the formula —NR 4 R 5 (R 4 and R 5 are the same or different and each represents a hydrogen atom or a C 1 -C 6 alkyl group).
  • a compound in which U is a carbonyl group or a pharmacologically acceptable salt thereof.
  • the group represented by the formula -UR 3 is a methoxy group, an ethoxy group, an isopropoxy group, a (1S) -2-fluoro-1-methylethoxy group, a difluoromethoxy group, or a 1,3-difluoro-2-propoxy group.
  • R 1 is the same or different and is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted with one or two hydroxy groups, (C 1- C 6 alkylthio)-(C 1 -C 6 alkyl) group, carboxyl group, carbamoyl group, mono-C 1 -C 6 alkylaminocarbonyl group or di- (C 1 -C 6 alkyl) aminocarbonyl group , R 2 is independently substituted with 1 to 5 groups independently selected from the substituent group A and independently substituted with 1 to 3 phenyl groups or groups selected from the substituent group A; A C 1 -C 6 alkyl group or a C 2 -C 6 alkenyl group, wherein R 3 may be independently substituted with 1 to 5 groups independently selected from Substituent Group B group, C 1 -C 6 A group consisting of an alkyl group and an hydroxy groups, (C
  • the 3- to 6-membered saturated ring may be bonded to U (carbon atom). Or a group represented by the formula —NR 4 R 5 , wherein R 4 and R 5 are the same or different and each represents a hydrogen atom, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group, Together with the nitrogen atom to which 4 and R 5 are attached, forms a 4- to 6-membered heterosaturated ring which may be independently substituted with 1 to 3 groups independently of the group consisting of a C 1 -C 6 alkyl group and an oxo group To do.
  • the 4- to 6-membered heterosaturated ring may further contain one oxygen atom or nitrogen atom.
  • U represents an oxygen atom or a carbonyl group (provided that a 2-hydroxy-1-methylethoxy group is excluded from the group represented by the formula —UR 3 ), n represents an integer of 0 to 3,
  • Group A is a halogen atom, a C 2 -C 7 alkylcarbonyl group, a C 2 -C 7 halogenated alkylcarbonyl group, a C 2 -C 7 alkoxycarbonyl group, a C 2 -C 7 halogenated alkoxycarbonyl group, C 1 -C 6 alkylsulfonyl group, C 1 -C 6 halogenated alkylsulfonyl group, C 3 -C 6 cycloalkylsulfonyl group, (C 1 -C 6 alkoxy)-(C 1 -C 6 alkylsulfonyl) group, (C 1- C 6 halogenated alkoxy)-(C 1 -C 6 alkylsulf
  • the substituent group B is a halogen atom, a C 2 -C 7 alkylcarbonyl group, a C 2 -C 7 alkoxycarbonyl group, a carbamoyl group, a mono- C 1 -C 6 alkylaminocarbonyl group, di- (C 1 -C 6 alkyl) aminocarbonyl group, C 1 -C 6 alkylthio group, C 1 -C 6 alkylsulfonyl group, hydroxy group and 3-6 membered ring ether Kara Indicating the group. Or a pharmacologically acceptable salt thereof.
  • R 1 is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted with one or two hydroxy groups, or a carbamoyl group
  • R 2 is A phenyl group in which one of the 4- or 3-positions is substituted with a group selected from substituent group C, a 5-pyridyl group in which one of the 2-positions is substituted with a group selected from substituent group C, or A 2-pyrazinyl group substituted at the 5-position with a group selected from substituent group C, wherein substituent group C is a C 1 -C 6 alkoxy group, C 1 -C 6 alkylsulfonyl group, and From a group represented by —V—NR 6 R 7 (V represents a carbonyl group or a sulfonyl group, and R 6 and R 7 are the same or different and represent a hydrogen atom or a
  • R 3 is a halogen atom and is independently 1 to 5
  • R 1 is a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted with one or two hydroxy groups, or a carbamoyl group
  • R 2 is A phenyl group in which one of the 4- or 3-positions is substituted with a group selected from substituent group C, a 5-pyridyl group in which one of the 2-positions is substituted with a group selected from substituent group C, or A 2-pyrazinyl group substituted at the 5-position with a group selected from substituent group C, wherein substituent group C is a C 1 -C 6 alkoxy group, C 1 -C 6 alkylsulfonyl group, and From a group represented by —V—NR 6 R 7 (V represents a carbonyl group or a sulfonyl group, and R 6 and R 7 are the same or different and represent a hydrogen atom or a
  • R 3 is a C 1 -C 6 alkyl group or a formula A group represented by —NR 4 R 5 (R 4 and R 5 are the same or different and each represents a hydrogen atom or a C 1 -C 6 alkyl group), U is a carbonyl group, and n is 0 A compound which is an integer of 1 to 3, or a pharmacologically acceptable salt thereof.
  • the general formula (I) is the general formula (Ia), R 1 is a carbamoyl group, R 2 is a 3-methoxyphenyl group, 2-methylaminocarbonyl-5-pyridyl group, 4-methylsulfonylphenyl.
  • the group represented by R 3 is a methoxy group, ethoxy group, isopropoxy group, (1S) -2-fluoro-1-methylethoxy group, difluoromethoxy group, 1,3-difluoro-2-propoxy group, cyclopentanone -2-yloxy group, tetrahydrofuran-3-yloxy group, 1-cyclopropylpyrrolidin-2-one-3-yloxy group, Propyl carbonyl group or compound or pharmacologically acceptable salt thereof is a dimethylamino group.
  • the general formula (I) is the general formula (Ib), R 1 is a methyl group, a hydroxymethyl group or a 2-hydroxyethyl group, R 2 is a 3-methoxyphenyl group, 2-methylaminocarbonyl- 5-pyridyl group, 4-methylsulfonylphenyl group, 2-methylsulfonyl-5-pyridyl group, 2-methylaminosulfonyl-5-pyridyl group, 5-methylsulfonyl-2-pyrazinyl group or 5-methylaminosulfonyl-2
  • a pyrazinyl group, the group represented by the formula -UR 3 is a methoxy group, an ethoxy group, an isopropoxy group, a (1S) -2-fluoro-1-methylethoxy group, a difluoromethoxy group, 1,3- Difluoro-2-propoxy group, cyclopentanone-2-yloxy group, tetrahydrofuran
  • the general formula (I) is the general formula (Ic), R 1 is a methyl group, a fluoromethyl group, a hydroxymethyl group, a 2-hydroxyethyl group or a (1S) -1,2-dihydroxyethyl group; R 2 represents 3-methoxyphenyl group, 2-methylaminocarbonyl-5-pyridyl group, 4-methylsulfonylphenyl group, 2-methylsulfonyl-5-pyridyl group, 2-methylaminosulfonyl-5-pyridyl group, 5 A methylsulfonyl-2-pyrazinyl group or a 5-methylaminosulfonyl-2-pyrazinyl group, and the group represented by the formula —UR 3 is a methoxy group, an ethoxy group, an isopropoxy group, (1S) -2- Fluoro-1-methylethoxy group, difluoromethoxy group, 1,3-difluoro-2-
  • a glucokinase activator comprising as an active ingredient the compound described in any one of (1) to (20) or a pharmacologically acceptable salt thereof.
  • a pharmaceutical composition comprising as an active ingredient the compound described in any one of (1) to (20) or a pharmacologically acceptable salt thereof.
  • the pharmaceutical composition activates glucokinase to achieve maintenance of glucose homeostasis or regulation of blood glucose, thereby treating and / or treating diseases that are treated, ameliorated, reduced and / or prevented. Or the pharmaceutical composition as described in (22) for prevention.
  • the pharmaceutical composition is diabetes, impaired glucose tolerance, gestational diabetes, chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome
  • diabetes impaired glucose tolerance
  • gestational diabetes chronic complications of diabetes (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome
  • the pharmaceutical composition according to (22) for treatment and / or prevention is provided.
  • a method for activating glucokinase comprising administering to a warm-blooded animal a pharmacologically effective amount of the compound described in any one of (1) to (20) or a pharmacologically acceptable salt thereof.
  • the disease is diabetes, impaired glucose tolerance, gestational diabetes, chronic diabetes complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) or metabolic syndrome (33 ) Method.
  • the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • a fluorine atom or a chlorine atom Preferable is a fluorine atom or a chlorine atom, and more preferable is a fluorine atom.
  • the “C 1 -C 6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms.
  • the “C 1 -C 6 halogenated alkyl group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 6 alkyl group”.
  • the same or different 1 to 5 “halogen atoms” are groups (C 1 -C 2 halogenated alkyl groups) bonded to the “C 1 -C 2 alkyl group”, Is more preferably a trifluoromethyl group or a fluoromethyl group, and particularly preferably a fluoromethyl group.
  • the “C 1 -C 6 alkyl group substituted by 1 or 2 hydroxy groups” is a group in which 1 or 2 hydroxy groups are bonded to the “C 1 -C 6 alkyl group”. is there.
  • the “C 1 -C 6 alkylthio group” is a group in which one “C 1 -C 6 alkyl group” is bonded to a sulfur atom, and is a straight chain or branched chain having 1 to 6 carbon atoms. It is a chain alkylthio group.
  • methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, 1-ethylpropylthio or hexylthio group preferably a linear or branched alkylthio group having 1 to 4 carbon atoms (C 1 -C 4 alkylthio group), more preferably methylthio or ethylthio group (C 1 -C 2 alkylthio group), and still more preferably methylthio group.
  • (C 1 -C 6 alkylthio)-(C 1 -C 6 alkyl) group means that one “C 1 -C 6 alkylthio group” is the above “C 1 -C 6 alkyl group”.
  • C 1 -C 4 alkylthio groups is the “C 1 1- C 4 alkyl group ”((C 1 -C 4 alkylthio)-(C 1 -C 4 alkyl) group), more preferably one of the above-mentioned“ C 1 -C 2 alkylthio groups ”.
  • Group is a group ((C 1 -C 2 alkylthio)-(C 1 -C 2 alkyl) group) bonded to the“ C 1 -C 2 alkyl group ”, and more preferably 2-methylthioethyl It is a group.
  • "mono--C 1 -C 6 alkylaminocarbonyl group” is an amino group in which one of the “C 1 -C 6 alkyl group” is bonded is a group attached to a carbonyl group.
  • a methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl or butylaminocarbonyl group preferably an amino group to which one of the above “C 1 -C 4 alkyl groups” is bonded is a carbonyl group A group bonded to (mono-C 1 -C 4 alkylaminocarbonyl group), more preferably a methylaminocarbonyl group or an ethylaminocarbonyl group (mono-C 1 -C 2 alkylaminocarbonyl group), Even more preferred is a methylaminocarbonyl group.
  • the “di- (C 1 -C 6 alkyl) aminocarbonyl group” is a group in which two identical or different “C 1 -C 6 alkyl groups” are bonded to a carbonyl group. is there.
  • dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-propylaminocarbonyl or N-butyl-N-methylaminocarbonyl group preferably
  • An amino group to which two identical or different “C 1 -C 4 alkyl groups” are bonded is a group bonded to a carbonyl group (di- (C 1 -C 4 alkyl) aminocarbonyl group), more preferably Is a dimethylaminocarbonyl group, a diethylaminocarbonyl group or an N-ethyl-N-methylaminocarbonyl group (di
  • the “C 2 -C 6 alkenyl group” is a group having 2 to 6 carbon atoms having one double bond in the “C 1 -C 6 alkyl group”.
  • the “C 1 -C 6 alkoxy group” is a group in which the “C 1 -C 6 alkyl group” is bonded to an oxygen atom, and is a linear or branched alkoxy group having 1 to 6 carbon atoms. It is.
