WO2017170765A1 - Nouveau composé hétérocyclique contenant de l'azote - Google Patents

Nouveau composé hétérocyclique contenant de l'azote Download PDF

Info

Publication number
WO2017170765A1
WO2017170765A1 PCT/JP2017/013051 JP2017013051W WO2017170765A1 WO 2017170765 A1 WO2017170765 A1 WO 2017170765A1 JP 2017013051 W JP2017013051 W JP 2017013051W WO 2017170765 A1 WO2017170765 A1 WO 2017170765A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
compound
alkyl
hydroxy
hydrogen
Prior art date
Application number
PCT/JP2017/013051
Other languages
English (en)
Japanese (ja)
Inventor
良 榊原
渉 佐々木
南実 山口
秀樹 後河内
文彦 赤星
Original Assignee
田辺三菱製薬株式会社
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 田辺三菱製薬株式会社 filed Critical 田辺三菱製薬株式会社
Publication of WO2017170765A1 publication Critical patent/WO2017170765A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/695—Silicon compounds
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages

Definitions

  • the present invention provides a novel nitrogen-containing heterocyclic compound having an inhibitory action on aldosterone synthase (hereinafter also referred to as “CYP11B2”) and useful for the prevention, treatment and / or improvement of prognosis of various diseases or conditions in which aldosterone is involved About.
  • CYP11B2 aldosterone synthase
  • Aldosterone is a mineral corticoid receptor (hereinafter also referred to as “MR”) specific ligand and is one of the mediators in the renin-angiotensin-aldosterone system (RAAS).
  • MR mineral corticoid receptor
  • RAAS renin-angiotensin-aldosterone system
  • MR antagonists eg eplerenone or spironolactone
  • ACE inhibitors eg ACE inhibitors
  • MR antagonists for example, spironolactone or eplerenone
  • side effects for example, hyperkalemia
  • spironolactone is often accompanied by gynecomastia, menstrual abnormalities, erectile dysfunction, etc.
  • CYP11B2 aldosterone synthase
  • CYP11B2 is a cytochrome P450 enzyme and is known as an enzyme that catalyzes a series of reactions from 11-deoxycorticosterone (ie, aldosterone precursor) to aldosterone.
  • CYP11B2 is mainly expressed in the glandular layer of the adrenal cortex, and aldosterone in plasma is regulated by the enzyme activity in the adrenal gland.
  • aldosterone expression has been confirmed outside the adrenal glands such as the cardiovascular system, kidney, adipose tissue, and brain, and attention has been paid to the fact that aldosterone produced locally in each organ is involved in organ damage.
  • Inhibitors of CYP11B2 have been reported to inhibit aldosterone production in studies using enzymes and cultured cells, and to suppress and treat aldosterone production in studies using various experimental animal models. Furthermore, it has been confirmed that CYP11B2 inhibitors show a decrease in plasma and urinary aldosterone levels and a hypotensive effect in hypertensive patients and primary aldosteronism patients (Non-patent Documents 3 and 4). Finding a means to inhibit the aldosterone biosynthetic pathway is a highly feasible approach for establishing effective therapies for various diseases involving aldosterone.
  • the present invention relates to a novel nitrogen-containing heterocyclic compound having an inhibitory action on aldosterone synthase (CYP11B2) or a pharmacologically acceptable salt thereof.
  • CYP11B2 aldosterone synthase
  • the compounds of the present invention are useful for the prevention, treatment and / or prognosis improvement of various diseases or conditions involving aldosterone.
  • the present invention relates to formula (I): (However, partial structural formula Ring A, m and n represented by (1) Ring A is a formula Or m is 1, 2 or 3, n is 0 or 1, and the sum of m and n is 2 or 3, or (2) Ring A is a formula Wherein m is 0 or 1, n is 1, 2 or 3, and the sum of m and n is 2 or 3, X is CR 6 R 7 , O, or NR 8 ; R 1 and R 2 are each independently hydrogen, hydroxy, halogen, cyano, optionally substituted alkyl, or optionally substituted alkoxy, or R 1 and R 2 are terminal to each other.
  • R 1 and R 2 are bonded to each other at the end to form an optionally substituted benzene fused aromatic heterocycle together with the benzene ring to which they are bonded;
  • R 3 is hydrogen or optionally substituted alkyl;
  • R 4, R 5, R 6 and R 7 are each independently hydrogen, hydroxy, halogen, cyano, alkyl optionally substituted, optionally substituted alkoxy, an aromatic substituted Heterocycle, optionally substituted aromatic heterocycle oxy, optionally substituted aliphatic heterocycle, optionally substituted aliphatic heterocycle oxy, optionally substituted phenyl, substituted An optionally substituted alkylsulfonyl, an optionally substituted alkylthio, an optionally substituted carbamoyloxy, an alkylsilyloxy, an optionally substituted amino, or an optionally substituted alkanoyl, or R 4 and R 5 and
  • the present invention also relates to aldosterone comprising administering to a patient a therapeutically effective amount of a compound represented by the above formula (I) (hereinafter also referred to as compound (I)) or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a method for preventing, treating, or improving prognosis of various diseases or symptoms involved.
  • the present invention also relates to a pharmaceutical composition comprising a compound represented by formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.
  • the present invention also provides a pharmaceutical composition comprising the compound (I) or a pharmacologically acceptable salt thereof as an active ingredient for use in the prevention, treatment, or prognosis improvement of various diseases or symptoms involving aldosterone.
  • the present invention also relates to the compound (I) or a pharmaceutically acceptable salt thereof for use in the prevention, treatment, or prognosis improvement of various diseases or symptoms involving aldosterone.
  • the present invention also relates to a method for producing the compound (I) or a pharmacologically acceptable salt thereof.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent inhibitory activity against aldosterone synthase (CYP11B2), it increases aldosterone levels such as hypertension, primary aldosteronism and / or aldosterone. It is useful for the prevention or treatment of various diseases and / or disease states caused by overproduction, or for improving the prognosis of these diseases.
  • alkyl means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms (C 1-6 ).
  • a group having 1 to 4 carbon atoms (C 1-4 ) is preferable.
  • Specific examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, 1,2-dimethylpropyl, t-butyl, i-amyl, n-pentyl, n-hexyl and the like. It is done.
  • methyl, ethyl, i-propyl, i-butyl, 1,2-dimethylpropyl, t-butyl and the like are preferable.
  • alkylene refers to a divalent group obtained by removing one hydrogen atom from the above alkyl.
  • Specific examples include methylene, ethylene, propylene, butylene, pentylene, hexylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and the like.
  • methylene, ethylene, trimethylene, tetramethylene and the like are preferable.
  • cycloalkyl refers to a monocyclic saturated hydrocarbon group having 3 to 7 carbon atoms (C 3-7 ).
  • a group having 5 to 6 carbon atoms (C 5-6 ) is preferable.
  • Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • cyclopentyl, cyclohexyl and the like are preferable.
  • alkoxy means a monovalent group in which the above alkyl is bonded to oxygen, and examples thereof include linear or branched alkyl-O— having 1 to 6 carbon atoms (C 1-6 ). Alkyl-O— of the number 1 to 4 (C 1-4 ) is preferred. Specific examples include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy and the like. In particular, methoxy is preferred.
  • halogen or halo means fluorine, chlorine, bromine or iodine. Preferred is fluorine, chlorine, or bromine.
  • alkanoyl refers to a monovalent group in which the above alkyl is bonded to carbonyl, and examples thereof include linear or branched alkyl-CO— having 1 to 6 carbon atoms (C 1-6 ). Alkyl-CO— having 1 to 4 carbon atoms (C 1-4 ) is preferred. Specific examples include acetyl, propionyl, pivaloyl, butanoyl, pentanoyl, hexanoyl, heptanoyl and the like.
  • the aromatic heterocyclic ring is a 5- to 10-membered monocyclic or bicyclic ring containing 1 to 4 hetero atoms independently selected from the group consisting of a sulfur atom, an oxygen atom, and a nitrogen atom.
  • An aromatic cyclic group of Preferably, it is a 5- to 10-membered monocyclic or bicyclic aromatic ring containing 1 to 2 hetero atoms independently selected from the group consisting of a sulfur atom, an oxygen atom and a nitrogen atom.
  • the benzene-fused aromatic heterocycle includes 5 to 4 heteroatoms independently selected from the group consisting of a sulfur atom, an oxygen atom, and a nitrogen atom among the above aromatic heterocycles.
  • a bicyclic heterocycle formed by condensation of a 6-membered monocyclic aromatic ring and a benzene ring includes, for example, indazole, indole, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolyl, isoquinolyl, benzopyranyl and the like. Indazole is preferable.
  • the aliphatic heterocyclic ring means a 4-9 membered saturated cyclic group containing 1 to 3 hetero atoms independently selected from the group consisting of a sulfur atom, an oxygen atom and a nitrogen atom.
  • Specific examples include azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrothienyl, tetrahydrofuranyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, tetrahydrothiopyranyl, tetrahydropyranyl, oxazolidinyl and the like.
  • optionally substituted alkyl examples include halogen, hydroxy, optionally substituted alkanoylamino, optionally substituted alkylsulfonylamino, optionally substituted alkylamino, ureido, carbamoyl, substituted And alkyl which may be substituted with 1 to 3 groups independently selected from alkyl carbamoyl which may be substituted, aliphatic heterocyclic ring which may be substituted, and aromatic heterocyclic oxy which may be substituted. It is done.
  • the optionally substituted alkyl is halogen, hydroxy, alkanoylamino optionally substituted with 1 to 2 hydroxy, alkylsulfonylamino optionally substituted with 1 to 2 hydroxy, 1 Alkylamino optionally substituted with 2 hydroxy, ureido, carbamoyl, alkylcarbamoyl optionally substituted with 1 to 2 hydroxy, aliphatic optionally substituted with 1 to 2 oxo Heterocycle and alkyl optionally substituted with 1 to 3 groups independently selected from aromatic oxy optionally substituted with 1 to 3 halogens.
  • optionally substituted alkoxy examples include halogen, hydroxy, optionally substituted alkoxycarbonyl, carbamoyl, optionally substituted alkylcarbamoyl, optionally substituted aliphatic heterocyclic carbamoyl, and optionally substituted
  • the optionally substituted alkoxy is halogen, hydroxy, alkoxycarbonyl optionally substituted with 1 to 2 hydroxy, carbamoyl, alkylcarbamoyl optionally substituted with 1 to 2 hydroxy, Aliphatic heterocyclic carbamoyl optionally substituted with 1 to 3 groups independently selected from alkoxycarbonyl and alkyl, alkylamino optionally substituted with 1 to 2 hydroxy, alkoxycarbonyl, alkyl, And cycloalkylcarbamoyl optionally substituted with 1 to 3 groups independently selected from alkanoylamino, aliphatic heterocyclic carbonyl optionally substituted with 1 to 3 alkyl, 1 to 3 From phenyl, alkyl and halogen optionally substituted with halogen.
  • optionally substituted alkylene examples include alkylene which may be substituted with 1 to 3 groups independently selected from halogen, hydroxy, alkyl, and alkoxy.
  • alkyleneoxy examples include alkyleneoxy and alkylenedioxy.
  • alkyleneoxy includes a group represented by —O— (CH 2 ) p — (wherein p is a natural number of 1 to 6) such as epoxymethano and epoxyethano.
  • Alkylenedioxy includes a group represented by —O— (CH 2 ) p —O— (p has the same meaning as described above) such as methylenedioxy and ethylenedioxy.
  • optionally substituted aromatic heterocycle examples include an aromatic heterocycle optionally substituted with 1 to 3 groups independently selected from halogen, hydroxy, alkyl, and alkoxy.
  • the aromatic heterocycle moiety may be substituted with 1 to 3 groups independently selected from halogen, hydroxy, alkyl, and alkoxy.
  • An aromatic heterocycle is mentioned.
  • aromatic heterocyclic oxy examples include aromatic heterocyclic oxy optionally substituted with 1 to 3 groups independently selected from halogen, alkyl, cyano, and alkoxy.
  • optionally substituted aliphatic heterocycle examples include an aliphatic heterocycle optionally substituted with 1 to 3 groups independently selected from halogen, alkyl, cyano, alkoxy, and oxo.
  • optionally substituted aliphatic heterocyclic oxy examples include an aliphatic heterocyclic oxy optionally substituted with 1 to 3 groups independently selected from halogen, alkyl, cyano, and alkoxy.
  • optionally substituted phenyl examples include phenyl optionally substituted with 1 to 3 groups independently selected from halogen, hydroxy, alkyl, alkoxy, and alkylcarbamoyl.
  • optionally substituted alkylsulfonyl examples include an alkylsulfonyl optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and alkoxy.
  • optionally substituted alkylthio examples include halogen, hydroxy, optionally substituted alkanoylamino, optionally substituted alkylsulfonylamino, optionally substituted alkylamino, carbamoylamino, carbamoyl, substituted And alkylthio optionally substituted with 1 to 3 groups independently selected from optionally substituted aromatic heterocyclic oxy.
  • the optionally substituted alkylthio is halogen, hydroxy, alkanoylamino optionally substituted with 1 to 2 hydroxy, alkylsulfonylamino optionally substituted with 1 to 2 hydroxy, 1 1 to 3 independently selected from alkylamino optionally substituted with 2 hydroxy, carbamoylamino, carbamoyl, alkylcarbamoyl optionally substituted with 1 to 2 hydroxy, and halogen and alkyl Alkylthio optionally substituted with 1 to 3 groups independently selected from aromatic heterocyclic oxy optionally substituted with 1 group.
  • optionally substituted carbamoyloxy examples include carbamoyloxy optionally substituted with 1 to 2 groups independently selected from halogen, hydroxy, and alkyl.
  • the optionally substituted amino is independent of optionally substituted alkyl, alkoxycarbonyl, optionally substituted aromatic heterocycle, alkanoyl, cycloalkylcarbonyl, and optionally substituted alkylsulfonyl. And amino optionally substituted with 1 to 2 groups selected from the above.
  • the optionally substituted amino is alkyl, alkoxycarbonyl, 1 to 3 optionally substituted with 1 to 2 aliphatic heterocycles optionally substituted with 1 to 2 oxo.
  • 1 to 2 groups independently selected from aromatic heterocycles optionally substituted with halogen, alkanoyl, cycloalkylcarbonyl, and alkylsulfonyl optionally substituted with 1 to 2 hydroxy Amino that may have been added.
