WO2011036889A1 - Composé hétérocyclique - Google Patents

Composé hétérocyclique Download PDF

Info

Publication number
WO2011036889A1
WO2011036889A1 PCT/JP2010/005771 JP2010005771W WO2011036889A1 WO 2011036889 A1 WO2011036889 A1 WO 2011036889A1 JP 2010005771 W JP2010005771 W JP 2010005771W WO 2011036889 A1 WO2011036889 A1 WO 2011036889A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
ring
reaction
acid
Prior art date
Application number
PCT/JP2010/005771
Other languages
English (en)
Japanese (ja)
Inventor
和義 麻生
倫代 望月
正太郎 三浦
稔博 今枝
昌志 豊福
Original Assignee
武田薬品工業株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 武田薬品工業株式会社 filed Critical 武田薬品工業株式会社
Publication of WO2011036889A1 publication Critical patent/WO2011036889A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/24—Antidepressants
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a heterocyclic compound, in particular, a heterocyclic compound having an AMPA ( ⁇ -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor function enhancing action.
  • AMPA ⁇ -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
  • Glutamate is the most abundant excitatory neurotransmitter in the mammalian central nervous system. Glutamate has an important role in the regulation of cognition, mood, and motor function, and these processes become unstable in psychiatric and neurological disorders. Glutamate receptors are classified into ion channel receptors and G protein-coupled receptors, and the ion channel receptors are further ⁇ -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. N-methyl-D-aspartate (NMDA) receptor, kainic acid (KA) receptor.
  • NMDA N-methyl-D-aspartate
  • KA kainic acid
  • the AMPA receptor is a type of receptor for the excitatory neurotransmitter glutamate and was named based on the selective activation of AMPA by AMPA.
  • the AMPA receptor is composed of four subunits (GluR1, GluR2, GluR3, GluR4). There are homomeric receptors composed of homologous subunits and heteromeric receptors composed of heterogeneous subunits. It has been reported that the physiological properties of AMPA receptors vary depending on the subunits that comprise them.
  • Non-patent documents 1, 2, 3 The importance of AMPA receptors in brain physiology is well known, and compounds having an AMPA receptor function enhancing action are expected to be useful as preventive or therapeutic agents for mental disorders, neurodegenerative diseases, memory disorders, sleep disorders, etc. ing.
  • Non-Patent Documents 4 and 5 The importance of AMPA receptors in brain physiology is well known, and compounds having an AMPA receptor function enhancing action are expected to be useful as preventive or therapeutic agents for mental disorders, neurodegenerative diseases, memory disorders, sleep disorders, etc. ing.
  • Patent Document 1 discloses a general formula.
  • action represented by these is disclosed.
  • Patent Document 2 discloses a general formula.
  • the heterocyclic compound which has the AMPA receptor function enhancement effect represented by these is disclosed.
  • Patent Document 3 discloses a general formula.
  • the heterocyclic compound which has the AMPA receptor function enhancement effect represented by these is disclosed.
  • Patent Document 4 discloses a general formula.
  • the heterocyclic compound which has the AMPA receptor function enhancement effect represented by these is disclosed.
  • Patent Document 5 discloses a general formula.
  • the heterocyclic compound which has the AMPA receptor function enhancement effect represented by these is disclosed.
  • Patent Document 6 discloses a general formula.
  • the heterocyclic compound which has the AMPA receptor function enhancement effect represented by these is disclosed.
  • Patent Document 7 discloses a general formula.
  • the heterocyclic compound which has the AMPA receptor function enhancement effect represented by these is disclosed.
  • Patent Document 8 discloses a general formula.
  • the heterocyclic compound which has the AMPA receptor function enhancement effect represented by these is disclosed.
  • Patent Document 9 includes a general formula. (R 2 and X 3 may form a 5- to 7-membered ring)
  • the heterocyclic compound which has the AMPA receptor function enhancement effect represented by these is disclosed.
  • Patent Document 10 discloses a general formula.
  • the heterocyclic compound which has the AMPA receptor function enhancement effect represented by these is disclosed.
  • the present invention relates to a heterocyclic compound having an AMPA receptor function-enhancing action (AMPA receptor function potentiator (AMPA receptor receptor potentiator);
  • AMPA receptor function potentiator AMPA receptor receptor potentiator
  • the purpose is to provide positive allosteric modulator, positive allosteric activator of AMPA receptor).
  • the inventors of the present invention describe a compound represented by the following formula (I) or a salt thereof (sometimes referred to herein as compound (I)) and a compound represented by the following formula (I 0 ).
  • the salt thereof (sometimes referred to as compound (I 0 ) in the present specification) has been found to have an AMPA receptor function enhancing action, and as a result of further studies, the present invention has been completed.
  • Compound (I) is included within the range of compound (I 0 ).
  • R a represents a C 1-6 alkyl group which may be substituted with a halogen atom
  • X 0 represents —CH 2 —, —O—, or —NR b —
  • Y 0 represents —CR c R d — or —NH—
  • R b represents a hydrogen atom, a C 1-6 alkyl group, a C 1-6 alkyl-carbonyl group optionally substituted with a halogen atom, or a C 1-6 alkoxy-carbonyl group
  • R c and R d are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group
  • L 0 represents —CH (R e ) —W a —, or —W b —
  • R e represents a hydrogen atom or a C 1-6 alky
  • R 1 represents a methyl group which may be substituted with a halogen atom
  • X represents —O— or —NR 2 —
  • R 2 represents a hydrogen atom, a C 1-6 alkyl group, or a C 1-6 alkyl-carbonyl group which may be substituted with a halogen atom
  • L represents a bond, —CONH—, or —CONHCH 2 —
  • Each ring A may have a substituent, 1) a thiophene ring, 2) dihydrocyclopentathiophene ring, 3) tetrahydrobenzothiophene ring, 4) isoxazole ring, 5) pyrazole ring, 6) benzene ring, 7) pyridine ring, 8) Indole ring, 9) imidazopyridine ring, 10) Triazolopyridine ring, 11) benzotriazole ring, 12) benzo
  • R a represents a methyl group substituted with a halogen atom
  • R b represents a C 1-6 alkyl group
  • a 0 ring is (a) a halogen atom, (b) a C 1-6 alkyl group optionally substituted with a halogen atom or a hydroxy group, (c) a C 1-6 alkoxy group, (d) a C 1-6 alkoxy-carbonyl group, (e) a
  • R a represents a methyl group substituted with a halogen atom
  • X 0 represents —CH 2 — or —O—
  • Y 0 represents —CH 2 — or —NH—
  • R e represents a hydrogen atom
  • W a is 1) -CONH-, 2) 1,3,4-thiadiazolyl, 3) 1,2,4-oxadiazolyl, or 4) represents 1,3,4-oxadiazolyl
  • W b represents azetidinediyl
  • a 0 ring is (a) a halogen atom, (b) a C 1-6 alkyl group which may be substituted with a halogen atom, (c) a C 1-6 alkoxy group, and (d) substituted with 1 to 3 substituents selected from carbamoyl groups, 1) tetrahydrobenzothiophene ring, 2)
  • the medicament according to [14] above which is a prophylactic or therapeutic drug for depression, schizophrenia, or attention deficit hyperactivity disorder.
  • a method for enhancing AMPA receptor function comprising administering an effective amount of the compound according to [1] above or a salt thereof, or a prodrug thereof to a mammal.
  • a method for preventing or treating depression, schizophrenia, or attention deficit / hyperactivity disorder which comprises administering an effective amount of the compound or salt thereof, or prodrug thereof according to [1] to a mammal. Method.
  • [20] Use of the compound of the above-mentioned [1] or a salt thereof, or a prodrug thereof for the manufacture of a prophylactic or therapeutic agent for depression, schizophrenia, or attention deficit hyperactivity disorder.
  • R 1 represents a methyl group which may be substituted with a halogen atom
  • X represents —O— or —NR 2 —
  • R 2 represents a hydrogen atom, a C 1-6 alkyl group, or a C 1-6 alkyl-carbonyl group which may be substituted with a halogen atom
  • L represents a bond, —CONH—, or —CONHCH 2 —
  • Each ring A may have a substituent, 1) a thiophene ring, 2) dihydrocyclopentathiophene ring, 3) tetrahydrobenzothiophene ring, 4) isoxazole ring, 5) pyrazole ring, 6) benzene ring, 7) pyridine ring, 8) Indole ring, 9) imidazopyridine ring
  • ADHD attention deficit hyperactivity disorder
  • the hydrogen atom in the chemical structural formula may be omitted in accordance with the custom in the chemical field.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • the “optionally halogenated” or “halogeno” may include one or more (eg, 1 to 3) halogen atoms as a substituent. Means good.
  • examples of the “alkyl (group)” include C 1-6 alkyl (group).
  • examples of the “C 1-6 alkyl (group)” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, Neopentyl and hexyl are mentioned.
  • examples of the “C 1-6 alkyl (group)” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, And hexyl.
  • the “optionally halogenated C 1-6 alkyl (group)” means a C 1-6 alkyl (group) optionally substituted with a halogen atom. Specific examples thereof include trifluoromethyl.
  • examples of the “alkenyl (group)” include C 2-6 alkenyl (group).
  • examples of the “C 2-6 alkenyl (group)” include vinyl, 1-propen-1-yl, 2-propen-1-yl, isopropenyl, 2-butene. 1-yl, 4-penten-1-yl, and 5-hexen-1-yl.
  • examples of the “alkynyl (group)” include a C 2-6 alkynyl group.
  • Examples of “C 2-6 alkynyl (group)” include ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 4-pentyn-1-yl, and 5-hexyn-1-yl. Is mentioned.
  • examples of the “C 3-7 cycloalkyl-C 2-6 alkynyl (group)” include cypropyl ethynyl.
  • non-aromatic cyclic hydrocarbon group each may be condensed with one or more (preferably one or two) hydrocarbon rings.
  • hydrocarbon ring examples include the “non-aromatic hydrocarbon ring” and the “aromatic hydrocarbon ring”.
  • examples of the “C 3-7 cycloalkyl (group)” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • examples of the “C 3-6 cycloalkyl (group)” include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • examples of the “C 3-7 cycloalkenyl (group)” include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • examples of the “C 4-10 cycloalkadienyl (group)” include cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, cycloocta Dienyl, cyclononadienyl, and cyclodecadienyl are included.
  • the “aromatic cyclic hydrocarbon group” may be monocyclic, bicyclic, or tricyclic.
  • examples of the “aromatic cyclic hydrocarbon group” include C 6-14 aryl (group).
  • examples of the “C 6-14 aryl (group)” include phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, and 2 -Anthril.
  • examples of the “C 7-16 aralkyl (group)” include benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, Examples include 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 2-biphenylylmethyl, 3-biphenylylmethyl, and 4-biphenylylmethyl.
  • examples of the “C 6-14 aryl-C 2-6 alkenyl (group)” include styryl.
  • examples of the “C 1-7 alkylene (group)” include, for example, methylene, ethylene, trimethylene, tetramethylene, 2-butenylene, Examples include 2-methyltetramethylene, pentamethylene, and hexamethylene.
  • examples of the “C 2-7 alkylene (group)” include an alkylene (group) having 2 to 7 carbon atoms in the “C 1-7 alkylene (group)”.
  • Examples of the “C 1-3 alkylene (group)” include alkylene (group) having 1 to 3 carbon atoms in the “C 1-7 alkylene (group)”.
  • examples of the “C 2-6 alkenylene (group)” include —CH ⁇ CH—, —CH ⁇ C (CH 3 ) —, —C (CH 3 ) ⁇ CH. —, —CH ⁇ CH—CH 2 —, —CH 2 —CH ⁇ CH—, —C (CH 3 ) 2 —CH ⁇ CH—, —CH 2 —CH ⁇ CH—CH 2 —, —CH 2 —CH 2 —CH ⁇ CH—, —CH ⁇ CH—CH ⁇ CH—, —CH ⁇ CH—CH 2 —CH 2 —CH 2 —, —CH ⁇ C (C 2 H 5 ) —).
  • examples of the “C 2-3 alkenylene (group)” include, for example, the alkenylene (group) having 2 to 3 carbon atoms in the “C 1-6 alkenylene (group)”. Is mentioned.
  • examples of the “C 2-6 alkynylene (group)” include —C ⁇ C—, —CH 2 —C ⁇ C—, —CH 2 —C ⁇ C—CH. (CH 3 ) —, —CH 2 —C ⁇ C—CH 2 —CH 2 —.
  • the “heterocyclic group” (and the heterocyclic moiety in the substituent) is a non-aromatic heterocyclic group or an aromatic heterocyclic group (ie, a heteroaryl group). .
  • the “heterocyclic group” may be monocyclic, bicyclic, or tricyclic.
  • the “heterocyclic group” means, for example, a 3 to 14-membered heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. is there.
  • the “non-aromatic heterocyclic group” may be saturated or unsaturated.
  • examples of the “non-aromatic heterocyclic group” include a 3 to 14-membered non-aromatic heterocyclic group.
  • the “3- to 14-membered non-aromatic heterocyclic group” is selected from, for example, an oxygen atom, a sulfur atom and a nitrogen atom which may be condensed with a 5- or 6-membered ring. 3 to 6-membered non-aromatic heterocyclic group containing 1 to 4 heteroatoms.
  • examples of the “3- to 6-membered non-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom” include tetrahydrofuryl , Oxazolidinyl, imidazolinyl (eg, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), aziridinyl (eg, 1-aziridinyl, 2-aziridinyl), azetidinyl (eg, 1-azetidinyl, 2-azetidinyl), pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), piperidinyl (eg, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl), azepanyl (eg, 1-azepanyl, 2-azepanyl
  • examples of the “5- or 6-membered ring” include a hydrocarbon ring having 5 or 6 carbon atoms (eg, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, Benzene) and 5- or 6-membered heterocycles.
  • examples of the “5- or 6-membered heterocycle” include 5- or 6-membered “heterocycle”.
  • a 3- to 6-membered non-aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom fused with a 5- or 6-membered ring examples include 2,3-dihydro-1H-imidazo [1,2-a] benzoimidazol-1-yl.
  • aromatic heterocyclic group examples include a 5- or 6-membered monocyclic aromatic heterocyclic group and a 5- to 10-membered aromatic condensed heterocyclic group. Can be mentioned.
  • examples of the “5- or 6-membered monocyclic aromatic heterocyclic group” include pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl ( Examples, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), imidazolyl (eg, 1-imidazolyl, 2 -Imidazolyl, 4-imidazolyl), isoxazolyl (eg, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (eg, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isothiazolyl (eg, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), thiazolyl (eg, 3-iso
  • examples of the “5- to 10-membered aromatic condensed heterocyclic group” include isoindolyl (eg, 1-isoindolyl, 2-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5 -Isoindolyl, 6-isoindolyl, 7-isoindolyl), indolyl (eg, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), benzo [b] furanyl (Eg, 2-benzo [b] furanyl, 3-benzo [b] furanyl, 4-benzo [b] furanyl, 5-benzo [b] furanyl, 6-benzo [b] furanyl, 7-benzo [b] furanyl ), Benzo [c] furanyl (eg, 1-isoindolyl,
  • examples of the “alkoxy (group)” include C 1-6 alkoxy (group).
  • examples of the “C 1-6 alkoxy (group)” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, Neopentyloxy and hexyloxy are mentioned.
  • examples of the “C 3-7 cycloalkyloxy (group)” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.
  • examples of the “C 6-14 aryloxy (group)” include phenyloxy, 1-naphthyloxy, and 2-naphthyloxy.
  • examples of the “C 7-16 aralkyloxy (group)” include benzyloxy and phenethyloxy.
  • examples of the “alkyl-carbonyloxy (group)” include C 1-6 alkyl-carbonyloxy (group).
  • examples of the “C 1-6 alkyl-carbonyloxy (group)” include acetoxy and propionyloxy.
  • examples of the “alkoxy-carbonyloxy (group)” include C 1-6 alkoxy-carbonyloxy (group).
  • examples of the “C 1-6 alkoxy-carbonyl (group)” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, and tert-butoxycarbonyl.
  • examples of the “mono-alkyl-carbamoyloxy (group)” include mono-C 1-6 alkyl-carbamoyloxy (group).
  • examples of the “mono-C 1-6 alkyl-carbamoyloxy (group)” include methylcarbamoyloxy and ethylcarbamoyloxy.
  • examples of the “di-alkyl-carbamoyloxy (group)” include di-C 1-6 alkyl-carbamoyloxy (group).
  • examples of the “di-C 1-6 alkyl-carbamoyloxy (group)” include dimethylcarbamoyloxy and diethylcarbamoyloxy.
  • examples of the “C 6-14 aryl-carbonyloxy (group)” include benzoyloxy and naphthylcarbonyloxy.
  • examples of the “mono- or di-C 6-14 aryl-carbamoyloxy (group)” include phenylcarbamoyloxy and naphthylcarbamoyloxy.
  • heterocyclic-oxy (group) examples include those similar to the above-mentioned “heterocyclic group”.
  • heterocycle-oxy (group) specifically, for example, a 3 to 14-membered heterocycle-oxy (group) having 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom Is mentioned.
  • aromatic heterocyclic-oxy (group) examples include “aromatic heterocyclic group” as an example of the above-mentioned “heterocyclic group”. And the like.
  • aromatic heterocycle-oxy (group) specifically, for example, a 5- to 14-membered aromatic heterocycle having 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom— An oxy (group) is mentioned.
  • examples of the “C 1-6 alkylsulfonyloxy group” include methylsulfonyloxy and ethylsulfonyloxy.
  • examples of the “halogeno C 1-6 alkylsulfonyloxy group” include halogenomethylsulfonyloxy and halogenoethylsulfonyloxy.
  • examples of the “alkylsulfanyl (group)” include C 1-6 alkylsulfanyl (group).
  • examples of the “C 1-6 alkylsulfanyl (group)” include methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, sec-butylsulfanyl, and tert- Butylsulfanyl is mentioned.
  • examples of the “C 3-7 cycloalkylsulfanyl (group)” include cyclopropylsulfanyl, cyclobutylsulfanyl, cyclopentylsulfanyl, and cyclohexylsulfanyl.
  • examples of the “C 6-14 arylsulfanyl (group)” include phenylsulfanyl, 1-naphthylsulfanyl, and 2-naphthylsulfanyl.
  • examples of the “C 7-16 aralkylsulfanyl (group)” include benzylsulfanyl and phenethylsulfanyl.
  • heterocyclic moiety of “heterocycle-sulfanyl (group)” include those similar to the aforementioned “heterocyclic group”.
  • heterocycle-sulfanyl (group) specifically, for example, a 3 to 14-membered heterocycle-sulfanyl (group) having 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom Is mentioned.
  • examples of the “alkyl-carbonyl (group)” include C 1-6 alkyl-carbonyl.
  • examples of the “C 1-6 alkyl-carbonyl (group)” include acetyl, propionyl, and pivaloyl.
  • examples of the “C 3-7 cycloalkyl-carbonyl (group)” include cyclopropylcarbonyl, cyclopentylcarbonyl, and cyclohexylcarbonyl.
  • examples of the “C 6-14 aryl-carbonyl (group)” include benzoyl, 1-naphthoyl, and 2-naphthoyl.
  • examples of the “C 7-16 aralkyl-carbonyl (group)” include phenylacetyl and 3-phenylpropionyl.
  • heterocyclic moiety of “heterocycle-carbonyl (group)” include those similar to the above-mentioned “heterocyclic group”. Specific examples include a 3 to 14-membered heterocyclic-carbonyl (group) having 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom, and more specifically, for example, Picolinoyl, nicotinoyl, isonicotinoyl, 2-thenoyl, 3-thenoyl, 2-furoyl, 3-furoyl, 1-morpholinylcarbonyl, 4-thiomorpholinylcarbonyl, aziridin-1-ylcarbonyl, aziridin-2-ylcarbonyl Azetidin-1-ylcarbonyl, azetidin-2-ylcarbonyl, pyrrolidin-1-ylcarbonyl, pyrrolidin-2-ylcarbonyl, pyrrolidin-2-ylcarbonyl, pyrrol
  • examples of the “optionally esterified carboxy (group)” include carboxy, optionally substituted alkoxy-carbonyl, and optionally substituted C 6- 14 aryloxy-carbonyl, optionally substituted C 7-16 aralkyloxy-carbonyl, optionally substituted silyloxy-carbonyl (eg, TMS-O—CO—, TES—O—CO—, TBS—O) -CO-, TIPS-O-CO-, TBDPS-O-CO-) and the like.
  • examples of the “alkoxy-carbonyl (group)” include “C 1-6 alkoxy-carbonyl (group)”.
  • examples of the “C 1-6 alkoxy-carbonyl (group)” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and tert-butoxycarbonyl.
  • examples of the “C 6-14 aryloxy-carbonyl (group)” include phenoxycarbonyl.
  • examples of the “C 7-16 aralkyloxy-carbonyl (group)” include benzyloxycarbonyl and phenethyloxycarbonyl.
  • examples of the “alkylsulfonyl (group)” include C 1-6 alkylsulfonyl (group).
  • examples of the “C 1-6 alkylsulfonyl (group)” include methylsulfonyl and ethylsulfonyl.
  • examples of the “C 3-7 cycloalkylsulfonyl (group)” include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, and cyclohexylsulfonyl.
  • examples of the “C 6-14 arylsulfonyl (group)” include phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.
  • heterocyclic moiety of “heterocycle-sulfonyl (group)” include those similar to the above-mentioned “heterocyclic group”.
  • Specific examples of the “heterocycle-sulfonyl (group)” include, for example, a 3 to 14-membered heterocycle-sulfonyl (group) having 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. Is mentioned.
  • examples of the “alkylsulfinyl (group)” include C 1-6 alkylsulfinyl (group).
  • examples of the “C 1-6 alkylsulfinyl (group)” include methylsulfinyl and ethylsulfinyl.
  • examples of the “C 3-7 cycloalkylsulfinyl (group)” include cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, and cyclohexylsulfinyl.
  • examples of the “C 6-14 arylsulfinyl (group)” include phenylsulfinyl, 1-naphthylsulfinyl, and 2-naphthylsulfinyl.
  • heterocyclic-sulfinyl (group) examples include those similar to the above-mentioned “heterocyclic group”.
  • heterocycle-sulfinyl (group) specifically, for example, a 3 to 14-membered heterocycle-sulfinyl (group) having 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom Is mentioned.
  • examples of the “alkyl-carbamoyl (group)” include mono- or di-C 1-6 alkyl-carbamoyl (group).
  • examples of the “mono- or di-C 1-6 alkyl-carbamoyl (group)” include methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, and propylcarbamoyl.
  • examples of the “mono- or di-alkylamino (group)” include mono- or di-C 1-6 alkylamino (group).
  • examples of the “mono- or di-C 1-6 alkylamino (group)” include methylamino, ethylamino, propylamino, dimethylamino, and diethylamino. .
  • examples of the “alkyl-carbonylamino (group)” include C 1-6 alkyl-carbonylamino.
  • examples of the “C 1-6 alkyl-carbonylamino (group)” include acetylamino, propionylamino, and pivaloylamino.
  • heterocycle (group) of the “heterocycle-amino (group)”, for example, those similar to the “heterocycle group” described above are used.
  • ring-amino (group) examples include 2-pyridyl-amino.
  • heterocycle-carbonyl of the “heterocycle-carbonylamino (group)”, for example, those similar to the above-mentioned “heterocycle-carbonyl” are used.
  • heterocycle-carbonylamino (group) examples include pyridyl-carbonylamino.
  • heterocycle (group) of the “heterocycle-oxycarbonylamino (group)”, for example, those similar to the above-mentioned “heterocycle group” are used,
  • heterocycle-oxycarbonylamino (group) examples include 2-pyridyl-oxycarbonylamino.
  • heterocycle (group) of the “heterocycle-sulfonylamino (group)”, for example, the same “heterocycle group” as described above can be used.
  • heterocycle-sulfonylamino (group) examples include 2-pyridyl-sulfonylamino.
  • examples of the “alkoxy-carbonylamino (group)” include C 1-6 alkoxy-carbonylamino (group).
  • examples of the “C 1-6 alkoxy-carbonylamino (group)” include methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, and butoxycarbonylamino.
  • examples of the “alkylsulfonylamino (group)” include C 1-6 alkylsulfonylamino (group).
  • examples of the “C 1-6 alkylsulfonylamino (group)” include methylsulfonylamino and ethylsulfonylamino.
  • examples of the “mono- or di-C 3-7 cycloalkylamino (group)” include cyclopropylamino, cyclopentylamino, and cyclohexylamino.
  • examples of the “C 3-7 cycloalkyl-carbonylamino (group)” include cyclopropylcarbonylamino, cyclopentylcarbonylamino, and cyclohexylcarbonylamino.
  • examples of the “C 3-7 cycloalkyloxy-carbonylamino (group)” include cyclopropoxycarbonylamino, cyclopentyloxycarbonylamino, and cyclohexyloxycarbonylamino.
  • examples of the “C 3-7 cycloalkylsulfonylamino (group)” include cyclopropylsulfonylamino, cyclopentylsulfonylamino, and cyclohexylsulfonylamino.
  • examples of the “mono- or di-C 6-14 arylamino (group)” include phenylamino and diphenylamino.
  • examples of the “mono- or di-C 7-16 aralkylamino (group)” include benzylamino.
  • examples of the “C 6-14 aryl-carbonylamino (group)” include benzoylamino and naphthoylamino.
  • examples of the “C 6-14 arylsulfonylamino (group)” include phenylsulfonylamino, 2-naphthylsulfonylamino, and 1-naphthylsulfonylamino.
  • the substituent group A comprises the following substituents (1) to (52).
  • a sulfanyl (mercapto) group (27) an optionally substituted alkylsulfanyl group (28) an optionally substituted C 3-7 cycloalkylsulfanyl group (29) an optionally substituted C 6-14
  • Arylsulfanyl group (30) optionally substituted C 7-16 aralkylsulfanyl group (31) optionally substituted heterocyclic-sulfanyl group
  • a formyl group (33) an optionally substituted alkyl-carbonyl group (34) an optionally substituted C 3-7 cycloalkyl-carbonyl group (35) an optionally substituted C 6-14 aryl A carbonyl group (36) an optionally substituted C 7-16 aralkyl-carbonyl group (37) an optionally substituted heterocycle-carbonyl group
  • an optionally substituted alkylsulfonyl group (39) an optionally substituted C 3-7 cycloalkylsulfonyl group (40) an optionally substituted C 6-14 arylsulfonyl group (41)
  • Optionally substituted heterocyclic-sulfonyl group (42) optionally substituted alkylsulfinyl group (43) optionally substituted C 3-7 cycloalkylsulfinyl group (44) optionally substituted C 6- 14 arylsulfinyl group (45) optionally substituted heterocyclic-sulfinyl group (46) sulfo group