  • a methoxy group preferably a methoxy group.
  • a “C 2 -C 7 alkylcarbonyl group” is a group in which one of the above “C 1 -C 6 alkyl groups” is bonded to a carbonyl group.
  • acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl or valeryl group and preferably a group (C 2 -C 5 alkyl) in which one said “C 1 -C 4 alkyl group” is bonded to a carbonyl group A carbonyl group), more preferably an acetyl group or a propionyl group (C 2 -C 3 alkylcarbonyl group), and even more preferably an acetyl group.
  • the “C 2 -C 7 halogenated alkylcarbonyl group” is a group in which one of the above “C 1 -C 6 halogenated alkyl groups” is bonded to a carbonyl group.
  • the aforementioned “C 1 -C 2 halogenated alkyl group” is a group (C 2 -C 3 halogenated alkylcarbony
  • a “C 2 -C 7 alkoxycarbonyl group” is a group in which one of the above “C 1 -C 6 alkoxy groups” is bonded to a carbonyl group.
  • methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl or t-butoxycarbonyl group, preferably one of the above-mentioned “C 1 -C 4 alkoxy” Group ” is a group bonded to a carbonyl group (C 2 -C 5 alkoxycarbonyl group), more preferably a methoxycarbonyl group or an ethoxycarbonyl group (C 2 -C 3 alkoxycarbonyl group), and even more preferably Is a methoxycarbonyl group.
  • the “C 1 -C 6 halogenated alkoxy group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 6 alkoxy group”.
  • trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 2-chloroethoxy, 2-fluoroethoxy or A pentafluoroethoxy group preferably a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 4 alkoxy group” (C 1 -C 4 halogenated alkoxy group) More preferably, the same or different 1 to 5 “halogen atoms” are groups bonded to the “C 1 -C 2 alkoxy group” (C 1 -C 2 halogenated alkoxy group)
  • a “C 1 -C 6 alkylsulfonyl group” is a group in which one of the above “C 1 -C 6 alkyl groups” is bonded to a sulfonyl group, and is a straight chain or branched group having 1 to 6 carbon atoms. It is a branched alkylsulfonyl group.
  • a methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, s-butylsulfonyl or pentylsulfonyl group preferably a linear or branched alkylsulfonyl group having 1 to 4 carbon atoms A group (C 1 -C 4 alkylsulfonyl group), more preferably a methylsulfonyl group or an ethylsulfonyl group (C 1 -C 2 alkylsulfonyl group), and even more preferably a methylsulfonyl group.
  • the “C 1 -C 6 halogenated alkylsulfonyl group” is a group in which one of the above “C 1 -C 6 halogenated alkyl groups” is bonded to a sulfonyl group, and has 1 to 6 carbon atoms.
  • a straight-chain or branched alkylsulfonyl halide group For example, trifluoromethylsulfonyl, trichloromethylsulfonyl, difluoromethylsulfonyl, dichloromethylsulfonyl, fluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl or 2-fluoroethylsulfonyl group, preferably having 1 carbon atom Or a straight chain or branched chain alkylsulfonyl group having 4 to 4 straight chain or branched chain (C 1 -C 4 halogenated alkylsulfonyl group), more preferably a straight chain or branched chain halogenated group having 1 or 2 carbon atoms.
  • An alkylsulfonyl group (C 1 -C 2 halogenated alkylsulfonyl group), and even more preferably a trifluoromethylsulfon
  • the “C 3 -C 6 cycloalkyl group” is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. Preferred is a cyclopropyl group.
  • the “C 3 -C 6 cycloalkylsulfonyl group” is a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a cyclopentylsulfonyl group or a cyclohexylsulfonyl group.
  • Preferred is a cyclopropylsulfonyl group.
  • (C 1 -C 6 alkoxy)-(C 1 -C 6 alkylsulfonyl) group means that one “C 1 -C 6 alkoxy group” is the above “C 1 -C 6 alkylsulfonyl”. A group bonded to “group”.
  • the “1- C 2 alkoxy group” is a group ((C 1 -C 2 alkoxy)-(C 1 -C 2 alkylsulfonyl) group) bonded to the “C 1 -C 2 alkylsulfonyl group”, and more preferably Is a methoxymethyls
  • (C 1 -C 6 halogenated alkoxy)-(C 1 -C 6 alkylsulfonyl) group means that one “C 1 -C 6 halogenated alkoxy group” is the above “C 1- A group bonded to a “C 6 alkylsulfonyl group”.
  • it is a trifluoromethoxymethylsulfonyl, trichloromethoxymethylsulfonyl, difluoromethoxymethylsulfonyl, dichloromethoxymethylsulfonyl or fluoromethoxymethylsulfonyl group, preferably one of the aforementioned “C 1 -C 4 halogenated alkoxy groups” Is a group ((C 1 -C 4 halogenated alkoxy)-(C 1 -C 4 alkylsulfonyl) group) bonded to the “C 1 -C 4 alkylsulfonyl group”, more preferably one A group ((C 1 -C 2 halogenated alkoxy)-(C 1 -C 2 alkylsulfonyl) group in which the “C 1 -C 2 halogenated alkoxy group” is bonded to the “C 1 -C 2 alkylsulfonyl group”; And more preferably a trifluo
  • the “phenyl group which may be independently substituted with 1 to 5 groups selected from the substituent group A” is independently 1 to 5 groups with a phenyl group or a group selected from the substituent group A. This is a phenyl group that is substituted.
  • a phenyl group substituted by one at 4-position or 3-position with a group selected from substituent group C is preferable.
  • a pyridyl group or a pyrazinyl group optionally substituted by 1 to 3 groups independently selected from the substituent group A is independently a group selected from the pyridyl group and the substituent group A. 1 to 3 substituted pyridyl groups, pyrazinyl groups, or a pyrazinyl group independently substituted with 1 to 3 groups selected from substituent group A.
  • a C 1 -C 6 alkyl group which may be independently substituted with 1 to 5 groups independently selected from the substituent group B refers to a C 1 -C 6 alkyl group or the substituent group B C 1 -C 6 alkyl group independently substituted with 1 to 5 selected groups.
  • it is a C 1 -C 6 alkyl group which may be independently substituted with 1 to 5 halogen atoms, more preferably a methyl group, an ethyl group, an isopropyl group, (1S) -2-fluoro.
  • the “3- to 6-membered cyclic ether” is oxirane, oxetane, tetrahydrofuran or tetrahydropyran. Tetrahydrofuran is preferred.
  • the “3- to 6-membered saturated ring optionally containing one oxygen atom or nitrogen atom” is a C 3 -C 6 cycloalkyl group, a 3- to 6-membered ring ether, or a 3- to 6-membered ring amine, Cyclopropane, cyclobutane, cyclopentane, cyclohexane, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, aziridine, azetidine, pyrrolidine or piperidine. Preference is given to cyclopentane, tetrahydrofuran or pyrrolidine.
  • one to three independently substituted oxygen groups or one nitrogen atom may be substituted with a group consisting of “(C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group and oxo group)”.
  • the “3- to 6-membered saturated ring which may be contained” means a 3- to 6-membered saturated ring which may contain one oxygen atom or nitrogen atom, or a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group and an oxo group.
  • “1 to 3 which may be independently substituted with a group consisting of a C 1 -C 6 alkyl group and an oxo group together with the nitrogen atom to which R 4 and R 5 are bonded may be used.
  • a 4 to 6-membered heterosaturated ring may further contain one oxygen atom or nitrogen atom ”is independently selected from the group consisting of a C 1 -C 6 alkyl group and an oxo group.
  • 4 to 6-membered hetero-saturated ring which may be substituted by 3 to 4 (a 4- to 6-membered fully-reduced saturated heterocyclic ring which contains one nitrogen atom and further contains one oxygen atom or nitrogen atom) Group), for example, azetidine, pyrrolidine, piperidine, morpholine, piperazine, 2-azetidinone, 2-pyrrolidinone, 2-piperidinone, dimethylmorpholine, methylpiperazine or dimethylpiperazine, and preferably Zechijin, pyrrolidine or morpholine.
  • the “group represented by the formula —V—NR 6 R 7 ” is the “group represented by the formula —C ( ⁇ O) —NR 6 R 7 ” or “the formula —SO 2 —NR 6 R 7” .
  • a 6 to 6-membered heterosaturated ring which may be independently substituted with one or two C 1 -C 6 alkyl groups together with the nitrogen atom to which R 6 and R 7 are bonded.
  • the 4- to 6-membered heterosaturated ring may further contain one oxygen atom or nitrogen atom.) ” May be independently substituted with one or two C 1 -C 6 alkyl groups.
  • To 6-membered heterosaturated ring (a 4- to 6-membered fully reduced saturated heterocyclic group containing one nitrogen atom and further containing one oxygen atom or nitrogen atom), such as azetidine, pyrrolidine , Piperidine, morpholine, piperazine, dimethylmorpholine, methylpiperazine or dimethylpiperazine, preferably azetidine or 4-methylpiperazine.
  • R 1 is preferably a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a C 1 -C 6 alkyl group substituted with one or two hydroxy groups, or a carbamoyl group.
  • R 1 is more preferably a carbamoyl group.
  • R 1 is a methyl group, a hydroxymethyl group or a 2-hydroxyethyl group.
  • R 1 is a methyl group, a fluoromethyl group, a hydroxymethyl group, a 2-hydroxyethyl group, or a (1S) -1,2-dihydroxyethyl group. is there.
  • R 2 is preferably a phenyl group substituted by one of the 4-position or 3-position with a group selected from Substituent Group C, and one 2-position of a group selected from Substituent Group C.
  • a substituted 5-pyridyl group or a 2-pyrazinyl group substituted at the 5-position with a group selected from Substituent Group C (Substituent Group C is a C 1 -C 6 alkoxy group, C 1- A C 6 alkylsulfonyl group and a group represented by the formula —V—NR 6 R 7 (V represents a carbonyl group or a sulfonyl group, and R 6 and R 7 are the same or different and each represents a hydrogen atom or C 1 -C 6; More preferably R 2 represents a 3-methoxyphenyl group, a 2-methylaminocarbonyl-5-pyridyl group, a 4-methylsulfonylphenyl group, a 2-methyl
  • preferred R 3 is a C 1 -C 6 alkyl group or a (C 3 -C 6 cycloalkyl group) which may be independently substituted with 1 to 5 halogen atoms.
  • a 3- to 6-membered saturated ring which may be independently substituted by 1 or 2 groups and may contain one oxygen atom or nitrogen atom.
  • preferred R 3 is a C 1 -C 6 alkyl group or a group represented by the formula —NR 4 R 5 (R 4 and R 5 may be the same or different and each represents a hydrogen atom or C 1 — A C 6 alkyl group).
  • the preferred group represented by the formula —NR 4 R 5 is a dimethylamino group.
  • preferable groups represented by the formula -UR 3 are methoxy group, ethoxy group, isopropoxy group, (1S) -2-fluoro-1-methylethoxy group, difluoromethoxy group, 1,3- A difluoro-2-propoxy group, a cyclopentanone-2-yloxy group, a tetrahydrofuran-3-yloxy group, a 1-cyclopropylpyrrolidin-2-one-3-yloxy group, an isopropylcarbonyl group or a dimethylaminocarbonyl group.
  • the preferred group represented by the formula —NR 6 R 7 is a methylamino group.
  • n is preferably 1.