  • optionally substituted alkanoyl examples include alkanoyl optionally substituted with 1 to 3 groups independently selected from halogen, hydroxy, cyano, and alkoxy.
  • the optionally substituted alkylamino is independently selected from alkyl, hydroxy, cyano, and alkoxy optionally substituted with 1-2 oxazolidine optionally substituted with 1-2 oxo. And alkylamino optionally substituted by 1 to 3 groups.
  • Alkylamino includes monoalkylamino and dialkylamino, preferably mono- or di-C 1-6 alkylamino;
  • Alkylcarbamoyl includes monoalkylcarbamoyl and dialkylcarbamoyl, preferably mono- or di-C 1-6 alkylcarbamoyl;
  • Optionally substituted alkylcarbamoyl includes optionally substituted alkylcarbamoyl with 1-2 hydroxy;
  • the optionally substituted aliphatic heterocyclic carbamoyl includes an aliphatic heterocyclic carbamoyl optionally substituted with 1 to 3 groups independently selected from alkyl and alkoxycarbonyl;
  • Optionally substituted cycloalkylcarbamoyl includes cycloalkylcarbamoyl optionally substituted with 1 to 3 groups independently selected from alkoxycarbonyl, alkyl, and alkanoylamino;
  • halogens In addition, “1 to 2 halogens”, “1 to 3 halogens”, “1 to 2 alkyls”, “1 to 3 alkyls”, “1 to 2 aliphatic heterocycles”, In notations such as “1 to 3 alkoxy” and “1 to 3 alkanoylamino”, 2 or more halogens, 2 or more alkyls, 2 or more aliphatic heterocycles, 2 or more alkoxys , And two or more alkanoylamino, etc., the halogen, alkyl, aliphatic heterocycle, alkoxy, alkanoylamino and the like are independent of each other and may be the same or different from each other.
  • Examples of such a group include a case where a group represented by the following formula is formed as a whole together with a phenyl group to which R 1 to R 2 are bonded: (In the formula, the symbols have the same meaning as described above.) Furthermore, when R 1 and R 2 are bonded to each other at an end to form an alkylene which may contain 1 to 2 oxygen atoms in the chain and may be further substituted, for example, R When the alkylene, alkyleneoxy, or alkylenedioxy group formed by bonding 1 and R 2 to each other at the end is substituted with, for example, 1 to 2 halogens (eg, fluorine, chlorine, bromine) For example, alkylene optionally substituted with 1 to 2 halogens, alkyleneoxy optionally substituted with 1 to 2 halogens, alkyl optionally substituted with 1 to 2 halogens Rangeoxy is mentioned.
  • halogens eg, fluorine, chlorine, bromine
  • the partial structural formula in compound (I) In the case where R 1 and R 2 are bonded to each other at the end to form a benzene fused aromatic heterocycle together with the benzene ring to which they are bonded, for example, In the case of forming a bicyclic aromatic heterocycle such as In the partial structural formula, for example, when forming a benzene-fused aromatic heterocycle optionally substituted with alkyl, for example, the partial structure is: (However, R means alkyl) It is a case where a group such as is formed.
  • R 1 and R 2 is a one is cyano and the other is hydrogen, hydroxy, halogen, alkyl optionally substituted or optionally substituted alkoxy, Or a pharmacologically acceptable salt thereof is preferred.
  • the compound (I) or the compound (IA) is represented by R 4 , R 5 , R 6 , and R 7 .
  • the optionally substituted alkyl is from hydroxy, carbamoyl, optionally substituted alkylcarbamoyl, alkylamino, alkanoylamino, alkylsulfonylamino, ureido, and optionally substituted aromatic heterocyclic oxy
  • optionally substituted alkoxy is hydroxy, halogen, alkoxycarbonyl, carbamoyl, optionally substituted alkylcarbamoyl, optionally substituted aliphatic heterocyclic carbamoyl, optionally substituted cycloalkyl Substituted with 1 to 4 groups independently selected from carbamoyl, optionally substituted aliphatic carbonyl, phenyl, aromatic heterocycle, and optionally substituted aromatic carbamoyl.
  • the optionally substituted aromatic heterocycle is an aromatic heterocycle optionally substituted with 1 to 3 alkoxy;
  • the optionally substituted aromatic heterocyclic oxy is an aromatic heterocyclic oxy optionally substituted with 1 to 3 groups independently selected from halogen, alkyl, cyano, and alkoxy ,
  • the optionally substituted aliphatic heterocycle is an aliphatic heterocycle;
  • the optionally substituted aliphatic heterocyclic oxy is an aliphatic heterocyclic oxy,
  • the optionally substituted phenyl is an optionally substituted phenyl having 1 to 3 groups independently selected from alkoxy and alkylcarbamoyl;
  • the optionally substituted alkylsulfonyl is alkylsulfonyl;
  • (I) optionally substituted alkylthio is alkylthio;
  • carbamoyloxy which may be substituted is carbamoyloxy which may be substituted with
  • R 1 and R 2 are substituted with one of cyano and the other with hydrogen, hydroxy, halogen or 1 to 3 halogens.
  • R 3 is hydrogen or alkyl;
  • (A) optionally substituted alkyl is hydroxy, carbamoyl, alkylcarbamoyl optionally substituted with 1 to 2 hydroxy, alkylamino, alkanoylamino, alkylsulfonylamino, ureido, and 1 to 3
  • the optionally substituted alkoxy is independently selected from hydroxy, halogen, alkoxycarbonyl, carbamoyl, alkylcarbamoyl optionally substituted with 1 to 2 hydroxy, alk
  • Aliphatic heterocyclic carbamoyl optionally substituted with 1 group cycloalkylcarbamoyl optionally substituted with 1 to 3 alkanoylamino, aliphatic heteroaromatic optionally substituted with 1 to 3 alkyl
  • the optionally substituted aromatic heterocycle is an aromatic heterocycle optionally substituted with 1 to 3 alkoxy;
  • the optionally substituted aromatic heterocyclic oxy is an aromatic heterocyclic oxy optionally substituted with 1 to 3 groups independently selected from halogen, alkyl, cyano, and alkoxy ,
  • the optionally substituted aliphatic heterocycle is an aliphatic heterocycle;
  • the optionally substituted aliphatic heterocyclic oxy is an aliphatic heterocyclic oxy,
  • the optionally substituted phenyl is an optionally substituted phenyl having 1 to 3 groups independently selected from alkoxy and alkylcarbamoyl;
  • the optionally substituted alkylsulfonyl is alkylsulfonyl;
  • (I) optionally substituted alkylthio is alkylthio;
  • carbamoyloxy which may be substituted is carbamoyloxy which may be substituted with 1 to 2
  • R 1 and R 2 are one of cyano and the other is hydrogen, hydroxy, halogen, alkyl optionally substituted with 1 to 3 halogens, or alkoxy
  • R 3 is hydrogen or alkyl
  • R 4 and R 5 are each independently hydrogen, hydroxy, tetrahydropyranyloxy, or an aromatic heterocyclic oxy optionally substituted with 1 to 3 halogens
  • R 6 and R 7 are each independently hydrogen; hydroxy; halogen; cyano; hydroxy, carbamoyl, alkylcarbamoyl optionally substituted with 1 to 2 hydroxy, alkylamino, alkanoylamino, alkylsulfonylamino, Ureido and alkyl optionally substituted with 1 to 3 groups independently selected from aromatic heterocyclic oxy optionally substituted with 1 to 3 halogens; hydroxy, halogen, alkoxycarbonyl, carbamoyl Aliphatic heterocyclic carbamoyl optionally substituted with 1
  • R 1 and R 2 are one of cyano and the other is hydrogen, hydroxy, halogen, alkyl optionally substituted with 1 to 3 halogens, or alkoxy
  • R 3 is hydrogen or alkyl
  • R 4 and R 5 are each independently hydrogen, hydroxy, tetrahydropyranyloxy, or pyrimidinyloxy optionally substituted with 1 to 3 halogens
  • R 6 and R 7 are each independently hydrogen; hydroxy; halogen; cyano; hydroxy, carbamoyl, alkylcarbamoyl optionally substituted with 1 to 2 hydroxy, alkylamino, alkanoylamino, alkylsulfonylamino, Ureido and alkyl optionally substituted with 1 to 3 groups independently selected from pyrimidinyloxy optionally substituted with 1 to 3 halogens; hydroxy, halogen, alkoxycarbonyl, carbamoyl, 1 to 3 Aliphatic heterocyclic carbamoyl optional
  • R 4 and R 5 are both hydrogen or a pharmaceutically acceptable salt thereof can be used.
  • m and n are each 1 and X is CR 6 R 7 (2) m is 2, n is 0, and X is O, (3) m is 2, n is 1, X is CR 6 R 7 , O or NR 8 or (4) m is 3, n is 0 and X is O or A compound that is NR 8 or a pharmaceutically acceptable salt thereof.
  • a 1 m and n are each, X can be mentioned compounds or a pharmaceutically acceptable salt thereof is CR 6 R 7.
  • compound (I) is represented by the general formula (Ia) Indicated by R 1 is hydrogen, hydroxy, halogen, alkyl optionally substituted with 1 to 3 halogens, or alkoxy; R 2 is cyano, X can be mentioned compounds or a pharmaceutically acceptable salt thereof is CR 6 R 7.
  • R 6 and R 7 are each independently hydrogen; hydroxy; halogen; cyano; hydroxy, carbamoyl, alkylcarbamoyl optionally substituted with 1 to 2 hydroxy, alkylamino, Alkyl optionally substituted with 1 to 3 groups independently selected from alkanoylamino, alkylsulfonylamino, ureido, and pyrimidinyloxy optionally substituted with 1 to 3 halogens; hydroxy, halogen, An aliphatic heterocyclic carbamoyl optionally substituted with 1 to 3 groups independently selected from alkoxycarbonyl, carbamoyl, alkylcarbamoyl optionally substituted with 1 to 2 hydroxy, alkoxycarbonyl and alkyl (
  • the aliphatic heterocycle is tetrahydropi And alkanoylaminocycloalkylcarbamoyl, an aliphatic heterocyclic carbonyl optionally substituted with 1
  • R 1 is hydrogen, halogen, or alkyl
  • R 6 is hydroxy
  • an aromatic heterocyclic oxy optionally substituted with 1 to 3 groups independently selected from halogen, alkyl, and alkoxy
  • Examples thereof include a compound wherein R 7 is hydrogen or a pharmaceutically acceptable salt thereof.
  • a compound in which the aromatic heterocycle in the aromatic heterocycle oxy is selected from pyrimidine, pyrazine, and thiazole, or a pharmaceutically acceptable salt thereof.
  • the compound (I) is represented by the general formula (IB) (However, the symbols have the same meaning as above.), Or a pharmaceutically acceptable salt thereof.
  • m and n are each 1, R 4 and R 5 are each hydrogen, and X is CR 6 R 7 , (2) m is 1, n is 2, R 4 and R 5 are each hydrogen, X is NR 8 , or (3) m is 0, n is 3, R 4 and R 5 are independently hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted aromatic heterocyclic oxy, or optionally substituted aliphatic heterocyclic oxy, X A compound in which is O or a pharmacologically acceptable salt thereof is preferred.
  • R 1 and R 2 are one of cyano, the other is hydrogen, hydroxy, halogen, optionally substituted alkyl, or optionally substituted alkoxy
  • R 3 is hydrogen or optionally substituted alkyl
  • R 6 and R 7 are each independently hydrogen, hydroxy, halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aromatic heterocycle, substituted Aromatic heterocyclic oxy which may be substituted, aliphatic heterocyclic which may be substituted, aliphatic heterocyclic oxy which may be substituted, phenyl which may be substituted, alkylsulfonyl which may be substituted, substituted Optionally substituted carbamoyloxy, alkylsilyloxy, or optionally substituted amino
  • R 8 is hydrogen, alkyl optionally substituted with 1 to 2 hydroxys, optionally substituted alkanoyl, or optionally substituted alkylsul
  • R 1 and R 2 are one of cyano and the other is hydrogen, halogen or alkyl, R 3 is hydrogen; m, n, R 4 , R 5 and X are (1) m and n are each 1, R 4 and R 5 are each hydrogen, and X is CR 6 R 7 , (2) m is 1, n is 2, R 4 and R 5 are each hydrogen, X is NR 8 , or (3) m is 0, n is 3, R 4 and R 5 are independently an aromatic heterocyclic oxy optionally substituted with hydrogen, hydroxy, 1 to 3 halogens, wherein the aromatic heterocyclic oxy moiety is preferably pyrimidinyloxy ), Or an aliphatic heterocyclic oxy (wherein the aliphatic heterocyclic oxy is preferably tetrahydropyranyloxy), X is O, R 6 and R 7 are hydrogen, And a compound or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen, alkyl optionally substituted with 1 to 2
  • Preferred compounds include those represented by the formula (IB) represented by the general formula (Ib) And R 1 is hydrogen, halogen, or alkyl; R 2 is cyano, A compound in which X is CH 2 or a pharmacologically acceptable salt thereof.
  • Preferred compounds of the present invention are: (5R) -3- (4-cyano-2-methylphenyl) -5-hydroxy-5,6-dihydro-4H-pyrrolo [1,2-b] pyrazole (Example 1, Example 110b); (5R) -3- (4-Cyano-2-fluorophenyl) -5- (5-fluoropyrimidin-2-yl) oxy-5,6-dihydro-4H-pyrrolo [1,2-b] pyrazole Example 10); (5R) -3- (4-Cyano-2-methylphenyl) -5- (pyrimidin-2-yl) oxy-5,6-dihydro-4H-pyrrolo [1,2-b] pyrazole (Example 15) ; (5R) -3- (4-Cyano-2-methylphenyl) -5- (pyrazin-2-yl) oxy-5,6-dihydro-4H-pyrrolo [1,2-b] pyrazole (Example 20)
  • the compound (I) of the present invention When the compound (I) of the present invention has an asymmetric carbon atom in the molecule, it can exist as a plurality of stereoisomers based on the asymmetric carbon atom (that is, diastereomeric isomer, optical isomer).
  • the present invention includes any one of these stereoisomers and mixtures thereof.
  • Compound (I) of the present invention includes compounds labeled with isotopes (for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 F, 32 P, 35 S, 125 I etc.) and the like Includes hydrogen converter.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof has an inhibitory activity on aldosterone synthase activity, various diseases and / or caused by increased aldosterone levels and / or excessive production of aldosterone. It is also useful for preventing or treating disease states or improving the prognosis of these diseases.
  • Examples of these diseases include primary aldosteronism (specifically, unilateral or bilateral adrenal adenoma, unilateral or bilateral adrenal hyperplasia, aldosterone-producing adrenal cancer, unilateral adrenal multiple nodular aldosteronism, Glucocorticoid-responsive aldosteronism, familial aldosteronism, or ectopic aldosterone-producing tumors, secondary aldosteronism (specifically, hypertension caused by estrogen, renovascular hypertension, pregnancy-induced hypertension) , Malignant hypertension, pheochromocytoma, congestive heart failure, pseudohypoaldosteronism, chronic liver disease associated with ascites (cirrhosis etc.), inappropriate use of laxatives and diuretics, or nephrotic syndrome, Barter syndrome or Gittermann syndrome Hyperaldosteronemia associated with hypertension), hypertension (specifically, essential hypertension, Secondary hypertension (such as renovascular hypertension, renal parenchymal hypertension, primary aldo
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof prevents, treats or prognoses primary aldosteronism, secondary aldosteronism, hypertension, heart failure, arteriosclerosis, nephropathy, or retinopathy. Useful for improvement.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent inhibitory activity against CYP11B2.
  • the compounds of the present application were examined for inhibitory activity against human CYP11B2 according to the assay method described in Experimental Example 1 below, and as a result, the IC 50 values were all 150 nM or less.