  • an optionally substituted amino group [eg, amino, An optionally substituted mono- or di-alkylamino group, An optionally substituted mono- or di-C 3-7 cycloalkylamino group, An optionally substituted mono- or di-C 6-14 arylamino group, An optionally substituted mono- or di-C 7-16 aralkylamino group, Optionally substituted heterocycle-amino group, An optionally substituted C 6-14 aryl-carbonylamino group, Formylamino group, Optionally substituted alkyl - carbonyl amino group (e.g., mono - (C 1-6 alkyl - carbonyl) - amino group), An optionally substituted C 3-7 cycloalkyl-carbonylamino group, Optionally substituted heterocycle-carbonylamino group, An optionally substituted alkoxy-carbonylamino group, Optionally substituted C 3-7 cycloalkyloxy-carbonylamino group, Optionally substituted hetero
  • substituent group B is composed of the following substituents (a) to (bb).
  • an optionally substituted C 6-14 aryl group [eg, halogen atom, hydroxy, cyano, amino, optionally halogenated C 1-6 alkyl, mono-, or di-C 1-6 Alkylamino, mono-, or di-C 6-14 arylamino, mono-, or di-C 7-16 aralkylamino, C 3-7 cycloalkyl, C 1-6 alkoxy, formyl, C 1-6 alkyl- Carbonyl, C 3-7 cycloalkyl-carbonyl, C 6-14 aryl-carbonyl, C 7-16 aralkyl-carbonyl, C 1-6 alkoxy-carbonyl, C 6-14 aryloxy-carbonyl, C 7-16 aralkyloxy - carbonyl, C 1-6 alkylsulfanyl, C 1-6 alkylsulfinyl, C 1-6 alkyl sulfonyl , Carbamoyl, thiocarbam
  • an optionally substituted C 6-14 aryloxy group [eg, halogen atom, hydroxy, cyano, amino, optionally halogenated C 1-6 alkyl, mono-, or di-C 1- 6 alkylamino, mono-, or di-C 6-14 arylamino, mono-, or di-C 7-16 aralkylamino, C 3-7 cycloalkyl, C 1-6 alkoxy, formyl, C 1-6 alkyl -Carbonyl, C 3-7 cycloalkyl-carbonyl, C 6-14 aryl-carbonyl, C 7-16 aralkyl-carbonyl, C 1-6 alkoxy-carbonyl, C 6-14 aryloxy-carbonyl, C 7-16 aralkyl oxy - carbonyl, C 1-6 alkylsulfanyl, C 1-6 alkylsulfinyl, C 1-6 Arukirusu Honiru, carbamoyl, thiocarb
  • an optionally substituted C 7-16 aralkyloxy group [eg, halogen atom, hydroxy, cyano, amino, optionally halogenated C 1-6 alkyl, mono-, or di-C 1- 6 alkylamino, mono-, or di-C 6-14 arylamino, mono-, or di-C 7-16 aralkylamino, C 3-7 cycloalkyl, C 1-6 alkoxy, formyl, C 1-6 alkyl -Carbonyl, C 3-7 cycloalkyl-carbonyl, C 6-14 aryl-carbonyl, C 7-16 aralkyl-carbonyl, C 1-6 alkoxy-carbonyl, C 6-14 aryloxy-carbonyl, C 7-16 aralkyl oxy - carbonyl, C 1-6 alkylsulfanyl, C 1-6 alkylsulfinyl, C 1-6 alkyl Ruhoniru, carbamoyl, thio
  • an optionally substituted amino group [eg, optionally substituted C 1-6 alkyl, C 2-6 alkenyl, C 6-14 aryl, C 7-16 aralkyl, heterocyclic group, and Heterocycle-amino group optionally substituted with one or two substituents selected from the group consisting of alkyl (the “optionally substituted C 1-6 alkyl, C 2-6 alkenyl, C Examples of the substituent of “ 6-14 aryl, C 7-16 aralkyl, heterocyclic group, and heterocyclic-alkyl” include, for example, a halogen atom, hydroxy, cyano, amino, optionally halogenated C 1-6 alkyl (wherein the alkyl, and not the alkenyl substituent), a mono - or di -C 1-6 alkylamino, mono - or di -C 6-14 arylamino, Roh -, or di -C 7-16 aralkylamino, C 3-7 cyclo
  • the number of the substituents is 1 or more (for example, 1 to 5), wherein “heterocyclic group”, and “Heterocycle-" of “heterocycle-alkyl” includes the same as the above-mentioned “heterocycle group”)]
  • (K) an optionally substituted C 1-6 alkoxy group [eg, halogen atom, hydroxy, amino, mono-, or di-C 1-6 alkylamino, mono-, or di-C 6-14 arylamino C 3-7 cycloalkyl, C 1-6 alkoxy, formyl, C 1-6 alkyl-carbonyl, C 3-7 cycloalkyl-carbonyl, C 6-14 aryl-carbonyl, C 7-16 aralkyl-carbonyl, C 1-6 alkoxy - carbonyl, C 6-14 aryloxy - carbonyl, C 7-16 aralkyloxy - carbonyl, C 1-6 alkylsulfanyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamoyl, thiocarbamoyl Mono- or di-C 1-6 alkyl-carbamoyl, and mono- Or a C 1-6 alkoxy group
  • (L) formyl group (m) C 1-6 alkyl - carbonyl group (e.g., acetyl, etc.) (N) C 3-7 cycloalkyl-carbonyl group (o) C 6-14 aryl-carbonyl group (p) C 7-16 aralkyl-carbonyl group (q) C 1-6 alkoxy-carbonyl group (r) C 6 -14 aryloxy-carbonyl group (s) C 7-16 aralkyloxy-carbonyl group
  • substituent group B ′ comprises the following substituents (a) to (c).
  • an optionally substituted C 2-6 alkenyl group [eg, halogen atom, hydroxy, cyano, amino, mono-, or di-C 1-6 alkylamino, mono-, or di-C 6-14 Arylamino, mono- or di-C 7-16 aralkylamino, C 3-7 cycloalkyl, C 1-6 alkoxy, formyl, C 1-6 alkyl-carbonyl, C 3-7 cycloalkyl-carbonyl, C 6 -14 aryl-carbonyl, C 7-16 aralkyl-carbonyl, C 1-6 alkoxy-carbonyl, C 6-14 aryloxy-carbonyl, C 7-16 aralkyloxy-carbonyl, C 1-6 alkylsulfanyl, C 1- 6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono-, or Or substituted with one or more (
  • R a represents a C 1-6 alkyl group which may be substituted with a halogen atom.
  • the number of the halogen atoms is preferably 0 (that is, unsubstituted) or 1 to 3.
  • R a is preferably, for example, a methyl group substituted with a halogen atom (the number of the halogen atoms is preferably 1 to 3), particularly preferably, for example, trifluoromethyl.
  • X 0 represents —CH 2 —, —O—, or —NR b —.
  • R b is a hydrogen atom, a C 1-6 alkyl group, or a C 1-6 alkyl-carbonyl group optionally substituted with a halogen atom (the number of the halogen atoms is preferably 1 to 3). Or a C 1-6 alkoxy-carbonyl group.
  • R b is preferably, for example, a C 1-6 alkyl group.
  • X 0 is more preferably, for example, —CH 2 — or —O—.
  • Y 0 represents —CR c R d — or —NH—.
  • R c and R d are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group.
  • Y 0 is preferably, for example, —CH 2 — or —NH—.
  • Ring D 0 represents a heterocyclic ring which may be further substituted and contains one hetero atom selected from an oxygen atom and a nitrogen atom as a ring constituent atom.
  • the heterocycle is a 5- to 6-membered ring, and preferably a 6-membered ring, for example. That is, m is 0 or 1, and is preferably 1, for example.
  • the “heterocycle containing one heteroatom selected from an oxygen atom and a nitrogen atom as a ring constituent atom” is preferably, for example, It is.
  • substituents other than R d include, for example, substituents selected from the substituent group A.
  • the substituent is preferably, for example, a C 1-6 alkyl group, and more preferably, for example, a methyl group.
  • the number of the substituents is 0 (that is, unsubstituted), or 1 to the maximum number that can be substituted, and is preferably 0, 1, or 2, for example.
  • Partial structure of formula (I 0 ) The portion represented by is preferably, for example, (In the formula, R X represents a hydrogen atom, a hydroxy group, or an oxo group, X 0 and Y 0 have the same meaning as described above, and the ring D 1 is selected from an oxygen atom and a nitrogen atom as ring-constituting atoms. A heterocyclic ring containing one hetero atom. It is a part (moiety) represented by.
  • L 0 represents a bond, —CH (R e ) —W a —, or —W b —.
  • the partial structural formula: —CH (R e ) —W a — is described in the direction from the pyrazole ring to the A 0 ring in the formula (I 0 ).
  • R e represents a hydrogen atom or a C 1-6 alkyl group.
  • R e is preferably, for example, a hydrogen atom or methyl.
  • R e is more preferably a hydrogen atom, for example.
  • the “phenylene” in the above 11) is preferably, for example, ,and Is mentioned.
  • the “thiophenediyl” in the above 12) is, for example, Is mentioned.
  • the “1,3,4-thiadiazolediyl” in the above 13) preferably, for example, Is mentioned.
  • the “1,2,4-oxadiazolediyl” in the above 14) for example, ,and Is mentioned.
  • the partial structural formulas of these divalent groups are described in the direction from the pyrazole ring to the A 0 ring in the formula (I 0 ).
  • W a is more preferably, for example, 1) -CONH-, 2) 1,3,4-thiadiazolediyl, 3) 1,2,4-oxadiazoldiyl, or 4) 1,3,4-oxadiazolediyl.
  • W b is 1) piperidine diyl, 2) pyrrolidine diyl, or 3) Indicates azetidinediyl.
  • piperidinediyl in the above 1), for example, Is mentioned.
  • pyrrolidinediyl in the above 2), for example, Is mentioned.
  • azetidine diyl in the above 3
  • the partial structural formulas of these divalent groups are described in the direction from the pyrazole ring to the A 0 ring in the formula (I 0 ).
  • W b is preferably, for example, azetidine diyl, and more preferably, for example, It is.
  • Each A 0 ring may have a substituent, 1) a thiophene ring, 2) dihydrocyclopentathiophene ring, 3) tetrahydrobenzothiophene ring, 4) isoxazole ring, 5) pyrazole ring, 6) benzene ring, 7) pyridine ring, 8) Indole ring, 9) imidazopyridine ring, 10) Triazolopyridine ring, 11) benzotriazole ring, 12) benzothiazole ring, 13) Thienopyrimidone ring, 14) pyrazolopyrimidine ring, or 15) Indicates an imidazopyrimidine ring.
  • skeleton portion excluding the substituent in the A 0 ring include the following.
  • the A 0 ring is more preferably, for example, each may have a substituent. 1) tetrahydrobenzothiophene ring, 2) benzene ring, 3) imidazopyridine ring, 4) Triazolopyridine ring, 5) pyrazolopyrimidine ring, or 6) Imidazopyrimidine ring.
  • Examples of the substituent in the A 0 ring include a substituent selected from the substituent group A.
  • a halogen atom for example, (i) a halogen atom, (ii) a cyano group, (iii) a hydroxy group, (iv) a nitro group, (v) formyl group, (vi) an amino group, (vii) mono- or di-C 1-6 alkylamino group (eg methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino), (viii) a C 1-6 alkyl-carbonylamino group (eg acetylamino, ethylcarbonylamino), (ix) a C 1-6 alkoxy-carbonylamino group (eg, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino), , (x) (a) a halogen atom, and (b) a C 3-8 cycloalky
  • C 1-6 alkoxy group e.g. methoxy
  • C 3-6 cycloalkyl It may be substituted with one or more (preferably 1 to 3) substituents selected from alkyl (eg, cyclopropyl) and may be condensed with a benzene ring (eg, benzothienyl).
  • a halogen atom preferably a fluorine atom, a chlorine atom, a bromine atom
  • a halogen atom preferably a fluorine atom, a chlorine atom, a bromine atom
  • a halogen atom preferably a fluorine atom, a chlorine atom, a bromine atom
  • a substituent C 3-8 cycloalkyl group e.g.
  • substituent in the A 0 ring for example, (a) a halogen atom, (b) a C 1-6 alkyl group optionally substituted with a halogen atom or a hydroxy group, (c) a C 1-6 alkoxy group, (d) a C 1-6 alkoxy-carbonyl group, (e) a pyrrolidinyl-carbonyl group, and (f) a carbamoyl group and the like.
  • Particularly preferred substituents in the A 0 ring include, for example, (a) a halogen atom, (b) a C 1-6 alkyl group which may be substituted with a halogen atom, (c) a C 1-6 alkoxy group, and (d) Carbamoyl group and the like can be mentioned.
  • one or more (preferably 1 to 3) of such substituents may be present at substitutable positions.
  • the A 0 ring is preferably, for example, (a) a halogen atom, (b) a C 1-6 alkyl group optionally substituted with a halogen atom or a hydroxy group, (c) a C 1-6 alkoxy group, (d) a C 1-6 alkoxy-carbonyl group, (e) a pyrrolidinyl-carbonyl group, and (f) each substituted with 1 to 3 substituents selected from carbamoyl groups, 1) a thiophene ring, 2) dihydrocyclopentathiophene ring, 3) tetrahydrobenzothiophene ring, 4) isoxazole ring, 5) pyrazole ring, 6) benzene ring, 7) pyridine ring, 8) Indole ring, 9) imidazopyridine ring, 10) Triazolopyridine ring, 11) benzotriazole ring, 12) benzothiazole ring, 13
  • a 0 ring is more preferably, for example, A 0 ring is (a) a halogen atom, (b) a C 1-6 alkyl group which may be substituted with a halogen atom, (c) a C 1-6 alkoxy group, and (d) substituted with 1 to 3 substituents selected from carbamoyl groups, 1) tetrahydrobenzothiophene ring, 2) benzene ring, 3) imidazopyridine ring, 4) Triazolopyridine ring, 5) pyrazolopyrimidine ring, or 6) Imidazopyrimidine ring.
  • R a is a methyl group substituted with a halogen atom
  • X 0 is —CH 2 — or —O—
  • Y 0 is —CH 2 — or —NH—
  • R e is a hydrogen atom
  • W a is 1) -CONH-, 2) 1,3,4-thiadiazolyl, 3) 1,2,4-oxadiazolyl, or 4) 1,3,4-oxadiazolyl
  • W b is azetidine diyl
  • a 0 ring is (a) a halogen atom, (b) a C 1-6 alkyl group which may be substituted with a halogen atom, (c) a C 1-6 alkoxy group, and (d) substituted with 1 to 3 substituents selected from carbamoyl groups, 1) tetrahydrobenzothiophene ring, 2) benzene ring, 3) imidazopyridine ring, 4) Tri
  • Example 29 2-( ⁇ [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] acetyl ⁇ amino) -4,5,6, 7-tetrahydro-1-benzothiophene-3-carboxamide or a salt thereof.
  • Example 79 1-( ⁇ 3- [5-Methyl-7- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-3-yl] -1,2,4-oxadiazole-5- Yl ⁇ methyl) -3- (trifluoromethyl) -1,4,5,6-tetrahydropyrano [2,3-c] pyrazole, or a salt thereof.
  • Example 96 1- ⁇ 1- [3-Methyl-6- (trifluoromethyl) [1,2,4] triazolo [4,3-a] pyridin-8-yl] azetidin-3-yl ⁇ - 3- (trifluoromethyl) -1,4,5,6-tetrahydropyrano [2,3-c] pyrazole, or a salt thereof.
  • Example 101 3- (Trifluoromethyl) -1-( ⁇ 3- [6- (trifluoromethyl) imidazo [1,2-a] pyridin-8-yl] -1,2,4-oxadi (Azol-5-yl ⁇ methyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine, or a salt thereof.
  • Example 78 1-( ⁇ 3- [3-Methyl-6- (trifluoromethyl) [1,2,4] triazolo [4,3-a] pyridin-8-yl] -1,2,4 -Oxadiazol-5-yl ⁇ methyl) -3- (trifluoromethyl) -1,4,5,6-tetrahydropyrano [2,3-c] pyrazole, or a salt thereof.
  • R 1 represents a methyl group which may be substituted with a halogen atom.
  • the number of the halogen atoms is preferably 0 (that is, unsubstituted) or 1 to 3.
  • R 1 is preferably, for example, trifluoromethyl.
  • X represents —O— or —NR 2 —.
  • R 2 is a hydrogen atom, C 1-6 alkyl group (preferably, methyl), or one or more (preferably 1 to 3) halogen atoms (preferably fluorine) may be substituted by C 1 A -6 alkyl-carbonyl group (preferably acetyl, trifluoroacetyl);
  • X is preferably, for example, -O-.
  • L represents a bond, —CONH—, or —CONHCH 2 —.
  • the A ring is linked to the nitrogen atom shown in Formula (I) via methylene.
  • L is preferably, for example, -CONH-.
  • Each ring A may have a substituent, 1) a thiophene ring, 2) dihydrocyclopentathiophene ring, 3) tetrahydrobenzothiophene ring, 4) isoxazole ring, 5) pyrazole ring, 6) benzene ring, 7) pyridine ring, 8) Indole ring, 9) imidazopyridine ring, 10) Triazolopyridine ring, 11) benzotriazole ring, 12) benzothiazole ring, or 13) Indicates a thienopyrimidone ring.
  • the A ring is preferably, for example, an imidazopyridine ring, a triazolopyridine ring, a tetrahydrobenzothiophene ring, or a benzene ring.
  • skeleton portion excluding the substituent in the A ring include the following.
  • Examples of the substituent in the A ring include the same groups as those exemplified as the “preferable substituent in the A 0 ring”.
  • substituent in the A ring among them, for example, the same groups as the substituents exemplified as “a more preferable substituent in the A 0 ring” are preferable.
  • the A ring may have one or more (preferably 1 to 3) such substituents at substitutable positions.
  • Compound (I) is preferably, for example, R 1 is trifluoromethyl; X is —O— or —NR 2 —; R 2 is a hydrogen atom, C 1-6 alkyl group (preferably, methyl), or one or more (preferably 1 to 3) halogen atoms (preferably fluorine) may be substituted by C 1 A -6 alkyl-carbonyl group (preferably acetyl, trifluoroacetyl); L is a bond, —CONH—, or —CONHCH 2 —; Each A ring is (i) a halogen atom (preferably a fluorine atom, a chlorine atom, a bromine atom), (ii) a C 3-8 cycloalkyl group (preferably cyclopropyl, cyclobutyl), (iii) a C 6-14 aryl group (preferably phenyl) optionally substituted with one or more (preferably 1 to 3) halogen atoms, (iv)
  • salts with inorganic bases include salts with organic bases, salts with inorganic acids, salts with organic acids, bases And salts with acidic or acidic amino acids.
  • the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt and the like.
  • the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Preferable examples of the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- Examples thereof include salts with toluenesulfonic acid and the like.
  • Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like.
  • Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • a Compound (I) is Compound (Ia): In the formula (wherein n represents an integer of 0 or 1 and other symbols are as defined above), the compound (I) is, for example, Compound (II): (Wherein each symbol is as defined above) and compound (III): (Each symbol in the formula is as defined above) can be reacted.
  • A-1) A method of condensing compound (II) and compound (III) with a generally known dehydration condensing agent;
  • A-2) A method of reacting compound (III) after activating the carboxyl group of compound (II) by a generally known activation method; Etc.
  • Step A-1 Compound (Ia) can be produced by condensing compound (II) and compound (III) with a generally known dehydration condensation agent.
  • the dehydrating condensing agent used in this reaction include N, N-dicyclohexylamide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) or its hydrochloride, carbonyldiimidazole, 1H-benzoic acid.
  • Triazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) ), Bromotripyrrolidinophosphonium hexafluorophosphate (PyBrop), diethyl phosphorocyanidate (diethyl cyanophosphate; DEPC), diphenylphosphoryl azide (diphenyl phosphate azide; DPPA), 4- (4,6-dimethoxy [1, , 5] triazin-2-yl) -4-methyl morpholinium chloride (DMTMM), or the like.
  • BOP Triazol-1-yloxytris
  • HATU O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate
  • This reaction may be carried out as necessary, for example, with a base such as 1-hydroxybenzotriazole (HOBt), N, N-diisopropylethylamine, N-methylmorpholine, triethylamine, 4- (N, N-dimethylamino) pyridine and the like. You may carry out in presence.
  • a base such as 1-hydroxybenzotriazole (HOBt), N, N-diisopropylethylamine, N-methylmorpholine, triethylamine, 4- (N, N-dimethylamino) pyridine and the like. You may carry out in presence.
  • This reaction is preferably carried out in a known solvent, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate Hydrocarbons such as cyclohexane and n-hexane; aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane; alcohols such as methanol and ethanol; water, etc.
  • solvents for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate Hydrocarbons such as cyclohexane and n-hexane; aromatic
  • compound (III) is preferably used in an amount of usually about 0.5 to about 10 mol, preferably about 1 to about 5 mol, relative to 1 mol of compound (II).
  • about 0.1 to about 100 equivalents, preferably about 1 to about 5 equivalents the base is used with about 0.1 to about 100 equivalents, preferably about 1 to about 5 equivalents.
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Step A-2 Compound (Ia) can also be produced by reacting compound (III) after activating the carboxyl group of compound (II) by a generally known activation method.
  • a method for activating the carboxyl group of compound (II) a general method is adopted, for example, mixed acid anhydride using chloroformate, pivaloyl chloride, 2,4,6-trichlorobenzoyl chloride and the like.
  • a typical example is a method of acid halide, and as acid halide, Compound (IIa): (Wherein Xa represents a halogen atom, and other symbols are as defined above)
  • a halogenating agent such as thionyl chloride or oxalyl chloride.
  • N, N-dimethylformamide may be added as an additive.
  • This reaction is preferably performed in a known solvent, for example, halogenated hydrocarbons such as dichloromethane; ethers such as tetrahydrofuran and diethyl ether; or aromatic hydrocarbons such as toluene or without solvent. .
  • This reaction is preferably carried out by adding oxalyl chloride to compound (II) in the presence of N, N-dimethylformamide in tetrahydrofuran.
  • the halogenating agent is usually used in an amount of about 1 to about 100 equivalents, preferably 1 to 5 equivalents, relative to 1 mol of the starting compound (Compound II).
  • the reaction temperature is usually ⁇ 78 ° C. to 100 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • reaction of compound (IIa) with compound (III) is preferably carried out in a known solvent, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone; halogenation such as dichloromethane Hydrocarbons; Esters such as ethyl acetate; Hydrocarbons such as cyclohexane and n-hexane; Aromatic hydrocarbons such as toluene; Ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane It is carried out in a solvent. These solvents may be mixed in an appropriate ratio or may not be used.
  • amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone
  • halogenation such as dichloromethane Hydrocarbons
  • Esters such as ethyl acetate
  • This reaction preferably uses about 0.5 to about 10 moles, preferably about 1 to about 5 moles of compound (III) per mole of compound (IIa), and the base is about 0.1 To about 100 equivalents, preferably from about 1 to about 5 equivalents.
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Compound (Ia) is Compound (VI): (Wherein R 3 represents an optionally substituted C 1-6 alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, etc.), and other symbols. Are as defined above) and compound (III): (In the formula, each symbol is as defined above).
  • This reaction is carried out, for example, by a method in which compound (VI) and compound (III) coexist and are heated. This reaction may be carried out in the presence of a base such as sodium hydride, sodium methoxide, alkyllithium, Grignard reagent; and a metal reagent such as trimethylaluminum as necessary.
  • a base such as sodium hydride, sodium methoxide, alkyllithium, Grignard reagent
  • a metal reagent such as trimethylaluminum as necessary.
  • This reaction is preferably carried out in a known solvent, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate Hydrocarbons such as cyclohexane and n-hexane; aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane.
  • solvents may be mixed in an appropriate ratio or may not be used.
  • reaction temperature is usually 0 ° C. to 200 ° C., preferably 40 ° C. to It is carried out at a reaction temperature of 200 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Compound (Ia) is Compound (IV): (Wherein each symbol is as defined above) and compound (V): (Wherein, Xb represents a leaving group, and other symbols are as defined above).
  • Examples of the “leaving group” represented by Xb include halogen atoms; sulfonyloxy groups such as p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, etc., preferably chlorine, bromine And halogen atoms such as iodine.
  • the reaction between compound (IV) and compound (V) is preferably potassium tert-butoxide, sodium hydride, triethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), carbonic acid
  • a base such as potassium and cesium carbonate
  • a solvent such as aromatic hydrocarbons such as toluene; ethers such as 1,4-dioxane and tetrahydrofuran; or amides such as N, N-dimethylformamide Done.
  • This reaction is preferably carried out by dissolving compound (IV) in a solvent such as N, N-dimethylformamide, adding potassium tert-butoxide, and then adding compound (V).
  • reaction about 1 to about 5 mol of compound (V) is usually used per 1 mol of the starting compound (compound (IV)), and the amount of the base is about 0.1 to about 100 equivalents, preferably 1 ⁇ 5 equivalents.
  • the reaction temperature is usually 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Compound (II) used for the production of compound (Ia) is, for example, Compound (VI): (Wherein each symbol has the same meaning as described above) can be produced by a method D-1) or D-2) of hydrolysis.
  • This reaction generally employs a method in which an ester is hydrolyzed under basic conditions, and is performed, for example, by treating with an alkali such as lithium hydroxide, sodium hydroxide, and potassium hydroxide.
  • an alkali such as lithium hydroxide, sodium hydroxide, and potassium hydroxide.
  • the compound (VI) is dissolved in an alcohol such as methanol and ethanol; or a water-soluble solvent such as tetrahydrofuran and dioxane; or a mixed solvent thereof, an aqueous sodium hydroxide solution, an aqueous lithium hydroxide solution, or the like. It is carried out by treating with an alkaline aqueous solution.
  • reaction temperature is generally 0 ° C. to 100 ° C., preferably 20 ° C. to 100 ° C.
  • reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Process D-2 Compound (II) can also be produced by a method in which an ester of compound (VI) is hydrolyzed under acidic conditions. For example, it is carried out by treatment with an acid such as hydrochloric acid, sulfuric acid, and nitric acid.
  • the compound (VI) is dissolved in an alcohol such as methanol and ethanol; or a water-soluble solvent such as tetrahydrofuran and dioxane; or a mixed solvent thereof and treated with an aqueous acid solution such as hydrochloric acid and sulfuric acid. Is done.
  • the reaction temperature is generally 0 ° C. to 100 ° C., preferably 20 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • the reaction between compound (IV) and compound (VII) is preferably potassium tert-butoxide, sodium hydride, triethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), carbonic acid
  • a base such as potassium and cesium carbonate
  • a solvent such as aromatic hydrocarbons such as toluene; ethers such as 1,4-dioxane and tetrahydrofuran; or amides such as N, N-dimethylformamide Done.
  • This reaction is preferably carried out by dissolving compound (IV) in a solvent such as N, N-dimethylformamide, adding potassium tert-butoxide, and then adding compound (VII).
  • reaction about 1 to about 5 mol of compound (VII) is usually used with respect to 1 mol of raw material compound (compound (IV)), and the amount of base is about 0.1 to about 100 equivalents, preferably 1 ⁇ 5 equivalents.
  • the reaction temperature is usually 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Compound (VI) is Compound (VIII): (Wherein each symbol is as defined above) can also be produced by intramolecular cyclization reaction. As this reaction, for example, F-1) A method using a dehydration condensing agent generally known for compound (VIII); F-2) A method of subjecting compound (VIII) to dehydration condensation under acidic conditions; Etc.
  • Process F-1 The intramolecular cyclization reaction of compound (VIII) is performed by using, for example, phosphines and azocarboxylic acid esters.
  • phosphines used in this reaction include triphenylphosphine and tributylphosphine.