  • the preferred substituent group A includes a C 1 -C 6 alkoxy group, a C 1 -C 6 alkylsulfonyl group, and a group represented by the formula —V—NR 6 R 7 (V is a carbonyl group or a sulfonyl group) R 6 and R 7 are the same or different and each represents a hydrogen atom or a C 1 -C 6 alkyl group.), And more preferred substituent group A includes a methoxy group, a methylaminocarbonyl group, a methyl group A sulfonyl group or a methylaminosulfonyl group.
  • a preferred substituent group B is a halogen atom, and a more preferred substituent group B is a fluorine atom.
  • the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has all isomers (keto-enol isomer, diastereoisomer, optical isomer, rotational isomer, etc.).
  • the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has various isomers because an asymmetric carbon atom is present in the molecule.
  • these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Therefore, the present invention includes all of these isomers and a mixture of these isomers in an arbitrary ratio.
  • an optically active raw material compound is used, or a compound according to the present invention is synthesized using an asymmetric synthesis or asymmetric induction method, or a synthesized compound according to the present invention is synthesized. If desired, it can be obtained by isolation using a conventional optical resolution method or separation method.
  • the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may also contain an unnatural proportion of atomic isotopes at one or more of atoms constituting such a compound.
  • the atomic isotope include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like.
  • the compound can also be radiolabeled with a radioisotope such as, for example, tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
  • the pharmacologically acceptable salt refers to a salt that has no significant toxicity and can be used as a medicine.
  • the compound having the general formula (I) of the present invention has a basic group, it is reacted with an acid, and when it has an acidic group, it is reacted with a base to form a salt. Can do.
  • Examples of the salt based on the basic group include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate, Inorganic acid salts such as phosphates; C 1 -C 6 alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.
  • Organic acid salts such as aryl sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, succinate, maleate; and glycine salt And amino acid salts such as lysine salt, arginine salt, ornithine salt, glutamate and aspartate.
  • examples of the salt based on the acidic group include alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, metal salts such as aluminum salt and iron salt.
  • Inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts , Dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt Amine salts such as organic salt
  • the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof absorbs moisture by being left in the atmosphere or recrystallized, and adsorbs water, or hydrates. Such hydrates are also included in the salts of the present invention.
  • the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may absorb a certain other solvent and become a solvate, and such a solvate is also the present invention. Included in the salt.
  • the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is preferably a compound having the general formula (I) of the present invention.
  • metabolic syndrome is based on insulin resistance, and a state in which the risk of coronary artery disease is significantly increased by accumulation of a plurality of coronary risk factors (lifestyle-related diseases such as hyperlipidemia, diabetes, Obesity, hypertension, etc. (Diabetes, Obesity and Metabolism, 9, 2007, 246-258, Journal of the American Medical Association, oci285: 2486-2497 (2001), Diabet. Med., 15: 539-553 ( 1998)).
  • lifestyle-related diseases such as hyperlipidemia, diabetes, Obesity, hypertension, etc.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent GK activation action, and is a warm-blooded animal (preferably a mammal, including humans).
  • the novel compound represented by the general formula (I) provided by the present invention or a pharmacologically acceptable salt thereof has an excellent GK activation action, and is a warm-blooded animal (preferably a mammalian animal).
  • Preferred diseases are diabetes or impaired glucose tolerance.
  • it can be used as a medicament for the treatment of the above-mentioned diseases.
  • the compound having the general formula (I) of the present invention can be produced according to Method A to Method U described below.
  • solvent used in the reaction in each step of the following methods A to U is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, and is selected from the following solvent group, for example.
  • Solvent groups include hydrocarbons such as pentane, hexane, octane, petroleum ether, ligroin, cyclohexane; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methyl Amides such as -2-pyrrolidinone and hexamethylphosphoric triamide; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and cyclopentyl methyl ether; methanol, ethanol, n-propanol, i -Propanol, n-butanol,
  • the base used in the reaction of each step of the following methods A to U is, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate; sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate Alkali metal bicarbonates such as sodium acetate, potassium acetate, lithium acetate, alkali metal acetates such as cesium acetate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; Alkali metal hydroxides such as sodium, potassium hydroxide, barium hydroxide, lithium hydroxide; inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium methoxide, sodium ethoxy Sodium-t-butoxide, potassium methoxide, Alkali metal alkoxides such as lithium ethoxide, potassium tert-butoxide, lithium methoxide; alkali metal trialkylsiloxides such as sodium trimethylsil
  • the condensing agent used in the reaction in each step of the following methods A to U is, for example, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexa Fluorophosphate (HATU), 1-propanephosphonic acid cyclic anhydride (T3P), dicyclohexylcarbodiimide (DCCD), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCI ⁇ HCl), 1-ethyl -3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDAC), 4- (4,6-dimethoxy-1,3,5- Triazin-2-yl) -4-methylmorpholinium chloride n-hydrate (DMT-MM), isobutyl chloroformat
  • Examples of the demethylating agent used in the reaction of each step of the following methods A to U include sodium thiomethoxide, sodium thioethoxide, sodium thiophenoxide, iodotrimethylsilane, aluminum chloride, aluminum bromide, and three odors. Boron iodide, boron triiodide, methylmagnesium iodide, and hydrogen bromide.
  • the palladium catalyst used in the reaction in each step of the following methods A to U is, for example, tetrakis (triphenylphosphine) palladium (0), palladium-activated carbon, palladium acetate (II), palladium trifluoroacetate (II) , Palladium black, palladium (II) bromide, palladium (II) chloride, palladium (II) iodide, palladium (II) cyanide, palladium (II) nitrate, palladium (II) oxide, palladium (II) sulfate, dichlorobis (Acetonitrile) palladium (II), dichlorobis (benzonitrile) palladium (II), dichloro (1,5-cyclooctadiene) palladium (II), acetylacetone palladium (II), palladium (II) sulfide, [1,1 ' -
  • the oxidizing agent used in the reaction of each step of the following methods A to U is an inorganic oxidizing agent such as m-chloroperbenzoic acid, hydrogen peroxide solution, oxone or manganese dioxide.
  • reaction temperature varies depending on the solvent, starting material, reagent, etc.
  • reaction time varies depending on the solvent, starting material, reagent, reaction temperature, and the like.
  • each target compound is collected from the reaction mixture according to a conventional method. For example, neutralize the reaction mixture as appropriate, or remove insoluble matter by filtration, add water and an immiscible organic solvent such as ethyl acetate, and separate the organic layer containing the target compound, It can be obtained by washing with water, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, etc., filtering, and then distilling off the solvent.
  • an immiscible organic solvent such as ethyl acetate
  • the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., usually using methods commonly used for separation and purification of organic compounds, applying chromatography, and the like. Can be separated and purified.
  • a target compound insoluble in a solvent the obtained solid crude product can be purified by washing with a solvent.
  • the target compound in each step can be directly used in the next reaction without purification.
  • Me represents a methyl group
  • iPr represents an isopropyl group
  • Ac represents an acetyl group
  • Bn represents a benzyl group
  • Boc represents a t-butoxycarbonyl group.
  • Method A is a method for producing a compound having the general formula (Id) in which U is an oxygen atom among the compounds having the general formula (I).
  • R 2 and R 3 are as defined above, R 8 represents a C 1 -C 6 alkyl group (preferably a methyl group or an ethyl group), R 9 , R 10 , R 11 and R 12 represent a hydrogen atom or one group of R 1 , and X is a halogen atom (preferably a chlorine atom, a bromine atom or an iodine atom, more preferably a bromine atom Y represents a halogen atom, a C 1 -C 6 alkylsulfonyloxy group, a C 1 -C 6 alkoxysulfonyloxy group or a C 6 -C 10 arylsulfonyloxy group (preferably a halogen atom)
  • R 2a , R 3a , R 9a , R 10a , R 11a, and R 12a are R, and more preferably a fluorine atom or a chlorine atom, and even more preferably a fluor
  • the group similar to the group in the definition of group of R ⁇ 2 >, R ⁇ 3 >, R ⁇ 9 >, R ⁇ 10 >, R ⁇ 11 > and R ⁇ 12 > is shown.
  • Step A1 This step is a step of producing a compound having the general formula (III).
  • This step is performed by reacting a compound having the general formula (II) with a demethylating agent in a solvent.
  • the compound having the general formula (II) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
  • the solvent used in this step is preferably an amide, more preferably N, N-dimethylformamide or N-methyl-2-pyrrolidinone.
  • the demethylating agent used in this step is preferably sodium thiomethoxide.
  • the reaction temperature in this step is usually 50 ° C. to 140 ° C., preferably 80 ° C. to 120 ° C.
  • the reaction time in this step is usually 0.5 to 12 hours, preferably 1 to 5 hours.
  • Step A2 This step is a step of producing a compound having the general formula (V).
  • This step is performed by reacting a compound having the general formula (III) with a compound having the general formula (IV) in a solvent in the presence of a base.
  • the compound having the general formula (IV) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
  • the solvent used in this step is preferably an amide or a nitrile, and more preferably N, N-dimethylformamide or acetonitrile.
  • the base used in this step is preferably an alkali metal carbonate, and more preferably potassium carbonate or cesium carbonate.
  • the reaction temperature in this step is usually ⁇ 10 ° C. to 140 ° C., preferably 0 ° C. to 120 ° C.
  • the reaction time in this step is usually 0.5 to 72 hours, preferably 1 to 48 hours.
  • Step A3 This step is a step of producing a compound having the general formula (VI).
  • This step is performed by reacting a compound having the general formula (V) with a demethylating agent in a solvent.
  • the solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
  • the demethylating agent used in this step is preferably boron tribromide.
  • the reaction temperature in this step is usually ⁇ 100 ° C. to 40 ° C., preferably ⁇ 78 ° C. to 25 ° C.
  • the reaction time in this step is usually 1 hour to 72 hours, preferably 12 hours to 36 hours.
  • Step A4 This step is a step of producing a compound having the general formula (VII).
  • This step is performed by reacting a compound having the general formula (VI) with bis (pinacolato) diboron in a solvent in the presence of a palladium catalyst and an inorganic base.
  • the solvent used in this step is preferably an amide, and more preferably N, N-dimethylformamide.
  • the palladium catalyst used in this step is preferably a divalent palladium catalyst, more preferably [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex. .
  • the inorganic base used in this step is preferably an alkali metal acetate, and more preferably potassium acetate.
  • the reaction temperature in this step is usually 50 ° C to 130 ° C, preferably 70 ° C to 110 ° C.
  • the reaction time in this step is usually 1 to 24 hours, preferably 2 to 10 hours.
  • Step A5 This step is a step of producing a compound having the general formula (IX).
  • This step is performed by reacting a compound having the general formula (VII) with a compound having the general formula (VIII) in the presence of triphenylphosphine and diethyl azodicarboxylate in a solvent.
  • the compound having the general formula (VIII) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
  • the solvent used in this step is preferably an ether, an aromatic hydrocarbon, or a mixed solvent thereof, more preferably tetrahydrofuran, toluene, or a mixed solvent of tetrahydrofuran and toluene.
  • the reaction temperature in this step is usually ⁇ 20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
  • the reaction time in this step is usually 0.5 to 72 hours, preferably 1 to 36 hours.
  • Step A6 This step is a step of producing a compound having the general formula (XI).
  • This step is performed by reacting a compound having the general formula (IX) with a compound having the general formula (X) in a solvent in the presence of a palladium catalyst and an inorganic base.
  • the solvent used in this step is preferably an ether, alcohol, aromatic hydrocarbon or a mixed solvent thereof, more preferably dioxane, ethanol, toluene or a mixed solvent thereof. Even more preferred is dioxane or a mixed solvent of ethanol and toluene.
  • the palladium catalyst used in this step is preferably a divalent palladium catalyst, more preferably [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex. .