  • the compound (I) of the present invention shows high selectivity for CYP11B2.
  • Example 49 the compound described in Example 49 (chemical name: 3- (4-cyanophenyl) -5,6-dihydro-4H-pyrrolo [1,2-b] pyrazole) inhibits the related enzyme CYP11B1
  • the ratio of IC 50 value (nM) in human to IC 50 (nM) in human CYP11B2 inhibition is 100 times or more, showing high selectivity for CYP11B2.
  • the compound (I) of the present invention can be used for pharmaceutical use in a free form or in the form of a pharmacologically acceptable salt.
  • the pharmaceutically acceptable salt include inorganic acid salts such as hydrochloride, sulfate, phosphate and hydrobromide, acetate, fumarate, oxalate, citrate, methanesulfone, and the like.
  • organic acid salts such as acid salts, benzenesulfonate, tosylate, and maleate.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof includes any of its internal salts and adducts, solvates or hydrates thereof.
  • Compound (I) or a pharmacologically acceptable salt thereof of the present invention is administered either orally or parenterally as a pharmaceutical composition containing alone or a pharmacologically acceptable carrier. can do.
  • a pharmaceutical composition containing alone or a pharmacologically acceptable carrier can do.
  • a carrier conventionally used in the art may be used.
  • diluent for example, diluent, binder (syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone, etc.), excipient (lactose, sucrose) Corn starch, potassium phosphate, sorbit, glycine, etc.), lubricants (magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrants (potato starch), wetting agents (sodium lauryl sulfate, etc.) and the like.
  • the dosage form of these pharmaceutical compositions is not particularly limited.
  • conventional pharmaceutical preparations such as tablets, granules, capsules, powders and the like can be mentioned.
  • conventional pharmaceutical preparations such as injections, inhalants, suppositories and the like can be mentioned.
  • the dose of compound (I) of the present invention or a pharmacologically acceptable salt thereof varies depending on the administration method, patient age, body weight, condition, etc.
  • parenteral administration it is usually 0.001 to 10 mg / kg, preferably 0.01 to 10 mg / kg.
  • oral administration it is usually 0.01 to 100 mg / kg, preferably 0.1 to 10 mg / kg per day.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof can be used alone or in combination with one or more other drugs depending on the disease to be treated.
  • these drugs include (1) angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, calcium antagonists, ⁇ blockers, ⁇ / ⁇ blockers and other antihypertensive drugs; (2) thiazide diuretics Diuretics such as loop diuretics; (3) heart failure treatment drugs such as nitroglycerin and digitalis preparations; (4) antiarrhythmic drugs such as Na channel blockers; and (5) high fats such as HMG-CoA reductase inhibitors.
  • Antithrombotic drugs such as blood coagulation inhibitors and thrombolytic agents
  • Insulin ⁇ -glucosidase inhibitors, insulin resistance improvers, insulin secretagogues, aldose reductase inhibitors, etc.
  • Diabetes / diabetic complication therapeutic agent (8) anti-obesity agent; (9) chemotherapeutic agent; and (10) one or more selected from the group consisting of immunomodulators such as immunosuppressants and immune enhancers Of drugs It is below.
  • Me means a methyl group
  • Et means an ethyl group
  • Boc means a tert-butoxycarbonyl group
  • THF means tetrahydrofuran
  • DMF means N, N-dimethylformamide.
  • the compound of the present invention or a pharmacologically acceptable salt thereof can be produced, for example, as follows.
  • the compound of formula (I) is represented by formula (II): (However, R a represents trialkylsilyl, R b represents alkyl, and other symbols have the same meaning as described above.) And a compound of the general formula (III) (However, R c means a leaving group, and other symbols have the same meaning as described above.) Can be prepared by removing the trialkylsilyl group after coupling the compound represented by the following: halogen (chlorine, bromine, or iodine), methanesulfonyloxy, p-toluenesulfonyloxy, etc. Can be suitably used.
  • the coupling reaction between compound (II) and compound (III) can be carried out according to a conventional method, in an appropriate solvent, in the presence of a palladium catalyst and a base, and in the presence or absence of a ligand.
  • Any solvent may be used as long as it does not interfere with this reaction.
  • examples thereof include ethers such as tetrahydrofuran, aromatic hydrocarbons such as toluene, amides such as dimethylformamide, water, and mixtures thereof.
  • the palladium catalyst include tris (dibenzylideneacetone) dipalladium, bis (triphenylphosphine) palladium dichloride, and the like.
  • Examples of the base include metal alkoxides such as sodium tert-butoxide, and alkali metal carbonates such as sodium carbonate.
  • Examples of the ligand include phosphines such as 4,5′-bis (diphenylphosphino) -9,9′-dimethylxanthene and triphenylphosphine.
  • the amount of compound (III) to be used can be 1.0 to 3.0 equivalents, preferably 1.1 to 1.5 equivalents, in molar ratio to compound (II).
  • the amount of the palladium catalyst used can be 0.01 to 0.1 equivalents, preferably 0.05 equivalents, in molar ratio to the compound (II).
  • the amount of the base used can be 2.0 to 6.0 equivalents, preferably 3.0 to 4.0 equivalents, in molar ratio with respect to compound (II).
  • the amount of the ligand used can be 0.02 to 0.2 equivalent, preferably 0.1 equivalent, in molar ratio with respect to compound (II). This reaction can be carried out at room temperature to 200 ° C, preferably 80-150 ° C.
  • Removal of the trialkylsilyl group can be carried out in a suitable solvent in the presence of a fluoride salt according to a conventional method.
  • the solvent is not particularly limited as long as it does not hinder this reaction, and examples thereof include ethers such as tetrahydrofuran.
  • fluoride salts include tetrabutylammonium fluoride.
  • the amount of the fluoride salt to be used can be 2.0 to 10 equivalents, preferably 4.0 to 6.0 equivalents, in molar ratio with respect to compound (II). This reaction can be carried out at 50 to 100 ° C., preferably 70 to 80 ° C.
  • Manufacturing method B The compound represented by the formula (I) is represented by the formula (IV): (However, the symbols have the same meaning as described above.) A compound of formula (V) (In the formula, the symbols have the same meaning as described above.) It can manufacture by coupling the compound shown by these.
  • the leaving group and reaction conditions the leaving group and conditions described in the above production method A can be preferably used.
  • the coupling reaction of compound (IV) and compound (V) can be carried out according to a conventional method in an appropriate solvent in the presence of a palladium catalyst and a base, in the presence or absence of a ligand.
  • a palladium catalyst Any solvent may be used as long as it does not interfere with this reaction.
  • ethers such as tetrahydrofuran
  • aromatic hydrocarbons such as toluene
  • amides such as dimethylformamide, water, and mixtures thereof.
  • the palladium catalyst include tris (dibenzylideneacetone) dipalladium, bis (triphenylphosphine) palladium dichloride, and the like.
  • Examples of the base include metal alkoxides such as sodium tert-butoxide, and alkali metal carbonates such as sodium carbonate.
  • Examples of the ligand include phosphines such as 4,5′-bis (diphenylphosphino) -9,9′-dimethylxanthene and triphenylphosphine.
  • the amount of compound (V) to be used can be 1.0 to 3.0 equivalents, preferably 1.1 to 1.5 equivalents, in molar ratio to compound (IV).
  • the amount of the palladium catalyst to be used can be 0.01 to 0.1 equivalent, preferably 0.05 equivalent, in molar ratio with respect to compound (IV).
  • the amount of the base to be used can be 2.0 to 6.0 equivalents, preferably 3.0 to 4.0 equivalents, in molar ratio with respect to compound (IV).
  • the amount of the ligand used can be 0.02 to 0.2 equivalent, preferably 0.1 equivalent, in molar ratio with respect to compound (IV). This reaction can be carried out at room temperature to under heating, specifically at room temperature to 200 ° C, preferably at 80 to 150 ° C.
  • R 4 , R 5 , R 6 or R 7 is an aromatic heterocyclic oxy which may be substituted.
  • R 4 , R 5 , R 6 or R 7 can be produced by reacting a compound in which R 7 is hydroxy with a corresponding optionally substituted aromatic heterocyclic halide. This reaction can be carried out in a suitable solvent in the presence of a base. Any solvent may be used as long as it does not affect the reaction. For example, amides such as N-methylpyrrolidone and N, N-dimethylformamide, ethers such as tetrahydrofuran, acetonitrile, dimethyl sulfoxide, or a mixture thereof may be used.
  • the base examples include inorganic bases such as alkyl metal hydrides such as lithium hydride and sodium hydride, and alkali metal carbonates such as sodium carbonate and potassium carbonate. Preferred are alkyl metal hydrides such as lithium hydride and sodium hydride.
  • This reaction can be carried out under cooling to heating, preferably from room temperature to heating. Specifically, it is carried out at 0 ° C. to 80 ° C., preferably room temperature to 60 ° C.
  • R 4, R 5, R 6 or R 7 compound is alkoxy optionally substituted, among the compound (I), the R 4, R 5, R 6 Alternatively, it can be produced by reacting a compound in which R 7 is hydroxy with a corresponding optionally substituted alkyl halide. This reaction can be carried out in a suitable solvent in the presence of a base. Any solvent may be used as long as it does not affect the reaction. For example, amides such as N-methylpyrrolidone and N, N-dimethylformamide, ethers such as tetrahydrofuran, acetonitrile, dimethyl sulfoxide, or a mixture thereof may be used. Can be mentioned.
  • the base examples include inorganic bases such as alkyl metal hydrides such as lithium hydride and sodium hydride, and alkali metal carbonates such as sodium carbonate and potassium carbonate. Preferred are alkyl metal hydrides such as lithium hydride and sodium hydride.
  • This reaction can be carried out under cooling to heating, preferably from room temperature to heating. Specifically, it is carried out at 0 ° C. to 80 ° C., preferably room temperature to 60 ° C.
  • a compound in which R 4 , R 5 , R 6 or R 7 is alkoxy substituted with hydroxy is R 4 , R 5 , R 6 or R among the compounds (I). It can be produced by reacting a compound in which 7 is hydroxy with an alkane substituted with an epoxy. This reaction can be carried out in a suitable solvent in the presence of a base.
  • the base include inorganic bases such as alkyl metal hydrides such as lithium hydride and sodium hydride, and alkali metal carbonates such as sodium carbonate and potassium carbonate. Preferred are alkyl metal hydrides such as lithium hydride and sodium hydride. Any solvent may be used as long as it does not interfere with the reaction.
  • This reaction can be carried out under cooling to heating, preferably from room temperature to heating. Specifically, it is carried out at 0 ° C. to 80 ° C., preferably room temperature to 60 ° C.
  • compound R 4, R 5, R 6 or R 7 is alkylcarbamoyloxy, among the compound (I), the R 4, R 5, R 6 or R 7 is It can be produced by reacting a compound that is hydroxy with the corresponding alkyl isocyanate. This reaction can be carried out in a suitable solvent. Any solvent may be used as long as it does not affect the reaction. For example, amides such as N-methylpyrrolidone and N, N-dimethylformamide, ethers such as tetrahydrofuran, acetonitrile, dimethyl sulfoxide, or a mixture thereof may be used. Can be mentioned.
  • This reaction can be carried out under cooling to heating, preferably from room temperature to heating. Specifically, it is carried out at 0 ° C. to 80 ° C., preferably room temperature to 60 ° C.
  • R 4 , R 5 , R 6 or R 7 is alkyl substituted with an optionally substituted alkylcarbamoyl, or alkoxy substituted with an optionally substituted alkylcarbamoyl.
  • Examples thereof include amides such as N, N-dimethylformamide, ethers such as tetrahydrofuran, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, toluene and the like. Aromatic hydrocarbons, acetonitrile, or a mixture thereof.
  • the condensing agent include O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU), 1-ethyl-3- ( And 3-dimethylaminopropyl) carbodiimide hydrochloride.
  • this reaction can be carried out in the presence of an activator (for example, 1-hydroxybenzotriazole and the like).
  • This reaction can be carried out under cooling to heating, preferably from room temperature to heating. Specifically, it is carried out at 0 ° C. to 80 ° C., preferably room temperature to 60 ° C.
  • the condensation converts a compound in which R 4 , R 5 , R 6 or R 7 is alkyl substituted with carboxy, or alkoxy substituted with carboxy to a mixed acid anhydride, and then the corresponding substituted It can also be carried out by reacting with an amine which may be used. Conversion to a mixed acid anhydride can be carried out by reacting with a haloformate alkyl ester such as ethyl chloroformate in a suitable solvent in the presence of a base.
  • a haloformate alkyl ester such as ethyl chloroformate
  • the base examples include alkyl hydrogen metals such as sodium hydrogen carbonate, alkali metal carbonates such as potassium carbonate, inorganic bases such as alkali metal hydroxides such as sodium hydroxide, alkyl amines such as triethylamine and diisopropylethylamine, and pyridine. And organic bases such as pyridines such as dimethylaminopyridine. Any solvent may be used as long as it does not interfere with this reaction. Examples thereof include amides such as N, N-dimethylformamide, ethers such as tetrahydrofuran, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, toluene and the like.
  • Aromatic hydrocarbons, acetonitrile, or a mixture thereof can be carried out under cooling to heating, and preferably under cooling to room temperature. Specifically, it is carried out at 0 ° C. to 80 ° C., preferably 0 ° C. to room temperature.
  • R 4 , R 5 , R 6 or R 7 is an alkyl substituted with alkanoylamino.
  • R 4 , R 5 , R 6 Alternatively, it can be produced by alkanoylating a compound in which R 7 is alkyl substituted with amino. Alkanoylation can be carried out by reacting with an alkanoylating agent in a suitable solvent, optionally in the presence of a base.
  • alkanoylating agent examples include halogenated alkanoyl (eg, acetyl chloride, acetyl bromide, pivaloyl chloride, etc.), the corresponding alkanecarboxylic acid anhydride (eg, acetic anhydride, etc.), and the like.