  • the azocarboxylic acid esters used in this reaction include diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1, 1 ′-(azodicarbonyl) dipiperidine (ADDP), and the like. This reaction can be performed in a solvent, if necessary.
  • the solvent examples include ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; esters such as ethyl acetate; halogenated carbonization such as chloroform and dichloromethane. Hydrogen; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidinone; Ketones such as acetone and 2-butanone; Sulfoxides such as dimethyl sulfoxide And the like. These solvents may be used alone or in a mixture of two or more at an appropriate ratio.
  • ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • esters such as eth
  • This reaction is preferably performed by dissolving compound (VIII) and a phosphine such as triphenylphosphine in a solvent such as tetrahydrofuran and using an azocarboxylic acid ester such as diethyl azodicarboxylate.
  • phosphines are usually used in an amount of about 1 to about 10 mol, preferably about 1 to about 5 mol, and azocarboxylic acid esters are usually used with respect to 1 mol of the starting compound (compound (VIII)).
  • the reaction temperature is usually -78 ° C to 100 ° C, preferably -78 ° C to 30 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.1 to about 50 hours.
  • Step F-2 The intramolecular cyclization reaction of compound (VIII) may be performed, for example, under acidic conditions.
  • the acid used in this reaction include p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, and boron fluoride acid. This reaction can be performed in a solvent, if necessary.
  • the solvent examples include water; alcohols such as methanol and ethanol; ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; esters such as ethyl acetate; Halogenated hydrocarbons such as chloroform and dichloromethane; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidinone; Acetone and 2-butanone Ketones such as sulfoxides such as dimethyl sulfoxide; acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid and the like.
  • alcohols such as methanol and ethanol
  • ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran
  • aromatic hydrocarbons such as
  • This reaction is preferably carried out in the presence of sulfuric acid or the like, if necessary, by dissolving compound (VIII) in a solvent such as methanol.
  • This reaction is preferably carried out using usually about 0.1 to about 10 moles, preferably about 0.1 to about 5 moles of acid per mole of starting compound (compound (VIII)).
  • An acid may be used as a solvent.
  • the reaction temperature is usually 0 ° C. to 200 ° C., preferably 25 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.1 to about 50 hours.
  • Compound (IV) used for the production of compound (VI) is, for example, Compound (IX): (Wherein each symbol is as defined above) can also be produced by intramolecular cyclization reaction.
  • G-1) A method using a dehydration condensing agent generally known for compound (IX);
  • G-2) A method of subjecting compound (IX) to dehydration condensation under acidic conditions; Etc.
  • Process G-1 The intramolecular cyclization reaction of compound (IX) is performed by using, for example, phosphines and azocarboxylic acid esters.
  • phosphines used in this reaction include triphenylphosphine and tributylphosphine.
  • the azocarboxylic acid esters used in this reaction include diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1, 1 ′-(azodicarbonyl) dipiperidine (ADDP), and the like. This reaction can be performed in a solvent, if necessary.
  • the solvent examples include ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; esters such as ethyl acetate; halogenated carbonization such as chloroform and dichloromethane. Hydrogen; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidinone; Ketones such as acetone and 2-butanone; Sulfoxides such as dimethyl sulfoxide And the like. These solvents may be used alone or in a mixture of two or more at an appropriate ratio.
  • ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • esters such as eth
  • This reaction is preferably carried out by dissolving compound (IX) and a phosphine such as triphenylphosphine in a solvent such as tetrahydrofuran and using an azocarboxylic acid ester such as diethyl azodicarboxylate.
  • phosphines are usually used in an amount of about 1 to about 10 moles, preferably about 1 to about 5 moles per mole of the raw material compound (compound (IX)), and azocarboxylic acid esters are usually used. , About 1 to about 10 moles, preferably about 1 to about 5 moles.
  • the reaction temperature is usually -78 ° C to 100 ° C, preferably -78 ° C to 30 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.1 to about 50 hours.
  • Process G-2 The intramolecular cyclization reaction of compound (IX) may be performed, for example, under acidic conditions.
  • the acid used in this reaction include p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, and boron fluoride acid. This reaction can be performed in a solvent, if necessary.
  • the solvent examples include water; alcohols such as methanol and ethanol; ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; esters such as ethyl acetate; Halogenated hydrocarbons such as chloroform and dichloromethane; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidinone; Acetone and 2-butanone Ketones such as sulfoxides such as dimethyl sulfoxide; acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid and the like.
  • alcohols such as methanol and ethanol
  • ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran
  • aromatic hydrocarbons such as
  • This reaction is preferably carried out in the presence of sulfuric acid or the like, if necessary, by dissolving compound (IX) in a solvent such as methanol.
  • This reaction is preferably carried out using usually about 0.1 to about 10 moles, preferably about 0.1 to about 5 moles of acid per mole of starting compound (compound (IX)).
  • An acid may be used as a solvent.
  • the reaction temperature is usually 0 ° C. to 200 ° C., preferably 25 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.1 to about 50 hours.
  • Compound (IX) used for the production of compound (IV) is, for example, Compound (Xa) or Compound (Xb): (Each symbol in the formula is as defined above) and hydrazine can be reacted.
  • the reaction of compound (Xa) or compound (Xb) with hydrazine is carried out, for example, using a catalyst or a dehydrating condensing agent as necessary.
  • Examples of the catalyst used as necessary in this reaction include acids such as p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, and boronic acid; acetic acid chloride, propionic acid chloride, benzoic acid chloride.
  • acid halides such as sodium methoxide, potassium tert-butoxide, sodium hydride, potassium carbonate, cesium carbonate, triethylamine, diisopropylamine and other bases, tetrabutylammonium bromide, sodium acetate and the like.
  • dehydrating condensing agent examples include Burgess reagent, N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) or its hydrochloride, N, N′-carbonyldiimidazole, 1H-benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluoro Phosphate (HATU), 2-chloro-1,3-dimethylimidazolium chloride, bromotripyrrolidinophosphonium hexafluorophosphate (PyBrop), diethyl phosphorocyanidate (diethyl cyanophosphate; DEPC), diphenylphosphoryl azide (Dipheny
  • This reaction is carried out using a known solvent such as water; alcohols such as methanol and ethanol; ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; Esters, such as chloroform, dichloromethane; nitriles, such as acetonitrile; amides, such as N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidinone; acetone, It is carried out in a solvent such as ketones such as 2-butanone; sulfoxides such as dimethyl sulfoxide; acids such as acetic acid and hydrochloric acid.
  • a solvent such as water; alcohols such as methanol and ethanol; ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran; aromatic hydrocarbons such as
  • This reaction is preferably carried out by dissolving compound (Xa) or compound (Xb) and hydrazine monohydrate in a solvent such as methanol and, if necessary, in the presence of an acid such as p-toluenesulfonic acid.
  • hydrazine is usually used in an amount of usually about 1 to about 10 moles, preferably about 1 to about 5 moles per mole of the starting compound (compound (Xa) or compound (Xb)), and the catalyst is usually used.
  • About 0.01 to about 1 mole preferably about 0.01 to about 0.1 mole.
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.1 to about 50 hours.
  • Compound (VIII) used for the production of compound (VI) is, for example, Compound (Xa) or Compound (Xb): (In the formula, each symbol is as defined above) and compound (XI): (Each symbol in the formula is as defined above) can be reacted.
  • the reaction of compound (Xa) or compound (Xb) with compound (XI) is carried out, for example, using a catalyst or a dehydrating condensing agent as necessary.
  • Examples of the catalyst or dehydrating condensing agent used in this reaction as necessary include acids such as p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, and boronic acid; acetic acid chloride and propionic acid chloride.
  • Acid halides such as benzoyl chloride; bases such as sodium methoxide, potassium tert-butoxide, sodium hydride, potassium carbonate, cesium carbonate, triethylamine, diisopropylamine, tetrabutylammonium bromide, sodium acetate, Burgess reagent, N, N '-Dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) or its hydrochloride, N, N'-carbonyldiimidazole, 1H-benzotriazol-1-yloxytris (dimethylamino) Suphonium hexafluorophosphate (BOP), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 2-chloro-1,3- Dimethylimidazolium chlor
  • This reaction is carried out using a known solvent such as water; alcohols such as methanol and ethanol; ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; Esters, such as chloroform, dichloromethane; nitriles, such as acetonitrile; amides, such as N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidinone; acetone, It is carried out in a solvent such as ketones such as 2-butanone; sulfoxides such as dimethyl sulfoxide; acids such as acetic acid and hydrochloric acid.
  • a solvent such as water; alcohols such as methanol and ethanol; ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran; aromatic hydrocarbons such as
  • This reaction is preferably carried out by dissolving compound (Xa) or compound (Xb) and compound (XI) in a solvent such as methanol and, if necessary, in the presence of an acid such as p-toluenesulfonic acid.
  • compound (XI) is usually used in an amount of about 1 to about 10 mol, preferably about 1 to about 5 mol, relative to 1 mol of starting compound (compound (Xa) or compound (Xb)),
  • the catalyst is usually used in an amount of about 0.01 to about 1 mole, preferably about 0.01 to about 0.1 mole.
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.1 to about 50 hours.
  • Compound (I) is Compound (Ib):
  • the compound (I) is, for example, Compound (XII): (Wherein each symbol has the same meaning as described above) can be produced by intramolecular cyclization reaction.
  • this reaction for example, J-1) A method using a dehydration condensing agent generally known for compound (XII); J-2) A method of subjecting compound (XII) to dehydration condensation under acidic conditions; Etc.
  • Process J-1 The intramolecular cyclization reaction of compound (XII) is performed by using, for example, phosphines and azocarboxylic acid esters.
  • phosphines used in this reaction include triphenylphosphine and tributylphosphine.
  • the azocarboxylic acid esters used in this reaction include diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1, 1 ′-(azodicarbonyl) dipiperidine (ADDP), and the like. This reaction can be performed in a solvent, if necessary.
  • the solvent examples include ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; esters such as ethyl acetate; halogenated carbonization such as chloroform and dichloromethane. Hydrogen; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidinone; Ketones such as acetone and 2-butanone; Sulfoxides such as dimethyl sulfoxide And the like. These solvents may be used alone or in a mixture of two or more at an appropriate ratio.
  • ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • esters such as eth
  • This reaction is preferably carried out by dissolving compound (XII) and a phosphine such as triphenylphosphine in a solvent such as tetrahydrofuran and using an azocarboxylic acid ester such as diethyl azodicarboxylate.
  • phosphines are usually used in an amount of about 1 to about 10 moles, preferably about 1 to about 5 moles per mole of the raw material compound (compound (XII)), and azocarboxylic acid esters are usually used. , About 1 to about 10 moles, preferably about 1 to about 5 moles.
  • the reaction temperature is usually -78 ° C to 100 ° C, preferably -78 ° C to 30 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.1 to about 50 hours.
  • Process J-2 The intramolecular cyclization reaction of compound (XII) may be performed, for example, under acidic conditions.
  • the acid used in this reaction include p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, and boron fluoride acid. This reaction can be performed in a solvent, if necessary.
  • the solvent examples include water; alcohols such as methanol and ethanol; ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; esters such as ethyl acetate; Halogenated hydrocarbons such as chloroform and dichloromethane; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidinone; Acetone and 2-butanone Ketones such as sulfoxides such as dimethyl sulfoxide; acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid and the like.
  • alcohols such as methanol and ethanol
  • ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran
  • aromatic hydrocarbons such as
  • This reaction is preferably carried out by dissolving compound (XII) in a solvent such as methanol and, if necessary, in the presence of sulfuric acid or the like. This reaction is preferably carried out using usually about 0.1 to about 10 moles, preferably about 0.1 to about 5 moles of acid per mole of starting compound (compound (XII)).
  • An acid may be used as a solvent.
  • the reaction temperature is usually 0 ° C. to 200 ° C., preferably 25 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.1 to about 50 hours.
  • Process K (XII) used for the production of compound (Ib) is, for example, Compound (Xa) or Compound (Xb): (Each symbol in the formula is as defined above) and Compound (XIII): (Each symbol in the formula is as defined above) can be reacted.
  • the reaction of compound (Xa) or compound (Xb) with compound (XIII) is carried out, for example, using a catalyst or a dehydrating condensing agent as necessary.
  • Examples of the catalyst or dehydrating condensing agent used in this reaction as necessary include acids such as p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, and boronic acid; acetic acid chloride and propionic acid chloride.
  • Acid halides such as benzoyl chloride; bases such as sodium methoxide, potassium tert-butoxide, sodium hydride, potassium carbonate, cesium carbonate, triethylamine, diisopropylamine, tetrabutylammonium bromide, sodium acetate, Burgess reagent, N, N '-Dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) or its hydrochloride, N, N'-carbonyldiimidazole, 1H-benzotriazol-1-yloxytris (dimethylamino) Suphonium hexafluorophosphate (BOP), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 2-chloro-1,3- Dimethylimidazolium chlor
  • This reaction is carried out using a known solvent such as water; alcohols such as methanol and ethanol; ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; Esters, such as chloroform, dichloromethane; nitriles, such as acetonitrile; amides, such as N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidinone; acetone, It is carried out in a solvent such as ketones such as 2-butanone; sulfoxides such as dimethyl sulfoxide; acids such as acetic acid and hydrochloric acid.
  • a solvent such as water; alcohols such as methanol and ethanol; ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran; aromatic hydrocarbons such as
  • This reaction is preferably carried out by dissolving compound (Xa) or compound (Xb) and compound (XIII) in a solvent such as methanol, and if necessary, in the presence of an acid such as p-toluenesulfonic acid.
  • compound (XIII) is usually used in an amount of usually about 1 to about 10 mol, preferably about 1 to about 5 mol, relative to 1 mol of starting compound (compound (Xa) or compound (Xb)).
  • the catalyst is usually used in an amount of about 0.01 to about 1 mole, preferably about 0.01 to about 0.1 mole.
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.1 to about 50 hours.
  • Compound (I) is Compound (Ic): In the formula (wherein R 4 and R 5 each represents an optionally substituted C 1-6 alkyl group, and other symbols are as defined above), the compound (I) is, for example, Compound (II): (Each symbol in the formula is as defined above) and Compound (XIV): (Each symbol in the formula is as defined above) can be reacted.
  • L-1 A method of condensing compound (II) and compound (XIV) with a generally known dehydration condensing agent
  • L-2) A method of reacting compound (XIV) after activating the carboxyl group of compound (II) by a generally known activation method
  • Etc A method of reacting compound (XIV) after activating the carboxyl group of compound (II) by a generally known activation method
  • Process L-1 Compound (Ic) can be produced by condensing compound (II) and compound (XIV) with a generally known dehydration condensing agent.
  • the dehydrating condensing agent used in this reaction include N, N-dicyclohexylamide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) or its hydrochloride, carbonyldiimidazole, 1H-benzoic acid.
  • Triazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) ), Butomotripyrrolidinophosphonium hexafluorophosphate (PyBrop), diethyl phosphorocyanidate (diethyl cyanophosphate; DEPC), diphenylphosphoryl azide (diphenyl phosphate azide; DPPA), 4- (4,6-dimethoxy [1, , 5] triazin-2-yl) -4-methyl morpholinium chloride (DMTMM), or the like.
  • BOP Triazol-1-yloxytris
  • HATU O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate
  • This reaction may be carried out as necessary, for example, with a base such as 1-hydroxybenzotriazole (HOBt), N, N-diisopropylethylamine, N-methylmorpholine, triethylamine, 4- (N, N-dimethylamino) pyridine and the like. You may carry out in presence.
  • a base such as 1-hydroxybenzotriazole (HOBt), N, N-diisopropylethylamine, N-methylmorpholine, triethylamine, 4- (N, N-dimethylamino) pyridine and the like. You may carry out in presence.
  • This reaction is preferably carried out in a known solvent, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate Hydrocarbons such as cyclohexane and n-hexane; aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane; alcohols such as methanol and ethanol; water, etc.
  • solvents for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate Hydrocarbons such as cyclohexane and n-hexane; aromatic
  • compound (XIV) is usually used in an amount of about 0.5 to about 10 mol, preferably about 1 to about 5 mol, relative to 1 mol of compound (II).
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Process L-2 It can also be produced by reacting compound (XIV) after activating the carboxyl group of compound (II) by a generally known activation method.
  • a method for activating the carboxyl group of compound (II) a general method is adopted, for example, mixed acid anhydride using chloroformate, pivaloyl chloride, 2,4,6-trichlorobenzoyl chloride and the like.
  • a typical example is a method of acid halide, and as acid halide, Compound (IIa): (Each symbol in the formula is as defined above)
  • the compound (IIa) can be produced by treating with a halogenating agent such as thionyl chloride or oxalyl chloride.
  • a halogenating agent such as thionyl chloride or oxalyl chloride.
  • N, N-dimethylformamide may be added as an additive.
  • This reaction is preferably performed in a known solvent, for example, halogenated hydrocarbons such as dichloromethane; ethers such as tetrahydrofuran and diethyl ether; or aromatic hydrocarbons such as toluene or without solvent. .
  • This reaction is preferably carried out by adding oxalyl chloride to compound (II) in the presence of N, N-dimethylformamide in tetrahydrofuran.
  • the halogenating agent is usually used in an amount of about 1 to about 100 equivalents, preferably 1 to 5 equivalents, relative to 1 mol of the starting compound (Compound II).
  • the reaction temperature is usually ⁇ 78 ° C. to 100 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • the reaction between compound (IIa) and compound (XIV) is preferably a known solvent, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone; halogenation such as dichloromethane Hydrocarbons; Esters such as ethyl acetate; Hydrocarbons such as cyclohexane and n-hexane; Aromatic hydrocarbons such as toluene; Ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane It is carried out in a solvent. These solvents may be mixed in an appropriate ratio or may not be used.
  • amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone
  • halogenation such as dichloromethane Hydrocarbons
  • Esters such as ethyl acetate
  • compound (XIV) is usually used in an amount of about 0.5 to about 10 mol, preferably about 1 to about 5 mol, relative to 1 mol of compound (IIa), and the base is about 0.1 To about 100 equivalents, preferably from about 1 to about 5 equivalents.
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Compound (I) is Compound (Id): In the formula (wherein R 6 represents a C 1-6 alkyl group which may be substituted with a halogen atom, and other symbols are as defined above), the compound (I) is, for example, Compound (XV): (In the formula, each symbol is as defined above) and compound (XVI):
  • the reaction between compound (XV) and compound (XVI) is preferably potassium tert-butoxide, sodium hydride, triethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), diisopropyl
  • a base such as ethylamine, potassium carbonate, and cesium carbonate
  • aromatic hydrocarbons such as toluene
  • ethers such as 1,4-dioxane and tetrahydrofuran
  • amides such as N, N-dimethylformamide It is carried out in a solvent.
  • This reaction is preferably carried out by dissolving compound (XV) in a solvent such as N, N-dimethylformamide, adding potassium carbonate and then adding compound (XVI).
  • the compound (XVI) is usually used in an amount of about 1 to about 5 moles per mole of the raw material compound (compound (XV)), and the amount of the base is about 0.1 to about 100 equivalents, preferably 1 ⁇ 5 equivalents.
  • the reaction temperature is usually 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Compound (Id) is Compound (XV): (Each symbol in the formula is as defined above) and Compound (XVII): (In the formula, R 7 represents a C 1-5 alkyl group which may be substituted with a halogen atom) and then a reduction reaction is performed.
  • the reaction between compound (XV) and compound (XVII) is, for example, halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane; ethers such as 1,4-dioxane and tetrahydrofuran; or organic acids such as acetic acid. In the solvent.
  • This reaction is preferably carried out by reacting compound (XV) and compound (XVII) with a solvent such as 1,2-dichloroethane, and then sodium borohydride, zinc borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride.
  • a reducing agent such as palladium
  • reduction by a hydrogenation reaction using a catalyst such as palladium carbon.
  • This reaction may be performed in the presence of an organic acid such as acetic acid, if necessary.
  • a typical example is a method using a reducing agent.
  • the compound (XVII) is usually used in an amount of about 1 to about 5 mol per 1 mol of the starting compound (compound (XV)).
  • the amount is performed using about 1 to about 100 equivalents, preferably about 1 to 5 equivalents.
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Compound (XV) used for the production of compound (Id) is, for example, Compound (XVIIIa) or Compound (XVIIIb): (Each symbol in the formula is as defined above) and Compound (XIII): (Each symbol in the formula is as defined above) can be reacted.
  • the reaction of compound (XVIIIa) or compound (XVIIIb) with compound (XIII) is carried out, for example, using a catalyst or a dehydrating condensing agent as necessary.
  • Examples of the catalyst or dehydrating condensing agent used in this reaction as necessary include acids such as p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, and boronic acid; acetic acid chloride and propionic acid chloride.
  • Acid halides such as benzoyl chloride; bases such as sodium methoxide, potassium tert-butoxide, sodium hydride, potassium carbonate, cesium carbonate, triethylamine, diisopropylamine, tetrabutylammonium bromide, sodium acetate, Burgess reagent, N, N '-Dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) or its hydrochloride, N, N'-carbonyldiimidazole, 1H-benzotriazol-1-yloxytris (dimethylamino) Suphonium hexafluorophosphate (BOP), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 2-chloro-1,3- Dimethylimidazolium chlor
  • This reaction is carried out using a known solvent such as water; alcohols such as methanol and ethanol; ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; Esters, such as chloroform, dichloromethane; nitriles, such as acetonitrile; amides, such as N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidinone; acetone, It is carried out in a solvent such as ketones such as 2-butanone; sulfoxides such as dimethyl sulfoxide; acids such as acetic acid and hydrochloric acid.
  • a solvent such as water; alcohols such as methanol and ethanol; ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran; aromatic hydrocarbons such as
  • This reaction is preferably performed by dissolving compound (XVIIIa) or compound (XVIIIb) and compound (XIII) in a solvent such as methanol, and if necessary, in the presence of an acid such as p-toluenesulfonic acid.