  • the inorganic base used in this step is preferably an alkali metal carbonate, more preferably potassium carbonate, and even more preferably an aqueous potassium carbonate solution.
  • the reaction temperature in this step is usually 25 ° C to 100 ° C, preferably 40 ° C to 70 ° C.
  • the reaction time in this step is usually 0.5 to 12 hours, preferably 1 to 5 hours.
  • Step A7 This step is a step of producing a compound having the general formula (XII).
  • This step is performed by reacting a compound having the general formula (XI) with an acid in a solvent.
  • the solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
  • Examples of the acid used in this step include hydrogen halides such as hydrogen chloride gas and hydrogen bromide gas; mineral acids such as sulfuric acid, hydrobromic acid and hydrochloric acid; methanesulfonic acid and p-toluenesulfonic acid , Organic sulfonic acids such as pyridinium p-toluenesulfonate (PPTS), camphorsulfonic acid and trifluoromethanesulfonic acid; carboxylic acids such as acetic acid, formic acid and trifluoroacetic acid; aluminum chloride, zinc chloride, zinc iodide, tetra Lewis acids such as tin chloride, titanium trichloride, boron trifluoride, boron tribromide; or acidic ion exchange resins, preferably carboxylic acids, and more preferably trifluoroacetic acid.
  • hydrogen halides such as hydrogen chloride gas and hydrogen bromide gas
  • mineral acids such as sulfuric acid, hydrobro
  • the reaction temperature in this step is usually ⁇ 20 ° C. to 60 ° C., preferably 0 ° C. to 40 ° C.
  • the reaction time in this step is usually 0.1 to 5 hours, preferably 0.5 to 3 hours.
  • Step A8 This step is a step of producing a compound having the general formula (XIII).
  • This step is performed by reacting a compound having the general formula (XII) with a base in a solvent.
  • the solvent used in this step is preferably an alcohol, and more preferably ethanol.
  • the base used in this step is preferably an alkali metal hydroxide, more preferably sodium hydroxide, and even more preferably an aqueous sodium hydroxide solution.
  • the reaction temperature in this step is usually 25 ° C to 100 ° C, preferably 50 ° C to 80 ° C.
  • the reaction time in this step is usually 0.1 to 24 hours, preferably 0.5 to 6 hours.
  • Step A9 This step is a step of producing a compound having the general formula (XV).
  • This step is performed by reacting a compound having the general formula (XIII) with a compound having the general formula (XIV) in a solvent in the presence of a condensing agent, in the presence or absence of a base.
  • the compound having the general formula (XIV) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
  • the solvent used in this step is preferably an alcohol, a halogenated hydrocarbon, an amide or a mixed solvent thereof, more preferably methanol, dichloromethane, N, N-dimethylformamide or dichloromethane. It is a mixed solvent of N, N-dimethylformamide.
  • the condensing agent used in this step is preferably DMT-MM, HATU or WSCI ⁇ HCl.
  • WSCI ⁇ HCl is used, HOBt or HOBT ⁇ H 2 O can coexist if necessary.
  • the base used in this step is preferably an organic base, and more preferably N-methylmorpholine, N, N-diisopropylethylamine or 4-dimethylaminopyridine.
  • the reaction temperature in this step is usually ⁇ 20 ° C. to 60 ° C., preferably 0 ° C. to 30 ° C.
  • the reaction time in this step is usually 0.5 hour to 72 hours, preferably 1 hour to 24 hours.
  • Step A10 This step is a step of producing a compound having the general formula (Id).
  • a compound having the general formula (XV) is reacted with a base and methanesulfonic anhydride or bis (2-methoxyethyl) aminosulfur trifluoride in a solvent, and then optionally R 2a , R 3a , R 9a , R 10a , R 11a and R 12a are carried out by removing amino, hydroxy and / or carboxyl protecting groups.
  • the solvent used in this step is preferably an ether, and more preferably tetrahydrofuran or dimethoxyethane.
  • the solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
  • the base used in this step is preferably an organic base, and more preferably triethylamine.
  • the base used in this step is preferably an alkali metal carbonate, more preferably potassium carbonate.
  • the reaction temperature in this step is usually ⁇ 100 ° C. to 85 ° C., and when methanesulfonic anhydride is used, it is preferably 10 ° C. to 60 ° C. When bis (2-methoxyethyl) aminosulfur trifluoride is used, it is preferably ⁇ 78 ° C. to 30 ° C.
  • the reaction time in this step is usually 0.5 hour to 72 hours, preferably 1 hour to 24 hours.
  • Method B is a method for producing a compound having the general formula (Id) in which U is an oxygen atom among the compounds having the general formula (I).
  • R 2 , R 3 , R 8 , R 9 , R 10 , R 11 , R 12 , R 2a , R 3a , R 9a , R 10a , R 11a , R 12a , X and Y are as described above. It shows the same meaning as the thing.
  • Step B1 This step is a step of producing a compound having the general formula (XVI).
  • This step comprises reacting the compound having the general formula (V) obtained in Step A2 Step A2 with bis (pinacolato) diboron in a solvent in the presence of a palladium catalyst and an inorganic base. This is performed in the same manner as in step A4.
  • Step B2 This step is a step of producing a compound having the general formula (XVII).
  • step (XVI) the compound having the general formula (XVI) is reacted with the compound having the general formula (X) in the presence of a palladium catalyst and an inorganic base in a solvent in the same manner as in step A6 of the method A. Done.
  • Step B3 This step is a step of producing a compound having the general formula (XVIII).
  • This step is performed in the same manner as in Step A8 of Method A above by reacting a compound having the general formula (XVII) with a base in a solvent.
  • Step B4 This step is a step of producing a compound having the general formula (XIX).
  • This step is performed by reacting a compound having the general formula (XVIII) with a compound having the general formula (XIV) in a solvent in the presence of a condensing agent, in the presence or absence of a base, and Performed in the same manner as in step A9.
  • Step B5 This step is a step of producing a compound having the general formula (XX).
  • the compound having the general formula (XIX) is reacted with a base and methanesulfonic anhydride or bis (2-methoxyethyl) aminosulfur trifluoride in a solvent to form the step A10 of the above method A. The same is done.
  • Step B6 This step is a step of producing a compound having the general formula (XXI).
  • This step is performed in the same manner as in Step A3 of Method A above by reacting a compound having the general formula (XX) with a demethylating agent in a solvent.
  • Step B7 This step is a step of producing a compound having the general formula (Id).
  • the compound having the general formula (XXI) is reacted with the compound having the general formula (VIII) in the presence of triphenylphosphine and diethyl azodicarboxylate in a solvent, whereby the A5
  • it is carried out by removing amino, hydroxy and / or carboxyl protecting groups in R 2a , R 3a , R 9a , R 10a , R 11a and R 12a as desired.
  • Step B8 This step is a step of producing a compound having the general formula (Id).
  • This step is carried out by reacting a compound having the general formula (XXI) with a compound having the general formula (XXII) in a solvent in the presence of a base, and then optionally R 2a , R 3a , R 9a , R 10a , R 11a and R 12a are carried out by removing the protective group for the amino group, hydroxy group and / or carboxyl group.
  • the compound having the general formula (XXII) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
  • the solvent used in this step is preferably an amide or a ketone, and more preferably N, N-dimethylformamide or 2-butanone.
  • the base used in this step is preferably an alkali metal carbonate, and more preferably potassium carbonate.
  • the reaction temperature in this step is usually 25 ° C to 120 ° C, preferably 40 ° C to 80 ° C.
  • the reaction time in this step is usually 1 hour to 72 hours, preferably 6 hours to 48 hours.
  • Method C is a method for producing a compound having the general formula (Id) in which U is an oxygen atom among the compounds having the general formula (I).
  • R 2 , R 3 , R 9 , R 10 , R 11 , R 12 , R 2a , R 3a , R 9a , R 10a , R 11a , R 12a , X and Y are the same as described above. Show significance.
  • Step C1 This step is a step of producing a compound having the general formula (XXIII).
  • This step comprises reacting the compound having the general formula (III) obtained in the above-mentioned Method A, Step A1 with a compound having the general formula (XXII) in a solvent in the presence of a base, thereby Performed in the same manner as in step B8.
  • Step C2 This step is a step of producing a compound having the general formula (XXIV).
  • This step is performed in the same manner as in Step A1 of Method A above by reacting a compound having the general formula (XXIII) with a demethylating agent in a solvent.
  • Step C3 This step is a step of producing a compound having the general formula (XXV).
  • This step is carried out in the same manner as in Step A4 of Method A above by reacting a compound having the general formula (XXIV) with bis (pinacolato) diboron in a solvent in the presence of a palladium catalyst and an inorganic base.
  • Step C4 This step is a step of producing a compound having the general formula (XXVII).
  • the compound having the general formula (XXV) is reacted with the compound having the general formula (XXVI) in the presence of a palladium catalyst and an inorganic base in a solvent in the same manner as in Step A6 of the above Method A. Done.
  • the compound having the general formula (XXVI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material.
  • Step C5 This step is a step of producing a compound having the general formula (XXVIII).
  • This step is performed in the same manner as in Step A7 of Method A above by reacting a compound having the general formula (XXVII) with an acid in a solvent.
  • Step C6 This step is a step of producing a compound having the general formula (XXIX).
  • This step is performed by reacting a compound having the general formula (XXVIII) with triisopropylsilyl chloride in a solvent in the presence of a base.
  • the solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
  • the base used in this step is preferably an organic base, and more preferably triethylamine or a mixed base of triethylamine and 4-dimethylaminopyridine.
  • the reaction temperature in this step is usually ⁇ 10 ° C. to 40 ° C., preferably 0 ° C. to 30 ° C.
  • the reaction time in this step is usually 0.1 hour to 72 hours, preferably 0.5 hour to 24 hours.
  • Step C7 This step is a step of producing a compound having the general formula (XXX).
  • This step is performed by reacting a compound having the general formula (XXIX) in a solvent in a hydrogen atmosphere in the presence of a palladium catalyst.
  • the solvent used in this step is preferably an ether, alcohol, ester or a mixed solvent thereof, more preferably tetrahydrofuran, methanol, ethanol, ethyl acetate or a mixed solvent of ethanol and ethyl acetate. It is.
  • the palladium catalyst used in this step is preferably a zero-valent palladium catalyst, and more preferably palladium-activated carbon.
  • the reaction temperature in this step is usually ⁇ 10 ° C. to 40 ° C., preferably 0 ° C. to 30 ° C.
  • the reaction time in this step is usually 0.1 hour to 72 hours, preferably 0.5 hour to 24 hours.
  • Step C8 This step is a step of producing a compound having the general formula (XXXI).
  • This step is performed by reacting a compound having the general formula (XXX) with a compound having the general formula (XIV) in a solvent in the presence of a condensing agent, in the presence or absence of a base. Performed in the same manner as in step A9.
  • Step C9 This step is a step of producing a compound having the general formula (XXXII).
  • This step comprises reacting the compound having the general formula (XXXI) with a base and methanesulfonic anhydride or bis (2-methoxyethyl) aminosulfur trifluoride in a solvent, The same is done.
  • Step C10 This step is a step of producing a compound having the general formula (XXXIII).
  • This step is performed by reacting a compound having the general formula (XXXII) with tetrabutylammonium fluoride in a solvent.
  • the solvent used in this step is preferably an ether, and more preferably tetrahydrofuran.
  • the reaction temperature in this step is usually ⁇ 10 ° C. to 40 ° C., preferably 0 ° C. to 30 ° C.
  • the reaction time in this step is usually 0.1 to 12 hours, preferably 0.5 to 3 hours.
  • Step C11 This step is a step of producing a compound having the general formula (Id).