  • the base examples include alkyl hydrogen metals such as sodium hydrogen carbonate, alkali metal carbonates such as potassium carbonate, inorganic bases such as alkali metal hydroxides such as sodium hydroxide, alkyl amines such as triethylamine and diisopropylethylamine, and pyridine. And organic bases such as pyridines such as dimethylaminopyridine.
  • Any solvent may be used as long as it does not interfere with this reaction.
  • Examples thereof include amides such as N, N-dimethylformamide, ethers such as tetrahydrofuran, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, toluene and the like. Aromatic hydrocarbons, acetonitrile, or a mixture thereof.
  • This reaction can be carried out under cooling to heating, and preferably under cooling to room temperature. Specifically, it is performed at 0 ° C. to 60 ° C., preferably 0 ° C. to room temperature.
  • the compounds in which R 4 , R 5 , R 6 or R 7 is alkyl substituted with alkylsulfonylamino are the R 4 , R 5 , R 6 among the compounds (I).
  • it can be produced by alkylsulfonylating a compound in which R 7 is alkyl substituted with amino.
  • Alkylsulfonylation can be carried out by reacting with a desired sulfonylating agent in a suitable solvent, optionally in the presence of a base.
  • Examples of the sulfonylating agent include a corresponding alkanesulfonyl halide (eg, methanesulfonyl chloride, ethanesulfonyl chloride, etc.).
  • Examples of the base include alkyl hydrogen metals such as sodium hydrogen carbonate, alkali metal carbonates such as potassium carbonate, inorganic bases such as alkali metal hydroxides such as sodium hydroxide, alkyl amines such as triethylamine and diisopropylethylamine, and pyridine. And organic bases such as pyridines such as dimethylaminopyridine. Any solvent may be used as long as it does not interfere with this reaction.
  • This reaction can be carried out under cooling to heating, and preferably under cooling to room temperature. Specifically, it is performed at 0 ° C. to 60 ° C., preferably 0 ° C. to room temperature.
  • the compound in which R 4 , R 5 , R 6 or R 7 is optionally substituted alkylsulfonyl is the R 4 , R 5 , R 6 among the compounds (I).
  • it can be produced by oxidizing a compound in which R 7 is alkylthio.
  • the oxidation can be carried out by treatment with an oxidizing agent in a suitable solvent.
  • the oxidizing agent a conventional one can be used, and as such, for example, peracids such as potassium peroxymonosulfate, perbenzoic acid, m-chloroperbenzoic acid and the like can be used. Any solvent may be used as long as it does not interfere with this reaction.
  • this reaction can be carried out in the presence of an alkyl ammonium salt (for example, benzenetrimethylammonium chloride).
  • This reaction can be carried out under cooling to heating, and preferably under cooling to room temperature. Specifically, it is performed at 0 ° C. to 40 ° C., preferably 0 ° C. to room temperature.
  • R 4 and R 5 are bonded to each other, or R 6 and R 7 are bonded to each other to form a hydroxyimino, and R 4 and R 5 are bonded to each other.
  • It can be produced by reacting a compound in which R 6 and R 7 are bonded to each other to form an oxo in an appropriate solvent in the presence of a base with hydroxylamine.
  • a base sodium acetate or the like can be preferably used.
  • the solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include alcohols such as methanol and ethanol, ethers such as dioxane, acetonitrile, and mixtures thereof.
  • This reaction can be carried out under cooling to heating, and preferably under cooling to room temperature. Specifically, it is performed at 0 ° C. to 60 ° C., preferably 0 ° C. to room temperature.
  • a compound in which one of R 4 and R 5 is amino and the other is hydrogen, or a compound in which one of R 6 and R 7 is amino and the other is hydrogen is R 4 and R It can be produced by reducing a compound in which 5 is bonded to each other and is a hydroxyimino, or a compound in which R 6 and R 7 are bonded to each other to be a hydroxyimino.
  • the reduction can be carried out by treating with a reducing agent in an appropriate solvent in the presence of an additive.
  • borohydrides such as sodium borohydride can be suitably used.
  • the additive include molybdenum oxide and nickel dichloride.
  • Any solvent may be used as long as it does not interfere with this reaction.
  • examples thereof include ethers such as tetrahydrofuran and dioxane, alcohols such as methanol and ethanol, aromatic hydrocarbons such as toluene, acetonitrile, and mixtures thereof. Is mentioned.
  • This reaction can be carried out under cooling to heating, and preferably under cooling to room temperature. Specifically, it is performed at 0 ° C. to 60 ° C., preferably 0 ° C. to room temperature.
  • a compound in which R 4 , R 5 , R 6 or R 7 is alkylsulfonylamino is a compound in which R 4 , R 5 , R 6 or R 7 is amino.
  • the alkylsulfonylation can be carried out by reacting with a desired sulfonylating agent in a suitable solvent in the presence of a base.
  • the sulfonylating agent include a corresponding alkanesulfonyl halide (eg, methanesulfonyl chloride, ethanesulfonyl chloride, etc.).
  • the base examples include alkyl hydrogen metals such as sodium hydrogen carbonate, alkali metal carbonates such as potassium carbonate, inorganic bases such as alkali metal hydroxides such as sodium hydroxide, alkyl amines such as triethylamine and diisopropylethylamine, and pyridine. And organic bases such as pyridines such as dimethylaminopyridine. Any solvent may be used as long as it does not interfere with this reaction. Examples thereof include amides such as N, N-dimethylformamide, ethers such as tetrahydrofuran, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, toluene and the like.
  • Aromatic hydrocarbons, acetonitrile, or a mixture thereof can be carried out under cooling to heating, and preferably under cooling to room temperature. Specifically, it is performed at 0 ° C. to 60 ° C., preferably 0 ° C. to room temperature.
  • a compound in which R 4 , R 5 , R 6 or R 7 is optionally substituted alkylamino is such that R 4 , R 5 , R 6 or R 7 is amino. It can be produced by alkylating certain compounds. The alkylation can be carried out by reacting with an alkylating agent in a suitable solvent in the presence of a base, or by reacting with an alkyl aldehyde having a desired alkyl group in the presence of a reducing agent. As the alkylating agent, an alkyl halide having a desired alkyl group can be used.
  • the base examples include alkyl hydrogen metals such as sodium hydrogen carbonate, alkali metal carbonates such as potassium carbonate, inorganic bases such as alkali metal hydroxides such as sodium hydroxide, alkyl amines such as triethylamine and diisopropylethylamine, and pyridine. And organic bases such as pyridines such as dimethylaminopyridine.
  • the reducing agent examples include borohydrides such as sodium triacetoxyborohydride and sodium cyanoborohydride. Any solvent may be used as long as it does not interfere with this reaction.
  • This reaction can be carried out under cooling to heating, and preferably under cooling to room temperature. Specifically, it is performed at 0 ° C. to 60 ° C., preferably 0 ° C. to room temperature.
  • a compound in which R 4 , R 5 , R 6 or R 7 is alkoxycarbonylamino is a compound in which R 4 , R 5 , R 6 or R 7 is amino.
  • Alkoxycarbonylation can be carried out by reacting a halogenated formic acid alkyl ester having a desired alkyl group in a suitable solvent in the presence of a base.
  • the base examples include alkyl hydrogen metals such as sodium hydrogen carbonate, alkali metal carbonates such as potassium carbonate, inorganic bases such as alkali metal hydroxides such as sodium hydroxide, alkyl amines such as triethylamine and diisopropylethylamine, and pyridine. And organic bases such as pyridines such as dimethylaminopyridine. Any solvent may be used as long as it does not interfere with this reaction. Examples thereof include amides such as N, N-dimethylformamide, ethers such as tetrahydrofuran, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, toluene and the like.
  • Aromatic hydrocarbons, acetonitrile, or a mixture thereof can be carried out under cooling to heating, and preferably under cooling to room temperature. Specifically, it is performed at 0 ° C. to 60 ° C., preferably 0 ° C. to room temperature.
  • a compound in which R 4 , R 5 , R 6 or R 7 is an optionally substituted aromatic heterocyclic amino is R 4 , R 5 , R 6 or R 7.
  • the base include alkyl hydrides such as lithium hydride and sodium hydride, alkyl hydrogen carbonates such as sodium bicarbonate, alkali carbonates such as potassium carbonate, alkali hydroxides such as sodium hydroxide, etc.
  • Organic bases such as inorganic bases, alkylamines such as triethylamine and diisopropylethylamine, and pyridines such as pyridine and dimethylaminopyridine. Any solvent may be used as long as it does not interfere with this reaction. Examples thereof include amides such as N, N-dimethylformamide, ethers such as tetrahydrofuran, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, toluene and the like. Aromatic hydrocarbons, acetonitrile, or a mixture thereof.
  • This reaction can be carried out from room temperature under heating, preferably under heating. Specifically, it is carried out at 80 ° C. to 180 ° C., preferably 140 ° C. to 160 ° C.
  • a compound in which R 4 , R 5 , R 6 or R 7 is cycloalkylcarbonylamino is a compound in which R 4 , R 5 , R 6 or R 7 is amino, It can be produced by reacting with a cycloalkylcarbonyl halide. This reaction can be carried out in a suitable solvent in the presence of a base.
  • the base include alkyl hydrogen metals such as sodium hydrogen carbonate, alkali metal carbonates such as potassium carbonate, inorganic bases such as alkali metal hydroxides such as sodium hydroxide, alkyl amines such as triethylamine and diisopropylethylamine, and pyridine.
  • organic bases such as pyridines such as dimethylaminopyridine.
  • Any solvent may be used as long as it does not interfere with this reaction.
  • examples thereof include amides such as N, N-dimethylformamide, ethers such as tetrahydrofuran, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, toluene and the like.
  • This reaction can be carried out under cooling to heating, and preferably under cooling to room temperature. Specifically, it is performed at 0 ° C. to 60 ° C., preferably 0 ° C. to room temperature.
  • Alkanoylation can be carried out by reacting with an alkanoylating agent having a desired alkanoyl group in an appropriate solvent, optionally in the presence of a base.
  • alkanoylating agent examples include halogenated alkanoyl (eg, acetyl chloride, acetyl bromide, pivaloyl chloride, etc.), the corresponding alkanecarboxylic acid anhydride (eg, acetic anhydride, etc.), and the like.
  • the base examples include alkyl hydrogen metals such as sodium hydrogen carbonate, alkali metal carbonates such as potassium carbonate, inorganic bases such as alkali metal hydroxides such as sodium hydroxide, alkyl amines such as triethylamine and diisopropylethylamine, and pyridine. And organic bases such as pyridines such as dimethylaminopyridine.
  • Any solvent may be used as long as it does not interfere with this reaction.
  • Examples thereof include amides such as N, N-dimethylformamide, ethers such as tetrahydrofuran, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, toluene and the like. Aromatic hydrocarbons, acetonitrile, or a mixture thereof.
  • This reaction can be carried out under cooling to heating, and preferably under cooling to room temperature. Specifically, it is performed at 0 ° C. to 60 ° C., preferably 0 ° C. to room temperature.
  • compounds in which one of R 4 and R 5 is hydroxy and the other is hydrogen, or compounds in which one of R 6 and R 7 is hydroxy and the other is hydrogen are R 4 and R 5 is oxo bonded to each other compound, or by reducing a compound is oxo R 6 and R 7 are bonded to each other, it can be produced.
  • the reduction can be carried out by treating with a reducing agent in a suitable solvent.
  • a reducing agent borohydrides such as sodium borohydride and aluminum hydrides such as lithium aluminum hydride can be suitably used. Any solvent may be used as long as it does not interfere with this reaction.
  • This reaction can be carried out under cooling to heating, and preferably under cooling to room temperature. Specifically, it is performed at 0 ° C. to 40 ° C., preferably 0 ° C. to room temperature.
  • one of R 4 and R 5 is hydroxy and the other alkyl may be substituted, or one of R 6 and R 7 is hydroxy and the other is substituted
  • a compound that may be an alkyl is a compound in which R 4 and R 5 are bonded to each other to form oxo, or a compound in which R 6 and R 7 are bonded to each other to form oxo and a desired Grignard reagent (for example, an alkylmagnesium halide). Etc.) can be reacted. This reaction can be carried out in a suitable solvent. Any solvent may be used as long as it does not interfere with this reaction.
  • This reaction can be carried out under cooling to heating, and preferably under cooling to room temperature. Specifically, it is performed at 0 ° C. to 40 ° C., preferably 0 ° C. to room temperature.
  • one of R 4 and R 5 may be substituted with phenyl and the other is hydrogen, or one of R 6 and R 7 may be substituted with phenyl
  • a compound in which R 4 and R 5 are both oxo or a compound in which R 6 and R 7 are both oxo is reacted with toluenesulfonylhydrazine so that R 4 and R 5 are both toluene.
  • the reaction with toluenesulfonylhydrazine can be carried out in a suitable solvent.
  • Any solvent may be used as long as it does not interfere with the reaction, and examples thereof include ethers such as tetrahydrofuran and dioxane.
  • This reaction can be carried out from room temperature under heating, preferably under heating. Specifically, it is performed at room temperature to 80 ° C, preferably 60 ° C to 80 ° C.
  • the coupling reaction with benzeneboronic acid can be carried out in a suitable solvent in the presence of a base according to a conventional method.
  • a suitable solvent may be used as long as it does not interfere with this reaction.
  • examples thereof include ethers such as tetrahydrofuran, aromatic hydrocarbons such as toluene, amides such as dimethylformamide, water, and mixtures thereof.
  • the base include alkali metal carbonates such as potassium carbonate and sodium carbonate. This reaction can be carried out at room temperature to under heating, specifically at room temperature to 200 ° C, preferably at 80 to 150 ° C.
  • one of R 4 and R 5 when R 4 and R 5 are bonded to each other or R 6 and R 7 are bonded to each other to form oxo, one of R 4 and R 5 is It can be produced by oxidizing a compound in which one is hydroxy and the other is hydrogen, or a compound in which one of R 6 and R 7 is hydroxy and the other is hydrogen.
  • the oxidation can be carried out by treatment with an oxidizing agent in a suitable solvent.