  • compound (XIII) is preferably used in an amount of usually about 1 to about 10 mol, preferably about 1 to about 5 mol, relative to 1 mol of starting compound (compound (XVIIIa) or compound (XVIIIb))
  • the catalyst is usually used in an amount of about 0.01 to about 1 mole, preferably about 0.01 to about 0.1 mole.
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.1 to about 50 hours.
  • Compound (XVIIIa) or Compound (XVIIIb) used for the production of compound (XV) is, for example, Compound (XIXa) or Compound (XIXb): (Wherein PG 1 represents an amino-protecting group such as tert-butoxycarbonyl, p-methoxybenzylamine, etc., and other symbols are as defined above), and is produced by deprotecting the protecting group Can do.
  • This reaction can be performed according to a known method, for example, the method described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980).
  • a solvent such as a solvent
  • ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • alcohols such as methanol and ethanol.
  • reaction about 1 to about 5 mol of compound (XXI) is usually used with respect to 1 mol of raw material compound (compound (XX)), and the amount of base is about 0.1 to about 50 equivalents, preferably 1 ⁇ 2 equivalents.
  • the reaction temperature is usually ⁇ 78 ° C. to 100 ° C., preferably ⁇ 78 ° C. to 20 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Compound (I) is Compound (Ie):
  • the compound (I) is, for example, Compound (XXII): (Wherein each symbol is as defined above) and compound (III): (Each symbol in the formula is as defined above) can be reacted.
  • R-1) A method of condensing compound (XXII) and compound (III) with a generally known dehydration condensing agent;
  • R-2) A method of reacting compound (III) after activating the carboxyl group of compound (XXII) by a generally known activation method; Etc.
  • Compound (Ie) can be produced by condensing compound (XXII) and compound (III) with a generally known dehydration condensation agent.
  • the dehydrating condensing agent used in this reaction include N, N-dicyclohexylamide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) or its hydrochloride, carbonyldiimidazole, 1H-benzoic acid.
  • Triazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) ), Butomotripyrrolidinophosphonium hexafluorophosphate (PyBrop), diethyl phosphorocyanidate (diethyl cyanophosphate; DEPC), diphenylphosphoryl azide (diphenyl phosphate azide; DPPA), 4- (4,6-dimethoxy [1, , 5] triazin-2-yl) -4-methyl morpholinium chloride (DMTMM), or the like.
  • BOP Triazol-1-yloxytris
  • HATU O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate
  • This reaction may be carried out as necessary, for example, with a base such as 1-hydroxybenzotriazole (HOBt), N, N-diisopropylethylamine, N-methylmorpholine, triethylamine, 4- (N, N-dimethylamino) pyridine and the like. You may carry out in presence.
  • a base such as 1-hydroxybenzotriazole (HOBt), N, N-diisopropylethylamine, N-methylmorpholine, triethylamine, 4- (N, N-dimethylamino) pyridine and the like. You may carry out in presence.
  • This reaction is preferably carried out in a known solvent, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate Hydrocarbons such as cyclohexane and n-hexane; aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane; alcohols such as methanol and ethanol; water, etc.
  • solvents for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate Hydrocarbons such as cyclohexane and n-hexane; aromatic
  • compound (III) is usually used in an amount of about 0.5 to about 10 mol, preferably about 1 to about 5 mol, relative to 1 mol of compound (XXII), and the amount of dehydrating condensing agent is About 0.1 to about 100 equivalents, preferably about 1 to about 5 equivalents, the base is used with about 0.1 to about 100 equivalents, preferably about 1 to about 5 equivalents.
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Process R-2 It can also be produced by reacting compound (III) after activating the carboxyl group of compound (XXII) by a generally known activation method.
  • a method for activating the carboxyl group of compound (XXII) a general method is adopted. For example, mixed acid anhydrides using chloroformate, pivaloyl chloride, 2,4,6-trichlorobenzoyl chloride, etc.
  • a typical example is a method of acid halide, and as acid halide, Compound (XXIIa): (In the formula, each symbol has the same meaning as described above).
  • the compound (XXII) can be produced by treating with a halogenating agent such as thionyl chloride or oxalyl chloride.
  • a halogenating agent such as thionyl chloride or oxalyl chloride.
  • N, N-dimethylformamide may be added as an additive.
  • This reaction is preferably performed in a known solvent, for example, halogenated hydrocarbons such as dichloromethane; ethers such as tetrahydrofuran and diethyl ether; or aromatic hydrocarbons such as toluene or without solvent. .
  • This reaction is preferably carried out by adding oxalyl chloride to compound (XXII) in the presence of N, N-dimethylformamide in tetrahydrofuran.
  • the halogenating agent is generally used in an amount of about 1 to about 100 equivalents, preferably 1 to 5 equivalents, relative to 1 mol of the raw material compound (Compound XXII).
  • the reaction temperature is usually ⁇ 78 ° C. to 100 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • the reaction of compound (XXIIa) with compound (III) is preferably a known solvent, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone; halogenation such as dichloromethane Hydrocarbons; Esters such as ethyl acetate; Hydrocarbons such as cyclohexane and n-hexane; Aromatic hydrocarbons such as toluene; Ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane It is carried out in a solvent. These solvents may be mixed in an appropriate ratio or may not be used.
  • amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone
  • halogenation such as dichloromethane Hydrocarbons
  • Esters such as ethyl acetate
  • compound (III) is preferably used in an amount of usually about 0.5 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of compound (XXIIa), and the base is about 0.1 To about 100 equivalents, preferably from about 1 to about 5 equivalents.
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Compound (Ie) is Compound (XXIII): (Wherein each symbol is as defined above) and compound (III): (In the formula, each symbol is as defined above).
  • This reaction is performed, for example, by a method in which compound (XXIII) and compound (III) coexist and are heated. This reaction may be carried out in the presence of a base such as sodium hydride, sodium methoxide, alkyllithium, Grignard reagent; and a metal reagent such as trimethylaluminum as necessary.
  • compound (III) is usually used in an amount of about 1 to about 5 mol per mol of the raw material compound (compound (XXIII)), and the reaction temperature is usually 0 ° C. to 200 ° C., preferably 40 ° C. to It is carried out at a reaction temperature of 200 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Compound (Ie) is Compound (XXIV): (Wherein each symbol is as defined above) and compound (V): (In the formula, each symbol is as defined above).
  • the reaction of compound (XXIV) with compound (V) is preferably potassium tert-butoxide, sodium hydride, triethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), carbonic acid In the presence of a base such as potassium and cesium carbonate in a solvent such as aromatic hydrocarbons such as toluene; ethers such as 1,4-dioxane and tetrahydrofuran; or amides such as N, N-dimethylformamide Done.
  • a base such as potassium and cesium carbonate
  • a solvent such as aromatic hydrocarbons such as toluene
  • ethers such as 1,4-dioxane and tetrahydrofuran
  • amides such as N, N-dimethyl
  • This reaction is preferably carried out by dissolving compound (XXIV) in a solvent such as N, N-dimethylformamide, adding potassium tert-butoxide, and then adding compound (V).
  • a solvent such as N, N-dimethylformamide
  • compound (V) about 1 to about 5 mol of compound (V) is usually used with respect to 1 mol of the starting compound (compound (XXIV)), and the amount of the base is about 0.1 to about 100 equivalents, preferably 1 ⁇ 5 equivalents.
  • the reaction temperature is usually 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • This reaction generally employs a method in which an ester is hydrolyzed under basic conditions, and is performed, for example, by treating with an alkali such as lithium hydroxide, sodium hydroxide, and potassium hydroxide.
  • an alkali such as lithium hydroxide, sodium hydroxide, and potassium hydroxide.
  • the compound (XXIII) is dissolved in an alcohol such as methanol and ethanol; or a water-soluble solvent such as tetrahydrofuran and dioxane; or a mixed solvent thereof. It is performed by treating with an alkaline aqueous solution.
  • about 1 to about 10 equivalent of an aqueous alkali solution is usually used per 1 mol of the raw material compound (Compound (XXIII)).
  • the reaction temperature is generally 0 ° C. to 100 ° C., preferably 20 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Process U-2 Compound (XXII) can also be produced by a method of hydrolyzing an ester of compound (XXIII) under acidic conditions. For example, it is carried out by treatment with an acid such as hydrochloric acid, sulfuric acid, and nitric acid.
  • an acid such as hydrochloric acid, sulfuric acid, and nitric acid.
  • compound (XXIII) is dissolved in alcohols such as methanol and ethanol; or water-soluble solvents such as tetrahydrofuran and dioxane; or a mixed solvent thereof, and treated with an aqueous acid solution such as hydrochloric acid and sulfuric acid. Is done.
  • about 1 to about 10 equivalent of an aqueous acid solution is usually used for 1 mol of the starting compound (compound (XXIII)).
  • the reaction temperature is generally 0 ° C. to 100 ° C., preferably 20 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours,
  • the reaction between compound (XXIV) and compound (VII) is preferably potassium tert-butoxide, sodium hydride, triethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), carbonic acid
  • a base such as potassium and cesium carbonate
  • a solvent such as aromatic hydrocarbons such as toluene; ethers such as 1,4-dioxane and tetrahydrofuran; or amides such as N, N-dimethylformamide Done.
  • This reaction is preferably carried out by dissolving compound (XXIV) in a solvent such as N, N-dimethylformamide, adding potassium tert-butoxide, and then adding compound (VII).
  • compound (VII) is usually used in an amount of about 1 to about 5 mol per mol of the raw material compound (compound (XXIV)), and the amount of the base is about 0.1 to about 100 equivalents, preferably 1 ⁇ 5 equivalents.
  • the reaction temperature is usually 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Compound (XXIV) used for the production of compound (XXIII) and compound (Ie) is, for example, Compound (XXV): (Wherein PG 2 represents a protecting group for an amino group such as tert-butoxycarbonyl, p-methoxybenzyl, etc., and other symbols are as defined above). It can.
  • This reaction can be performed according to a known method, for example, the method described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980).
  • the reaction between compound (XXVI) and compound (XVI) is preferably potassium tert-butoxide, sodium hydride, triethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), diisopropyl
  • a base such as ethylamine, potassium carbonate, and cesium carbonate
  • aromatic hydrocarbons such as toluene
  • ethers such as 1,4-dioxane and tetrahydrofuran
  • amides such as N, N-dimethylformamide It is carried out in a solvent.
  • This reaction is preferably carried out by dissolving compound (XXVI) in a solvent such as N, N-dimethylformamide, adding potassium carbonate and then adding compound (XVI).
  • a solvent such as N, N-dimethylformamide
  • compound (XVI) about 1 to about 5 mol of compound (XVI) is usually used per 1 mol of the starting compound (compound (XXVI)), and the amount of the base is about 0.1 to about 100 equivalents, preferably 1 ⁇ 5 equivalents.
  • the reaction temperature is usually 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • compound (XXV) is Compound (XXVI): (Each symbol in the formula is as defined above) and Compound (XVII): (The symbols in the formula have the same meanings as described above), followed by a reduction reaction.
  • Reaction of compound (XXVI) with compound (XVII) is, for example, halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane; ethers such as 1,4-dioxane and tetrahydrofuran; or organic acids such as acetic acid. In the solvent.
  • This reaction is preferably carried out by reacting compound (XXVI) and compound (XVII) with a solvent such as 1,2-dichloroethane, and then sodium borohydride, zinc borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride.
  • a reducing agent such as palladium; carried out by reduction by a hydrogenation reaction using a catalyst such as palladium carbon. This reaction may be performed in the presence of an organic acid such as acetic acid, if necessary.
  • a typical example is a method using a reducing agent.
  • the compound (XVII) is usually used in an amount of about 1 to about 5 moles per 1 mole of the starting compound (compound (XXVI)).
  • the amount is performed using about 1 to about 100 equivalents, preferably about 1 to 5 equivalents.
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Compound (XXVI) used for the production of compound (XXV) is, for example, Compound (XVIIIa) or Compound (XVIIIb): (Wherein each symbol is as defined above) and compound (XXVII): (Each symbol in the formula is as defined above) can be reacted.
  • the reaction of compound (XVIIIa) or compound (XVIIIb) with compound (XXVII) is carried out, for example, using a dehydration condensing agent or an activator as necessary.
  • Examples of the dehydrating condensing agent or activating agent used in this reaction include p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, and boronic acid; acetic acid chloride, propion Acid halides such as acid chloride and benzoic acid chloride; sodium methoxide, potassium tert-butoxide, bases such as sodium hydride, potassium carbonate, cesium carbonate, triethylamine, diisopropylamine, tetrabutylammonium bromide, sodium acetate, Burgess reagent, N , N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) or its hydrochloride, N, N′-carbonyldiimidazole, 1H-benzotriazol-1-yloxytris (dimethylamido
  • This reaction is carried out using a known solvent such as water; alcohols such as methanol and ethanol; ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; Esters, such as chloroform, dichloromethane; nitriles, such as acetonitrile; amides, such as N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidinone; acetone, It is carried out in a solvent such as ketones such as 2-butanone; sulfoxides such as dimethyl sulfoxide; acids such as acetic acid and hydrochloric acid.
  • a solvent such as water; alcohols such as methanol and ethanol; ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran; aromatic hydrocarbons such as
  • This reaction is preferably performed by dissolving compound (XVIIIa) or compound (XVIIIb) and compound compound (XXVII) in a solvent such as methanol, and if necessary, in the presence of an acid such as p-toluenesulfonic acid.
  • compound (XXVII) is usually used in an amount of usually about 1 to about 10 mol, preferably about 1 to about 5 mol, relative to 1 mol of starting compound (compound (XVIIIa) or compound (XVIIIb)),
  • the catalyst is usually used in an amount of about 0.01 to about 1 mole, preferably about 0.01 to about 0.1 mole.
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.1 to about 50 hours.
  • Compound (I) is Compound (If): In the case where each symbol in the formula is as defined above, the compound (I) is, for example, Compound (XXVIII): (Wherein each symbol is as defined above) and compound (III): (Each symbol in the formula is as defined above) can be reacted. Examples of this reaction include a method of condensing compound (XXVIII) and compound (III) with a generally known dehydration condensing agent.
  • Examples of the dehydrating condensing agent used in this reaction include N, N-dicyclohexylamide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) or its hydrochloride, carbonyldiimidazole, 1H-benzoic acid.
  • Triazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) ), Bromotripyrrolidinophosphonium hexafluorophosphate (PyBrop), diethyl phosphorocyanidate (diethyl cyanophosphate; DEPC), diphenylphosphoryl azide (diphenyl phosphate azide; DPPA), 4- (4,6-dimethoxy [1, , 5] triazin-2-yl) -4-methyl morpholinium chloride (DMTMM), or the like.
  • BOP Triazol-1-yloxytris
  • HATU O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate
  • This reaction may be carried out as necessary, for example, with a base such as 1-hydroxybenzotriazole (HOBt), N, N-diisopropylethylamine, N-methylmorpholine, triethylamine, 4- (N, N-dimethylamino) pyridine and the like. You may carry out in presence.
  • a base such as 1-hydroxybenzotriazole (HOBt), N, N-diisopropylethylamine, N-methylmorpholine, triethylamine, 4- (N, N-dimethylamino) pyridine and the like. You may carry out in presence.
  • This reaction is preferably carried out in a known solvent, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate Hydrocarbons such as cyclohexane and n-hexane; aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane; alcohols such as methanol and ethanol; water, etc.
  • solvents for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate Hydrocarbons such as cyclohexane and n-hexane; aromatic
  • This reaction preferably uses about 0.5 to about 10 moles, preferably about 1 to about 5 moles of compound (III) relative to 1 mole of compound (XXVIII), and the amount of dehydrating condensing agent is About 0.1 to about 100 equivalents, preferably about 1 to about 5 equivalents, the base is used with about 0.1 to about 100 equivalents, preferably about 1 to about 5 equivalents.
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • This reaction is preferably carried out in a known solvent, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate Hydrocarbons such as cyclohexane and n-hexane; aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane.
  • solvents may be mixed in an appropriate ratio or may not be used.
  • compound (III) is usually used in an amount of about 1 to about 5 mol per mol of the raw material compound (compound (XXIX)), and the reaction temperature is usually 0 ° C. to 200 ° C., preferably 40 ° C. to It is carried out at a reaction temperature of 200 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • This reaction is preferably carried out by dissolving compound (XXX) in a solvent such as N, N-dimethylformamide, adding potassium tert-butoxide, and then adding compound (V).
  • compound (V) is usually used in an amount of about 1 to about 5 mol per mol of the raw material compound (compound (XXX)), and the amount of the base is about 0.1 to about 100 equivalents, preferably 1 ⁇ 5 equivalents.
  • the reaction temperature is usually 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • This reaction generally employs a method in which an ester is hydrolyzed under basic conditions, and is performed, for example, by treating with an alkali such as lithium hydroxide, sodium hydroxide, and potassium hydroxide.
  • an alkali such as lithium hydroxide, sodium hydroxide, and potassium hydroxide.
  • the compound (XXIX) is dissolved in an alcohol such as methanol and ethanol; or a water-soluble solvent such as tetrahydrofuran and dioxane; or a mixed solvent thereof, an aqueous sodium hydroxide solution, an aqueous lithium hydroxide solution, or the like. It is carried out by treating with an alkaline aqueous solution.
  • reaction temperature is generally 0 ° C. to 100 ° C., preferably 20 ° C. to 100 ° C.
  • reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Process AD-2 Compound (XXVIII) can also be produced by a method in which an ester of compound (XXIX) is hydrolyzed under acidic conditions. For example, it is carried out by treatment with an acid such as hydrochloric acid, sulfuric acid, and nitric acid.
  • an acid such as hydrochloric acid, sulfuric acid, and nitric acid.
  • compound (XXIX) is dissolved in methanol and alcohols such as ethanol; or water-soluble solvents such as tetrahydrofuran and dioxane; or a mixed solvent thereof, and treated with an aqueous acid solution such as hydrochloric acid and sulfuric acid. Is done.
  • reaction temperature is generally 0 ° C. to 100 ° C., preferably 20 ° C. to 100 ° C.
  • reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • the reaction between compound (XXX) and compound (VII) is preferably potassium tert-butoxide, sodium hydride, triethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), carbonic acid
  • a base such as potassium and cesium carbonate
  • a solvent such as aromatic hydrocarbons such as toluene; ethers such as 1,4-dioxane and tetrahydrofuran; or amides such as N, N-dimethylformamide Done.
  • This reaction is preferably carried out by dissolving compound (XXX) in a solvent such as N, N-dimethylformamide, adding potassium tert-butoxide, and then adding compound (VII).
  • reaction about 1 to about 5 mol of compound (VII) is usually used with respect to 1 mol of the starting compound (compound (XXX)), and the amount of the base is about 0.1 to about 100 equivalents, preferably 1 ⁇ 5 equivalents.
  • the reaction temperature is usually 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Compound (I) is Compound (Ig): In the formula (wherein R 8 represents a C 1-6 alkyl group, and other symbols are as defined above), the compound (I) is, for example, Compound (If): (Wherein each symbol is as defined above) and compound (XXXI): (Each symbol in the formula is as defined above) can be reacted.
  • reaction between compound (If) and compound (XXXI) is preferably aromatic hydrocarbons such as toluene in the presence of a base such as triethylamine, pyridine, diisopropylethylamine; ethers such as 1,4-dioxane and tetrahydrofuran Or in a solvent such as amides such as N, N-dimethylformamide.
  • a base such as triethylamine, pyridine, diisopropylethylamine
  • ethers such as 1,4-dioxane and tetrahydrofuran Or in a solvent such as amides such as N, N-dimethylformamide.
  • This reaction is preferably carried out by dissolving compound (If) in a solvent such as tetrahydrofuran, adding triethylamine, and then adding compound (XXXI).
  • reaction about 1 to about 5 mol of compound (XXXI) is usually used with respect to 1 mol of raw material compound (compound (If)), and the amount of base is about 0.1 to about 100 equivalents, preferably 1 ⁇ 5 equivalents.
  • the reaction temperature is usually 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Process AH Also compounds: (Each symbol in the formula is as defined above) is, for example, Compound (If): (Wherein each symbol is as defined above) and compound (XXXII): (Wherein each symbol is as defined above) can be produced by a method of condensing with a generally known dehydration condensing agent.
  • the dehydrating condensing agent used in this reaction include N, N-dicyclohexylamide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) or its hydrochloride, carbonyldiimidazole, 1H-benzoic acid.
  • Triazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) ), Bromotripyrrolidinophosphonium hexafluorophosphate (PyBrop), diethyl phosphorocyanidate (diethyl cyanophosphate; DEPC), diphenylphosphoryl azide (diphenyl phosphate azide; DPPA), 4- (4,6-dimethoxy [1, , 5] triazin-2-yl) -4-methyl morpholinium chloride (DMTMM), or the like.
  • BOP Triazol-1-yloxytris
  • HATU O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate
  • This reaction may be carried out as necessary, for example, with a base such as 1-hydroxybenzotriazole (HOBt), N, N-diisopropylethylamine, N-methylmorpholine, triethylamine, 4- (N, N-dimethylamino) pyridine and the like. You may carry out in presence.
  • a base such as 1-hydroxybenzotriazole (HOBt), N, N-diisopropylethylamine, N-methylmorpholine, triethylamine, 4- (N, N-dimethylamino) pyridine and the like. You may carry out in presence.
  • This reaction is preferably carried out in a known solvent, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate Hydrocarbons such as cyclohexane and n-hexane; aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane; alcohols such as methanol and ethanol; water, etc.
  • solvents for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate Hydrocarbons such as cyclohexane and n-hexane; aromatic
  • compound (XXXII) is usually used in an amount of about 0.5 to about 10 mol, preferably about 1 to about 5 mol, relative to 1 mol of compound (If), and the amount of dehydration condensing agent is About 0.1 to about 100 equivalents, preferably about 1 to about 5 equivalents, the base is used with about 0.1 to about 100 equivalents, preferably about 1 to about 5 equivalents.
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • AI Compound (Ig) is Compound (XXXIII): (Wherein each symbol is as defined above) and compound (III): (Each symbol in the formula is as defined above) can be reacted.
  • AI-1) A method of condensing compound (XXXIII) and compound (III) with a generally known dehydration condensing agent;
  • AI-2) A method of reacting compound (III) after activating the carboxyl group of compound (XXXIII) by a generally known activation method; Etc.
  • Step AI-1 Compound (Ig) can be produced by condensing compound (XXXIII) and compound (III) with a generally known dehydration condensing agent.
  • the dehydrating condensing agent used in this reaction include N, N-dicyclohexylamide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) or its hydrochloride, carbonyldiimidazole, 1H-benzoic acid.
  • Triazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) ), Butomotripyrrolidinophosphonium hexafluorophosphate (PyBrop), diethyl phosphorocyanidate (diethyl cyanophosphate; DEPC), diphenylphosphoryl azide (diphenyl phosphate azide; DPPA), 4- (4,6-dimethoxy [1, , 5] triazin-2-yl) -4-methyl morpholinium chloride (DMTMM), or the like.
  • BOP Triazol-1-yloxytris
  • HATU O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate
  • This reaction may be carried out as necessary, for example, with a base such as 1-hydroxybenzotriazole (HOBt), N, N-diisopropylethylamine, N-methylmorpholine, triethylamine, 4- (N, N-dimethylamino) pyridine and the like. You may carry out in presence.
  • a base such as 1-hydroxybenzotriazole (HOBt), N, N-diisopropylethylamine, N-methylmorpholine, triethylamine, 4- (N, N-dimethylamino) pyridine and the like. You may carry out in presence.
  • This reaction is preferably carried out in a known solvent, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate Hydrocarbons such as cyclohexane and n-hexane; aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane; alcohols such as methanol and ethanol; water, etc.
  • solvents for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate Hydrocarbons such as cyclohexane and n-hexane; aromatic
  • compound (III) is usually used in an amount of about 0.5 to about 10 mol, preferably about 1 to about 5 mol, relative to 1 mol of compound (XXXIII).
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Step AI-2 It can also be produced by reacting compound (III) after activating the carboxyl group of compound (XXXIII) by a generally known activation method.
  • a method for activating the carboxyl group of compound (XXXIII) a general method is adopted. For example, mixed acid anhydrides using chloroformate, pivaloyl chloride, 2,4,6-trichlorobenzoyl chloride and the like are used.
  • a typical example is a method of acid halide, and as acid halide, Compound (XXXIIIa): (Wherein each symbol has the same meaning as described above), and for example, it can be produced by treating compound (XXXIII) with a halogenating agent such as thionyl chloride or oxalyl chloride.
  • a halogenating agent such as thionyl chloride or oxalyl chloride.
  • N, N-dimethylformamide may be added as an additive.
  • This reaction is preferably performed in a known solvent, for example, halogenated hydrocarbons such as dichloromethane; ethers such as tetrahydrofuran and diethyl ether; or aromatic hydrocarbons such as toluene or without solvent.
  • This reaction is preferably carried out by adding oxalyl chloride to compound (XXXIII) in the presence of N, N-dimethylformamide in tetrahydrofuran.
  • the halogenating agent is usually used in an amount of about 1 to about 100 equivalents, preferably 1 to 5 equivalents, relative to 1 mol of the raw material compound (Compound XXXIII).
  • the reaction temperature is usually ⁇ 78 ° C. to 100 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • the reaction of compound (XXXIIIa) with compound (III) is preferably a known solvent, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone; halogenation such as dichloromethane Hydrocarbons; Esters such as ethyl acetate; Hydrocarbons such as cyclohexane and n-hexane; Aromatic hydrocarbons such as toluene; Ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane It is carried out in a solvent. These solvents may be mixed in an appropriate ratio or may not be used.
  • amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone
  • halogenation such as dichloromethane Hydrocarbons
  • Esters such as ethyl acetate
  • compound (III) is usually used in an amount of about 0.5 to about 10 mol, preferably about 1 to about 5 mol, and base is about 0.1 to 1 mol of compound (XXXIIIa). To about 100 equivalents, preferably from about 1 to about 5 equivalents.
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Compound (Ig) is Compound (XXXIV): (Wherein each symbol is as defined above) and compound (III): (In the formula, each symbol is as defined above).
  • This reaction is performed, for example, by a method in which compound (XXXIV) and compound (III) coexist and are heated.
  • This reaction may be carried out in the presence of a base such as sodium hydride, sodium methoxide, alkyllithium, Grignard reagent; and a metal reagent such as trimethylaluminum as necessary.
  • This reaction is preferably carried out in a known solvent, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate Hydrocarbons such as cyclohexane and n-hexane; aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane.
  • solvents may be mixed in an appropriate ratio or may not be used.
  • reaction temperature is usually 0 ° C. to 200 ° C., preferably 40 ° C. to It is carried out at a reaction temperature of 200 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • AK Compound (XXXIII) used for the production of compound (Ig) is, for example, Compound (XXXIV): (Wherein each symbol has the same meaning as described above) can be produced by a method AK-1) or AK-2) of hydrolysis.
  • This reaction generally employs a method in which an ester is hydrolyzed under basic conditions, and is performed, for example, by treating with an alkali such as lithium hydroxide, sodium hydroxide, and potassium hydroxide.
  • an alkali such as lithium hydroxide, sodium hydroxide, and potassium hydroxide.
  • the compound (XXXIV) is dissolved in an alcohol such as methanol and ethanol; or a water-soluble solvent such as tetrahydrofuran and dioxane; or a mixed solvent thereof, an aqueous sodium hydroxide solution, an aqueous lithium hydroxide solution, or the like. It is carried out by treating with an alkaline aqueous solution.
  • reaction temperature is generally 0 ° C. to 100 ° C., preferably 20 ° C. to 100 ° C.
  • reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Process AK-2 Compound (XXXIII) can also be produced by a method of hydrolyzing an ester of compound (XXXIV) under acidic conditions. For example, it is carried out by treatment with an acid such as hydrochloric acid, sulfuric acid, and nitric acid.
  • an acid such as hydrochloric acid, sulfuric acid, and nitric acid.
  • Compound (XXXIV) is dissolved in methanol and alcohols such as ethanol; or water-soluble solvents such as tetrahydrofuran and dioxane; or a mixed solvent thereof, and treated with an aqueous acid solution such as hydrochloric acid and sulfuric acid. Is done.
  • reaction temperature is generally 0 ° C. to 100 ° C., preferably 20 ° C. to 100 ° C.
  • reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • reaction between compound (XXIX) and compound (XXXI) is preferably an aromatic hydrocarbon such as toluene in the presence of a base such as triethylamine, pyridine or diisopropylethylamine; an ether such as 1,4-dioxane and tetrahydrofuran Or in a solvent such as amides such as N, N-dimethylformamide.
  • a base such as triethylamine, pyridine or diisopropylethylamine
  • an ether such as 1,4-dioxane and tetrahydrofuran Or in a solvent such as amides such as N, N-dimethylformamide.
  • This reaction is preferably performed by dissolving compound (XXIX) in a solvent such as tetrahydrofuran, adding triethylamine, and then adding compound (XXXI).
  • compound (XXXI) is usually used in an amount of about 1 to about 5 mol per mol of the starting compound (compound (XXIX)), and the amount of the base is about 0.1 to about 100 equivalents, preferably 1 ⁇ 5 equivalents.
  • the reaction temperature is usually 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Compound (XXXIV) is, for example, Compound (XXIX): (Wherein each symbol is as defined above) and compound (XXXII): (Wherein each symbol is as defined above) can be produced by a method of condensing with a generally known dehydration condensing agent.
  • the dehydrating condensing agent used in this reaction include N, N-dicyclohexylamide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) or its hydrochloride, carbonyldiimidazole, 1H-benzoic acid.
  • Triazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) ), Bromotripyrrolidinophosphonium hexafluorophosphate (PyBrop), diethyl phosphorocyanidate (diethyl cyanophosphate; DEPC), diphenylphosphoryl azide (diphenyl phosphate azide; DPPA), 4- (4,6-dimethoxy [1, , 5] triazin-2-yl) -4-methyl morpholinium chloride (DMTMM), or the like.
  • BOP Triazol-1-yloxytris
  • HATU O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate
  • This reaction may be carried out as necessary, for example, with a base such as 1-hydroxybenzotriazole (HOBt), N, N-diisopropylethylamine, N-methylmorpholine, triethylamine, 4- (N, N-dimethylamino) pyridine and the like. You may carry out in presence.
  • a base such as 1-hydroxybenzotriazole (HOBt), N, N-diisopropylethylamine, N-methylmorpholine, triethylamine, 4- (N, N-dimethylamino) pyridine and the like. You may carry out in presence.
  • This reaction is preferably carried out in a known solvent, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate Hydrocarbons such as cyclohexane and n-hexane; aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane; alcohols such as methanol and ethanol; water, etc.
  • solvents for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate Hydrocarbons such as cyclohexane and n-hexane; aromatic
  • compound (XXXII) is usually used in an amount of about 0.5 to about 10 mol, preferably about 1 to about 5 mol, relative to 1 mol of compound (XXIX).
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • the compound (I 0 ) of the present invention can be obtained, for example, by the method shown by the following reaction formula or a method analogous thereto.
  • Each symbol of the compound in the reaction formula has the same meaning as described above.
  • the compound in the formula includes a case where a salt is formed. Examples of such a salt include the same salts as the salt of compound (I 0 ).
  • the compound obtained in each step can be used in the next reaction as a reaction solution or as a crude product, but can be isolated from the reaction mixture according to a conventional method. , Extraction, concentration, neutralization, filtration, distillation, recrystallization, distillation, chromatography, and other separation means. Or when the compound in a formula is marketed, a commercial item can also be used as it is.
  • Compound (2) can be produced by reacting Compound (1) and Compound (XXIa) in Step 1 by the same method as in Step Q.
  • Compound (3) can be produced by reacting Compound (2) and hydrazine in Step 2 by the same method as in Step Z.
  • Compound (4) can be produced by reacting Compound (2) and hydrazine in Step 3 in the same manner as in Step H.
  • Compound (3) can be produced in Step 4 by subjecting Compound (4) to an intramolecular cyclization reaction in the same manner as in Step G.
  • Compound (5) is obtained by reacting compound (3) with compound (VIIa) (in the formula, Yx represents a functional group such as a cyano group or an ester group) in Step 5 by the same method as in Step E. Can be manufactured.
  • Compound (7) can be produced by reacting Compound (6) with Compound (XIa) in Step 6 in the same manner as in Step I.
  • Compound (8) can be produced in Step 7 by acylating from compound (7) using compound (XXXV) in the presence of a suitable base according to a known method or the like.
  • the amount of compound (XXXV) to be used is about 1 mol to 5 mol, preferably about 1 mol to 2.0 mol, per 1 mol of compound (7).
  • the amount of the base used is about 1 mol to 10 mol, preferably about 1 mol to 3.0 mol, per 1 mol of the compound (7).
  • Suitable bases include, for example, tertiary organic bases such as triethylamine, ethyldiisopropylamine, pyridine, sodium hydride, potassium carbonate, potassium tert-butoxide, potassium hydride, calcium hydride, sodium amide, sodium ethoxide, sodium Using methoxide, magnesium ethoxide and the like, an appropriate solvent such as an aprotic solvent (for example, a polar compound (for example, DMF, DMSO, HMPA), a nitrile compound (for example, acetonitrile, propionitrile), an ether compound ( THF, dioxane, diethyl ether, dibutyl ether, dimethoxyethane), ketone compounds (acetone, methyl ethyl ketone, methyl isobutyl ketone), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.) , Halogen
  • the reaction temperature is usually about The temperature is -78 to about 100 ° C., preferably about 0 to about 100 ° C. A temperature higher or lower can be selected as necessary.
  • the reaction time is usually about 30 minutes to about 48 hours, preferably About 1 to 24 hours, a time longer or shorter can be selected as required.
  • Compound (5) can be produced in Step 8 by subjecting Compound (8) to an intramolecular cyclization reaction in the same manner as in Step G-2.
  • step 9 compound (I 0 ) is obtained from compound (3) according to known methods and the like using compound (XXXVI) (where Xx represents a hydroxyl group or a hydrogen atom). It can be produced by alkylation by a method or the like, or a coupling reaction.
  • the alkylation reaction by the Mitsunobu method is performed by using, for example, phosphines and azocarboxylic acid esters.
  • phosphines used in this reaction include triphenylphosphine and tributylphosphine.
  • the azocarboxylic acid esters used in this reaction include diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1, 1 ′-(azodicarbonyl) dipiperidine (ADDP), and the like. This reaction can be performed in a solvent, if necessary.
  • the solvent examples include ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; esters such as ethyl acetate; halogenated carbonization such as chloroform and dichloromethane. Hydrogen; Nitriles such as acetonitrile; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidinone; Ketones such as acetone and 2-butanone; Sulfoxides such as dimethyl sulfoxide And the like. These solvents may be used alone or in a mixture of two or more at an appropriate ratio.
  • ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • esters such as eth
  • This reaction is preferably carried out by dissolving compound (3), compound (XXXVI) and phosphines such as triphenylphosphine in a solvent such as tetrahydrofuran and using azocarboxylic acid esters such as diethyl azodicarboxylate.
  • phosphines are usually used in an amount of about 1 to about 10 mol, preferably about 1 to about 5 mol
  • azocarboxylic acid esters are usually used in an amount of about 1 to about 1 mol per 1 mol of compound (3). It is carried out using about 10 moles, preferably about 1 to about 5 moles.
  • the reaction temperature is usually -78 ° C to 100 ° C, preferably -78 ° C to 30 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.1 to about 50 hours.
  • the coupling reaction is performed using, for example, a base, a palladium reagent, or a copper reagent.
  • a phosphine ligand may be used as necessary.
  • the base used in this reaction include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal hydrogen carbonates such as sodium hydrogen carbonate; alkali metal carbonates such as sodium carbonate and potassium carbonate; cesium carbonate and the like.
  • alkali metal phosphate such as tripotassium phosphate
  • alkali metal hydride such as sodium hydride and potassium hydride
  • sodium amide alkali metal alkoxide such as sodium methoxide and sodium ethoxide
  • trimethylamine triethylamine
  • N- Amines such as ethyl N-isopropylpropan-2-amine and diisopropylamine
  • cyclic amines such as pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), etc.
  • DBU 1,8-diazabicyclo [5.4.0] undec-7-ene
  • Examples of the palladium reagent include tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) dichloride, tris (dibenzylideneacetone) dipalladium (0), trans-dichlorobis (tri- o-Tolylphosphine) palladium (II), palladium (II) trifluoroacetate, palladium (II) acetate and the like.
  • Examples of the copper catalyst include copper iodide, copper bromide, copper chloride, copper acetate and the like.
  • phosphine ligand examples include triphenylphosphine, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2- (di-tert-butylphosphino) biphenyl, and 2- (dicyclohexylphosphino).
  • Biphenyl 2- (dicyclohexylphosphino) -2 ′, 6′-dimethoxy-1,1′-biphenyl, 2- (dicyclohexylphosphino) -2 ′,-4 ′, 6′-triisopropyl-1,1 ′ -Biphenyl, 2- (dicyclohexylphosphino) -2 '-(N, N-dimethylamino) biphenyl, 1,1'-bis (diphenylphosphino) ferrocene, tri-tert-butylphosphine, tricyclohexylphosphine, (9 , 9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphine).
  • cyclohexyl-1,2-diamine, N, N′-dimethylcyclohexyl-1,2-diamine, or picolinic acid may be used as necessary.
  • This reaction is carried out using a known solvent such as water; alcohols such as methanol and ethanol; ethers such as diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane and tetrahydrofuran; and aromatics such as benzene, toluene and xylene.
  • Aromatic hydrocarbons Aromatic hydrocarbons; Esters such as ethyl acetate; Halogenated hydrocarbons such as chloroform and dichloromethane; Nitriles such as acetonitrile; N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidinone Amides such as; ketones such as acetone and 2-butanone; and sulfoxides such as dimethyl sulfoxide. These solvents may be mixed in an appropriate ratio or may not be used. This reaction may be performed under an atmosphere of nitrogen, argon, or the like as necessary.
  • (XXXVI) is usually used in an amount of about 0.5 to about 10 mol, preferably about 1 to about 5 mol, relative to the compound (3) mol, and the amount of the base is about 0.1 To about 100 equivalents, preferably about 1 to about 5 equivalents, palladium or copper reagent is about 0.01 to about 2 equivalents, preferably about 0.01 to about 0.5 equivalents, and the phosphine ligand is about 0.01 to about 2 equivalents, preferably about 0.01 to about 0.5 equivalents, and cyclohexyl-1,2-diamines are about 0.01 to about 2 equivalents, preferably about 0.01 to about 1 equivalent is used.
  • the reaction temperature is usually 0 ° C. to 200 ° C., preferably 50 ° C. to 150 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • compound (9) is compound (XXXVII) (wherein Xxa represents a hydroxyl group or a leaving group, and Yz represents boric acid, or from compound (3) according to a known method, etc. Represents a boric acid ester, etc.
  • the “leaving group” include a halogen atom, a sulfonyloxy group such as a p-toluenesulfonyloxy group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, etc.
  • Xxa is preferred.
  • the amount of compound (XXXVII) to be used is about 1 mol to 5 mol, preferably about 1 mol to 2.0 mol, per 1 mol of compound (3).
  • the amount of the base used is about 1 mol to 10 mol, preferably about 1 mol to 3.0 mol, per 1 mol of the compound (3).
  • Suitable bases include, for example, tertiary organic bases such as triethylamine, ethyldiisopropylamine, pyridine, sodium hydride, potassium carbonate, potassium tert-butoxide, potassium hydride, calcium hydride, sodium amide, sodium ethoxide, sodium Using a methoxide or the like, an appropriate solvent such as an aprotic solvent (for example, a polar compound (for example, DMF, DMSO, HMPA), a nitrile compound (for example, acetonitrile, propionitrile), an ether compound (THF, dioxane, Diethyl ether, dibutyl ether, dimethoxyethane), ketone compounds (acetone, methyl ethyl ketone, methyl isobutyl ketone), aromatic hydrocarbons (eg benzene, toluene, xylene, etc.), halogenated aromatic carbonization
  • the reaction temperature is usually about ⁇ 78 to about 150 ° C.
  • the temperature is preferably about 0 to about 100 ° C. If necessary, a temperature higher or lower can be selected, and the reaction time is usually about 30 minutes to about 48 hours, preferably about 1 hour to 24 hours. More or less time can be selected as needed.
  • Compound (I 0 ) can be produced in Step 11 from compound (9) by a coupling reaction using compound (XXXVIII) according to a known method or the like.
  • the coupling reaction is performed using, for example, a base, a palladium reagent, or a copper reagent.
  • a phosphine ligand may be used as necessary.
  • the base used in this reaction include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal hydrogen carbonates such as sodium hydrogen carbonate; alkali metal carbonates such as sodium carbonate and potassium carbonate; cesium carbonate and the like.
  • alkali metal phosphate such as tripotassium phosphate
  • alkali metal hydride such as sodium hydride and potassium hydride
  • sodium amide alkali metal alkoxide such as sodium methoxide and sodium ethoxide
  • trimethylamine triethylamine
  • N- Amines such as ethyl N-isopropylpropan-2-amine and diisopropylamine
  • cyclic amines such as pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), etc.
  • DBU 1,8-diazabicyclo [5.4.0] undec-7-ene
  • Examples of the palladium reagent include tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) dichloride, tris (dibenzylideneacetone) dipalladium (0), trans-dichlorobis (tri- o-Tolylphosphine) palladium (II), palladium (II) trifluoroacetate, palladium (II) acetate and the like.
  • Examples of the copper catalyst include copper iodide, copper bromide, copper chloride, copper acetate and the like.
  • phosphine ligand examples include triphenylphosphine, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2- (di-tert-butylphosphino) biphenyl, and 2- (dicyclohexylphosphino).
  • Biphenyl 2- (dicyclohexylphosphino) -2 ′, 6′-dimethoxy-1,1′-biphenyl, 2- (dicyclohexylphosphino) -2 ′,-4 ′, 6′-triisopropyl-1,1 ′ -Biphenyl, 2- (dicyclohexylphosphino) -2 '-(N, N-dimethylamino) biphenyl, 1,1'-bis (diphenylphosphino) ferrocene, tri-tert-butylphosphine, tricyclohexylphosphine, (9 , 9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphine).
  • cyclohexyl-1,2-diamine, N, N′-dimethylcyclohexyl-1,2-diamine, or picolinic acid may be used as necessary.
  • This reaction is carried out using a known solvent such as water; alcohols such as methanol and ethanol; ethers such as diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane and tetrahydrofuran; and aromatics such as benzene, toluene and xylene.
  • Aromatic hydrocarbons Aromatic hydrocarbons; Esters such as ethyl acetate; Halogenated hydrocarbons such as chloroform and dichloromethane; Nitriles such as acetonitrile; N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidinone Amides such as; ketones such as acetone and 2-butanone; and sulfoxides such as dimethyl sulfoxide. These solvents may be mixed in an appropriate ratio or may not be used. This reaction may be performed under an atmosphere of nitrogen, argon, or the like as necessary.
  • (XXXVIII) is usually used in an amount of about 0.5 to about 10 mol, preferably about 1 to about 5 mol, relative to 1 mol of compound (9), and the amount of base is about 0.00. 1 to about 100 equivalents, preferably about 1 to about 5 equivalents, palladium reagent or copper reagent is about 0.01 to about 2 equivalents, preferably about 0.01 to about 0.5 equivalents, and the phosphine ligand is About 0.01 to about 2 equivalents, preferably about 0.01 to about 0.5 equivalents, and cyclohexyl-1,2-diamines are about 0.01 to about 2 equivalents, preferably about 0.01 to about About 1 equivalent is used.
  • the reaction temperature is usually 0 ° C. to 200 ° C., preferably 50 ° C. to 150 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Compound (I 01 ) can be produced from step (12) by reductive alkylation together with an aldehyde using compound (XXXIX) from compound (3) according to a known method and the like.
  • the aldehyde paraformaldehyde or the like is used.
  • the amount of the aldehyde to be used is about 0.5 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of compound (3).
  • an acid catalyst may be added together with the aldehyde.
  • a protonic acid for example, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, etc.
  • a Lewis acid for example, aluminum chloride
  • This reaction is advantageously carried out without solvent or using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • alcohols such as water, methanol, ethanol, and propanol
  • hydrocarbons such as cyclohexane, hexane, benzene, toluene, xylene, and mesitylene
  • Organic acids such as acetic acid
  • ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether and diisopropyl ether
  • anilines such as N, N-dimethylaniline and N, N-diethylaniline, dichloromethane, chloroform
  • four Halogenated hydrocarbons such as carbon chloride and 1,2-dichloroethane or mixed solvents thereof are used.
  • the reaction temperature is usually about 0 to about 150 ° C., preferably about 60 to about 120 ° C. More or less temperatures can be selected as required.
  • the reaction time is usually about 10 minutes to about 24 hours, preferably about 30 minutes to 12 hours. More or less time can be selected as needed.
  • Compound (I 01 ) can be produced in Step 13 by reacting Compound (5) and Compound (XXXX) (wherein Xya represents an amino group or the like) in the same manner as in Step B. .
  • Compound (10) (wherein Yy represents a carboxy group, a hydroxyamidine, an aminomethyl group, etc.) is hydrolyzed, reduced or hydroxyamined from compound (5) in step 14 according to a known method or the like. It can be produced by an addition reaction or the like.
  • the hydrolysis reaction generally employs a method of hydrolysis under basic conditions or acidic conditions, and the basic conditions include, for example, treatment with an alkali such as lithium hydroxide, sodium hydroxide, and potassium hydroxide. Is done.
  • the compound (5) is dissolved in an alcohol such as methanol and ethanol; or a water-soluble solvent such as tetrahydrofuran and dioxane; or a mixed solvent thereof, an aqueous sodium hydroxide solution, an aqueous lithium hydroxide solution, or the like. It is performed by treating with an alkaline aqueous solution. In this reaction, about 1 to about 10 equivalent of an aqueous alkaline solution is usually used per 1 mol of compound (5).
  • the reaction temperature is generally 0 ° C. to 100 ° C., preferably 20 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • acidic conditions for example, it is carried out by treatment with an acid such as hydrochloric acid, sulfuric acid, and nitric acid.
  • the compound (5) is dissolved in an alcohol such as methanol and ethanol; or a water-soluble solvent such as tetrahydrofuran and dioxane; or a mixed solvent thereof, and treated with an aqueous acid solution such as hydrochloric acid, sulfuric acid or nitric acid. Is done.
  • an aqueous acid solution such as hydrochloric acid, sulfuric acid or nitric acid.
  • the reaction temperature is generally 0 ° C. to 100 ° C., preferably 20 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • metal hydrides such as sodium borohydride, lithium aluminum hydride and diisopropylaluminum hydride, and boranes such as borane tetrahydrofuran complex are used as a reducing agent.