  • This step is carried out in the same manner as in Step A2 of Method A above by reacting a compound having the general formula (XXXIII) with a compound having the general formula (IV) in the presence of a base in a solvent. If necessary, the amino group, hydroxy group and / or carboxyl group-protecting group in R 2a , R 3a , R 9a , R 10a , R 11a and R 12a is removed.
  • Method D is a method for producing a compound having the general formula (XIII) used in the above-mentioned Method A, Step A9.
  • R 2a , R 3a , X and Y have the same meaning as described above.
  • Step D1 This step is a step of producing a compound having the general formula (XXXIV).
  • This step is performed in (i) or (ii).
  • Step A3 is converted to the compound having the general formula (VIII). Is carried out in the same manner as in step A5 of the method A.
  • Step B8 of Method B above This step is carried out in the same manner as in Step B8 of Method B above by reacting a compound having the general formula (VI) with a compound having the general formula (XXII) in the presence of a base in a solvent. Is called.
  • Step D2 This step is a step of producing a compound having the general formula (XXXV).
  • a compound having the general formula (XXXIV) is converted into benzyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl in a solvent in the presence of a palladium catalyst and an inorganic base. ) -1H-pyrrole-2-carboxylate.
  • the solvent used in this step is preferably an ether, and more preferably dioxane.
  • the palladium catalyst used in this step is preferably a divalent palladium catalyst, more preferably [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex. .
  • the inorganic base used in this step is preferably an alkali metal carbonate, more preferably potassium carbonate, and even more preferably an aqueous potassium carbonate solution.
  • the reaction temperature in this step is usually 25 ° C to 100 ° C, preferably 40 ° C to 70 ° C.
  • the reaction time in this step is usually 0.5 to 12 hours, preferably 1 to 5 hours.
  • Step D3 This step is a step of producing a compound having the general formula (XIII).
  • This step is performed in the same manner as in Step C7 of Method C above by reacting a compound having the general formula (XXXV) in a solvent in a hydrogen atmosphere in the presence of a palladium catalyst.
  • Method E is a method for producing a compound having the general formula (XIII) used in the above-mentioned Method A, Step A9.
  • R 8 , R 2a , R 3a , X and Y have the same meaning as described above.
  • Step E1 This step is a step of producing a compound having the general formula (XXXVI).
  • This step comprises reacting a compound having the general formula (XXV) obtained in the above-mentioned Method C, Step C3 with a compound having the general formula (X) in a solvent in the presence of a palladium catalyst and an inorganic base. This is performed in the same manner as in step A6 of method A.
  • Step E2 This step is a step of producing a compound having the general formula (XXXVII).
  • This step is performed in the same manner as in Step A7 of Method A above by reacting a compound having the general formula (XXXVI) with an acid in a solvent.
  • Step E3 This step is a step of producing a compound having the general formula (XXXVIII).
  • This step is carried out in the same manner as in Step A2 of Method A above by reacting a compound having the general formula (XXXVII) with a compound having the general formula (IV) in the presence of a base in a solvent.
  • Step E4 This step is a step of producing a compound having the general formula (XIII).
  • This step is performed in the same manner as in Step A8 of Method A above by reacting a compound having the general formula (XXXVIII) with a base in a solvent.
  • Method F is a method for producing a compound having the general formula (XIII) used in the above-mentioned Method A, Step A9.
  • R 2a , R 3a and Y have the same meaning as described above.
  • Step F1 This step is a step of producing a compound having the general formula (XXXV).
  • Step C5 the compound having the general formula (XXVIII) obtained in the above-mentioned Method C, Step C5 is reacted with the compound having the general formula (IV) in a solvent in the presence of a base, thereby This is performed in the same manner as in step A2.
  • Step F2 This step is a step of producing a compound having the general formula (XIII).
  • This step is performed in the same manner as in Step C7 of Method C above by reacting a compound having the general formula (XXXV) in a solvent in a hydrogen atmosphere in the presence of a palladium catalyst.
  • Method G is a method for producing a compound having the general formula (XVIII) used in Method B, Step B4.
  • R 2a , X and Y are as defined above.
  • Step G1 This step is the step of producing compound (XXXIX).
  • This step comprises reacting the compound having the general formula (III) obtained in Step A1 Step A1 with bis (pinacolato) diboron in a solvent in the presence of a palladium catalyst and an inorganic base. This is performed in the same manner as in step A4.
  • Step G2 This step is a step of producing compound (XL).
  • This step is carried out in the same manner as in Step A6 of Method A above by reacting compound (XXXIX) with a compound having the general formula (XXVI) in the presence of a palladium catalyst and an inorganic base in a solvent.
  • Step G3 This step is a step of producing a compound having the general formula (XLI).
  • This step is performed in the same manner as in Step A2 of Method A above by reacting compound (XL) with a compound having the general formula (IV) in a solvent in the presence of a base.
  • Step G4 This step is a step of producing a compound having the general formula (XLII).
  • This step is performed in the same manner as in Step A7 of Method A above by reacting a compound having the general formula (XLI) with an acid in a solvent.
  • Step G5 This step is a step of producing a compound having the general formula (XVIII).
  • This step is performed in the same manner as in Step C7 of Method C above by reacting a compound having the general formula (XLII) in the presence of a palladium catalyst in a solvent under a hydrogen atmosphere.
  • Method H is a method for producing a compound having the general formula (XXVIII) used in Step C6 of Method C.
  • R 3a and X are as defined above.
  • Step H1 This step is a step of producing a compound having the general formula (XXVIII).
  • Step C2 in the presence of a palladium catalyst and an inorganic base in a solvent, the compound having the general formula (XXIV) obtained in the above-mentioned Method C, Step C2 is converted to benzyl 5- (4,4,5,5-tetramethyl-1, The reaction is carried out in the same manner as in Step D2 of Method D above by reacting with 3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate.
  • Method I is a method for producing a compound having the general formula (XXIV) used in the above-mentioned Method C, Step C3.
  • R 3a and X are as defined above.
  • Step I1 This step is a step of producing a compound having the general formula (XLIV).
  • the compound having the general formula (XLIII) is reacted with the compound having the general formula (IV) in the presence of triphenylphosphine and diethyl azodicarboxylate in a solvent, whereby the A5 of the above method A It is performed in the same manner as the process.
  • the compound having the general formula (XLIII) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
  • Step I2 This step is a step of producing a compound having the general formula (XXIV).
  • This step is performed by reacting a compound having the general formula (XLIV) with trimethyl borate in a solvent in the presence of a base, and further with acetic acid and an oxidizing agent.
  • the solvent used in this step is preferably an ether, and more preferably diethyl ether.
  • the base used in this step is preferably an organometallic base, and more preferably n-butyllithium.
  • the oxidizing agent used in this step is preferably an inorganic oxidizing agent, and more preferably 30% hydrogen peroxide solution.
  • the reaction temperature in this step is usually ⁇ 120 ° C. to 40 ° C., preferably ⁇ 78 ° C. to 25 ° C.
  • the reaction time in this step is usually 1 hour to 48 hours, preferably 6 hours to 24 hours.
  • Method J is a method for producing a compound having the general formula (Ie) in which U is a carbonyl group among the compounds having the general formula (I).
  • R 2 , R 3 , R 8 , R 9 , R 10 , R 11 , R 12 , R 2a , R 9a , R 10a , R 11a , R 12a , X and Y are the same as described above. Show significance.
  • Step J1 This step is a step of producing a compound having the general formula (XLVI).
  • This step is performed in the same manner as in Step A2 of Method A above by reacting a compound having the general formula (XLV) with a compound having the general formula (IV) in a solvent in the presence of a base.
  • the compound having the general formula (XLV) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
  • Step J2 This step is a step of producing a compound having the general formula (XLVIII).
  • This step is performed by reacting a compound having the general formula (XLVI) with a compound having trifluoromethanesulfonic anhydride (XLVII) in a solvent in the presence of a base.
  • the solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
  • the base used in this step is preferably an organic base, and more preferably pyridine.
  • the reaction temperature in this step is usually ⁇ 20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
  • the reaction time in this step is usually 0.5 to 12 hours, preferably 1 to 6 hours.
  • Step J3 This step is a step of producing a compound having the general formula (XLIX).
  • This step is carried out in the same manner as in Step A4 of Method A above by reacting a compound having the general formula (XLVIII) with bis (pinacolato) diboron in the presence of a palladium catalyst and an inorganic base in a solvent.
  • Step J4 This step is a step of producing a compound having the general formula (L).
  • the compound having the general formula (XLIX) is reacted with the compound having the general formula (XXVI) in the presence of a palladium catalyst and an inorganic base in a solvent in the same manner as in Step A6 of the above Method A. Done.
  • Step J5 This step is a step of producing a compound having the general formula (LI).
  • This step is performed in the same manner as in Step A7 of Method A above by reacting a compound having the general formula (L) with an acid in a solvent.
  • Step J6 This step is a step of producing a compound having the general formula (LII).
  • This step is performed in the same manner as in Step C7 of Method C above by reacting a compound having the general formula (LI) in a solvent in a hydrogen atmosphere in the presence of a palladium catalyst.
  • Step J7 This step is a step of producing a compound having the general formula (LIII).
  • This step is performed by reacting a compound having the general formula (LII) with a compound having the general formula (XIV) in a solvent in the presence of a condensing agent or in the presence or absence of a base. Performed in the same manner as in step A9.
  • Step J8 This step is a step of producing a compound having the general formula (LIV).
  • the compound having the general formula (LIII) is reacted with a base and methanesulfonic anhydride or bis (2-methoxyethyl) aminosulfur trifluoride in a solvent to obtain the step A10 of the above-mentioned method A; The same is done.
  • Step J9 This step is a step of producing a compound having the general formula (Ie).
  • R 8 O of the compound having the general formula (LIV) is converted to R 3a (R 3a is as defined above), and then R 2a , R 3a , R 9a as desired. , R 10a , R 11a and R 12a are carried out by removing the protective group for the amino group, hydroxy group and / or carboxyl group.
  • the L method described below is an example of the J9th step.
  • Method K is a method for producing a compound having the general formula (Ie) in which U is a carbonyl group among the compounds having the general formula (I).
  • R 2 , R 3 , R 9 , R 10 , R 11 , R 12 , R 2a , R 3a , R 9a , R 10a , R 11a , R 12a , X and Y are the same as described above. Show significance.
  • Step K1 This step is a step of producing a compound having the general formula (LVII).
  • This step is performed by reacting 3,5-dimethoxybenzaldehyde (LV) with a compound having the general formula (LVI) in a solvent.
  • the compound having the general formula (LVI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
  • the solvent used in this step is preferably an ether, and more preferably tetrahydrofuran.
  • the reaction temperature in this step is usually ⁇ 110 ° C. to 40 ° C., preferably ⁇ 80 ° C. to 25 ° C.
  • the reaction time in this step is usually 0.5 to 12 hours, preferably 1 to 6 hours.
  • Step K2 This step is a step of producing a compound having the general formula (LVIII).
  • This step is performed by reacting a compound having the general formula (LVII) with an oxidizing agent in a solvent.
  • the solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
  • the oxidizing agent used in this step is preferably an inorganic oxidizing agent, and more preferably manganese dioxide.
  • the reaction temperature in this step is usually 0 ° C. to 60 ° C., preferably 25 ° C. to 40 ° C.
  • the reaction time in this step is usually 6 hours to 72 hours, preferably 12 hours to 36 hours.
  • Step K3 This step is a step of producing a compound having the general formula (LIX).
  • This step is performed in the same manner as in Step A1 of Method A above by reacting a compound having the general formula (LVIII) with a demethylating agent in a solvent.
  • Step K4 This step is a step of producing a compound having the general formula (LX).
  • This step is performed in the same manner as in Step A2 of Method A above by reacting a compound having the general formula (LIX) with a compound having the general formula (IV) in a solvent in the presence of a base.
  • Step K5 This step is a step of producing a compound having the general formula (LXI).
  • This step is performed in the same manner as in Step A3 of Method A above by reacting a compound having the general formula (LX) with a demethylating agent in a solvent.
  • Step K6 This step is a step of producing a compound having the general formula (LXII).
  • Step K7 This step is a step of producing a compound having the general formula (LXIII).
  • This step is performed in the same manner as in Step A4 of Method A above by reacting a compound having the general formula (LXII) with bis (pinacolato) diboron in the presence of a palladium catalyst and an inorganic base in a solvent.
  • Step K8 This step is a step of producing a compound having the general formula (LXIV).
  • Step K9 This step is a step of producing a compound having the general formula (LXV).
  • This step is performed in the same manner as in Step A7 of Method A above by reacting a compound having the general formula (LXIV) with an acid in a solvent.
  • Step K10 This step is a step of producing a compound having the general formula (LXVI).
  • This step is performed in the same manner as in Step C7 of Method C above by reacting a compound having the general formula (LXV) in a solvent in a hydrogen atmosphere in the presence of a palladium catalyst.
  • Step K11 This step is a step of producing a compound having the general formula (LXVII).
  • This step comprises reacting a compound having the general formula (LXVI) with a compound having the general formula (XIV) in a solvent in the presence of a condensing agent, in the presence or absence of a base, Performed in the same manner as in step A9.
  • Step K12 This step is a step of producing a compound having the general formula (Ie).
  • the compound having the general formula (LXVII) is reacted with a base and methanesulfonic anhydride or bis (2-methoxyethyl) aminosulfur trifluoride in a solvent to obtain the step A10 of the above-mentioned method A; The same is done.
  • Method L is a method for producing a compound having the general formula (If) wherein U is a carbonyl group and R 3 is a group represented by the formula —NR 4 R 5 among the compounds having the general formula (I). It is.
  • R 2 , R 4 , R 5 , R 8 , R 9 , R 10 , R 11 , R 12 , R 2a , R 9a , R 10a , R 11a and R 12a are as defined above.
  • R 4a and R 5a each represents an amino group contained as a substituent in the groups of R 4 and R 5 which may be protected, and groups in the definition of the groups of R 4 and R 5. Similar groups are shown.
  • Step L1 This step is a step of producing a compound having the general formula (LXVIII).
  • This step is performed by reacting a compound having the general formula (LIV) obtained in the above-mentioned J method, step J8, with a base in a solvent.
  • the solvent used in this step is preferably ethers or alcohols, and more preferably tetrahydrofuran or ethanol.
  • the base used in this step is preferably an alkali metal hydroxide, more preferably sodium hydroxide or lithium hydroxide, and still more preferably an aqueous sodium hydroxide solution or hydroxide. Lithium aqueous solution.
  • the reaction temperature in this step is usually 0 ° C. to 100 ° C., preferably 25 ° C. to 70 ° C.
  • the reaction time in this step is usually 0.5 to 24 hours, preferably 1 to 12 hours.
  • Step L2 This step is a step of producing a compound having the general formula (If).
  • a compound having the general formula (LXVIII) is reacted with a compound having the general formula (LXIX) in a solvent in the presence of a condensing agent, in the presence or absence of a base, and then optionally R 2a , R 4a , R 5a , R 9a , R 10a , R 11a and R 12a are carried out by removing amino, hydroxy and / or carboxyl protecting groups.
  • the compound having the general formula (LXIX) used in this step is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material.
  • the solvent used in this step is preferably amides, alcohols or halogenated hydrocarbons, and more preferably N, N-dimethylformamide, methanol or dichloromethane.
  • the condensing agent used in this step is preferably WSCI ⁇ HCl, DMT-MM or HATU.
  • the base used in this step is preferably an organic base, and more preferably triethylamine, diisopropylethylamine or a combination of triethylamine and 4-dimethylaminopyridine.
  • the reaction temperature in this step is usually ⁇ 20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
  • the reaction time in this step is usually 1 hour to 72 hours, preferably 6 hours to 36 hours.
  • Method M is a method for producing a compound having the general formula (LI) used in the J method, J6 step.
  • R 8 and R 2a have the same meaning as described above.
  • Step M1 This step is a step of producing a compound having the general formula (LI).
  • Method N is a method for producing a compound having the general formula (X) used in Method A, Step A6, Method B, Step B2, and Method E, Step E1.
  • R 8 and X are as defined above.
  • Step N1 This step is a step of producing a compound having the general formula (LXXI).
  • This step is performed by reacting a compound having the general formula (LXX) with a halogenating agent in a solvent.
  • the compound having the general formula (LXX) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
  • the solvent used in this step is preferably ethers or a mixed solvent of ethers and alcohols, more preferably tetrahydrofuran or a mixed solvent of tetrahydrofuran and methanol.
  • the halogenating agent used in this step is, for example, an inorganic acid such as hydrochloric acid, hydrogen bromide or hydrogen iodide; a halogen molecule such as chlorine, bromine or iodine, or N-chlorosuccinimide, N-bromo.
  • Succinimides such as succinimide and N-iodosuccinimide, preferably succinimide, and more preferably N-bromosuccinimide.
  • the reaction temperature in this step is usually ⁇ 100 ° C. to 40 ° C., preferably ⁇ 78 ° C. to 25 ° C.
  • the reaction time in this step is usually 0.5 to 48 hours, preferably 1 to 24 hours.
  • Step N2 This step is a step of producing a compound having the general formula (X).
  • This step is performed by reacting a compound having the general formula (LXXI) with di-t-butyl dicarbonate in the presence of a base in a solvent.
  • the solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
  • the base used in this step is preferably an organic base, more preferably triethylamine, 4-dimethylaminopyridine, or a mixed base thereof, and still more preferably triethylamine and 4-dimethyl.
  • a mixed base of aminopyridine is preferably an organic base, more preferably triethylamine, 4-dimethylaminopyridine, or a mixed base thereof, and still more preferably triethylamine and 4-dimethyl.
  • the reaction temperature in this step is usually ⁇ 20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
  • the reaction time in this step is usually 0.1 to 12 hours, preferably 0.5 to 3 hours.
  • Method O is a method for producing a compound having the general formula (XXVI) used in Step C, Step C4, Method G, Step G2, Step J, Step J4 and Method K, Step K8.
  • X has the same meaning as described above.
  • Step O1 This step is a step of producing a compound having the general formula (LXXIII).
  • This step is carried out in the same manner as the Nth step of the N method by reacting pyrrole-1-carboxylate t-butyl (LXXII) with a halogenating agent in a solvent.
  • the pyrrole-1-carboxylic acid t-butyl (LXXII) used in this step is easily produced according to a known method or a similar method using a known compound as a starting material.
  • Step O2 This step is a step of producing a compound having the general formula (XXVI).
  • This step is performed by reacting a compound having the general formula (LXXIII) with a compound having the general formula (LXXIV) in a solvent in the presence of a base.
  • the compound having the general formula (LXXIV) used in this step is a known compound, or is easily produced according to a known method or a similar method using the known compound as a starting material.
  • the solvent used in this step is preferably an ether, and more preferably diethyl ether.
  • the base used in this step is preferably an organometallic base, and more preferably n-butyllithium.
  • the reaction temperature in this step is usually ⁇ 100 ° C. to 40 ° C., preferably ⁇ 78 ° C. to 25 ° C.
  • the reaction time in this step is usually 0.5 to 24 hours, preferably 1 to 12 hours.
  • Method P is benzyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl used in Method D, Step D2, Method H, Step H1 and Method M, Step M1. ) -1H-pyrrole-2-carboxylate (LXXVIII).
  • Y has the same meaning as described above.
  • Step P1 This step is a step for producing benzyl 1H-pyrrole-2-carboxylate (LXXVII).
  • This step is performed by reacting pyrrole-2-carboxylic acid (LXXV) with a compound having the general formula (LXXVI) in a solvent in the presence of a base.
  • the pyrrole-2-carboxylic acid (LXXV) used in this step is easily produced according to a known method or a similar method using a known compound as a starting material.
  • the compound having the general formula (LXXVI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
  • the solvent used in this step is preferably an amide, and more preferably N, N-dimethylformamide.
  • the base used in this step is preferably an alkali metal carbonate, and more preferably potassium carbonate.
  • the reaction temperature in this step is usually ⁇ 10 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
  • the reaction time in this step is usually 0.5 to 48 hours, preferably 1 to 24 hours.
  • Step P2 This step is a step for producing benzyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate (LXXVIII). .
  • benzyl 1H-pyrrole-2-carboxylate (LXXVII) is converted to bis (pinacolato) diboron in the presence of an iridium catalyst and 4,4′-di-t-butyl-2,2′-dipyridyl in a solvent. By reacting with.
  • the solvent used in this step is preferably a hydrocarbon, and more preferably hexane.
  • the iridium catalyst used in this step is preferably methoxy (cyclooctadiene) iridium (I) dimer.
  • the reaction temperature in this step is usually 0 ° C. to 70 ° C., preferably 25 ° C. to 60 ° C.
  • the reaction time in this step is usually 0.1 to 12 hours, preferably 0.5 to 6 hours.
  • Method Q is a method for producing a compound having the general formula (Id) in which U is an oxygen atom among the compounds having the general formula (I).
  • R 2 , R 3 , R 8 , R 9 , R 10 , R 11 , R 12 , R 2a , R 3a , R 9a , R 10a , R 11a , R 12a and Y are as described above. Shows the same significance.
  • Step Q1 This step is a step of producing a compound having the general formula (LXXX).
  • Step A8 in the presence of a condensing agent and a base in a solvent, the compound having the general formula (XIII) obtained in the above-mentioned Method A, Step A8 is reacted with a compound having the general formula (LXXIX), thereby This is carried out in the same manner as in step A9 of the law.
  • the compound having the general formula (LXXIX) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
  • Step Q2 This step is a step of producing a compound having the general formula (Id).
  • a compound having the general formula (LXXX) is reacted with a base in a solvent, and then optionally, an amino group, a hydroxy group, and R 2a , R 3a , R 9a , R 10a , R 11a and R 12a It is carried out by removing the protecting group of the carboxyl group.
  • the solvent used in this step is preferably an ether, and more preferably tetrahydrofuran.
  • the base used in this step is preferably an alkali metal hydride, and more preferably sodium hydride.
  • the reaction temperature in this step is usually ⁇ 20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
  • the reaction time in this step is usually 0.5 to 48 hours, preferably 1 to 24 hours.
  • Method R is a method for producing a compound having the general formula (LI) used in Method J, Step J6.
  • R 8 , R 2a and X are as defined above.
  • Step R1 This step is a step of producing a compound having the general formula (LXXXII).
  • a compound having the general formula (LXXXI) is converted into benzyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl in a solvent in the presence of a palladium catalyst and an inorganic base. ) By reacting with -1H-pyrrole-2-carboxylate, the reaction is performed in the same manner as in Step D2 of Method D above.
  • the compound having the general formula (LXXXI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
  • Step R2 This step is a step of producing a compound having the general formula (LI).
  • This step is performed by reacting a compound having the general formula (LXXXII) with a compound having the general formula (LXXXIII) in the presence of a copper catalyst, a base and molecular sieves 4A in a solvent.
  • the compound having the general formula (LXXXIII) used in this step is a known compound, or is easily produced according to a known method or a similar method using the known compound as a starting material.
  • the solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
  • the copper catalyst used in this step is preferably copper (II) acetate.
  • the base used in this step is preferably an organic base, and more preferably triethylamine.
  • the reaction temperature in this step is usually ⁇ 20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
  • the reaction time in this step is usually 12 hours to 360 hours, preferably 24 hours to 240 hours.
  • Method S is a method for producing a compound having the general formula (LXVI) used in Method K, Step K11.
  • R 2a and R 3a have the same meaning as described above.
  • Step S1 This step is a step of producing a compound having the general formula (LXXXIV).
  • Step K6 a compound having the general formula (LXII) obtained in Step K6, Step K6 in the presence of a palladium catalyst and an inorganic base in a solvent is converted to methyl 5- (4,4,5,5-tetramethyl-1, Performed by reacting with 3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate.
  • the solvent used in this step is preferably an ether, and more preferably dioxane.
  • the palladium catalyst used in this step is preferably a divalent palladium catalyst, more preferably [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex. .
  • the inorganic base used in this step is preferably an alkali metal carbonate, more preferably potassium carbonate, and even more preferably an aqueous potassium carbonate solution.
  • the reaction temperature in this step is usually 25 ° C to 100 ° C, preferably 40 ° C to 70 ° C.
  • the reaction time in this step is usually 0.5 to 12 hours, preferably 1 to 5 hours.
  • Step S2 This step is a step of producing a compound having the general formula (LXVI).
  • This step is performed by reacting a compound having the general formula (LXXXIV) with a base in a solvent.
  • the solvent used in this step is preferably ethers or a mixed solvent of ethers and alcohols, more preferably tetrahydrofuran or a mixed solvent of tetrahydrofuran and methanol.
  • the base used in this step is preferably an alkali metal hydroxide, more preferably lithium hydroxide, and even more preferably an aqueous lithium hydroxide solution.
  • the reaction temperature in this step is usually 0 ° C. to 100 ° C., preferably 25 ° C. to 70 ° C.
  • the reaction time in this step is usually 0.5 to 24 hours, preferably 1 to 12 hours.
  • Method T is a method for producing a compound having the general formula (LXXXIV) used in Step S2 of Method S.
  • R 2a , R 3a and X are as defined above.
  • Step T1 This step is a step of producing a compound having the general formula (LXXXVII).
  • This step is performed by reacting a compound having the general formula (LXXXV) with a compound having the general formula (LXXXVI) in the presence of a base in a solvent.
  • the compound having the general formula (LXXXV) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
  • the compound having the general formula (LXXXVI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
  • the solvent used in this step is preferably an amide, and more preferably N, N-dimethylformamide.
  • the base used in this step is preferably an alkali metal carbonate, and more preferably cesium carbonate.
  • the reaction temperature in this step is usually 60 ° C to 180 ° C, preferably 100 ° C to 150 ° C.
  • the reaction time in this step is usually 1 hour to 48 hours, preferably 12 hours to 36 hours.
  • Step T2 This step is a step of producing a compound having the general formula (LXXXIV).
  • Method U is a method for producing a compound having the general formula (LXXXIV) used in Step S2 of Method S.
  • R 2a , R 3a , X and Y have the same meaning as described above.
  • Step U1 This step is a step of producing a compound having the general formula (LXXXIX).
  • This step is performed by reacting a compound having the general formula (LXXXVIII) with acetic anhydride in the presence of an acid.
  • the compound having the general formula (LXXXVIII) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
  • Examples of the acid used in this step include hydrogen halides such as hydrogen chloride gas and hydrogen bromide gas; mineral acids such as sulfuric acid, hydrobromic acid and hydrochloric acid; acetic acid, formic acid and trifluoroacetic acid.
  • Carboxylic acids preferably mineral acids, and more preferably sulfuric acid.
  • the reaction temperature in this step is usually ⁇ 20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
  • the reaction time in this step is usually 0.1 to 12 hours, preferably 0.5 to 3 hours.
  • Step U2 This step is a step of producing a compound having the general formula (LXL).
  • This step is performed by reacting a compound having the general formula (LXXXIX) with a chlorinating agent.
  • the chlorinating agent used in this step is, for example, an inorganic acid such as hydrochloric acid; a halogen molecule such as chlorine; a phosphorus reagent such as phosphorus trichloride, phosphorus pentachloride, or phosphorus oxychloride; Oxalic acid chlorides; sulfinic acid reagents such as thionyl chloride; or sulfonic acid reagents such as sulfonyl chloride and toluenesulfonic acid chloride, preferably sulfinic acid reagents or oxalate chlorides More preferred is thionyl chloride or oxalyl chloride, and even more preferred is thionyl chloride.
  • an inorganic acid such as hydrochloric acid
  • a halogen molecule such as chlorine
  • a phosphorus reagent such as phosphorus trichloride, phosphorus pentachloride, or phosphorus oxy
  • the reaction temperature in this step is usually ⁇ 20 ° C. to 100 ° C., preferably 25 ° C. to 80 ° C.
  • the reaction time in this step is usually 0.1 to 12 hours, preferably 0.5 to 3 hours.
  • Step U3 This step is a step of producing a compound having the general formula (LXLII).
  • This step is performed by reacting a compound having the general formula (LXL) with a compound having the general formula (LXLI) in a solvent.
  • the compound having the general formula (LXLI) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.
  • the solvent used in this step is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
  • the reaction temperature in this step is usually ⁇ 20 ° C. to 40 ° C., preferably 0 ° C. to 25 ° C.
  • the reaction time in this step is usually 0.1 to 12 hours, preferably 0.5 to 6 hours.
  • Step U4 This step is a step of producing a compound having the general formula (LXLIII).
  • a compound having the general formula (LXLII) is converted into methyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl in a solvent in the presence of a palladium catalyst and an inorganic base. ) By reacting with -1H-pyrrole-2-carboxylate, the reaction is carried out in the same manner as in Step S1 of Method S.
  • Step U5 This step is a step of producing a compound having the general formula (LXXXIV).
  • This step is performed in the same manner as in Step A2 of Method A above by reacting a compound having the general formula (LXLIII) with a compound having the general formula (IV) in a solvent in the presence of a base.
  • R 2a , R 3a , R 4a , R 5a , R 9a , R 10a , R 11a and R 12a in the definition of “amino group which may be protected”, “hydroxy group which may be protected” and “
  • the protecting group of “optionally protected carboxyl group” means a protecting group that can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis, and is generally used in organic synthetic chemistry. Protecting groups are indicated (see, for example, TW Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)).
  • “protective group” of “optionally protected hydroxy group” in the definition of R 2a , R 3a , R 9a , R 10a , R 11a and R 12a is a hydroxy group used in the field of synthetic organic chemistry
  • the protecting group is not particularly limited, and examples thereof include a formyl group, the “C 2 -C 7 alkylcarbonyl group”, the “C 2 -C 7 halogenated alkylcarbonyl group”, and an alkoxyalkyl such as methoxyacetyl.
  • Alkylcarbonyl groups such as carbonyl groups, acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, unsaturated alkylcarbonyl groups such as (E) -2-methyl-2-butenoyl; benzoyl, ⁇ -naphthoyl, ⁇ -naphthoyl Arylcarbonyl groups such as 2-bromobenzoyl, 4-chloro Halogenated arylcarbonyl groups such as Nzoiru, 2,4,6-trimethylbenzoyl, 4-C 1 -C 6 alkylated ants such as toluoyl - ylcarbonyl group, C 1 -C 6 alkoxy such as 4-anisoyl Arylcarbonyl groups, 4-nitrobenzoyl, nitrated arylcarbonyl groups such as 2-nitrobenzoyl, C 2 -C 7 alkoxycarbonylated arylcarbon
  • “protective group” of “optionally protected carboxyl group” in the definition of R 2a , R 3a , R 9a , R 10a , R 11a and R 12a is a carboxyl group used in the field of synthetic organic chemistry
  • the protecting group is not particularly limited, but for example, the “C 1 -C 6 alkyl group”; the “C 2 -C 6 alkenyl group”; ethynyl, 1-propynyl, 2-propynyl, 1-methyl- A C 2 -C 6 alkynyl group such as 2-propynyl and 1-butynyl; the aforementioned “C 1 -C 6 halogenated alkyl group”; a C 1 -C 6 hydroxyalkyl group such as hydroxymethyl and 2-hydroxyethyl; (C 2 -C 7 alkylcarbonyl)-(C 1 -C 6 alkyl group) such as acetylmethyl; said “aralkyl group”; or
  • protecting group of “amino group which may be protected” in the definition of R 2a , R 3a , R 4a , R 5a , R 9a , R 10a , R 11a and R 12a is a field of synthetic organic chemistry.
  • alkylcarbonyl group preferably an alkylcarbonyl group, an arylcarbonyl group or an alkoxycarbonyl group, and more preferably an alkoxycarbonyl group .
  • the compound of the present invention or a pharmacologically acceptable salt thereof can be administered in various forms.
  • the administration form include oral administration by tablets, capsules, granules, emulsions, pills, powders, syrups (solutions), etc., or injections (intravenous, intramuscular, subcutaneous or intraperitoneal administration), Examples include parenteral administration such as instillation and suppository (rectal administration).
  • these various preparations are usually used in the pharmaceutical preparation technical field such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension agents, coating agents, etc. It can be formulated with the resulting adjuvant.
  • excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid; water, ethanol, propanol, simple syrup, glucose Solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc .; dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid Disintegrating agents such as esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose; disintegrating inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil; quaternary ammonium salts, sodium lauryl sulfate Moisturizers such as glycerin and starch; Adsorbents such as
  • the tablet which gave the normal coating for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, and a multilayer tablet.
  • excipients such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oil, kaolin, talc; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol; laminaran, Disintegrants such as agar can be used.
  • a carrier conventionally known in this field can be widely used as a carrier, and examples thereof include polyethylene glycol, cocoa butter, higher alcohol, esters of higher alcohol, gelatin, semi-synthetic glyceride and the like.
  • solutions, emulsions or suspensions When used as an injection, it can be used as a solution, emulsion or suspension. These solutions, emulsions or suspensions are preferably sterilized and isotonic with blood.
  • the solvent used in the production of these solutions, emulsions or suspensions is not particularly limited as long as it can be used as a medical diluent.
  • water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isoforms are used. Examples include stearyl alcohol and polyoxyethylene sorbitan fatty acid esters.
  • a sufficient amount of sodium chloride, glucose or glycerin may be included in the preparation to prepare an isotonic solution, and a normal solubilizing agent, buffer, soothing agent, etc. may be included. You may go out.
  • the above-mentioned preparation may contain a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and the like as required, and may further contain other medicines.
  • the amount of the active ingredient compound contained in the preparation is not particularly limited and is appropriately selected within a wide range, but is usually 0.5 to 70% by weight, preferably 1 to 30% by weight, based on the total composition.
  • the amount used varies depending on the symptoms, age, etc. of the patient (warm-blooded animal, particularly human), but in the case of oral administration, the upper limit is 2000 mg (preferably 100 mg) per day, and the lower limit is 0.1 mg ( Preferably 1 mg, more preferably 10 mg) is administered to adults 1 to 6 times per day depending on the symptoms.
  • Elution in the column chromatography of the examples was performed under observation by TLC (Thin Layer Chromatography).
  • TLC Thin Layer Chromatography
  • the TLC plate silica gel 60F 254 manufactured by Merck or the NH-TLC plate manufactured by Fuji Silysia Chemical Co. was used as the TLC plate, and the solvent used as the elution solvent in the column chromatography was used as the detection method.
  • a UV detector was adopted.
  • silica gel for the column silica gel SK-85 (230-400 mesh) manufactured by Merck or silica gel FL100B manufactured by Fuji Silysia Chemical Ltd. was used.
  • HATU O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate
  • WSCI.HCl 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
  • HOBT.H 2 O 1-hydroxybenzotriazole monohydrate
  • DMT-MM 4- (4,6-dimethoxy -1,3,5-triazin-2-yl) -4-methylmorpholinium chloride n hydrate.
  • 1 H-NMR nuclear magnetic resonance
  • MS Mass spectrometry
  • diethyl azodicarboxylate 50% toluene solution, 16.2 mL, 37.2 mmol
  • diethyl azodicarboxylate 50% toluene solution, 16.2 mL, 37.2 mmol
  • Water 300 mL
  • ethyl acetate 300 mL
  • the organic layer was washed with saturated brine and dried over sodium sulfate.
  • the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product (4.06 g, yield 99%) as a white solid.
  • WSCI ⁇ HCl (71 mg, 0.37 mmol) was added at room temperature, and the mixture was stirred under a nitrogen atmosphere for 2 hours.
  • the reaction mixture was diluted with methylene chloride (150 mL), washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate.
  • Example 2a The compound synthesized in Example (2a) (56 mg, 0.11 mmol) was dissolved in tetrahydrofuran (10 mL), sodium thiomethoxide (25 mg, 0.36 mmol) was added, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. A saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (30 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • Example 3 The compound synthesized in Example 3 (150 mg, 0.31 mmol) was dissolved in methylene chloride (5.0 mL), and m-chloroperbenzoic acid (about 65%, 170 mg, about 0.64 mmol) was added at 0 ° C. In addition, the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (10 mL) was added, and the mixture was extracted with methylene chloride (15 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • Example (6a) Using the compound (220 mg, 0.552 mmol) synthesized in Example (6a), ⁇ -bromo- ⁇ -butyrolactone (110 ⁇ L, 1.19 mmol), potassium carbonate (230 mg, 1.66 mmol), and Example (6b) The target product (175 mg, 66% yield) was obtained in the same manner as a white solid.
  • Tetrahydro-3-furanol 130 ⁇ L, 1.61 mmol
  • triphenylphosphine 410 mg, 1.56 mmol
  • diethyl azodicarboxylate 40% toluene solution, 720 ⁇ L, 1).
  • 58 mmol was added dropwise.
  • the compound synthesized in Example (6a) 250 mg, 0.627 mmol was dissolved in tetrahydrofuran (10 mL) and added to the reaction solution, followed by stirring at room temperature for 14 hours under a nitrogen atmosphere.
  • Example 14 The compound synthesized in Example 14 (72.5 mg, 0.154 mmol) was dissolved in methylene chloride (5 mL), and bis (2-methoxyethyl) aminosulfur trifluoride (70 ⁇ L, 0.534 mmol) at 0 ° C. Was added. After stirring at room temperature for 4 hours, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with methylene chloride (10 mL). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • reaction mixture was diluted with methylene chloride (100 mL), washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • Example (1a) 1-Bromo-3-ethoxy-5-methoxybenzene
  • the compound synthesized in Example (1a) (4.10 g, 20.2 mmol) was dissolved in N, N-dimethylformamide (100 mL), and iodoethane ( 2.43 mL, 30.4 mmol) and potassium carbonate (7.00 g, 50.6 mmol) were added, and the mixture was stirred at 60 ° C. for 25 hours under a nitrogen atmosphere.
  • the reaction mixture was cooled to room temperature, potassium carbonate was removed by celite filtration, 1N hydrochloric acid (100 mL) was added, and the mixture was extracted twice with diethyl ether (100 mL).
  • Example (17b) 3-Bromo-5-ethoxyphenol Using the compound synthesized in Example (17a) (4.75 g, 20.6 mmol) and sodium thiomethoxide (1.56 g, 22.3 mmol), Example (1a ) To give the target compound (4.19 g, 94% yield) as a white solid.
  • reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted 3 times with diethyl ether (50 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was dissolved in methylene chloride (30 mL), and trifluoroacetic acid (30 mL) was added dropwise. After stirring at room temperature for 1 hour in a nitrogen atmosphere, the solvent was distilled off under reduced pressure. The mixture was diluted with methylene chloride (50 mL), and a saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to separate the layers. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate.
  • Example (18c) 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -5- (2,2,2-trifluoroethoxy) phenol
  • Example (18b) Synthesized compound (3.57 g, 13.2 mmol), bis (pinacolato) diboron (5.02 g, 19.8 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex ( 540 mg, 0.661 mmol) and potassium acetate (6.48 g, 66.0 mmol) were used to obtain the target compound (4.11 g, yield 98%) as a white solid in the same manner as in Example (1d).
  • the reaction mixture was cooled to 0 ° C., and acetic acid (3.63 mL, 63.4 mmol) and 30% aqueous hydrogen peroxide (7.40 mL, 65.3 mmol) were added dropwise in this order. After stirring at room temperature for 21 hours, water (100 mL) was added to separate the layers. The organic layer was washed successively with a saturated aqueous sodium thiosulfate solution and saturated brine, and then dried over anhydrous magnesium sulfate.
  • the reaction mixture was diluted with ethyl acetate (60 mL), washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate.
  • the reaction mixture was diluted with ethyl acetate (50 mL), washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • the reaction mixture was diluted with ethyl acetate (20 mL), washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • the reaction mixture was diluted with ethyl acetate (20 mL), washed with saturated brine, and dried over anhydrous magnesium sulfate.
  • methylmagnesium iodide (3.0 mol / L tetrahydrofuran solution, 0.58 mL, 1.74 mmol) was added, and the mixture was returned to room temperature and stirred for 2 hours.
  • the reaction mixture was diluted with ethyl acetate (30 mL), washed with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous magnesium sulfate.
  • the organic layer was extracted with a separatory funnel previously cooled with ice, cooled to ⁇ 78 ° C., and a commercially available 40% methylamine / methanol solution (1.33 mL, 17.2 mmol) in methylene chloride (10 mL) was added. The temperature was raised to ° C and stirred for 2 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate.
  • the organic layer was extracted with a separatory funnel previously cooled with ice, cooled to ⁇ 78 ° C., and a commercial maze of azetidine hydrochloride (2.24 mg, 17.2 mmol) in methylene chloride (10 mL) was added. The temperature was raised and the mixture was stirred for 30 minutes. Water (30 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate.
  • the reaction mixture was diluted with ethyl acetate (100 mL), washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • Example (30b) The compound synthesized in Example (30b) (620 mg, 1.24 mmol) was dissolved in ethanol (12 mL), 2N aqueous sodium hydroxide solution (6.21 mL) was added, and the mixture was heated to reflux for 1 hour under a nitrogen atmosphere. The reaction solution was neutralized with 2N hydrochloric acid, and the solvent was distilled off under reduced pressure. Water (50 ml) was added and extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound (600 mg, yield 100%) as a white solid.
  • Example 31 Compound synthesized in Example 31 (156 mg, 0.32 mmol), dimethylamine hydrochloride (78 mg, 0.96 mmol), WSCI ⁇ HCl (123 mg, 0.64 mmol), 4-dimethylaminopyridine (118 mg, 0. 96 mmol) was used to obtain the target compound (111 mg, yield 67%) as a white solid in the same manner as in Example (1k).
  • the mixture was extracted with ethyl acetate (200 mL), and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • reaction mixture was diluted with methylene chloride (60 mL), washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate.

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Abstract

L'invention porte sur un composé ayant un excellent effet d'activation de la glucokinase ou sur un sel pharmacologiquement acceptable de celui-ci. De façon spécifique, l'invention porte sur un composé représenté par la formule générale (I) ou sur un sel pharmacologiguement acceptable de celui-ci (Dans la formule, les R1 peuvent être identiques ou différents et chacun représente un groupe alkyle en C1-C6, un groupe alkyle halogéné en C1-C6, un groupe alkyle en C1-C6 substitué par un ou deux groupes hydroxy ou similaires ; R2 représente un groupe phényle qui peut être mono- à penta-substitué indépendamment par un groupe choisi parmi le groupe substituant A ou un groupe pyridyle ou un groupe pyrazinyle qui peut être mono- à tri-substitué indépendamment par un groupe choisi parmi le groupe substituant A ; R3 représente un groupe alkyle qui peut être mono- à penta-substitué indépendamment par un groupe choisi parmi le groupe substituant B, ou similaire ; U représente un atome d'oxygène ou un groupe carbonyle ; n représente un entier de 0-3 ; le groupe substituant A comprend des atomes d'halogène, des groupes alcoxy en C1-C6, des groupes alkylcarbonyle en C2-C7, des groupes alkylcarbonyle halogénés en C2-C7, des groupes alcoxycarbonyle en C2-C7 et similaires ; et le groupe substituant B comprend des atomes d'halogène, des groupes alkylcarbonyle en C2-C7 ; des groupes alcoxycarbonyle en C2-C7, un groupe carbamoyle et similaires).
PCT/JP2010/050339 2009-01-16 2010-01-14 Nouveau dérivé de pyrrole 2,5-disubstitué WO2010082601A1 (fr)

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JPWO2012105574A1 (ja) * 2011-01-31 2014-07-03 国立大学法人 長崎大学 光学活性化合物又はその塩の製造方法

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CN108250193B (zh) * 2018-01-09 2021-05-28 江苏中邦制药有限公司 一锅法制备利伐沙班的方法

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WO2004076420A1 (fr) * 2003-02-26 2004-09-10 Banyu Pharmaceutical Co., Ltd. Derives d'heteroarylcarbamoylbenzene
WO2007031739A1 (fr) * 2005-09-16 2007-03-22 Astrazeneca Ab Composés hétérobicycliques utilisés comme activateurs de la glucokinase
JP2007523142A (ja) * 2004-02-18 2007-08-16 アストラゼネカ アクチボラグ ベンズアミド誘導体、およびグルコキナーゼ活性化物質としてのそれらの使用
WO2008136428A1 (fr) * 2007-04-27 2008-11-13 Takeda Pharmaceutical Company Limited Composé hétérocyclique à cinq chaînons à teneur en azote
WO2009099080A1 (fr) * 2008-02-06 2009-08-13 Daiichi Sankyo Company, Limited Nouveau dérivé de phénylpyrrole

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Publication number Priority date Publication date Assignee Title
WO2004076420A1 (fr) * 2003-02-26 2004-09-10 Banyu Pharmaceutical Co., Ltd. Derives d'heteroarylcarbamoylbenzene
JP2007523142A (ja) * 2004-02-18 2007-08-16 アストラゼネカ アクチボラグ ベンズアミド誘導体、およびグルコキナーゼ活性化物質としてのそれらの使用
WO2007031739A1 (fr) * 2005-09-16 2007-03-22 Astrazeneca Ab Composés hétérobicycliques utilisés comme activateurs de la glucokinase
WO2008136428A1 (fr) * 2007-04-27 2008-11-13 Takeda Pharmaceutical Company Limited Composé hétérocyclique à cinq chaînons à teneur en azote
WO2009099080A1 (fr) * 2008-02-06 2009-08-13 Daiichi Sankyo Company, Limited Nouveau dérivé de phénylpyrrole

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2012105574A1 (ja) * 2011-01-31 2014-07-03 国立大学法人 長崎大学 光学活性化合物又はその塩の製造方法
EP2671877A4 (fr) * 2011-01-31 2015-07-01 Univ Nagasaki Procédé de fabrication d'un composé optiquement actif ou d'un sel de celui-ci

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