  • the oxidizing agent a conventional one can be used.
  • 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one can be used. Any solvent may be used as long as it does not interfere with this reaction.
  • amides such as N, N-dimethylformamide, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, and aromatic hydrocarbons such as toluene. , Acetonitrile, water, or a mixture thereof.
  • This reaction can be carried out under cooling to heating, and preferably under cooling to room temperature. Specifically, it is performed at 0 ° C. to 40 ° C., preferably 0 ° C. to room temperature.
  • the compound in which X is NR 8 and R 8 is optionally substituted alkylates the compound in which X is NR 8 and R 8 is hydrogen Can be manufactured.
  • the alkylation can be carried out according to a conventional method by treating with an alkylating agent having a desired alkyl group in a suitable solvent in the presence of a base.
  • an alkylating agent an alkyl halide having a desired alkyl group can be used.
  • the base include alkyl hydrides such as lithium hydride and sodium hydride, alkyl hydrogen carbonates such as sodium bicarbonate, alkali carbonates such as potassium carbonate, alkali hydroxides such as sodium hydroxide, etc.
  • Organic bases such as inorganic bases, alkylamines such as triethylamine and diisopropylethylamine, and pyridines such as pyridine and dimethylaminopyridine. Any solvent may be used as long as it does not interfere with this reaction. Examples thereof include amides such as N, N-dimethylformamide, ethers such as tetrahydrofuran, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, toluene and the like. Aromatic hydrocarbons, acetonitrile, or a mixture thereof.
  • This reaction can be carried out under cooling to heating, and preferably under cooling to room temperature. Specifically, it is performed at 0 ° C. to 60 ° C., preferably 0 ° C. to room temperature.
  • a compound in which X is NR 8 and R 8 is optionally substituted alkanoyl is obtained by alkanoylating a compound in which X is NR 8 and R 8 is hydrogen
  • Alkanoylation can be carried out according to a conventional method by treatment with an alkanoylating agent having a desired alkanoyl group in an appropriate solvent in the presence of a base.
  • alkanoylating agent examples include halogenated alkanoyl (eg, acetyl chloride, acetyl bromide, pivaloyl chloride, etc.), the corresponding alkanecarboxylic acid anhydride (eg, acetic anhydride, etc.), and the like.
  • the base examples include alkyl hydrogen metals such as sodium hydrogen carbonate, alkali metal carbonates such as potassium carbonate, inorganic bases such as alkali metal hydroxides such as sodium hydroxide, alkyl amines such as triethylamine and diisopropylethylamine, and pyridine. And organic bases such as pyridines such as dimethylaminopyridine.
  • Any solvent may be used as long as it does not interfere with this reaction.
  • Examples thereof include amides such as N, N-dimethylformamide, ethers such as tetrahydrofuran, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, toluene and the like. Aromatic hydrocarbons, acetonitrile, or a mixture thereof.
  • This reaction can be carried out under cooling to heating, and preferably under cooling to room temperature. Specifically, it is performed at 0 ° C. to 60 ° C., preferably 0 ° C. to room temperature.
  • a compound in which X is NR 8 and R 8 is an optionally substituted alkylsulfonyl is an alkylsulfonylated compound in which X is NR 8 and R 8 is hydrogen
  • the alkylsulfonylation can be carried out according to a conventional method by treating with a sulfonylating agent having a desired alkylsulfonyl group in a suitable solvent in the presence of a base.
  • Examples of the sulfonylating agent include a corresponding alkanesulfonyl halide (eg, methanesulfonyl chloride, ethanesulfonyl chloride, etc.).
  • Examples of the base include alkyl hydrogen metals such as sodium hydrogen carbonate, alkali metal carbonates such as potassium carbonate, inorganic bases such as alkali metal hydroxides such as sodium hydroxide, alkyl amines such as triethylamine and diisopropylethylamine, and pyridine. And organic bases such as pyridines such as dimethylaminopyridine. Any solvent may be used as long as it does not interfere with this reaction.
  • This reaction can be carried out under cooling to heating, and preferably under cooling to room temperature. Specifically, it is performed at 0 ° C. to 60 ° C., preferably 0 ° C. to room temperature.
  • compounds in which X is NR 8 and R 8 is alkyl substituted with hydroxy are compounds in which the X is NR 8 and R 8 is hydrogen in compound (I) And an alkane substituted with epoxy.
  • This reaction can be carried out in a suitable solvent in the presence of a perchlorate.
  • the perchlorate lithium perchlorate is suitable. Any solvent may be used as long as it does not interfere with the reaction. Examples thereof include amides such as N, N-dimethylformamide, ethers such as tetrahydrofuran, aromatic hydrocarbons such as toluene, and mixtures thereof. Can be mentioned.
  • This reaction can be carried out under cooling to heating, preferably from room temperature to heating. Specifically, it is carried out at 0 ° C. to 80 ° C., preferably room temperature to 60 ° C.
  • the ring A moiety is The compound represented by can be produced, for example, by the following method.
  • R d represents an alkyl group.
  • Z 1 represents an amino-protecting group (for example, an alkoxycarbonyl group such as a tert-butoxycarbonyl group).
  • Other symbols have the same meaning as described above.
  • the compound represented by the general formula (A) is hydrolyzed to obtain the compound represented by the general formula (B).
  • the obtained compound (B) is deprotected to obtain a compound represented by the general formula (C).
  • the compound (C) is nitrosated to obtain a compound represented by the general formula (D).
  • the obtained compound (D) is subjected to dehydration condensation to obtain a compound represented by the general formula (E).
  • the compound represented by the general formula (E) and the compound represented by the general formula (F) are cycloadded to obtain the compound represented by the general formula (II).
  • Hydrolysis of compound (A) to compound (B) can be carried out according to a conventional method in an appropriate solvent in the presence of a base and water.
  • Any solvent may be used as long as it does not interfere with this reaction, and examples thereof include alcohols such as ethanol, ethers such as tetrahydrofuran, and mixtures thereof.
  • the base include alkali metal hydroxides such as sodium hydroxide. This reaction can be carried out at 0 ° C. to room temperature, preferably at room temperature.
  • the amount of the base used can be 1.0 to 3.0 equivalents, preferably 2.0 equivalents, in molar ratio to the compound (A).
  • the deprotection from the compound (B) to the compound (C) can be carried out by removing the protecting group by a conventional method according to the kind of the protecting group Z 1 .
  • Z 1 is a tert-butoxycarbonyl group
  • the protecting group can be removed by treating compound (B) with an acid in a suitable solvent according to a conventional method.
  • the solvent is not particularly limited as long as it does not interfere with this reaction, and examples thereof include esters such as ethyl acetate, halogenated aliphatic hydrocarbons such as chloroform, alcohols such as methanol, and mixtures thereof.
  • the acid include hydrochloric acid and trifluoroacetic acid. This reaction can be carried out at 0 ° C. to 60 ° C., preferably at room temperature.
  • the nitrosation from compound (C) to compound (D) can be carried out in the presence of nitrite in a suitable solvent according to a conventional method.
  • the solvent include acetic acid, hydrochloric acid, and sulfuric acid.
  • the nitrite include sodium nitrite.
  • the amount of nitrite to be used can be 1.0 to 2.0 equivalents, preferably 1.2 to 1.5 equivalents, in molar ratio with respect to compound (C). This reaction can be carried out at room temperature to 50 ° C., preferably at room temperature.
  • the dehydration condensation from compound (D) to compound (E) can be carried out in a suitable solvent in the presence of an acid anhydride.
  • Any solvent may be used as long as it does not interfere with this reaction, and examples thereof include ethers such as tetrahydrofuran, halogenated aliphatic hydrocarbons such as chloroform, and mixtures thereof.
  • the acid anhydride include trifluoroacetic anhydride and acetic anhydride.
  • the amount of the acid anhydride to be used can be 1.0 to 6.0 equivalents, preferably 3.0 to 5.0 equivalents, in molar ratio to the compound (D). This reaction can be carried out at 0 ° C. to 80 ° C., preferably at room temperature.
  • Cycloaddition of compound (E) and compound (F) can be carried out in a suitable solvent. Any solvent may be used as long as it does not interfere with this reaction, and examples thereof include aromatic hydrocarbons such as xylene and dichlorobenzene.
  • the amount of compound (F) to be used can be 2.0 to 6.0 equivalents, preferably 3.0 to 4.0 equivalents, in molar ratio to compound (E). This reaction can be carried out at 140 ° C. to 200 ° C., preferably 170 ° C. to 190 ° C.
  • the compound represented by the general formula (E) and the compound represented by the general formula (K) are cycloadded to obtain the compound represented by the general formula (L) and the compound represented by the general formula (M).
  • a compound represented by the general formula (N) can be obtained.
  • Compound (N) is halogenated to obtain a compound represented by the general formula (O).
  • Cycloaddition of compound (E) and compound (K) can be carried out in a suitable solvent. Any solvent may be used as long as it does not interfere with this reaction, and examples thereof include aromatic hydrocarbons such as xylene and dichlorobenzene.
  • the amount of compound (K) to be used can be 2.0 to 6.0 equivalents, preferably 3.0 to 4.0 equivalents, in molar ratio to compound (E). This reaction can be carried out at 140 ° C. to 200 ° C., preferably 170 ° C. to 190 ° C.
  • Desilylation of compound (L) and compound (M) to compound (N) can be carried out in the presence of a fluoride salt in a suitable solvent according to a conventional method.
  • the solvent is not particularly limited as long as it does not hinder this reaction, and examples thereof include ethers such as tetrahydrofuran.
  • fluoride salts include tetrabutylammonium fluoride.
  • the amount of the fluoride salt used can be 2.0 to 10 equivalents, preferably 4.0 to 6.0 equivalents in terms of molar ratio with respect to the total of compound (L) and compound (M). This reaction can be carried out at 50 to 100 ° C., preferably 70 to 80 ° C.
  • the halogenation from compound (N) to compound (O) can be carried out in the presence of a halogenating agent in a suitable solvent according to a conventional method.
  • a halogenating agent in a suitable solvent according to a conventional method.
  • Any solvent may be used as long as it does not interfere with this reaction.
  • examples thereof include ethers such as tetrahydrofuran, amides such as dimethylformamide, halogenated aliphatic hydrocarbons such as chloroform, and mixtures thereof.
  • the halogenating agent include N-chlorosuccinimide, N-bromosuccinimide, bromine and the like.
  • the amount of the halogenating agent to be used can be 1.0 to 1.5 equivalents, preferably 1.0 to 1.2 equivalents, in molar ratio with respect to compound (N). This reaction can be carried out at 0 to 70 ° C., preferably 0 ° C. to room temperature.
  • the compound represented by the formula (A) can be produced by a known method, and can be produced, for example, by the steps shown in the following formula when it is necessary to produce the compound by controlling the stereotype of the substituent.
  • R e represents a methyl group or a p-toluyl group.
  • R f represents a cyano group or a thioalkoxy group.
  • Other symbols have the same meaning as described above.
  • the compound represented by the general formula (A-1) can be produced, for example, as follows.
  • a compound represented by the general formula (Q) is sulfonylated with a compound represented by the general formula (R) to obtain a compound represented by the general formula (S).
  • a compound represented by the general formula (A-1) can be obtained by a substitution reaction between the obtained compound (S) and the compound represented by the general formula (T).
  • the sulfonylation reaction of compound (Q) and compound (R) can be carried out in a suitable solvent in the presence of a base.
  • the solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include ethers such as tetrahydrofuran, halogenated aliphatic hydrocarbons such as chloroform, and mixtures thereof.
  • the base include amines such as triethylamine.
  • the amount of compound (R) to be used can be 1.0 to 2.0 equivalents, preferably 1.0 to 1.5 equivalents, in molar ratio to compound (Q).
  • the amount of the base used can be 1.5 to 4.0 equivalents, preferably 2.0 to 3.0 equivalents, in molar ratio with respect to compound (Q). This reaction can be carried out at 0 ° C. to room temperature, preferably 0 ° C.
  • substitution reaction of compound (S) and compound (T) can be carried out in a suitable solvent.
  • Any solvent may be used as long as it does not interfere with this reaction. Examples thereof include ethers such as tetrahydrofuran, amides such as dimethylformamide, and mixtures thereof.
  • the amount of compound (T) to be used can be 2.0 to 6.0 equivalents, preferably 2.0 to 3.0 equivalents, in molar ratio with respect to compound (S). This reaction can be carried out at room temperature to 80 ° C, preferably room temperature to 60 ° C.
  • ring A is A compound in which n is 0 and X is O can be produced by the following method. [Wherein, R g represents an alkyl group. Other symbols have the same meaning as described above. ]
  • the compound represented by the general formula (c) is formylated to obtain the compound represented by the general formula (d).
  • the obtained compound (d) is condensed with hydrazine to obtain a compound represented by the general formula (e).
  • the compound (f) or a pharmacologically acceptable salt thereof can be produced.
  • the formylation from compound (c) to compound (d) can be carried out in the presence of methyl formate and a base in a suitable solvent or in the absence of a solvent.
  • the solvent is not particularly limited as long as it does not interfere with this reaction, and examples thereof include ethers such as tetrahydrofuran, amides such as dimethylformamide, and mixtures thereof.
  • the base include alkali metal hydrides such as sodium hydride.
  • the amount of methyl formate used can be 2.0 to 20 equivalents, preferably 10 to 20 equivalents, in molar ratio with respect to compound (c).