  • the amount of the reducing agent to be used is about 0.5 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of the compound.
  • an acid catalyst may be added together with the reducing agent.
  • a protonic acid for example, acetic acid, trifluoroacetic acid and the like
  • a Lewis acid for example, aluminum chloride and the like
  • This reaction is advantageously carried out without solvent or using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • alcohols such as water, methanol, ethanol, and propanol
  • hydrocarbons such as cyclohexane, hexane, benzene, toluene, xylene, and mesitylene
  • Organic acids such as acetic acid
  • ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether and diisopropyl ether
  • anilines such as N, N-dimethylaniline and N, N-diethylaniline, dichloromethane, chloroform
  • four Halogenated hydrocarbons such as carbon chloride and 1,2-dichloroethane or mixed solvents thereof are used.
  • the reaction temperature is usually about 0 to about 120 ° C., preferably about 25 to about 60 ° C. More or less temperatures can be selected as required.
  • the reaction time is usually about 10 minutes to about 24 hours, preferably about 30 minutes to 12 hours. More or less time can be selected as needed.
  • Hydroxyamine addition reaction is carried out by using known solvents such as water; alcohols such as methanol and ethanol; ethers such as diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane and tetrahydrofuran; benzene, toluene and xylene.
  • Aromatic hydrocarbons such as ethyl acetate; halogenated hydrocarbons such as chloroform and dichloromethane; nitriles such as acetonitrile; N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl- It is carried out in a solvent such as amides such as 2-pyrrolidinone; ketones such as acetone and 2-butanone; sulfoxides such as dimethyl sulfoxide. These solvents may be mixed in an appropriate ratio or may not be used.
  • the reaction may be performed in the presence of a suitable base or acid according to a known method.
  • the amount of hydroxylamine to be used is about 1 mol to 5 mol, preferably about 1 mol to 2.0 mol, per 1 mol of compound (5).
  • the amount of the base used is about 1 mol to 10 mol, preferably about 1 mol to 3.0 mol, per 1 mol of the compound (5) used.
  • Suitable bases include, for example, tertiary organic bases such as triethylamine, ethyldiisopropylamine, pyridine, sodium hydride, potassium carbonate, sodium carbonate, potassium tert-butoxide, potassium hydride, calcium hydride, sodium amide, sodium ethoxy. , Sodium methoxide, magnesium ethoxide and the like can be used.
  • a protonic acid for example, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, etc.
  • a Lewis acid for example, aluminum chloride
  • the reaction temperature is generally about ⁇ 78 to about 100 ° C., preferably about 0 to about 100 ° C. More or less temperatures can be selected as required.
  • the reaction time is usually about 30 minutes to about 48 hours, preferably about 1 hour to 24 hours. More or less time can be selected as needed.
  • Compound (I 01 ) is compounded in Step 15, compound (10) with compound (XXXXI) (wherein Xyb represents an amino group, a carboxy group, a hydroxyamidine group, etc.)
  • Diacyl obtained by condensing an acid as an acid chloride with an amine, converting it to an isocyanate by a rearrangement reaction of a carboxylic acid, condensing it with an amine, condensing the carboxylic acid with hydrazine, and then condensing with another carboxylic acid
  • Oxadiazole cyclization by intramolecular dehydration condensation of acylhydroxyamidine obtained by condensation of hydrazine or carboxylic acid with hydroxyamidine, thiadiazole cyclization reaction by intramolecular dehydration condensation of diacylhydrazine with niline pentasulfide, etc.
  • Step A Amidation via acid chloride and production of diacylhydrazine and acylhydroxyamidine are carried out in the same manner as in Step A.
  • Examples of the rearrangement reaction from carboxylic acid to isocyanate include Curtius rearrangement, Schmitt rearrangement, Rossen rearrangement, Hoffman rearrangement and the like, and Curtius rearrangement is preferable.
  • diphenylphosphoryl azide (DPPA) is preferable when performing the Curtius rearrangement.
  • the carboxylic acid represented by the compound (5) is converted to an acyl azide by reacting with DPPA in the presence of a solvent, and this acyl azide is easily rearranged into an isocyanate by heating in the solvent.
  • the amount of DPPA used is calculated to be 1 mol or more with respect to the carboxylic acid, but preferably 1 to 3 mol.
  • Any reaction solvent can be used as long as it is an inert solvent, but aromatic hydrocarbon solvents such as benzene, toluene and xylene can be preferably used.
  • the reaction temperature is, for example, ⁇ 10 to 150 ° C., preferably 60 to 110 ° C.
  • a base may be used as necessary.
  • Examples of the base used in the reaction include triethylamine, diisopropylethylamine, 4-methylmorpholine, 4-ethylmorpholine, pyridine, 1-methylimidazole, 1,2-dimethylimidazole, 1,5-diazabicyclo [4.3. 0] -5-nonene, organic bases such as 1,5-diazabicyclo [5.4.0] -5-undecene, lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide , Alkali metal alkoxides such as potassium methoxide, potassium ethoxide, potassium tert-butoxide, and the like.
  • the reaction temperature usually ranges from ⁇ 70 ° C. to the boiling point of the solvent used, and preferably from ⁇ 10 ° C. to the boiling point of the solvent used.
  • the intramolecular dehydration condensation reaction is preferably carried out using a known solvent, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; ethyl acetate Esters such as cyclohexane, hydrocarbons such as n-hexane, aromatic hydrocarbons such as toluene and xylene, aromatic heterocycles such as pyridine, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone
  • Ethers such as methanol and ethanol; nitriles such as acetonitrile; organic acids such as acetic acid; inorganic acid aqueous solutions such as hydrochloric acid; or solvents such as water.
  • This reaction may be carried out, if necessary, for example, acid halides such as acetic acid chloride, propionic acid chloride, benzoic acid chloride; acids such as p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, hydrochloric acid; sodium methoxide, potassium tert- Bases such as butoxide, sodium hydride, potassium carbonate, and cesium carbonate; tetrabutylammonium bromide; sodium acetate; or Burgess reagent; or N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl ) Carbodiimide (WSC) or its hydrochloride
  • the reaction may be performed under Mitsunobu reaction conditions using azocarboxylic acid esters such as diethyl azodicarboxylate and diisopropyl azodicarboxylate, and phosphines such as triphenylphosphine.
  • azocarboxylic acid esters such as diethyl azodicarboxylate and diisopropyl azodicarboxylate
  • phosphines such as triphenylphosphine.
  • This reaction is usually performed at a reaction temperature of 0 ° C to 200 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • the thiadiazole cyclization reaction is preferably carried out in a known solvent, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; ethyl acetate and the like Esters; hydrocarbons such as cyclohexane and n-hexane; aromatic hydrocarbons such as toluene and xylene; aromatic heterocycles such as pyridine; tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone
  • halogenated hydrocarbons such as dichloromethane
  • ethyl acetate and the like Esters hydrocarbons such as cyclohexane and n-he
  • this reaction is carried out by dissolving diacylhydrazine in a solvent such as THF / toluene and irradiating with heating and stirring or microwaves.
  • This reaction is usually performed at a reaction temperature of 0 ° C to 200 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • the functional group in the molecule can be converted to the target functional group by combining known chemical reactions.
  • the chemical reaction include an oxidation reaction, a reduction reaction, an alkylation reaction, a hydrolysis reaction, an amination reaction, an amidation reaction, an esterification reaction, an aryl coupling reaction, and a deprotection reaction.
  • a protective group generally used in peptide chemistry or the like is introduced into these groups.
  • the target compound can be obtained by removing the protecting group as necessary after the reaction.
  • amino-protecting group examples include, for example, formyl, C 1-6 alkylcarbonyl (eg, acetyl, ethylcarbonyl, etc.), phenylcarbonyl, C 1-6 alkoxy-carbonyl (which may each have a substituent) For example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), phenyloxycarbonyl, C 7-10 aralkyl-carbonyl (eg, benzylcarbonyl, etc.), trityl, phthaloyl, N, N-dimethylaminomethylene, etc. .
  • Substituents for the “amino-protecting group” include halogen atoms (eg, fluorine, chlorine, bromine, iodine), C 1-6 alkyl-carbonyl (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), and The number of substituents including a nitro group is 1 to several (eg, 3).
  • Examples of the protecting group for the carboxyl group include a C 1-6 alkyl group, a C 7-11 aralkyl group (eg, benzyl), a phenyl group, a trityl group, a substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), and C 2-6 alkenyl groups (eg, 1-allyl). These groups may be substituted with 1 to 3 halogen atoms, C 1-6 alkoxy groups, nitro groups and the like.
  • Examples of the protecting group for the hydroxy group include a C 1-6 alkyl group, a phenyl group, a trityl group, a C 7-10 aralkyl group (eg, benzyl), a formyl group, a C 1-6 alkyl-carbonyl group, a benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert -Butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like.
  • a C 1-6 alkyl group eg, phenyl group, a trityl group, a C 7-10
  • These groups may be substituted with 1 to 3 halogen atoms, a C 1-6 alkyl group, a C 1-6 alkoxy group, a nitro group and the like.
  • the protecting group for the carbonyl group include cyclic acetals (eg, 1,3-dioxane), acyclic acetals (eg, di-C 1-6 alkylacetal) and the like.
  • the method for removing the protecting group described above can be carried out according to a known method such as the method described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980).
  • compound (I) or (I 0 ) can be synthesized.
  • compound (I) or (I 0 ) has an isomer such as an optical isomer, a stereoisomer, a positional isomer, a rotational isomer, etc., either one of the isomers or a mixture thereof is compound (I) or Included in (I 0 ).
  • optical resolution examples include methods known per se, such as a fractional recrystallization method, a chiral column method, a diastereomer method, and the like.
  • the “fractional recrystallization method” includes racemates and optically active compounds [eg, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1 -Phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.) to form a salt, which is separated by fractional recrystallization, etc., and optionally subjected to a neutralization step, free
  • the method of obtaining the optical isomer of this is mentioned.
  • Examples of the “chiral column method” include a method in which a racemate or a salt thereof is applied to an optical isomer separation column (chiral column).
  • a racemate is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series (manufactured by Daicel Corporation), and water, buffer solution (eg, phosphate buffer solution), organic solvent (eg, hexane) , Ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, triethylamine, etc.) or a mixed solvent thereof to separate optical isomers.
  • buffer solution eg, phosphate buffer solution
  • organic solvent eg, hexane
  • Ethanol eg, methanol
  • isopropanol acetonitrile
  • trifluoroacetic acid diethylamine
  • triethylamine triethylamine
  • a separation method using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences) can be mentioned.
  • a racemic mixture and an optically active reagent are reacted to obtain a mixture of diastereomers, and then one diastereomer is obtained by a usual separation means (eg, fractional recrystallization, chromatography method, etc.).
  • a chemical reaction eg, acid hydrolysis reaction, basic hydrolysis reaction, hydrogenolysis reaction, etc.
  • optically active reagent examples include optically active organic acids such as MTPA [ ⁇ -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid] and ( ⁇ )-menthoxyacetic acid; (1R-endo) -2 And optically active alkoxymethyl halides such as-(chloromethoxy) -1,3,3-trimethylbicyclo [2.2.1] heptane.
  • optically active organic acids such as MTPA [ ⁇ -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid] and ( ⁇ )-menthoxyacetic acid; (1R-endo) -2
  • optically active alkoxymethyl halides such as-(chloromethoxy) -1,3,3-trimethylbicyclo [2.2.1] heptane.
  • Compound (I) or (I 0 ) may be in the form of a crystal, and is included in compound (I) or (I 0 ), respectively, whether the crystal form is single or a crystal form mixture. Crystals can be produced by crystallization by applying a crystallization method known per se.
  • Compound (I) or (I 0 ) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). Means a crystalline substance composed of a solid.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • Compound (I) or (I 0 ) may be a solvate (eg, a hydrate) or a non-solvate (eg, an anhydride), and both are compound (I) Or (I 0 ).
  • a compound labeled or substituted with an isotope eg, 2 H, 3 H, 11 C, 14 C, 18 F, 35 S, 125 I, etc.
  • the prodrug of compound (I) or (I 0) the compound by reaction with an enzyme, gastric acid, etc.
  • a prodrug of compound (I) or (I 0 ) a compound in which amino of compound (I) or (I 0 ) is acylated, alkylated or phosphorylated (eg, compound (I) or (I 0 )) Amino is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxy Methylated or tert-butylated compounds, etc.); compounds wherein the hydroxy group of compound (I) or (I 0 ) is acylated, alkylated, phosphorylated or borated (eg, compound (I) or (I 0 ) hydroxy is acetylated, palmitoylated, propanoylated, pivaloy
  • compound (I) or (I 0 ) can be produced from compound (I) or (I 0 ) by a method known per se.
  • the prodrug of compound (I) or (I 0 ) is compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Development of Drugs”, Volume 7, Molecular Design, pages 163 to 198. Alternatively, it may be changed to (I 0 ).
  • Compounds (I) and (I 0 ), and their prodrugs (hereinafter sometimes simply referred to as the compounds of the present invention) exhibit excellent AMPA receptor function-enhancing action, and thus are based on these actions. It is also useful as a safe medicine.
  • the compound of the present invention having an excellent AMPA receptor function-enhancing action is effective against mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human, etc.)
  • mammals eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human, etc.
  • Psychiatric disorders eg, depression, major depression, bipolar depression, mood disorders, affective disorders (such as seasonal affective disorders), recurrent depression, postpartum depression, stress disorder, depressive symptoms, Gonorrhea, anxiety, generalized anxiety disorder, anxiety syndrome, panic disorder, phobia, social phobia, social anxiety disorder, obsessive compulsive disorder, post-traumatic stress syndrome, post-traumatic stress disorder, taurette syndrome, autism ,
  • the compound of the present invention has an excellent AMPA receptor function enhancing action, an excellent therapeutic effect on the above diseases can be expected.
  • the compounds of the present invention have excellent pharmacokinetics (eg, blood drug half-life) and low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.) From the point of view, mammals (eg, humans, monkeys, cows, horses, pigs, mice, Rats, hamsters, rabbits, cats, dogs, sheep, goats, etc.) and can be safely administered orally or parenterally.
  • “Parenteral” includes intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, rectal, intravaginal, intraperitoneal, and direct lesion administration. Including.
  • the medicament containing the compound of the present invention can be prepared by singly using the compound of the present invention alone or pharmaceutically with the compound of the present invention according to a method known per se (eg, a method described in the Japanese Pharmacopoeia) as a method for producing a pharmaceutical preparation. It can be used as a pharmaceutical composition mixed with an acceptable carrier.
  • examples of the medicament containing the compound of the present invention include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (soft capsules, microcapsules).
  • controlled release formulations eg, immediate release formulations, sustained release
  • excipient examples include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
  • lubricant examples include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • binder examples include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, and the like.
  • Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like.
  • Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone And hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and the like.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate
  • polyvinyl alcohol polyvinylpyrrolidone
  • hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose
  • Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of preservatives include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid, and the like.
  • Examples of the antioxidant include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • the dose of the compound of the present invention varies depending on the administration route, symptoms and the like.
  • a schizophrenic patient adult, body weight 40 to 80 kg, eg 60 kg
  • Kg body weight preferably 0.01 to 100 mg / kg body weight per day, more preferably 0.1 to 10 mg / kg body weight per day. This amount can be administered in 1 to 3 divided doses per day.
  • pharmaceutically acceptable carrier various organic or inorganic carriers conventionally used as pharmaceutical materials can be used.
  • excipients lubricants, binders and disintegrants
  • liquid preparations solvents, solubilizers, suspending agents, isotonic agents, buffering agents, and the like Soothing agents and the like are used.
  • preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
  • the pharmaceutical composition varies depending on the dosage form, administration method, carrier, etc., but the compound of the present invention is usually 0.01 to 100% (w / w), preferably 0.1 to 95% (w / W), it can be produced according to a conventional method.
  • the compound of the present invention may be used in combination with other active ingredients (hereinafter abbreviated as concomitant drugs).
  • concomitant drug examples include the following. Benzodiazepines (chlordiazepoxide, diazepam, potassium chlorazebuate, lorazepam, clonazepam, alprazolam, etc.), L-type calcium channel inhibitors (pregabalin, etc.), tricyclic or tetracyclic antidepressants (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, Clomipramine hydrochloride, etc.), selective serotonin reuptake inhibitors (fluvoxamine maleate, floxetine hydrochloride, citalopram hydrochloride, sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate, etc.), serotonin-noradrenaline reuptake inhibitors (venlafaxine hydrochloride, hydrochloric acid) Duroxetine, desvenlafaxine hydrochloride, etc.
  • the compound of the present invention By combining the compound of the present invention and a concomitant drug, (1) The dose can be reduced compared to when the compound of the present invention or the concomitant drug is administered alone. (2) The drug used in combination with the compound of the present invention can be selected according to the patient's symptoms (mild, severe, etc.), (3) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the treatment period can be set longer. (4) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the therapeutic effect can be sustained. (5) By using the compound of the present invention in combination with a concomitant drug, excellent effects such as a synergistic effect can be obtained.
  • the combined use of the compound of the present invention and the concomitant drug is referred to as “the combination drug of the present invention”.
  • the timing of administration of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention or the pharmaceutical composition thereof and the concomitant drug or the pharmaceutical composition thereof are administered to the subject of administration. They may be administered at the same time or may be administered with a time difference.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration form of the concomitant drug of the present invention is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
  • Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and (2) separate preparation of the compound of the present invention and the concomitant drug. Simultaneous administration of the two preparations obtained by the same administration by the same administration route, (3) with a time difference in the same administration route of the two preparations obtained by separately formulating the compound of the present invention and the concomitant drug.
  • the medicament containing the compound of the present invention is a pharmacologically acceptable compound of the present compound alone or with the compound of the present invention according to a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia). It can be used as a pharmaceutical composition mixed with a carrier.
  • examples of the medicament containing the compound of the present invention include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (soft capsules, microcapsules).
  • excipients for example, in solid preparations, excipients, lubricants, binders and disintegrants can be used.
  • solvents, solubilizers, suspending agents, tonicity agents, buffers, soothing agents, and the like can be used.
  • additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
  • Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, and the like.
  • Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like.
  • Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone And hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and the like.
  • Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of preservatives include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid, and the like.
  • Examples of the antioxidant include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • the compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation. More preferably, it is about 0.5 to 20% by weight.
  • the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about the whole preparation. About 0.5 to 20% by weight.
  • the content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. .
  • the same content may be used when the compound of the present invention and the concomitant drug are formulated separately.
  • room temperature usually indicates about 10 ° C. to about 35 ° C.
  • % Indicates weight percent unless otherwise specified.
  • Other abbreviations used in the text have the following meanings. s is a singlet, d is a doublet, t is a triplet, q is a quartet, spt is a septet, m is a multiplet, and br is a broad, “brs” is a broad singlet, and “J” is a coupling constant.
  • LC-MS Liquid chromatography-mass spectrometry spectrum
  • ESI Electrospray ionization method
  • TLC Thin layer chromatography M: Molar concentration N: Standard mp: melting point
  • BINAP 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl
  • BSA bovine serum albumin
  • DCM dichloromethane
  • DIAD diisopropyl azodicarboxylate
  • DIEA N, N-diisopropylethylamine
  • DMA N, N -Dimethylacetamide
  • DMF N, N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • EDCI 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • EDTA ethylenediaminetetraacetic acid
  • HATU O- (7-azabenzotriazol-1-yl )
  • Measuring instruments Burker AVANCE III plus 400 MHz, Bruker AVANCE 300, Varian VNMRS-400 Internal standard: trimethylsilane MS values in the following examples were measured under the following conditions.
  • Measuring instrument Waters LC-MS system HPLC part: Agilent HP1100 MS Department: Waters company micromassZQ Ionization method: ESI Or HPLC part: Agilent 1200 MS Department: Agilent 6300 Ionization method: ESI Or Measuring equipment: FINNIGAN Thermo LCQ Advantage MAX, Agilent LC 1200 series Ionization method: ESI Further, purification by preparative HPLC in the following examples was carried out under the following conditions.
  • the resulting THF solution of lithium diisopropylamide (LDA) was added dropwise to a solution of tetrahydro-2H-pyran-2-one (33.37 g, 333 mmol) in THF (450 ml) at ⁇ 78 ° C. over 1.5 hours.
  • Fluoroacetic acid 2,2,2-trifluoroethyl ester was added dropwise at ⁇ 78 ° C. over 20 minutes, and the mixture was further stirred for 30 minutes.
  • the reaction mixture was poured into a mixture of 6N hydrochloric acid (100 mL) and ice (600 mL), and extracted with ethyl acetate.
  • Reference Example 8 4- (3-Hydroxypropyl) -3- (trifluoromethyl) -1H-pyrazol-5-ol under nitrogen atmosphere, (3Z) -3- (2,2,2-trifluoro-1-hydroxyethylidene) tetrahydro -H-pyran-2-one (43.06 g, 220 mmol), p-toluenesulfonic acid monohydrate (2.09 g, 11 mmol) and toluene (400 ml) in a mixture of hydrazine monohydrate (14.29 g, 286 mmol), and the mixture was stirred at 80 ° C. for 4 hours.
  • the mixture was poured into an aqueous ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel chromatography [developing solvent: petroleum ether / dichloromethane (1: 1)] to obtain 3.26 g (yield 44%) of the product as a white solid.
  • the product was dissolved in ethyl acetate (50 mL) and 4N hydrogen chloride ethyl acetate solution (20 mL) was added. The reaction mixture was stirred at room temperature for 5 hours and concentrated under reduced pressure.
  • Reference Example 14 7-methyl-3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridine 1- (4-methoxybenzyl) -7-methyl-3- (tri Fluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridine (300 mg, 0.92 mmol) in trifluoroacetic acid (10 mL) and chloroform (10 mL) Stir overnight. The mixture was adjusted to pH 7 with saturated aqueous sodium hydrogen carbonate solution.
  • reaction solution was added to a mixture of 5-chloro-2-methoxyphenylamine (5.1 g, 32.4 mmol) and triethylamine (6 mL, 0.68 mmol) and stirred at room temperature for 4 hours.
  • 200 mL of dichloromethane was added to the mixture and washed with 50 mL of saturated aqueous sodium hydrogen carbonate solution.
  • the organic layer was washed with 200 mL of water, 100 mL of 1N hydrochloric acid, 100 mL of saturated aqueous sodium hydrogen carbonate solution and 100 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the mixture was washed with 10 mL of 1N hydrochloric acid.
  • the aqueous layer was extracted twice with 50 mL of ethyl acetate.
  • the organic layer was washed with 30 mL saturated aqueous sodium hydrogen carbonate solution and 30 mL water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Reference Example 29 8-Bromo-3-methyl-6- (trifluoromethyl) imidazo [1,2-a] pyridine 2-amino-3-bromo-5-trifluoromethylpyridine (3.00 g, 12.4 mmol), 2- A mixture of bromopropanal (3.41 g, 24.9 mmol), disodium hydrogen phosphate (2.65 g, 18.6 mmol) and n-butanol (25 mL) was stirred at 120 ° C. for 3 days and cooled to room temperature. . The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 ⁇ 50 mL).
  • Reference Example 32 8-Bromo-2-methyl-6- (trifluoromethyl) imidazo [1,2-a] pyridine 2-amino-3-bromo-5-trifluoromethylpyridine (3.00 g, 12.4 mmol), bromoacetone A mixture of (1.14 mL, 13.6 mmol), disodium hydrogen phosphate (2.65 g, 18.6 mmol) and n-butanol (25 mL) was stirred at 120 ° C. for 3 days and cooled to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 ⁇ 50 mL).
  • Reference Example 40 8-bromo-2-ethyl-3-methyl-6- (trifluoromethyl) imidazo [1,2-a] pyridine 2-amino-3-bromo-5-trifluoromethylpyridine (500 mg, 2.07 mmol), A mixture of 2-bromopentan-3-one (856 mg, 5.19 mmol), titanium tetrachloride (171 ⁇ L, 1.55 mmol), and triethylamine (173 ⁇ l, 1.24 mmol) and chloroform (2.0 mL) was stirred while stirring. Microwave irradiation at 25 ° C. for 25 minutes. The reaction mixture was diluted with dichloromethane (15 mL) and 10% aqueous potassium carbonate (15 mL).
  • Example 2 4- ⁇ [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] methyl ⁇ benzoic acid Methyl 4- ⁇ [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] methyl ⁇ benzoate (480 mg, 1.41 mmol) and lithium hydroxide mono Hydrate (178 mg, 4.23 mmol) in THF (2.8 mL) / methanol (2.8 mL) / water (1.4 mL) was stirred at room temperature for 1.5 hours.
  • Example 3 N, N-dimethyl-4- ⁇ [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] methyl ⁇ benzamide 4- ⁇ [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] methyl ⁇ benzoic acid (100 mg, 0.31 mmol) in dichloromethane (3.2 mL) ) Solution with diisopropylethylamine (DIEA) (0.34 mL, 1.86 mmol), dimethylamine hydrochloride (78 mg, 0.94 mmol), 1-hydroxybenzotriazole (HOBt, 127 mg, 0.94 mmol) and 1- (3- Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI, 191 mg, 0.94 mmol) was added at 0 ° C.
  • Example 6 [4- (Pyrrolidin-1-ylcarbonyl) benzyl] -3- (trifluoromethyl) -1,4,5,6-tetrahydropyrano [2,3-c] pyrazole 4- ⁇ [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] methyl ⁇ benzoic acid (100 mg, 0.31 mmol) in dichloromethane (3.2 mL) ) DIEA (0.34 mL, 1.86 mmol), pyrrolidine (0.1 mL, 0.94 mmol), HOBt (127 mg, 0.94 mmol) and EDCI (191 mg, 0.94 mmol) were added to the solution at 0 ° C.
  • Example 7 Methyl 3- ⁇ [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] methyl ⁇ benzoate Methyl 3- ⁇ [5-hydroxy-4- (3-hydroxypropyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] methyl ⁇ benzoate (compound of Reference Example 7) (350 mg, 0. To a solution of 98 mmol) and triphenylphosphine (514 mg, 1.96 mmol) in THF (36 mL) was added DIAD (0.38 mL, 1.96 mmol). The mixture was stirred at 0 ° C. for 1 hour and concentrated under reduced pressure.
  • Example 8 3- ⁇ [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] methyl ⁇ benzoic acid Methyl 3- ⁇ [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] methyl ⁇ benzoate (267 mg, 0.78 mmol), and lithium hydroxide A solution of monohydrate (98 mg, 2.36 mmol) in THF (2.0 mL) / methanol (2.0 mL) / water (1.0 mL) was stirred at room temperature for 1.5 hours.
  • Example 11 N- (1-methylethyl) -3- ⁇ [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] methyl ⁇ benzamide 3- ⁇ [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] methyl ⁇ benzoic acid (100 mg, 0.31 mmol) in dichloromethane (3.2 mL) ) To the solution was added DIEA (0.34 mL, 1.86 mmol), isopropylamine (0.1 mL, 0.94 mmol), HOBt (127 mg, 0.94 mmol) and EDCI (191 mg, 0.94 mmol) at 0 ° C.
  • DIEA 0.34 mL, 1.86 mmol
  • isopropylamine 0.1 mL, 0.94 mmol
  • HOBt 127 mg,
  • Example 12 [3- (Pyrrolidin-1-ylcarbonyl) benzyl] -3- (trifluoromethyl) -1,4,5,6-tetrahydropyrano [2,3-c] pyrazole 3- ⁇ [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] methyl ⁇ benzoic acid (200 mg, 0.61 mmol) in dichloromethane (6 mL) DIEA (0.66 mL, 3.68 mmol), pyrrolidine (0.2 mL, 1.83 mmol), HOBt (254 mg, 1.83 mmol) and EDCI (382 mg, 1.83 mmol) were added at 0 ° C.
  • Example 13 3- ⁇ [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] methyl ⁇ benzamide 3- ⁇ [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] methyl ⁇ benzoic acid (130 mg, 0.40 mmol) in dichloromethane (2 mL) was added with oxalyl chloride (0.052 mL, 0.60 mmol) and DMF (1 drop) at room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 2 mL of THF.
  • Example 14 N-methyl-3- ⁇ [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] methyl ⁇ benzamide 3- ⁇ [3- (Trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] methyl ⁇ benzoic acid (130 mg, 0.40 mmol) in dichloromethane (2 mL) Oxalyl chloride (0.052 mL, 0.60 mmol) and DMF (1 drop) were added at room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was added to 2 mL of THF.
  • Example 16 Methyl 4- ⁇ [3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridin-1-yl] methyl ⁇ benzoate 3- (trifluoroacetyl) piperidin-2-one (565 mg, 2.9 mmol) (compound of reference example 13), methyl 4- (hydrazinomethyl) benzoate (compound of reference example 3) (522 mg, 2.9 mmol) ), Toluene (50 mL) and p-toluenesulfonic acid monohydrate (23 mg, 0.05 mmol) were refluxed for 4 hours and then concentrated under reduced pressure.
  • Example 17 4- ⁇ [3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridin-1-yl] methyl ⁇ benzoic acid
  • Lithium hydroxide monohydrate 430 mg, 10.2 mmol
  • Example 18 N, N-diethyl-4- ⁇ [3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridin-1-yl] methyl ⁇ benzamide 4- ⁇ [3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridin-1-yl] methyl ⁇ benzoic acid (compound of Example 17) ( 300 mg, 0.92 mmol) in dichloromethane (9 mL) was cooled to 0 ° C., then diisopropylethylamine (0.96 mL, 5.6 mmol), diethylamine (0.30 mL, 2.8 mmol), HOBt (378 mg, 2.8 mmol) , EDCI (540 mg, 2.8 mmol) was added.
  • Example 19 7-Methyl-1- [4- (pyrrolidin-1-ylcarbonyl) benzyl] -3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridine 4- ⁇ [3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridin-1-yl] methyl ⁇ benzoic acid (compound of Example 17) ( After cooling a solution of 100 mg, 0.30 mmol) in dichloromethane (3 mL) to 0 ° C., diisopropylethylamine (0.32 mL, 1.8 mmol), pyrrolidine (0.077 mL, 0.92 mmol), HOBt (124 mg, 2.8 mmol) , And EDCI (177 mg, 2.8 mmol) were added.
  • Example 21 1- (4-Methoxybenzyl) -3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridine 3- (trifluoroacetyl) piperidin-2-one (Compound of Reference Example 13) (8.0 g, 40 mmol) and (4-methoxybenzyl) hydrazine (6.2 g, 40 mmol) in toluene (100 mL) / ethyl acetate The solution (10 mL) was refluxed for 4 hours and then concentrated under reduced pressure.
  • Example 22 (4-Methoxybenzyl) -7-methyl-3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridine
  • 4-methoxybenzyl) -3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridine (311 mg, 1.0 mmol) at 0 ° C.
  • DMF To the (20 mL) solution, sodium hydride (60%, in mineral oil, 60 mg, 1.5 mmol) was added and after 5 minutes iodomethane (0.075 mL, 1.2 mmol) was added. The reaction mixture was warmed to room temperature and stirred overnight.
  • Example 23 7-acetyl-1- (4-methoxybenzyl) -3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridine
  • 4-methoxybenzyl) -3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridine (311 mg, 1.0 mmol) at 0 ° C.
  • DMF To (20 mL) was added sodium hydride (60%, in mineral oil, 60 mg, 1.5 mmol). After 5 minutes, acetic anhydride (0.15 mL, 1.5 mmol) was added. The reaction mixture was warmed to room temperature and stirred overnight.
  • Example 24 (4-Methoxybenzyl) -7- (trifluoroacetyl) -3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridine
  • 4-Methoxybenzyl) -3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridine (compound of Example 21) (311 mg, 1.
  • Triethylamine (0.83 mL, 6.0 mmol
  • dichloromethane 5 mL
  • Example 25 N- (5-Chloro-2-methoxyphenyl) -2- [7-methyl-3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridine 1-yl] acetamide [7-Methyl-3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridin-1-yl] acetic acid (compound of Reference Example 16) (320 mg, To a solution of 1.22 mmol) in dichloromethane (5 mL) were added oxalyl chloride (0.16 mL, 1.83 mmol) and DMF (1 drop) at 0 ° C., and the mixture was stirred under a nitrogen atmosphere for 1 hour.
  • reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 2 mL of 1,2-dichloroethane.
  • the mixture was further stirred at room temperature for 4 hours. 50 mL of dichloromethane was added to the mixture, and the mixture was washed with 30 mL of saturated aqueous sodium hydrogen carbonate solution.
  • Example 26 2- [7-acetyl-3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridin-1-yl] -N- (5-chloro-2 -Methoxyphenyl) acetamide [7-Acetyl-3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridin-1-yl] acetic acid (72 mg, 0.25 mmol) in dichloromethane ( 2 mL) were added oxalyl chloride (0.033 mL, 0.37 mmol) and DMF (1 drop) at 0 ° C., and the mixture was stirred under a nitrogen atmosphere for 1 hour.
  • reaction mixture was concentrated under reduced pressure and the residue was dissolved in 2 mL of 1,2-dichloroethane.
  • the reaction solution was added to a mixture of 5-chloro-2-methoxyphenylamine (39 mg, 0.25 mmol), DMAP (3 mg, 0.025 mmol) and pyridine (0.03 mL, 0.50 mmol) and stirred at room temperature for 4 hours. did. 20 mL of dichloromethane was added to the mixture, and the mixture was washed with 10 mL of saturated aqueous sodium hydrogen carbonate solution.
  • Example 28 7-methyl-1-[(2-methyl-1,3-benzothiazol-5-yl) methyl] -3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3 4-b] pyridine 7-methyl-3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b] pyridine (Compound of Reference Example 14) (102 mg, 0.50 mmol) at 0 ° C. To a DMF (2 mL) solution of sodium hydride (60%, 30 mg, 0.75 mmol in mineral oil) was added.
  • Example 30 4,5-dimethyl-2-( ⁇ [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] acetyl ⁇ amino) thiophene-3-carboxamide [3- (Trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] acetic acid (compound of Reference Example 11) (100 mg, 0.40 mmol) in dichloromethane (3.
  • Example 31 N- (5-Chloro-2-methoxyphenyl) -2- [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] acetamide [3- (Trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] acetic acid (compound of Reference Example 11) (80 mg, 0.32 mmol) in dichloromethane (2 mL) Oxalyl chloride (0.055 mL, 0.64 mmol) and DMF (1 drop) were added dropwise at 0 ° C. under a nitrogen atmosphere.
  • Example 32 N- (3-Chloro-4-fluorobenzyl) -2- [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] acetamide [3- (Trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] acetic acid (compound of Reference Example 11) (100 mg, 0.40 mmol) and DMF (5 mL) To this mixture was added EDCI (115 mg, 0.60 mmol), HOBt monohydrate (81 mg, 0.60 mmol), and 1- (3-chloro-4-fluorophenyl) methanamine (96 mg, 0.60 mmol) at room temperature.
  • EDCI 115 mg, 0.60 mmol
  • HOBt monohydrate 81 mg, 0.60 mmol
  • 1- (3-chloro-4-fluorophenyl) methanamine
  • Example 33 N- ⁇ [3- (1-Methylethyl) isoxazol-5-yl] methyl ⁇ -2- [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazole-1 (4H ) -Il] acetamide [3- (Trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] acetic acid (compound of Reference Example 11) (300 mg, 1.2 mmol), THF (6 ml) Then, oxalyl chloride (304 mg, 2.4 mmol) was added to a mixture of DMF (6 drops) at 0 ° C.
  • Example 36 N- [5- (Cyclopropylsulfamoyl) -2-methoxyphenyl] -2- [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl Acetamide [3- (Trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] acetic acid (compound of Reference Example 11) (100 mg, 0.40 mmol) and DMF (5 mL) EDCI (115 mg, 0.60 mmol), HOBt monohydrate (81 mg, 0.60 mmol), and 3-amino-N-cyclopropyl-4-methoxybenzenesulfonamide (107 mg, 0.60 mmol) at room temperature.
  • compound of Reference Example 11 100 mg, 0.40 mmol
  • DMF 5 mL
  • EDCI 115 mg, 0.60 mmol
  • Example 37 2-( ⁇ [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] acetyl ⁇ amino) -5,6-dihydro-4H-cyclopenta [b ] Thiophene-3-carboxamide [3- (Trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] acetic acid (compound of Reference Example 11) (100 mg, 0.4 mmol), THF (2 mL) And oxalyl chloride (102 mg, 0.8 mmol) was added to a mixture of DMF (2 drops) at 0 ° C.
  • Example 38 2- [3- (Trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] -N- [6- (trifluoromethyl) imidazo [1,2-a ] Pyridin-8-yl] acetamide [3- (Trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] acetyl chloride (compound of Reference Example 12) (268 mg, 0.999 mmol) in dichloromethane (8 .00 mL) solution in triethylamine (0.232 mL, 1.66 mmol) followed by 6- (trifluoromethyl) imidazo [1,2-a] pyridin-8-amine (compound of Reference Example 28) (168 mg, 0.833 mmol) ) Was added dropwise at 0 ° C.
  • Example 45 N- (6-Bromo-2,3-dimethylimidazo [1,2-a] pyridin-8-yl) -2- [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] Pyrazol-1 (4H) -yl] acetamide 6-Bromo-2,3-dimethylimidazo [1,2-a] pyridin-8-amine (compound of Reference Example 53) (1.50 g, 6.25 mmol), [3- (trifluoromethyl) -5, 6-Dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] acetic acid (compound of Reference Example 11) (1.56 g, 6.25 mmol), boric acid (1.16 g, 18.75 mmol) in chlorobenzene The (300 mL) solution was refluxed for 24 hours, water was removed using calcium hydride in a dean stark apparatus, cooled and concentrated under reduced pressure.
  • Example 46 N- (2,3-Dimethyl-6-phenylimidazo [1,2-a] pyridin-8-yl) -2- [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] Pyrazol-1 (4H) -yl] acetamide N- (6-Bromo-2,3-dimethylimidazo [1,2-a] pyridin-8-yl) -2- [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] Pyrazol-1 (4H) -yl] acetamide (Compound of Example 45) (268 mg, 0.57 mmol), phenylboronic acid (139 mg, 1.14 mmol), 1,1′-bis (diphenylphosphino) ferrocene] dichloro Palladium (51 mg, 0.11 mmol), potassium carbonate (236 mg, 1.71 mmol) in dimethoxyethane (24
  • Example 48 2- [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] -N- (2,3,6-trimethylimidazo [1,2-a ] Pyridin-8-yl) acetamide N- (6-Bromo-2,3-dimethylimidazo [1,2-a] pyridin-8-yl) -2- [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] Pyrazol-1 (4H) -yl] acetamide (Compound of Example 45) (800 mg, 1.69 mmol), dimethylzinc (17 mL, 17 mmol), tetrakistriphenylphosphine palladium (192 mg, 0.08 mmol), copper iodide ( A mixture of I) (16 mg, 0.08 mmol) and 1,2-dimethoxyethane (32 mL) was stirred at
  • Example 51 N- (1H-Indol-3-ylmethyl) -2- [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] acetamide [3- (Trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] acetic acid (compound of Reference Example 11) (143 mg, 0.57 mmol) and DMF (9 ml) To this mixture was added triethylamine (174 mg, 1.72 mmol), 1- (1H-indol-3-yl) methanamine (84 mg, 0.57 mmol), and PyBrop (401 mg, 0.86 mmol) at 0 ° C., then at room temperature.
  • Example 52 1-methyl-4-( ⁇ [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] acetyl ⁇ amino) -1H-pyrazole-5-carboxamide [3- (Trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] acetic acid (compound of Reference Example 11) (100 mg, 0.40 mmol), THF (2 mL) And oxalyl chloride (102 mg, 0.80 mmol) was added to a mixture of DMF (2 drops) at 0 ° C. and stirred for 2 hours.
  • the reaction mixture was concentrated under reduced pressure, and DMA (2 mL) was added. This was added to a mixture of 4-amino-1-methyl-1H-pyrazole-5-carboxamide (62 mg, 0.44 mmol) and DMA (2 mL) at 0 ° C., stirred for 10 minutes, and then stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • reaction mixture was stirred for 20 minutes under ice-cooling and then stirred for 40 minutes at room temperature.
  • the solvent and excess oxalyl chloride were distilled off under reduced pressure, and dehydrated THF (3 mL) was added.
  • the reaction mixture was stirred at room temperature for 4 hours, and water was added.
  • the reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate.
  • the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) .
  • the resulting solid was crystallized from an ethyl acetate-hexane mixed solvent to give the title compound (34 mg) as a white solid. It was.
  • reaction mixture was stirred at ⁇ 78 ° C. for 10 minutes under a nitrogen atmosphere, and then stirred at room temperature for 4 hours.
  • Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off using celite. The filtrate was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate / hexane) to give the title compound (20 mg) as a white solid.
  • Example 56 3- (Trifluoromethyl) -1- ⁇ 4- [6- (trifluoromethyl) imidazo [1,2-a] pyridin-8-yl] benzyl ⁇ -1,4,5,6-tetrahydropyrano [ 2,3-c] pyrazole
  • the reaction mixture was stirred at room temperature for 20 hours, 1N hydrochloric acid (60 mL) was added under ice-cooling, and the mixture was extracted with ethyl acetate.
  • the extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution, and anhydrous sodium sulfate. And dried.
  • the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (5.50 g) as a pale yellow liquid.
  • Example 70 2- [6,6-Dimethyl-3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] -N- ⁇ [3- (1-methylethyl ) Isoxazol-5-yl] methyl ⁇ acetamide
  • Example 72 N- ⁇ [3- (1-methylethyl) isoxazol-5-yl] methyl ⁇ -2- [6-methyl-3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazole -1 (4H) -yl] acetamide
  • Example 75 2-( ⁇ [6-Methyl-3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] acetyl ⁇ amino) -4,5,6,7 -Tetrahydro-1-benzothiophene-3-carboxamide
  • Example 78 1-( ⁇ 3- [3-Methyl-6- (trifluoromethyl) [1,2,4] triazolo [4,3-a] pyridin-8-yl] -1,2,4-oxadiazole- 5-yl ⁇ methyl) -3- (trifluoromethyl) -1,4,5,6-tetrahydropyrano [2,3-c] pyrazole
  • Example 79 1-( ⁇ 3- [5-Methyl-7- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-3-yl] -1,2,4-oxadiazol-5-yl ⁇ methyl)- 3- (Trifluoromethyl) -1,4,5,6-tetrahydropyrano [2,3-c] pyrazole N'-hydroxy-5-methyl-7- (trifluoromethyl) pyrazolo [1,5-a ] Pyrimidine-3-carboximidamide (0.26 g), [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] acetic acid (0.25 g) and HOBt To a solution of monohydrate (0.23 g) in DMF (5 mL) were added WSC (0.29 g) and triethylamine (0.15 g), and the mixture was stirred at room temperature for 3 hr.
  • the reaction mixture was purified by silica gel column chromatography (ethyl acetate / hexane), and the mixture of 6N hydrochloric acid (5 mL) of the obtained light brown solid (0.20 g) was heated with stirring at 120 ° C. for 16 hours, and then concentrated under reduced pressure. did.
  • the obtained residue was dissolved in water (5 mL), triethylamine (1 mL) was added, and the mixture was concentrated under reduced pressure.
  • the obtained residue was crystallized from methanol and ether to give the title compound (0.23 g) as a pale brown solid.
  • reaction solution was irradiated with microwaves at 180 ° C. for 20 minutes.
  • the reaction mixture was diluted with water and extracted with ethyl acetate.
  • the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate / hexane). The obtained solid was recrystallized from ethyl acetate / hexane to give the title compound (43.9 mg).
  • reaction mixture was stirred at room temperature for 2 days, and water was added.
  • the reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate.
  • the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (94 mg) as a colorless liquid.
  • Example 85 1- ⁇ [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] methyl ⁇ -3- [6- (trifluoromethyl) imidazo [1, 2-a] pyridin-8-yl] urea [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) yl] acetic acid (compound of Reference Example 11) (370 mg), toluene (4 mL), dehydrated THF (4 mL), and triethylamine (180 mg) were added with diphenylphosphoric acid azide (451 mg).
  • the reaction mixture was stirred at 100 ° C. for 2 hours under a nitrogen atmosphere, and then allowed to cool to room temperature.
  • 6- (trifluoromethyl) imidazo [1,2-a] pyridin-8-amine (the compound of Reference Example 28) (300 mg) was added.
  • the reaction mixture was stirred at 60 ° C. overnight, and water was added.
  • the reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate.
  • Example 86 1- ⁇ [3- (1-methylethyl) isoxazol-5-yl] methyl ⁇ -3- ⁇ [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazole-1 ( 4H) -yl] methyl ⁇ urea
  • Example 87 1- (5-chloro-2,4-dimethoxyphenyl) -3- ⁇ [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] methyl ⁇ Urea
  • reaction mixture was stirred at room temperature for 20 minutes under a nitrogen atmosphere and then stirred at 50 ° C. overnight.
  • the solvent was removed under reduced pressure, and the residue was stirred in air at room temperature until a white precipitate formed.
  • the reaction mixture was purified by silica gel column chromatography (ethyl acetate / hexane). The solvent was evaporated under reduced pressure, and trifluoroacetic acid (8 mL) was added to the obtained residue under ice-cooling.
  • the reaction mixture was stirred at room temperature for 5 hours, and saturated aqueous sodium hydrogen carbonate solution was added.
  • reaction mixture was stirred at 90 ° C. for 3 hours under a nitrogen atmosphere, and then rac-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (68 mg) and tris (dibenzylideneacetone) dipalladium (33 mg) was added.
  • the reaction mixture was stirred at 90 ° C. overnight under a nitrogen atmosphere, and water was added.
  • the reaction mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane).
  • Example 89 3- (Trifluoromethyl) -1- ⁇ 3- [6- (trifluoromethyl) imidazo [1,2-a] pyridin-8-yl] propyl ⁇ -1,4,5,6-tetrahydropyrano [ 2,3-c] pyrazole 3- (trifluoromethyl) -1- ⁇ (2E) -3- [6- (trifluoromethyl) imidazo [1,2-a] pyridin-8-yl] -2-propene 1-yl ⁇ -1,4,5,6-tetrahydropyrano [2,3-c] pyrazole (compound of Example 84) (35 mg) and ethanol (2 mL) in a mixture of 10% palladium-carbon (50% wet, 20 mg) was added.
  • Example 90 3- (Trifluoromethyl) -1- ⁇ 1- [6- (trifluoromethyl) imidazo [1,2-a] pyridin-8-yl] pyrrolidin-3-yl ⁇ -1,4,5,6- Tetrahydropyrano [2,3-c] pyrazole
  • Example 92 5-chloro-2-methoxy-N- ⁇ [3- (trifluoromethyl) -5,6-dihydropyrano [2,3-c] pyrazol-1 (4H) -yl] methyl ⁇ benzamide 3- (trifluoromethyl ) -1,4,5,6-tetrahydropyrano [2,3-c] pyrazole (compound of Reference Example 9) (50 mg), 5-chloro-2-methoxybenzamide (48 mg), paraformaldehyde (23 mg), anhydrous magnesium sulfate (31 mg), and toluene (1 mL) were added with p-toluenesulfonic acid monohydrate (4.5 mg).
  • Example 96 1- ⁇ 1- [3-Methyl-6- (trifluoromethyl) [1,2,4] triazolo [4,3-a] pyridin-8-yl] azetidin-3-yl ⁇ -3- (trifluoro Methyl) -1,4,5,6-tetrahydropyrano [2,3-c] pyrazole
  • the reaction mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere and then stirred at 60 ° C. overnight.
  • the solvent was removed under reduced pressure, and the residue was stirred in air at room temperature until a white precipitate formed.
  • the reaction mixture was purified by silica gel column chromatography (ethyl acetate / hexane). The solvent was evaporated under reduced pressure, and trifluoroacetic acid (4 ml) was added to the resulting residue under ice cooling.
  • the reaction mixture was stirred at room temperature overnight, and saturated aqueous sodium hydrogen carbonate solution was added.
  • the reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate.
  • the reaction mixture was stirred at 100 ° C for 270 minutes under a nitrogen atmosphere, then cesium carbonate (342 mg), rac-2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (76 mg) and tris (di- Benzylideneacetone) dipalladium (37 mg) was added.
  • cesium carbonate 342 mg
  • rac-2,2'-bis (diphenylphosphino) -1,1'-binaphthyl 76 mg
  • tris di- Benzylideneacetone dipalladium
  • Example 97 3- (Trifluoromethyl) -1- ⁇ 1- [6- (trifluoromethyl) imidazo [1,2-a] pyridin-8-yl] azetidin-3-yl ⁇ -1,4,5,6- Tetrahydropyrano [2,3-c] pyrazole
  • ethyl trifluoroacetate (3.0 g) was added to the reaction solution at -78 ° C over 15 minutes, and the mixture was stirred at the same temperature for 75 minutes.
  • the reaction mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne un composé hétérocyclique qui a un effet d'amélioration de la fonction de récepteur AMPA. Plus spécifiquement, un composé représenté par la formule (I0) ou un sel de celui-ci est décrit. (Dans la formule, Ra représente un groupe alkyle C1-6 éventuellement substitué ; X0 représente un groupe -CH2- ou autre ; Y0 représente un groupe -CRcRd- ou autre ; Rb représente un atome d'hydrogène ou autre ; Rc et Rd peuvent être identiques ou différents et chacun représente un atome d'hydrogène ; le cycle A0 représente un cycle thiophène qui peut porter un substituant, ou autre ; le cycle D0 représente un cycle hétérocyclique éventuellement substitué qui contient, à titre d'atome constitutif de cycle, un hétéroatome qui est choisi parmi un atome d'oxygène et un atome d'azote ; et m représente 0 ou 1).
PCT/JP2010/005771 2009-09-25 2010-09-24 Composé hétérocyclique WO2011036889A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2009-221360 2009-09-25
JP2009221360 2009-09-25