  • the amount of the base used can be 2.0 to 5.0 equivalents, preferably 3.0 to 4.0 equivalents, in molar ratio to the compound (c). This reaction can be carried out at 0 ° C. to room temperature, preferably at room temperature.
  • the condensation reaction from compound (d) to compound (e) can be carried out in a suitable solvent in the presence of hydrazine hydrate and an acid.
  • Any solvent may be used as long as it does not interfere with this reaction.
  • Examples thereof include ethers such as tetrahydrofuran, amides such as dimethylformamide, water, and mixtures thereof.
  • Examples of the acid include acetic acid and the like.
  • the amount of hydrazine hydrate to be used can be 1.0 to 1.5 equivalents, preferably 1.0 to 1.2 equivalents, in molar ratio with respect to compound (d).
  • the amount of the acid to be used can be 1.0 to 2.0 equivalents, preferably 1.0 to 1.5 equivalents, in molar ratio with respect to compound (d).
  • This reaction can be carried out at 80 to 140 ° C, preferably 80 to 100 ° C.
  • Alkylation from compound (e) to compound (f) can be carried out in a suitable solvent in the presence of a dihaloalkane (eg, 1,2-dibromoethane) and a base.
  • a dihaloalkane eg, 1,2-dibromoethane
  • the solvent is not particularly limited as long as it does not interfere with this reaction, and examples thereof include ethers such as tetrahydrofuran, amides such as dimethylformamide, and mixtures thereof.
  • the base include amines such as triethylamine and alkali metal carbonates such as sodium carbonate.
  • the amount of dihaloalkane used can be 1.0 to 1.2 equivalents, preferably 1.1 equivalents, in molar ratio with respect to compound (e).
  • the amount of the base used can be 2.0 to 5.0 equivalents, preferably 2.0 to 4.0 equivalents, in molar ratio with respect to compound (e).
  • This reaction can be carried out at 50 to 80 ° C.
  • the compound of the present invention and the intermediate compound can be produced by the above production method, and can also be produced according to the methods described in Examples and Reference Examples described later. Furthermore, the compounds and intermediate compounds of the present invention can be converted into other target compounds or intermediates by the methods described above, the methods described in the Examples and Reference Examples below and / or known methods or combinations thereof. . Examples of such a method include the methods described in the following (1) to (23):
  • the carboxyl group can be converted to a corresponding alkoxycarbonyl group by reacting with an alkylating agent in the presence of a base.
  • (4) Conversion from carboxyl group to hydroxymethyl group After the carboxyl group is activated with isobutyl chloroformate or the like, it can be converted into a hydroxymethyl group by reduction with sodium borohydride or the like. Alternatively, it can be converted into a hydroxymethyl group by reduction with lithium aluminum hydride or the like.
  • Conversion from carbonyl group to amino group The carbonyl group can be converted to an amino group by reacting the desired amine in the presence of a reducing agent.
  • Conversion from amino group to alkoxycarbonylamino group By reacting an amino group with a desired alkoxycarbonyl halide, the amino group can be converted into a corresponding alkoxycarbonylamino group.
  • Conversion from amino group to sulfonylamino group By reacting the amino group with a desired sulfonyl halide, the amino group can be converted into the corresponding sulfonylamino group.
  • Conversion from formyl group to hydroxymethyl group The formyl group can be converted to a hydroxymethyl group by reducing with sodium borohydride or the like.
  • halogen atom Conversion from a halogen atom to a haloalkyl group
  • the compound having a halogen atom can be converted into a corresponding haloalkyl group by reacting with a haloalkyl donor.
  • haloalkyl donors include methyl fluorosulfonyldifluoroacetate.
  • Introduction of halogen atom to carbonyl group ⁇ -position A corresponding halogen atom can be introduced to the carbonyl group ⁇ -position by reacting, for example, bromine with a carbonyl group having methylene at the ⁇ -position.
  • aryl group can be reacted with a base such as s-butyllithium and then reacted with N, N-dimethylformamide to carry out the corresponding formylation.
  • a base for example, 2,6-lutidine
  • Tetrahydropyranyloxylation of hydroxy group The hydroxy group can be converted to tetrahydropyranyloxy by treatment with dihydropyran in the presence of an acid (eg, pyridinium p-toluenesulfonic acid).
  • an acid eg, pyridinium p-toluenesulfonic acid
  • the compound of the present invention or the raw material compound produced as described above is isolated and purified in its free form or as a salt thereof.
  • the salt can be produced by subjecting it to a commonly used salt formation treatment. Isolation and purification can be performed by applying ordinary chemical operations such as extraction, concentration, crystallization, filtration, recrystallization, and various chromatography.
  • optical resolution can be performed by ordinary optical resolution means (for example, fractional crystallization, resolution using a chiral column). It can be separated into isomers.
  • Optical isomers can also be synthesized using optically pure starting materials.
  • optical isomers can also be synthesized by stereoselectively performing each reaction using an asymmetric auxiliary group or an asymmetric catalyst.
  • Example 1 (1) Compound 1 (14 g), Compound 2 (13 g) and dichlorobistriphenylphosphine palladium (1.5 g) were added to 1,2-dimethoxyethane (500 mL), and then a 2 mol / L sodium carbonate aqueous solution (107 mL) was added. In addition, the mixture was stirred under reflux with heating at 100 ° C. for 18 hours under an argon atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted twice with ethyl acetate.
  • Example 10 Sodium hydride (10 mg) was added to a THF (1.2 mL) solution of Compound 1 (30 mg), and the mixture was stirred for 15 minutes under an argon atmosphere. Compound 2 (20 mg) was added and stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted three times with chloroform. The organic layer was dried over anhydrous sodium sulfate.
  • Example 28 Compound 1 (50 mg) was dissolved in a mixed solution of THF (1.0 mL) and DMF (1.0 mL), sodium hydride (17 mg) was added, and the mixture was stirred under an argon atmosphere for 30 minutes. Compound 2 (39 mg) was added and stirred at room temperature for 16 hours. The mixture was further heated to 60 ° C. and stirred for 4 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted three times with chloroform. The organic layer was dried over anhydrous sodium sulfate.
  • Examples 34-35 Compound 1 (100 mg) was dissolved in a mixed solvent of THF (2.0 mL) and DMF (2.0 mL), sodium hydride (33 mg) was added, and the mixture was stirred under an argon atmosphere for 30 minutes. Compound 2 (66 mg) was added and stirred at room temperature for 16 hours. Further, sodium hydride (17 mg) was added, and the mixture was stirred at the same temperature for 2.5 hours. The reaction mixture was diluted with water and extracted three times with chloroform. The organic layer was dried over anhydrous sodium sulfate.
  • Example 36 Compound 1 (29 mg) and Compound 2 (13 ⁇ L) were suspended in DMF (1 mL), and diisopropylethylamine (42 ⁇ L) and O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′- Tetramethyluronium hexafluorophosphoric acid (45 mg) was added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate.
  • Example 45 Compound 1 (50 mg) and N-hydroxysuccinimide (24 mg) were suspended in chloroform (1 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (43 mg) was added, and 3 at room temperature was added. Stir for hours. Concentrated aqueous ammonia (200 ⁇ L) was added, and the mixture was stirred at the same temperature for 40 minutes. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate.
  • Example 46 To a solution of compound 1 (53 mg) and triethylamine (54 mg) in THF (5 mL) was added ethyl chloroformate (39 mg) under ice cooling, and the mixture was stirred at the same temperature for 20 min. Dimethylamine (2 mol / L THF solution, 450 ⁇ L) was added under ice cooling, followed by stirring 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 washed with saturated brine and then dried over anhydrous sodium sulfate.
  • Example 47 The corresponding starting material compound was treated in the same manner as in Example 46 to obtain a compound in which R A has the structure described in Table 5 below in the following general formula.
  • Example 48 A 2 mol / L aqueous sodium carbonate solution (0.6 mL) was added to a mixed solution of Compound 1 (56 mg), Compound 2 (114 mg) and dichlorobistriphenylphosphine palladium (11 mg) in dioxane (2 mL), and a microwave reactor (Initiator) was added. , Manufactured by Biotage Corporation) at 150 ° C. for 10 minutes. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted 3 times with chloroform. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
  • Example 78 Compound 1 (30 mg) was dissolved in chloroform (1.2 mL), triethylamine (33 ⁇ L) and methanesulfonyl chloride (12 ⁇ L) were added, and the mixture was stirred at room temperature for 17 hours. Further, triethylamine (17 ⁇ L) and methanesulfonyl chloride (10 ⁇ L) were added and stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The combined organic layers were dried over anhydrous sodium sulfate.
  • Example 79 After dissolving Compound 1 (30 mg) in methanol (1 mL), acetic acid (41 ⁇ L), 35% formalin (54 ⁇ L) and sodium triacetoxyborohydride (151 mg) were sequentially added and stirred at room temperature for 4 hours. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate.
  • Example 81 Compound 1 (118 mg) and triethylamine (77 ⁇ L) were added to THF (3 mL), isobutyl chloroformate (58 ⁇ L) was added dropwise, and the mixture was stirred at room temperature for 2 hours.
  • Sodium borohydride (28 mg) and methanol (3 mL) were added to the reaction mixture, and the mixture was stirred at the same temperature for 21 hours.
  • Example 82 Compound 1 (100 mg) was suspended in acetonitrile (3.5 mL) and diisopropylethylamine (123 ⁇ L), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (102 mg), 1-hydroxybenzotriazole (58 mg) ), Concentrated aqueous ammonia (2 mL) was added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then dried over anhydrous sodium sulfate.
  • Example 82a Colorless solid, 8.0mg Retention time: 8.99 minutes (Chiralpak IC (4.6 ⁇ 150), methyl t-butyl ether / methanol / diethylamine 80/20 / 0.1, flow rate 0.5 mL / min) Optical purity: 99.99% ee MS (ESI): 281 (M + H) +
  • Example 82b Colorless solid, 7.7 mg Retention time: 10.5 minutes (Chiralpak IC (4.6 ⁇ 150), methyl-t-butyl ether / methanol / diethylamine 80/20 / 0.1, flow rate 0.5 mL / min) Optical purity: 99.73% ee MS (ESI): 281 (M + H) +
  • Example 83 Compound 1 (50 mg) was suspended in acetonitrile (2 mL), diisopropylethylamine (62 ⁇ L) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (51 mg), 1-hydroxybenzotriazole (29 mg), Compound 2 (47 mg) was added and stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then dried over anhydrous sodium sulfate.
  • Example 84 Compound 1 (28 mg) was suspended in DMF (1 mL), diisopropylethylamine (46 ⁇ L) and compound 2 (15 ⁇ L), O- (7-azabenzotriazol-1-yl) -N, N, N ′, N ′. -Tetramethyluronium hexafluorophosphoric acid (51 mg) was added and stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
  • Example 85 (1) Compound 1 (602 mg) was dissolved in chloroform (3 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure to obtain Compound 2 as an orange liquid. Compound 2 was dissolved in acetic acid (8 mL), sodium nitrite (183 mg) was added under an argon atmosphere, and the mixture was stirred at room temperature for 3 hr. The solvent was distilled off under reduced pressure to obtain crude compound 3.
  • Example 86 (1) Compound 1 (1000 mg) was dissolved in chloroform (34 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 21 hours. The solvent was distilled off under reduced pressure to obtain Compound 2 as a colorless liquid. Compound 2 was dissolved in acetic acid (34 mL), sodium nitrite (284 mg) was added under an argon atmosphere, and the mixture was stirred at room temperature for 2 days. Further, sodium nitrite (284 mg) was added, and the mixture was stirred at the same temperature for 3 days. The solvent was distilled off under reduced pressure to obtain Compound 3 as a brown liquid.
  • Trifluoroacetic anhydride (1.9 mL) was dissolved in THF (34 mL) and purged with argon, followed by stirring under ice cooling, and a crude compound 3 solution in THF (10 mL) was added dropwise over 10 minutes. The mixture was warmed to room temperature and stirred for 22 hours.
  • Example 88 Compound 1 (4 mg) was dissolved in chloroform (0.2 mL), water (1 drop), benzyltrimethylammonium chloride (0.3 mg) and potassium peroxymonosulfate (14 mg) were added, and the mixture was stirred at room temperature for 25 hours. The reaction mixture was dried over anhydrous sodium sulfate, filtered and the solvent was distilled off under reduced pressure.
  • Example 89 To a solution of compound 1 (1.40 g) in dimethyl sulfoxide (57 mL) was added sodium cyanide (2.9 g), and the mixture was stirred at 60 ° C. for 15 hours. After allowing to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 2 (1.78 g) as a colorless liquid.
  • Trifluoroacetic anhydride (2.5 mL) was dissolved in THF (20 mL), purged with argon and stirred under ice-cooling, and a THF (10 mL) solution of the compound 5 crude product was added dropwise over 10 minutes. The mixture was warmed to room temperature and stirred for 1 day. The solvent was distilled off under reduced pressure, and the resulting residue was suspended and washed with diethyl ether, collected by filtration, and dried to obtain Compound 6 (337 mg) as a brown solid.
  • Example 90 A 2 mol / L aqueous sodium carbonate solution (2.4 mL) was added to a mixed solution of compound 1 (500 mg), compound 2 (265 ⁇ L) and dichlorobis (triphenylphosphine) palladium (85 mg) in dioxane (6 mL). The mixture was stirred for 15 minutes at 150 ° C. in a wave reactor (Initiator, manufactured by Biotage). The reaction mixture was cooled to room temperature, diluted with water and extracted twice with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound 3.
  • a wave reactor Initiator, manufactured by Biotage
  • Example 95 The corresponding starting material compound was treated in the same manner as in Example 94 to obtain a compound having the structure represented by R A in Table 8 below in the following general formula.
  • Example 96 Compound 1 (46 mg) was dissolved in DMF (1 mL), sodium hydride (9 mg) was added, and the mixture was stirred at room temperature for 20 minutes under an argon atmosphere. Further, triethylamine (29 mg) and compound 2 (63 mg) were added and stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layer was washed with water, and then the organic layer was dried over anhydrous sodium sulfate.
  • Example 97 Compound 1 (25 mg) and copper (I) chloride (11 mg) were suspended in DMF (1 mL), ethyl isocyanate (10 ⁇ L) was added, and the mixture was stirred at room temperature for 17 hours. Ethyl isocyanate (3 ⁇ L) was added, and the mixture was further stirred at the same temperature for 24 hours. The reaction mixture was diluted with 0.2 mol / L hydrochloric acid and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, and then the organic layer was dried over anhydrous sodium sulfate.
  • Example 98 Compound 1 (30 mg) was dissolved in a mixed solvent of THF (0.5 mL) and DMF (0.5 mL), sodium hydride (8.1 mg) was added, and the mixture was stirred at room temperature for 20 minutes. Compound 2 (14 ⁇ L) was added and stirred at the same temperature for 1.5 hours. Further, sodium hydride (5.5 mg) was added and stirred for 2.5 hours. The reaction mixture was diluted with water and extracted twice with chloroform. The organic layer was dried over anhydrous sodium sulfate.
  • Example 99 Compound 1 (20 mg) was dissolved in THF (0.8 mL), compound 2 (11 mg) and pyridinium p-toluenesulfonic acid (5.2 mg) were added, and the mixture was stirred at room temperature for 4 hours. After heating to 50 ° C. and stirring for 22 hours, Compound 2 (46 mg) was added, and the mixture was stirred at the same temperature for 22 hours. Further, Compound 2 (46 mg) was added and stirred at the same temperature for 8 hours. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate.
  • Example 100 Compound 1 (202 mg) was dissolved in chloroform (4 mL), 2,6-lutidine (117 ⁇ L) and compound 2 (267 mg) were added under ice-cooling, and the mixture was stirred at room temperature for 7 days. Further, Compound 2 (46 mg) was added and stirred for 1 day, and then the reaction mixture was diluted with a saturated aqueous sodium hydrogen carbonate solution and extracted twice with chloroform. The organic layer was dried over anhydrous sodium sulfate.
  • Example 101 Compound 1 (100 mg) was suspended in methanol (10 mL), sodium acetate (69 mg) and hydroxyamine hydrochloride (58 mg) were added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with water and extracted twice with chloroform. The organic layer was dried over anhydrous sodium sulfate.
  • Example 101a Colorless solid, 61 mg MS (ESI): 253 (M + H) + Example 101b Colorless solid, 20mg MS (ESI): 253 (M + H) +
  • Example 102 (1) Compound 1 (53 mg) was dissolved in a mixed solvent of methanol (2.5 mL) and THF (2.5 mL), and then molybdenum (VI) oxide (27 mg) and sodium borohydride (70 mg) were added under ice cooling. In addition, the mixture was stirred at the same temperature for 30 minutes. After further stirring at room temperature for 15 hours, water and a saturated aqueous potassium carbonate solution were added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate.
  • Example 103 After dissolving Compound 1 (30 mg) in chloroform (1 mL), acetic acid (7 ⁇ L), 35% formalin (52 ⁇ L) and sodium triacetoxyborohydride (82 mg) were sequentially added and stirred at room temperature for 1.5 hours. Water and a saturated aqueous potassium carbonate solution were added to the reaction mixture, and the mixture was extracted with chloroform. The combined organic layers were dried over anhydrous sodium sulfate.
  • Example 105 (1) Compound 1 (70 mg) was dissolved in dimethylacetamide (2.9 mL), diisopropylethylamine (100 ⁇ L) and compound 2 (47 mg) were added, and 160 in a microwave reactor (Initiator, Biotage). Stir at 0 ° C. for 2 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate.
  • Example 107 Compound 1 (30 mg) was dissolved in DMF (1.2 mL), potassium carbonate (35 mg), sodium iodide (57 mg) and compound 2 (36 mg) were added, and the mixture was heated and stirred at 80 ° C. for 24 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate.
  • Example 107a Brown sticky body, 6.5mg Retention time: 10.6 minutes (Chiralpak IF (4.6 ⁇ 150), hexane / ethanol / THF / diethylamine 20/75/5 / 0.1, flow rate 0.5 mL / min) Optical purity: 99.97% ee MS (ESI): 309 (M + H) +
  • Example 107b Brown sticky body, 5.9mg Retention time: 13.9 minutes (Chiralpak IF (4.6 ⁇ 150), hexane / ethanol / THF / diethylamine 20/75/5 / 0.1, flow rate 0.5 mL / min) Optical purity: 99.84% ee MS (ESI): 309 (M + H) +
  • Example 108 Compound 1 (60 mg) was dissolved in DMF (2.5 mL), potassium carbonate (70 mg), sodium iodide (113 mg) and compound 2 (122 mg) were added, and the mixture was stirred with heating at 80 ° C. for 6 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate.
  • Example 110 Compound 1 (30 mg) was dissolved in a mixed solvent of methanol (1 mL) and THF (0.5 mL), sodium borohydride (6.0 mg) was added, and the mixture was stirred at room temperature for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate isocratic) to obtain a racemate.
  • the fractions containing the respective isomers are concentrated under reduced pressure to give two stereoisomers ((5S) -3- (4-cyano-2-methylphenyl) -5-hydroxy-5,6-dihydro-4H.
  • Example 112 Sodium hydride (4.0 mg) and methyl iodide (8.5 mg) were added to a solution of compound 1 (12 mg) in THF (0.5 mL), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layer was washed twice with water, and then the organic layer was dried over anhydrous sodium sulfate.
  • Example 113 Compound 1 (60 mg) was dissolved in a mixed solvent of diethyl ether (1 mL) and THF (2 mL), methylmagnesium bromide (0.92 mol / L THF solution, 300 ⁇ L) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. . After warming to room temperature and further stirring for 3 hours, the reaction mixture was diluted with water and saturated aqueous ammonium chloride and extracted with chloroform. The organic layer was washed twice with water, and then the organic layer was dried over anhydrous sodium sulfate.
  • Example 114 (1) Sodium hydride (1.3 g) was added to a mixture of compound 1 (2.0 g) and methyl formate (10 mL) at room temperature over 30 minutes. The mixture was further stirred for 3 hours, cooled on ice, added with water and 1 mol / L hydrochloric acid, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was suspended and washed with a mixed solvent of ethyl acetate / hexane, collected by filtration and dried.
  • Example 116 A solution of compound 1 (855 mg) and 4-methylbenzenesulfonylhydrazine (672 mg) in dioxane (36 mL) was stirred at 60 ° C. for 2 hours under an argon atmosphere. The reaction mixture was cooled to room temperature, and then diluted with saturated brine and ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate.
  • Example 117-119 The corresponding starting material compound was treated in the same manner as in Example 116, whereby each compound having the structure represented by R A in the following general formula shown in Table 9 was obtained.
  • Example 121 A 2 mol / L aqueous sodium carbonate solution (0.6 mL) was added to a mixed solution of Compound 1 (60 mg), Compound 2 (97 mg) and dichlorobistriphenylphosphine palladium (11 mg) in dioxane (2 mL), and a microwave reactor (Initiator) was added. , Manufactured by Biotage Corporation) at 150 ° C. for 10 minutes. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted 3 times with chloroform. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
  • Example 124 A 2 mol / L aqueous sodium carbonate solution (0.5 mL) was added to a mixed solution of Compound 1 (50 mg), Compound 2 (79 mg) and dichlorobistriphenylphosphine palladium (17 mg) in dioxane (1.2 mL), and a microwave reactor was added. (Initiator, manufactured by Biotage Corporation) was stirred at 150 ° C. for 15 minutes. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted 3 times with chloroform. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
  • Initiator manufactured by Biotage Corporation
  • Example 125 A 2 mol / L aqueous sodium carbonate solution (0.66 mL) was added to a mixed solution of compound 1 (100 mg), compound 2 (107 mg) and dichlorobistriphenylphosphine palladium (23 mg) in dioxane (1.7 mL). The mixture was stirred for 15 minutes at 150 ° C. in a wave reactor (Initiator, manufactured by Biotage). The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted 3 times with chloroform. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
  • a wave reactor Initiator, manufactured by Biotage
  • Example 126 Compound 1 (500 mg) was dissolved in dioxane (6 mL), triethylamine (0.95 mL) and 1,3-dibromopropane (380 ⁇ L) were added, and the mixture was heated and stirred at 100 ° C. for 21 hours. The reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with chloroform. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
  • Example 127 Compound 1 (100 mg) was dissolved in a mixed solvent of DMF (1 mL) and THF (1 mL), sodium hydride (30 mg) and methyl iodide (37 ⁇ L) were added, and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (40 ⁇ L) was added and stirred at the same temperature for 45 minutes, and then methyl iodide (10 ⁇ L) was further added and stirred for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
  • Example 128 (1) Hydrazine monohydrate (1.0 mL) was dissolved in methanol (20 mL), and Compound 1 (1.66 mL) was added dropwise under ice cooling, followed by stirring at room temperature for 2 hours. Compound 1 (0.28 mL) was added dropwise at the same temperature, and the mixture was further stirred at room temperature for 16 hours. After raising the temperature to 60 ° C. and heating and stirring for 3.5 hours, the mixture was allowed to cool to room temperature and the solvent was distilled off under reduced pressure. To the residue was added saturated brine, and the mixture was extracted with ethyl acetate.
  • Example 129 A 2 mol / L aqueous sodium carbonate solution (535 ⁇ L) was added to a mixture of compound 1 (50 mg), compound 2 (109 mg) and dichlorobistriphenylphosphine palladium (19 mg) in dioxane (1.3 mL), and a microwave reactor (Initiator) was added. , Manufactured by Biotage Corporation) at 150 ° C. for 10 minutes. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted 3 times with chloroform. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
  • Example 133 Compound 1 (28 mg) was dissolved in chloroform (1.2 mL), diisopropylethylamine (40 ⁇ L) and methanesulfonyl chloride (11 ⁇ L) were added, and the mixture was stirred at room temperature for 30 minutes. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate.
  • Example 134 Compound 1 (40 mg) was dissolved in a mixed solvent of diethyl ether (2 mL) and THF (2 mL), compound 2 (76 ⁇ L) and lithium perchlorate (90 mg) were added, and the mixture was stirred at room temperature for 21 hours. Further, Compound 2 (150 ⁇ L) and lithium perchlorate (180 mg) were added, and the mixture was heated and stirred at 50 ° C. for 6 hours. After allowing to cool to room temperature, water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate.
  • Example 135 Compound 1 (40 mg) was dissolved in chloroform (2 mL), acetic acid (10 ⁇ L), acetone (25 ⁇ L) and sodium triacetoxyborohydride (110 mg) were added, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off.
  • Example 136 Compound 1 (40 mg) was dissolved in chloroform (1.7 mL), acetic acid (10 ⁇ L), 35% formalin (41 ⁇ L) and sodium triacetoxyborohydride (71 mg) were added, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off.
  • Example 137 To a solution of compound 1 (70 mg) in DMF (2 mL), compound 2 (101 mg), palladium acetate (6.3 mg), tricyclohexylphosphine (17 ⁇ L), pivalic acid (19 ⁇ L), potassium carbonate (116 mg) were added, and microwaves were added. The mixture was stirred at 150 ° C. for 15 minutes in a reactor (Initiator, manufactured by Biotage). After allowing to cool to room temperature, water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate.
  • a reactor Initiator, manufactured by Biotage
  • Example 138-139 The corresponding starting material compound was treated in the same manner as in Example 137, whereby each compound having the following general formula and R A having the structure described in Table 12 was obtained.
  • Reference example 1 (1) Compound 1 (45 g) was dissolved in chloroform (360 mL), trifluoroacetic acid (90 mL) was added dropwise over 20 minutes under ice-cooling, and the mixture was warmed to room temperature and stirred for 18 hours. After the reaction mixture was diluted with chloroform, the solvent was distilled off under reduced pressure to obtain Compound 2 as a brown viscous body. Compound 2 was dissolved in acetic acid (360 mL), sodium nitrite (11 g) was added under an argon atmosphere, and the mixture was stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure to obtain Compound 3 as a yellow liquid.
  • Reference example 2 (1) Compound 1 (400 mg) and ethyl chloroacetate (356 ⁇ L) were dissolved in THF (17 mL), sodium hydride (80 mg) was added under ice cooling, and the mixture was stirred at room temperature for 21 hours. Ethyl chloroacetate (178 ⁇ L) and sodium hydride (40 mg) were added, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate.
  • Reference example 3 (1) Sodium hydride (56 mg) was suspended in THF (8 mL), a solution of compound 2 (350 mg) in THF (2 mL) was added dropwise at room temperature, and the mixture was stirred at the same temperature for 20 minutes. A solution of compound 1 (300 mg) in THF (3 mL) was added dropwise, and the mixture was stirred at room temperature for 20 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution and then dried over anhydrous sodium sulfate.
  • Reference example 4 A 2 mol / L aqueous sodium carbonate solution (4.6 mL) was added to a dioxane (12 mL) solution of compound 1 (700 mg), compound 2 (750 mg) and dichlorobis (triphenylphosphine) palladium (160 mg), and a microwave reactor ( The mixture was stirred at 150 ° C. for 15 minutes. After allowing to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate.
  • Mitochondrial fraction diluted with a buffer containing 10 mmol / L KH 2 PO 4 , 10 mmol / L Tris, 20 mmol / L KCl, 25 mmol / L sucrose, 5 mmol / L MgCl 2 , 0.05% bovine serum albumin in a 96-well plate Dispense minutes.
  • 0.5 ⁇ mol / L deoxycorticosterone, 150 ⁇ mol / L NADPH each concentration of the compound was added, and incubated at room temperature for 1.5 to 2 hours to produce aldosterone.
  • the amount of aldosterone produced in the solution was measured using the HTRF (Homogenous Time Resolved Fluorescence) method.
  • IC 50 (nmol / L) was calculated by non-linear regression using a logistic curve from the aldosterone production inhibition rate (%) of the compound at each concentration.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof has an inhibitory activity on aldosterone synthase activity, it increases aldosterone levels such as hypertension, primary aldosteronism and / or overproduction of aldosterone. It is useful as a medicament for preventing or treating various diseases and / or disease states caused, or for improving the prognosis of these diseases.

Abstract

L'invention concerne : un nouveau composé hétérocyclique contenant de l'azote, qui présente une activité d'inhibition de l'aldostérone synthase et qui, par conséquent, est utile pour prévenir et/ou traiter diverses maladies ou divers symptômes associés à l'aldostérone et/ou pour améliorer le pronostic de telles maladies ou de tels symptômes, ou un sel pharmacologiquement acceptable correspondant ; un procédé pour sa production ; son utilisation ; une composition médicinale qui comprend le composé susmentionné ou un sel pharmacologiquement acceptable correspondant en tant que principe actif, etc. Plus particulièrement, l'invention concerne : un composé représenté par la formule générale (I) [dans laquelle chaque symbole est tel que défini dans la description] ou un sel pharmacologiquement acceptable correspondant ; un procédé pour sa production ; son utilisation ; une composition médicinale qui comprend le composé susmentionné ou un sel pharmacologiquement acceptable correspondant en tant que principe actif, etc.
PCT/JP2017/013051 2016-03-30 2017-03-29 Nouveau composé hétérocyclique contenant de l'azote WO2017170765A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2016069076 2016-03-30
JP2016-069076 2016-03-30

Publications (1)

Publication Number Publication Date
WO2017170765A1 true WO2017170765A1 (fr) 2017-10-05

Family

ID=59965796

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2017/013051 WO2017170765A1 (fr) 2016-03-30 2017-03-29 Nouveau composé hétérocyclique contenant de l'azote

Country Status (1)

Country Link
WO (1) WO2017170765A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
WO2023284775A1 (fr) * 2021-07-14 2023-01-19 上海海雁医药科技有限公司 Dérivé de pyrazole, et intermédiaire de celui-ci et son procédé de préparation
RU2789610C1 (ru) * 2022-02-08 2023-02-06 Общество с ограниченной ответственностью "Таргет Медикалс" Ингибиторы цитохрома 11В2 человека
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009506048A (ja) * 2005-08-25 2009-02-12 ノバルティス アクチエンゲゼルシャフト アルドステロンシンターゼおよびアロマターゼの阻害のための縮合イミダゾ路誘導体
WO2013043521A1 (fr) * 2011-09-22 2013-03-28 Merck Sharp & Dohme Corp. Composés pyrazolopyridyle à utiliser en tant qu'inhibiteurs de l'aldostérone synthase
JP2013512271A (ja) * 2009-11-30 2013-04-11 ノバルティス アーゲー アルドステロン合成酵素阻害剤としてのイミダゾール誘導体
WO2013055793A1 (fr) * 2011-10-12 2013-04-18 University Of Pittsburg-Of The Commonwealth System Of Higher Education Petites molécules ciblant la localisation et/ou le niveau nucléaire des récepteurs de l'androgène dans le cancer de la prostate
WO2013062074A1 (fr) * 2011-10-28 2013-05-02 大正製薬株式会社 Dérivé d'imidazolone
WO2015060348A1 (fr) * 2013-10-23 2015-04-30 大日本住友製薬株式会社 Dérivé de pyrazole fusionné

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009506048A (ja) * 2005-08-25 2009-02-12 ノバルティス アクチエンゲゼルシャフト アルドステロンシンターゼおよびアロマターゼの阻害のための縮合イミダゾ路誘導体
JP2013512271A (ja) * 2009-11-30 2013-04-11 ノバルティス アーゲー アルドステロン合成酵素阻害剤としてのイミダゾール誘導体
WO2013043521A1 (fr) * 2011-09-22 2013-03-28 Merck Sharp & Dohme Corp. Composés pyrazolopyridyle à utiliser en tant qu'inhibiteurs de l'aldostérone synthase
WO2013055793A1 (fr) * 2011-10-12 2013-04-18 University Of Pittsburg-Of The Commonwealth System Of Higher Education Petites molécules ciblant la localisation et/ou le niveau nucléaire des récepteurs de l'androgène dans le cancer de la prostate
WO2013062074A1 (fr) * 2011-10-28 2013-05-02 大正製薬株式会社 Dérivé d'imidazolone
WO2015060348A1 (fr) * 2013-10-23 2015-04-30 大日本住友製薬株式会社 Dérivé de pyrazole fusionné

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
AGGARWAL, R. ET AL.: "Synthesis and biological evaluation of 7-trifluoromethylpyrazolo[1,5-a] pyrimidines as anti-inflammatory and antimicrobial agents", JOURNAL OF FLUORINE CHEMISTRY, vol. 168, 2014, pages 16 - 24, XP055431359 *
ALLIN, S. M. ET AL.: "Radical cyclisation onto pyrazoles: synthesis of withasomnine", TETRAHEDRON LETTERS, vol. 43, no. 23, 2002, pages 4191 - 4193, XP004354672 *
BELLEC, C. ET AL.: "Chemical and Electrochemical Reduction of some Pyrazolo[1,5-a]pyrimidines", J. HETEROCYCLIC CHEM., vol. 32, no. 6, 1995, pages 1793 - 1800, XP000973720 *
DATABASE FILE REGISTRY 7 December 2000 (2000-12-07), retrieved from STN Database accession no. RN 307325-28-6 *
DATABASE REGISTRY [O] 3 August 2006 (2006-08-03), retrieved from STN Database accession no. 898522-30-0 *
DEMCHENKO, A. M. ET AL.: "Synthesis and antimycotic activity of 3-aryl-6,7-dihydro-5H- pyrrolo[1,2-a]imidazoles", KHIMIKO- FARMATSEVTICHESKII ZHURNAL, vol. 21, no. 11, 1987, pages 1335 - 1338 *
I CHIKAWA, H. ET AL.: "Divergent synthesis of withasomnines via synthesis of 4-hydroxy-lH- pyrazoles and Claisen rearrangement of their 4-O-allylethers", TETRAHEDRON LETTERS, vol. 52, no. 34, 2011, pages 4448 - 4451, XP028244273 *
KUZMENOK, N. M. ET AL.: "Synthesis of 3-aryl- 5-methylpyrrolidino[1,2-b]pyrazoles", KHIMIYA GETEROTSIKLICHESKIKH SOEDINENNI, vol. 1, 1994, pages 49 - 51 *
KUZMENOK, N. M. ET AL.: "Wolff-Kishner reduction of 5-methyl- and 6,6-dimethyl-5-hydroxy-4-oxo- 3-phenylpyrrolo[1,2-b]pyrazoles", CHEMISTRY OF HETEROCYCLIC COMPOUNDS, vol. 29, no. 10, 1993, pages 1152 - 1155, XP055431361 *
SCARPELLI, R. ET AL.: "Studies of the metabolic stability in cells of 5-(trifluoroacetyl) thiophene-2-carboxamides and identification of more stable class II histone deacetylase (HDAC) inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 18, no. 23, 2008, pages 6078 - 6082, XP029871164 *
USAMI, Y. ET AL.: "Divergent Synthesis and Evaluation of Inhibitory Activities against Cyclooxygenases-1 and -2 of Natural Withasomnines and Anallogues", CHEM. PHARM. BULL., vol. 60, no. 12, 2012, pages 1550 - 1560 *
VERMA, D. ET AL.: "Synthesis of Withasomnines and Their Non- natural Analogues from Aldehydes and 4-Nitro-l-butanol in Three Steps", J. ORG. CHEM., vol. 78, no. 7, 2013, pages 3482 - 3486, XP055431358 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
WO2023284775A1 (fr) * 2021-07-14 2023-01-19 上海海雁医药科技有限公司 Dérivé de pyrazole, et intermédiaire de celui-ci et son procédé de préparation
RU2789610C1 (ru) * 2022-02-08 2023-02-06 Общество с ограниченной ответственностью "Таргет Медикалс" Ингибиторы цитохрома 11В2 человека

Similar Documents

Publication Publication Date Title
KR101921404B1 (ko) 신규 2치환 1,2,4-트리아진 화합물
JP7305196B2 (ja) ハロアリルアミン類のｓｓａｏ／ｖａｐ－１阻害剤とその用途
JP6564406B2 (ja) カゼインキナーゼ１デルタ／イプシロン阻害剤としてのイミダゾ−ピリダジン誘導体
US20200031805A1 (en) Aryl hydrocarbon receptor (ahr) modulator compounds
JP2019537610A (ja) Ｆｇｆｒ４阻害剤、その製造方法と薬学的な応用
KR102580087B1 (ko) 자가포식 조절인자(autophagy regulator)로서 사용된 화합물, 및 이에 대한 제조 방법 및 이의 용도
WO2005095419A1 (fr) Dérivé de thiazolopyrimidine
JP2008514628A (ja) 蛋白質キナーゼ類のイミダゾ｛４，５−ｂ｝ピラジノン阻害剤
JP2016517412A (ja) Ｆａｓｎを阻害するための新規化合物および組成物
JP2022538917A (ja) Ｂｅｔ阻害剤としてのヘテロ環式化合物
CN112707854B (zh) 吡咯酰胺类化合物及其用途
CN107207504B (zh) 酞嗪酮衍生物、其制备方法及用途
CN115697986A (zh) 同位素取代的螺芳环化合物及其应用
WO2017170765A1 (fr) Nouveau composé hétérocyclique contenant de l'azote
CN107108586A (zh) 多环类间变性淋巴瘤激酶抑制剂
JP2022517723A (ja) Ｃｄｋ阻害剤としての大環状化合物、その製造方法及びその医薬品における応用
JP2013542259A (ja) 置換アザインダゾール化合物
CN116322697A (zh) 一种喹唑啉化合物及其药物组合物
EP4166542A1 (fr) Composé bicyclique et son application
TW201900644A (zh) Fgfr4抑制劑及其制備與應用
GB2572526A (en) Heterocyclic small molecule modulators of human STING
JP6545275B2 (ja) 新規含窒素芳香族複素環化合物
JP7051855B2 (ja) プロテインキナーゼ調節剤
WO2019029554A1 (fr) Dérivé sulfonamide, sa méthode de préparation et son application en médecine
JP6314196B2 (ja) 医薬組成物

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: JP

122 Ep: pct application non-entry in european phase

Ref document number: 17775299

Country of ref document: EP

Kind code of ref document: A1