Publications (1)

Publication Number Publication Date
WO2011036889A1 true WO2011036889A1 (fr) 2011-03-31

Family

ID=43795656

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2010/005771 WO2011036889A1 (fr) 2009-09-25 2010-09-24 Composé hétérocyclique

Country Status (1)

Country Link
WO (1) WO2011036889A1 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8575154B2 (en) 2010-08-10 2013-11-05 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
CN104193745A (zh) * 2014-07-30 2014-12-10 天津市斯芬克司药物研发有限公司 一种咪唑并嘧啶羧酸类化合物及其制备方法
US9351954B2 (en) 2009-12-04 2016-05-31 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US9493484B2 (en) 2012-02-08 2016-11-15 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US10196403B2 (en) 2016-07-29 2019-02-05 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
WO2019070044A1 (fr) 2017-10-06 2019-04-11 武田薬品工業株式会社 Composés hétérocycliques
WO2019070043A1 (fr) 2017-10-06 2019-04-11 武田薬品工業株式会社 Composé hétérocyclique
KR20190067239A (ko) * 2016-10-26 2019-06-14 얀센 파마슈티카 엔.브이. 융합된 바이사이클릭 피리딘 화합물 및 ampa 수용체 조절제로서의 이들의 용도
US10780074B2 (en) 2017-08-02 2020-09-22 Sunovion Pharmaceuticals Inc. Compounds and uses thereof
US10815249B2 (en) 2018-02-16 2020-10-27 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US11077090B2 (en) 2016-07-29 2021-08-03 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11129807B2 (en) 2017-02-16 2021-09-28 Sunovion Pharmaceuticals Inc. Methods of treating schizophrenia
US11136304B2 (en) 2019-03-14 2021-10-05 Sunovion Pharmaceuticals Inc. Salts of a heterocyclic compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof
CN114057748A (zh) * 2021-09-30 2022-02-18 枣阳市福星化工有限公司 三氮唑嘧啶酮的制备方法
US11738002B2 (en) 2020-04-14 2023-08-29 Sunovion Pharmaceuticals Inc. Methods of treating neurological and psychiatric disorders
US11919879B2 (en) 2021-06-16 2024-03-05 Celgene Corporation Carboxylic acid containing azetidinyl compounds for the treatment of neurodegenerative diseases

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007125405A2 (fr) * 2006-05-01 2007-11-08 Pfizer Products Inc. Composés hétérocycliques 2-amino-substitués à cycles fusionnés
WO2008003452A1 (fr) * 2006-07-04 2008-01-10 N.V. Organon Thiophènes substitués par pyrazolealcanamide comme potentiateurs de l'ampa
WO2008148836A1 (fr) * 2007-06-08 2008-12-11 Glaxo Group Limited Composés qui potentialisent le récepteur ampa et leurs utilisations dans des médicaments
WO2009119088A1 (fr) * 2008-03-25 2009-10-01 武田薬品工業株式会社 Composé hétérocyclique

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007125405A2 (fr) * 2006-05-01 2007-11-08 Pfizer Products Inc. Composés hétérocycliques 2-amino-substitués à cycles fusionnés
WO2008003452A1 (fr) * 2006-07-04 2008-01-10 N.V. Organon Thiophènes substitués par pyrazolealcanamide comme potentiateurs de l'ampa
WO2008148836A1 (fr) * 2007-06-08 2008-12-11 Glaxo Group Limited Composés qui potentialisent le récepteur ampa et leurs utilisations dans des médicaments
WO2009119088A1 (fr) * 2008-03-25 2009-10-01 武田薬品工業株式会社 Composé hétérocyclique

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9351954B2 (en) 2009-12-04 2016-05-31 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US10894033B2 (en) 2009-12-04 2021-01-19 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US10085968B2 (en) 2009-12-04 2018-10-02 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US11279713B2 (en) 2010-08-10 2022-03-22 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US9150591B2 (en) 2010-08-10 2015-10-06 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US8916551B2 (en) 2010-08-10 2014-12-23 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US8778934B2 (en) 2010-08-10 2014-07-15 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US10654874B2 (en) 2010-08-10 2020-05-19 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US9499568B2 (en) 2010-08-10 2016-11-22 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US9884875B2 (en) 2010-08-10 2018-02-06 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US8575154B2 (en) 2010-08-10 2013-11-05 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US9493484B2 (en) 2012-02-08 2016-11-15 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
CN104193745A (zh) * 2014-07-30 2014-12-10 天津市斯芬克司药物研发有限公司 一种咪唑并嘧啶羧酸类化合物及其制备方法
CN104193745B (zh) * 2014-07-30 2016-09-28 斯芬克司药物研发（天津）股份有限公司 一种咪唑并嘧啶羧酸类化合物及其制备方法
US10196403B2 (en) 2016-07-29 2019-02-05 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11077090B2 (en) 2016-07-29 2021-08-03 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US10927124B2 (en) 2016-07-29 2021-02-23 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11958862B2 (en) 2016-07-29 2024-04-16 Sumitomo Pharma America, Inc. Compounds and compositions and uses thereof
KR102416798B1 (ko) 2016-10-26 2022-07-04 얀센 파마슈티카 엔.브이. 융합된 바이사이클릭 피리딘 화합물 및 ampa 수용체 조절제로서의 이들의 용도
JP2019536760A (ja) * 2016-10-26 2019-12-19 ヤンセン ファーマシューティカ エヌ．ベー． 縮合二環ピリジン化合物、及びａｍｐａ受容体調節因子としてのそれらの使用
KR20190067239A (ko) * 2016-10-26 2019-06-14 얀센 파마슈티카 엔.브이. 융합된 바이사이클릭 피리딘 화합물 및 ampa 수용체 조절제로서의 이들의 용도
US11129807B2 (en) 2017-02-16 2021-09-28 Sunovion Pharmaceuticals Inc. Methods of treating schizophrenia
US10780074B2 (en) 2017-08-02 2020-09-22 Sunovion Pharmaceuticals Inc. Compounds and uses thereof
US11491133B2 (en) 2017-08-02 2022-11-08 Sunovion Pharmaceuticals Inc. Heteroaryl-isochroman compounds and uses thereof
WO2019070043A1 (fr) 2017-10-06 2019-04-11 武田薬品工業株式会社 Composé hétérocyclique
US11447488B2 (en) 2017-10-06 2022-09-20 Takeda Pharmaceutical Company Limited Heterocyclic compounds
EP3693360A4 (fr) * 2017-10-06 2021-02-17 Takeda Pharmaceutical Company Limited Composés hétérocycliques
US11939327B2 (en) 2017-10-06 2024-03-26 Takeda Pharmaceutical Company Limited Heterocyclic compounds
WO2019070044A1 (fr) 2017-10-06 2019-04-11 武田薬品工業株式会社 Composés hétérocycliques
US11407748B2 (en) 2017-10-06 2022-08-09 Takeda Pharmaceutical Company Limited Substituted pyrido[1,2-a]pyrimidines and pyrazino[1,2-a]pyrimidines for enhancing AMPA receptor function
EP3693368A4 (fr) * 2017-10-06 2021-02-24 Takeda Pharmaceutical Company Limited Composé hétérocyclique
US11440921B2 (en) 2018-02-16 2022-09-13 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US10815249B2 (en) 2018-02-16 2020-10-27 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US11987591B2 (en) 2018-02-16 2024-05-21 Sumitomo Pharma America, Inc. Salts, crystal forms, and production methods thereof
US11136304B2 (en) 2019-03-14 2021-10-05 Sunovion Pharmaceuticals Inc. Salts of a heterocyclic compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof
US11738002B2 (en) 2020-04-14 2023-08-29 Sunovion Pharmaceuticals Inc. Methods of treating neurological and psychiatric disorders
US11919879B2 (en) 2021-06-16 2024-03-05 Celgene Corporation Carboxylic acid containing azetidinyl compounds for the treatment of neurodegenerative diseases
CN114057748A (zh) * 2021-09-30 2022-02-18 枣阳市福星化工有限公司 三氮唑嘧啶酮的制备方法

Similar Documents

Publication Publication Date Title
WO2011036889A1 (fr) Composé hétérocyclique
US11279713B2 (en) Heterocyclic compound and use thereof
JPWO2009119088A1 (ja) 複素環化合物
WO2011036885A1 (fr) Composé hétérocyclique
JP6134654B2 (ja) 複素環化合物およびその用途
WO2010140339A1 (fr) Composé hétérocyclique
JPWO2008032764A1 (ja) 縮環複素環誘導体

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10818566

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10818566

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP