WO2017188369A1 - Pharmaceutical composition for treatment or prevention of atopic dermatitis - Google Patents

Pharmaceutical composition for treatment or prevention of atopic dermatitis Download PDF

Info

Publication number
WO2017188369A1
WO2017188369A1 PCT/JP2017/016701 JP2017016701W WO2017188369A1 WO 2017188369 A1 WO2017188369 A1 WO 2017188369A1 JP 2017016701 W JP2017016701 W JP 2017016701W WO 2017188369 A1 WO2017188369 A1 WO 2017188369A1
Authority
WO
WIPO (PCT)
Prior art keywords
dimethyl
trimethylsilyl
cyclobutanecarboxamide
pyrazole
group
Prior art date
Application number
PCT/JP2017/016701
Other languages
French (fr)
Japanese (ja)
Inventor
徳明 岩瀬
康弘 阿賀
繁行 河野
茂 牛山
和弘 大沼
高志 松下
彩矢佳 小木
あゆみ 小川
木村　富美夫
Original Assignee
宇部興産株式会社
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=60159958&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2017188369(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by 宇部興産株式会社 filed Critical 宇部興産株式会社
Publication of WO2017188369A1 publication Critical patent/WO2017188369A1/en

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
    • A61K31/695—Silicon compounds

Definitions

  • the present invention relates to a pharmaceutical composition useful for the treatment and / or prevention of atopic dermatitis, comprising a substituted dihydropyrrolopyrazole compound or a pharmacologically acceptable salt thereof, or a prodrug thereof.
  • Non-Patent Document 1 The number of patients with allergic diseases such as bronchial asthma, atopic dermatitis, hay fever, allergic rhinitis, and food allergies is increasing year by year. In recent years, about 1/3 of the total population in Japan suffers from allergic diseases. (See Non-Patent Document 1).
  • Atopic dermatitis is a chronic skin disease with itching caused by various stimuli on allergic constitution called atopic predisposition, such as allergic asthma, allergic rhinitis, dermatitis urticaria .
  • atopic predisposition such as allergic asthma, allergic rhinitis, dermatitis urticaria .
  • it presents symptoms of chronic eczema over a wide area, with strong itching.
  • some patients have red eczema, nodules, etc., accompanied by severe itching, and tissue fluid oozes from the moistened phase, causing severe pain.
  • antihistamines have a certain level of antipruritic effect, they are not durable and may cause fatigue and drowsiness after administration, which may interfere with daily life.
  • steroids are highly effective in improving skin symptoms, they have strong side effects such as adrenal cortical dysfunction due to large-scale use. It was. Therefore, safety is sufficiently established, and a more effective therapeutic drug for atopic dermatitis is desired.
  • CDK7 cyclin-dependent kinase 7
  • Saccharomyces cerevisiae 7 CDK7 (cyclin-dependent kinase 7) was initially identified as an mRNA transcription factor in Saccharomyces cerevisiae, and subsequently became clear to play two roles, cell cycle control and mRNA transcription control.
  • CDK family including CDK7 CDKs
  • CDKs CDKs
  • CDKs is known to be involved in inflammatory reaction through proliferation of inflammatory cells and immune cells, regulation of apoptosis, transcriptional regulation of inflammatory mediators, etc. It is considered promising for the disease to be performed (see Non-Patent Document 3).
  • Non-Patent Document 4 atopicity It has been reported that Th17 differentiation deeply associated with dermatitis is suppressed (see Non-Patent Documents 5 and 6).
  • the inventors of the present invention have conducted intensive research aimed at developing an excellent CDK7 inhibitor useful for the treatment and / or prevention of atopic dermatitis.
  • a novel substituted dihydropyrrolopyrazole compound having a specific structure or a pharmacologically acceptable salt thereof has excellent CDK7 inhibitory activity, and a pharmaceutical composition comprising the compound or a pharmacologically acceptable salt thereof is provided.
  • the inventors have found that it is useful as a therapeutic agent and / or preventive agent (preferably a therapeutic agent) for atopic dermatitis, and has also found a compound that can be a prodrug of the compound, thereby completing the present invention.
  • Patent Documents 1 to 9 and Non-Patent Documents 8 to 10 describe compounds having a 6,6-dimethyl-4,6-dihydropyrrolo [3,4-c] pyrazole skeleton.
  • the compound according to the present invention or a pharmacologically acceptable salt thereof is not disclosed.
  • Patent Document 10 discloses pyrazolopyrimidine derivatives, Patent Documents 11 and 12, pyrazolotriazine derivatives, Patent Document 13 and Non-Patent Document 7, phenyl derivatives, Patent Document 14 Although heterocyclic compounds are disclosed in -20 to 20, a compound having a 4,6-dihydropyrrolo [3,4-c] pyrazole skeleton is not disclosed.
  • the present invention relates to a pharmaceutical composition for treating or preventing atopic dermatitis, comprising a novel substituted dihydropyrrolopyrazole compound having excellent CDK7 inhibitory activity or a pharmacologically acceptable salt thereof, or a prodrug thereof; Use of a substituted dihydropyrrolopyrazole compound or a pharmacologically acceptable salt thereof, or a prodrug thereof for the manufacture of a pharmaceutical composition for the treatment or prevention (preferably treatment) of atopic dermatitis; and substituted dihydropyrrolo Treatment or prevention of atopic dermatitis by administration of a pharmaceutically effective amount of a pyrazole compound or a pharmacologically acceptable salt thereof or a prodrug thereof to a warm-blooded animal (preferably a human) (preferably, A method for treatment).
  • a pharmaceutically effective amount of a pyrazole compound or a pharmacologically acceptable salt thereof or a prodrug thereof to a warm-blooded animal (preferably a
  • the present invention provides the following [1] to [37] from one aspect.
  • a pharmaceutical composition for treating or preventing atopic dermatitis comprising a compound represented by the formula: or a pharmacologically acceptable salt thereof.
  • a pharmaceutical composition for treating or preventing atopic dermatitis comprising a compound represented by the formula: or a pharmacologically acceptable salt thereof.
  • a pharmaceutical composition for treating or preventing atopic dermatitis comprising a compound represented by the formula: or a pharmacologically acceptable salt thereof.
  • a pharmaceutical composition for treating or preventing atopic dermatitis comprising a compound represented by the formula: or a pharmacologically acceptable salt thereof.
  • L 2 and L 3 represent a single bond.
  • L 2 is a divalent group represented by -NH-, L 3 indicates a straight chain may be substituted or branched C 1-6 alkylene group, [2] according Pharmaceutical composition.
  • L 2 represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—
  • L 3 represents a single bond or a linear or branched C 1-6 alkylene group which may be substituted
  • R 1 , R 2 and R 3 each independently represents an optionally substituted linear or branched C 1-4 alkyl group
  • R 4 is an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-10 aryl group, or
  • R 5 represents a hydrogen atom, an optionally substituted linear or branched C 1-16 alkyl group, an optionally substituted C 3-6 cycloalkyl group, or an optionally substituted C 6-10 aryl group.
  • a pharmaceutical composition for treating or preventing atopic dermatitis comprising a compound represented by the formula: or a pharmacologically acceptable salt thereof.
  • a pharmaceutical composition for treating or preventing atopic dermatitis comprising a compound represented by the formula: or a pharmacologically acceptable salt thereof.
  • L 2 is a divalent group represented by -NH-, L 3 indicates a straight chain may be substituted or branched C 1-6 alkylene group, [5] according Pharmaceutical composition.
  • L 2 represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—
  • L 3 represents a single bond or a linear or branched C 1-6 alkylene group which may be substituted
  • R 1 , R 2 and R 3 each independently represents an optionally substituted linear or branched C 1-4 alkyl group
  • R 4 is an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-10 aryl group, or
  • R 5 represents a hydrogen atom, an optionally substituted linear or branched C 1-16 alkyl group, an optionally substituted C 3-6 cycloalkyl group, or an optionally substituted C 6-10 aryl group.
  • a pharmaceutical composition for treating or preventing atopic dermatitis comprising a compound represented by the formula: or a pharmacologically acceptable salt thereof.
  • L 2 is a divalent group represented by -NH-, L 3 indicates a straight chain may be substituted or branched C 1-6 alkylene group, [8] described Pharmaceutical composition.
  • L 2 is a divalent group represented by -NH-
  • L 3 indicates a straight chain may be substituted or branched C 1-6 alkylene group, [11] according Pharmaceutical composition.
  • a pharmaceutical composition for treating or preventing atopic dermatitis comprising pyrazol-3-yl ⁇ -1- (trimethylsilyl) cyclobutanecarboxamide or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for treating or preventing atopic dermatitis comprising pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof.
  • Treatment or prevention of atopic dermatitis comprising administering the compound according to any one of [1] to [33] or a pharmacologically acceptable salt thereof to a subject in need thereof.
  • Specific examples of the compound represented by the general formula (I) of the present invention include compounds shown in Tables 1 to 20 below.
  • Me represents a methyl group
  • Et represents an ethyl group
  • nPr represents an n-propyl group
  • iPr represents an isopropyl group
  • cPr represents a cyclopropyl group
  • nBu represents n -Butyl group
  • iBu represents isobutyl group
  • tBu represents tert-butyl group
  • cHex represents cyclohexyl group
  • Ph represents phenyl group
  • 2-F-Ph represents 2-fluorophenyl group
  • 3-F-Ph represents 3-fluorophenyl group
  • 4-F-Ph represents 4-fluorophenyl group
  • 2-Cl-Ph represents 2-chlorophenyl group
  • 3-Cl-Ph represents 3-chlorophenyl group
  • 4-Cl-Ph represents a 4-chloroph
  • CH 2 (CMe) 2 corresponding to L 3 is bonded to a carbon atom to which a methylene carbon atom (CH 2 ) is marked with “*”, and a dimethylmethylene carbon atom ( CMe) 2 means bonded to the oxygen atom adjacent to R 5 .
  • novel substituted dihydropyrrolopyrazole compound having a specific structure represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has excellent CDK7 inhibitory activity, kinase inhibition, when the compound itself or its metabolite is excellent. High selectivity for action and excellent safety. Therefore, the pharmaceutical composition containing the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof is useful as a therapeutic and / or prophylactic agent for atopic dermatitis.
  • the “prodrug” means a compound or a salt thereof that undergoes a metabolic reaction to produce a compound having a CDK7 inhibitory action when administered into an animal body.
  • One embodiment of the present invention is a pharmaceutical composition for treating or preventing atopic dermatitis comprising a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof.
  • R's each independently represent a C 1-3 alkyl group, or a group bonded to each other to form a C 2-5 alkylene group
  • L 2 represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—
  • L 3 represents a single bond or a linear or branched C 1-6 alkylene group which may be substituted
  • R 1 , R 2 and R 3 each independently represents an optionally substituted linear or branched C 1-4 alkyl group
  • R 4 is an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-10 aryl group, or
  • R 5 represents a hydrogen atom, an optionally substituted linear or branched C 1-16 alkyl group, an optionally substituted C 3-6 cycloalkyl group, or an optionally substituted C 6-10 aryl group.
  • an optionally substituted heterocyclic group R 5 represents a hydrogen
  • the term “may be substituted” means that the group may be unsubstituted or further substituted with a substituent.
  • the above substituent means a monovalent group, for example, a linear or branched C 1-6 alkyl group, a C 3-6 cycloalkyl group, a linear or branched C 2-6 alkenyl group, a C 3-6 cyclo An alkenyl group, a linear or branched C 2-6 alkynyl group, a C 1-6 alkoxy group, a halogen atom, a hydroxyl group, a cyano group, an oxo group ( ⁇ O), an amino group, a C 1-6 alkylamino group, a nitro group, Carboxy group (—COOH), carbamoyl group (—CONH 2 ), N-mono C 1-6 alkylcarbamoyl group, N, N-diC 1-6 alkylcarbamoyl group, C 1-6 alkanoyloxy group (—OCOR, R is C 1-6 alkyl group), C 6-10 aryl group, a heterocyclic group,
  • the above substituents may be further substituted with a halogen atom, a hydroxyl group, an amino group, a cyano group, an oxo group ( ⁇ O), a linear or branched C 1-6 alkyl group, and the like.
  • a halogen atom a hydroxyl group, an amino group, a cyano group, an oxo group ( ⁇ O), a linear or branched C 1-6 alkyl group, and the like.
  • the substituent is an amino group or a carboxy group, it may be in the form of a salt thereof.
  • the two substituents may be bonded to each other to form a cyclic structure.
  • examples of the case where two substituents are bonded to each other to form a cyclic structure include a cyclopropyl group, a cyclobutyl group, and a methylenedioxy group.
  • the substituent is a 1,3-benzodioxole group, which has two methyl groups on the same carbon atom of the 1,2-ethylene group.
  • the group When bonded to each other, the group becomes a group represented by the following formula (M-1) or (M-2), and has a methyl group and an ethyl group on the same carbon atom of the 1,2-ethylene group.
  • the group When the 2-position of the ethyl group is bonded to the methyl group, the group is a group represented by the following formula (N-1) or (N-2).
  • the linear or branched C 1-6 alkyl group described in the present specification means a linear or branched alkyl group having 1 to 6 carbon atoms.
  • Examples of linear or branched C 1-6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, and neopentyl.
  • the Substituent is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, butyl group, isobutyl group, sec- butyl group, a tert- butyl group.
  • Examples of the C 1-6 alkyl group substituted with a halogen atom include a chloromethyl group, a bromomethyl group, an iodomethyl group, a difluoromethyl group, a dichloromethyl group, a dibromomethyl group, a diiodomethyl group, a trifluoromethyl group, and a trichloromethyl group.
  • Examples include a til group, 1-fluoro-1-methylethyl group, 4-fluorobutyl group, perfluorobutyl group, 5-fluoropentyl group, perfluoropentyl group, 6-fluorohex
  • the C 1-6 alkyl group substituted with an aryl group may be, for example, a C 7-11 aralkyl group.
  • the C 7-11 aralkyl group means an alkyl group having an aryl group having a total carbon number of 7 to 11, and examples thereof include a benzyl group, a phenylethyl group, and a naphthylmethyl group.
  • the C 3-6 cycloalkyl group described in the present specification means a cyclic alkyl group having 3 to 6 carbon atoms.
  • Examples of the C 3-6 cycloalkyl group include monocyclic rings such as cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group; condensed rings such as bicyclo [3.1.0] hexyl group; spiro [2.3] Spiro rings such as a hexyl group can be mentioned.
  • the substituent is preferably a cyclopropyl group or a cyclobutyl group.
  • the linear or branched C 2-6 alkenyl group described herein means a linear or branched alkenyl group having 2 to 6 carbon atoms.
  • Examples of the linear or branched C 2-6 alkenyl group include a vinyl group, a propen-1-yl group, a propen-2-yl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, and 1-methyl.
  • -1-propenyl group 2-methyl-1-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 5-pentenyl group, 1-methyl-1-butenyl group, 2 -Methyl-1-butenyl group, 3-methyl-1-butenyl group, 4-methyl-1-butenyl group, 1-methyl-2-butenyl group, 2-methyl-2-butenyl group, 3-methyl-2- Butenyl group, 4-methyl-2-butenyl group, 1-methyl-3-butenyl group, 2-methyl-3-butenyl group, 3-methyl-3-butenyl group, 4-methyl-3-butenyl group, 1, 2-dimethyl-1-p Examples include an alkenyl group such as a lopenyl group, a 1-hexenyl group, a 2-hexenyl group, a 3-hexenyl group, a 4-hexenyl group, a 5-hexenyl group
  • the C 3-6 cycloalkenyl group described herein means a cycloalkenyl group having 3 to 6 carbon atoms.
  • Examples of the C 3-6 cycloalkenyl group include a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, and a cyclohexenyl group.
  • the C 2-6 alkynyl group described herein means an alkynyl group having 2 to 6 carbon atoms.
  • Examples of the C 2-6 alkynyl group include an ethynyl group, a propargyl group, a butynyl group, a pentynyl group, and a hexynyl group.
  • the C 1-6 alkoxy group described herein includes an oxy group (—O—) and a linear or branched C 1-6 alkyl group bonded to the oxy group, or a C 3-6 cycloalkyl group.
  • Examples of the C 1-6 alkoxy group include a methoxy group, ethoxy group, propyloxy group, isopropyloxy group, cyclopropyloxy group, butoxy group, cyclobutyloxy group, pentyloxy group, cyclopentyloxy group, hexyloxy group, A cyclohexyloxy group is mentioned.
  • the C 1-6 alkylamino group described herein is substituted with one or two independently selected linear or branched C 1-6 alkyl groups or C 3-6 cycloalkyl groups. Means an amino group formed.
  • Examples of the C 1-6 alkylamino group include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a cyclopropylamino group, a butoxy group, a cyclobutylamino group, a pentylamino group, a cyclopentylamino group, and hexyl.
  • Examples thereof include an amino group, a cyclohexylamino group, a dimethylamino group, a diethylamino group, an ethylmethylamino group, an isopropylmethylamino group, and a cyclopropylmethylamino group.
  • the halogen atom described in this specification means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the C 6-10 aryl group described in the present specification means an aryl group having 6 to 10 carbon atoms.
  • Examples of the C 6-10 aryl group include a phenyl group and a naphthyl group.
  • the heterocyclic group described in the present specification means a cyclic group having at least one nitrogen atom, oxygen atom or sulfur atom, which may be an aromatic heterocyclic group or a non-aromatic heterocyclic group. Also good.
  • aromatic heterocyclic groups include pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyrrole, imidazole, pyrazole, indole, indazole, furan, benzofuran, thiophene, benzo Examples include thiophene group, thiazole group, isothiazole group, oxazole group, isoxazole group and oxadiazole group.
  • the non-aromatic heterocyclic group include a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, and a thiomorpholinyl group.
  • the C 6-10 aryloxy group described herein means a group consisting of an oxy group (—O—) and the above C 6-10 aryl group bonded to the oxy group.
  • Examples of the C 6-10 aryloxy group include phenyloxy group, 1-naphthyloxy group, 2-naphthyloxy group and the like.
  • the C 7-12 aralkyl group described in the present specification means the above C 1-6 alkyl group substituted by the above C 6-10 aryl group.
  • Examples of the C 7-12 aralkyl group include a benzyl group, a phenylethyl group, a naphthylmethyl group, and a naphthylethyl group.
  • the C 7-12 aralkyloxy group described herein means a group consisting of an oxy group (—O—) and the C 7-12 aralkyl group bonded to the oxy group.
  • Examples of the C 7-12 aralkyloxy group include a benzyloxy group, a phenylethyloxy group, a naphthylmethyloxy group, and a naphthylethyloxy group.
  • the C 1-3 alkyl group as R is an alkyl group having 1 to 3 carbon atoms, and corresponds to one having 1 to 3 carbon atoms among the above C 1-6 alkyl groups.
  • Examples of the C 1-3 alkyl group include a methyl group, an ethyl group, a propyl group, and an isopropyl group.
  • C 2 bind two R each other - 5
  • the groups form an alkylene group of the C 1-6 alkyl group
  • a C 2-5 alkyl group corresponds to that of 2 to 5 carbon atoms Further, it means a divalent group formed by removing one hydrogen atom.
  • C 2-5 alkylene group includes 1,2-ethylene group, 1,2-propylene group, 1,3-propylene group, 1,2-butylene group, 1,3-butylene group, 1,4-butylene group 2,3-butylene group, 1,2-pentylene group, 1,3-pentylene group, 1,4-pentylene group, 1,5-pentylene group, 2,3-pentylene group, 2,4-pentylene group Can be mentioned.
  • the straight chain or branched C 1-6 alkylene group as L 3 means a divalent group obtained by removing one hydrogen atom from the C 1-6 alkyl group.
  • Examples of the C 1-6 alkylene group include a methylene group, 1,1-ethylene group, 1,2-ethylene group, 1,1-propylene group, 1,2-propylene group, 2,2-propylene group, , 3-propylene group.
  • Straight or branched C 1-4 alkyl group as R 1, R 2 or R 3 is a linear or branched alkyl group having 1 to 4 carbon atoms, among the above C 1-6 alkyl group, carbon number 1 It corresponds to the thing of thru
  • the linear or branched C 1-6 alkyl group, C 3-6 cycloalkyl group, C 6-10 aryl group and heterocyclic group as R 4 are defined in the same manner as the above substituents.
  • the linear or branched C 1-16 alkyl group as R 5 means an alkyl group having 1 to 16 carbon atoms.
  • Examples of the linear or branched C 1-16 alkyl group include a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a pentyl group, an isopentyl group, a neopentyl group, a hexyl group, a heptyl group, an octyl group, and a nonyl group.
  • C 1-16 alkyl groups such as decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group and the like.
  • the C 3-6 cycloalkyl group, C 6-10 aryl group and heterocyclic group as R 5 are defined in the same manner as the above substituents.
  • the compound according to this embodiment may be a compound represented by any one of the general formula (II), general formula (III), or general formula (IV).
  • L 2 , L 3 , R 1 , R 2 , R 3 , R 4 and R 5 are the same as in general formula (I). Defined in
  • L 2 may be a divalent amino group represented by an oxygen atom or -NH-,.
  • L 3 may be a single bond or an optionally substituted linear or branched C 1-6 alkylene group.
  • L 2 and L 3 in the general formulas (I) to (IV) preferably, L 2 and L 3 are a single bond, or L 2 is a divalent amino group represented by —NH—. And L 3 is a linear or branched C 1-6 alkylene group which may be substituted.
  • R 1 , R 2 and R 3 may each independently be a linear or branched C 1-4 alkyl group which may be substituted.
  • R 4 represents a hydrogen atom, an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-10 aryl group Alternatively, it may be an optionally substituted heterocyclic group.
  • R 5 represents a hydrogen atom, an optionally substituted linear or branched C 1-16 alkyl group, an optionally substituted C 3-6 cycloalkyl group, or an optionally substituted C 6-10 aryl group. Or a heterocyclic group which may be substituted.
  • L 2 is a single bond or a divalent amino group represented by —NH—
  • L 3 may be a single bond or substituted.
  • a linear or branched C 1-6 alkylene group, R 1 , R 2 and R 3 are each independently an optionally substituted linear or branched C 1-4 alkyl group, and R 4 is An optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 6-10 aryl group or an optionally substituted heterocyclic group
  • R 5 is a hydrogen atom, substituted A linear or branched C 1-16 alkyl group which may be substituted, or a C 3-6 cycloalkyl group which may be substituted.
  • L 2 and L 3 are a single bond, and R 1 , R 2 and R 3 may each independently be substituted.
  • a linear or branched C 1-4 alkyl group, and R 4 is an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 6-10 aryl group, or a substituted
  • R 5 is a hydrogen atom, an optionally substituted linear or branched C 1-16 alkyl group, or an optionally substituted C 3-6 cycloalkyl group.
  • L 2 is a divalent amino group represented by —NH—
  • L 3 is a linear chain which may be substituted.
  • R 1 , R 2 and R 3 are each independently a linear or branched C 1-4 alkyl group which may be substituted
  • R 4 is a substituted A linear or branched C 1-6 alkyl group which may be substituted, a C 6-10 aryl group which may be substituted or a heterocyclic group which may be substituted
  • R 5 is a hydrogen atom, substituted It may be a linear or branched C 1-16 alkyl group, or an optionally substituted C 3-6 cycloalkyl group.
  • L 2 is a single bond or a divalent amino group represented by —NH—
  • L 3 may be a single bond or a substituted group.
  • Good linear or branched C 1-6 alkylene group, R 1 , R 2 and R 3 are each independently a linear or branched C 1-4 alkyl group, and R 4 may be substituted A good linear or branched C 1-6 alkyl group, an optionally substituted C 6-10 aryl group or an optionally substituted heterocyclic group
  • R 5 is a hydrogen atom, linear or branched C 1 A -16 alkyl group, a halogen atom, an oxo group, or a linear or branched C 1-16 alkyl group substituted with a linear or branched C 1-6 alkyl group, or C optionally substituted with a halogen atom 3-6 cycloalkyl It is a group.
  • L 2 and L 3 are preferably a single bond, and R 1 , R 2 and R 3 are each independently a straight-chain or branched C 1-4 alkyl group, and R 4 is an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 6-10 aryl group, or an optionally substituted heterocyclic ring R 5 represents a linear or branched C 1 substituted with a hydrogen atom, a linear or branched C 1-16 alkyl group, a halogen atom, an oxo group, or a linear or branched C 1-6 alkyl group.
  • a -16 alkyl group or a C 3-6 cycloalkyl group optionally substituted with a halogen atom;
  • L 2 is a divalent amino group represented by —NH—
  • L 3 is an optionally substituted amino group.
  • a chain or branched C 1-6 alkylene group, R 1 , R 2 and R 3 are each independently a straight chain or branched C 1-4 alkyl group, and R 4 is an optionally substituted A chain or branched C 1-6 alkyl group, an optionally substituted C 6-10 aryl group or an optionally substituted heterocyclic group, and R 5 is a hydrogen atom, linear or branched C 1-16 An alkyl group, a halogen atom, an oxo group, or a linear or branched C 1-16 alkyl group substituted with a linear or branched C 1-6 alkyl group, or a C 3- optionally substituted with a halogen atom With 6 cycloalkyl groups is there.
  • L 2 represents a single bond or a divalent group represented by -NH-
  • L 3 represents a single bond, or the following formula A group represented by (O-1), (O-2), (M-2) or (N-1), wherein R 1 , R 2 and R 3 are each independently a linear or branched C 1-4 alkyl group, R 4 is an optionally substituted phenyl group or thienyl group, R 5 is a hydrogen atom, a linear or branched C 1-16 alkyl group, substituted with a halogen atom Straight chain or branched C 1-16 alkyl group or C 3-6 cycloalkyl group.
  • the chemical structure represented by the formula (O-1) is also referred to as “C (Me) 2 CH 2 ”
  • the chemical structure represented by the formula (O-2) is represented by “CH 2 C ( Me) 2 ”
  • the chemical structure represented by the formula (M-2) is also referred to as“ CH 2 -1,1-cyclopropylene ”
  • the chemical structure represented by the formula (N-1) is“ 1, ” Also referred to as “1-cyclobutylene-CH 2 ”.
  • L 2 is particularly preferably a divalent amino group represented by —NH—
  • L 3 represents the above formula (O-1), A group represented by (O-2), (M-2) or (N-1), wherein R 1 , R 2 and R 3 are each independently a linear or branched C 1-4 alkyl group
  • R 4 is an optionally substituted phenyl group or thienyl group
  • R 5 is a hydrogen atom, a linear or branched C 1-16 alkyl group, a linear or branched group substituted with a halogen atom A C 1-16 alkyl group or a C 3-6 cycloalkyl group
  • R 1 , R 2 and R 3 are each independently a linear or branched C 1-4 alkyl group
  • R 4 is an optionally substituted phenyl group or thienyl group
  • R 5 is a hydrogen atom, a linear or branched C 1-16 alkyl group, a linear or branched group substituted with a halogen
  • R 5 is substituted with an oxo group
  • the oxo group and R 5 are A compound in which an oxygen atom to be bonded forms an ester bond or an alkylene group in which R 5 is substituted with a substituent containing an oxygen atom as represented by the general formula (VI), and the oxygen atom and R 5
  • a compound in which an acetal group containing an oxygen atom to which is bonded can be a compound that acts as a prodrug.
  • Compound (V) or Compound (VI) tends to be superior in oral absorption and skin permeability, and can yield Compound (I) (wherein R 5 is a hydrogen atom) by metabolism.
  • R, R 1 , R 2 , R 3 , R 4 , L 2 and L 3 are defined in the same manner as in the general formula (I).
  • R 6 represents a hydrogen atom, an optionally substituted linear or branched C 1-15 alkyl group, an optionally substituted C 3-6 cycloalkyl group, or an optionally substituted C 1-6 alkoxy group.
  • R 8 and R 9 each independently represents a hydrogen atom or a C 1-4 alkyl group. .
  • R 7 is a linear or branched C 1-15 alkyl group which may have a substituent, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-10 aryl group, Or the heterocyclic group which may be substituted is shown.
  • the linear or branched C 1-15 alkyl group, the C 3-6 cycloalkyl group, the C 6-10 aryl group, and the heterocyclic group as R 6 or R 7 , and the substituents that replace them are represented by the general formula Defined similarly to the groups in (I) to (IV).
  • R 6 may be a linear or branched C 1-15 alkyl group which may be substituted, or a C 6-10 aryl group which may be substituted.
  • R 7 may be an optionally substituted straight chain or branched C 1-16 alkyl group.
  • L 2 and L 3 in the general formula (V) and the general formula (VI) preferably L 2 is a divalent amino group represented by —NH—, and L 3 may be substituted. Good linear or branched C 1-6 alkylene group.
  • two Rs are groups bonded to each other to form a 1,2-ethylene group or a 1,3-propylene group
  • L 2 is a single bond
  • L 3 is a single bond or a linear or branched C 1-6 alkylene group which may be substituted
  • R 1 , R 2 and R 3 is each independently a linear or branched C 1-4 alkyl group which may be substituted
  • R 4 is a linear or branched C 1-6 alkyl group which may be substituted
  • R 6 is an optionally substituted linear or branched C 1-15 alkyl group.
  • two Rs are a group bonded to each other to form a 1,2-ethylene group or a 1,3-propylene group
  • L 2 is a group represented by — A divalent amino group represented by NH—
  • L 3 is an optionally substituted linear or branched C 1-6 alkylene group
  • R 1 , R 2 and R 3 are each independently ,
  • R 4 is an optionally substituted linear or branched C 1-6 alkyl group, optionally substituted C 6- A 10 aryl group or an optionally substituted heterocyclic group
  • R 6 is an optionally substituted linear or branched C 1-15 alkyl group.
  • R 2 is represented by a single bond or —NH—.
  • a divalent amino group L 3 is a single bond or an optionally substituted linear or branched C 1-6 alkylene group
  • R 1 , R 2 and R 3 are each independently
  • R 4 is an optionally substituted linear or branched C 1-4 alkyl group
  • R 4 is an optionally substituted linear or branched C 1-6 alkyl group, optionally substituted C 6-10.
  • R 6 is an optionally substituted linear or branched C 1-15 alkyl group.
  • two Rs are groups that are bonded to each other to form a 1,3-propylene group
  • L 2 is a group represented by —NH—.
  • L 3 is a linear or branched C 1-6 alkylene group which may be substituted
  • R 1 , R 2 and R 3 may each independently be substituted.
  • a linear or branched C 1-4 alkyl group, and R 4 is an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 6-10 aryl group, or a substituted group.
  • An optionally substituted heterocyclic group, and R 6 is an optionally substituted linear or branched C 1-15 alkyl group.
  • two Rs are groups that are bonded to each other to form a 1,2-ethylene group or a 1,3-propylene group, and L 2 is a single bond, or A divalent amino group represented by —NH—, L 3 is a single bond or a linear or branched C 1-6 alkylene group which may be substituted, and R 1 , R 2 and R 3 is each independently a linear or branched C 1-4 alkyl group which may be substituted; R 4 is a linear or branched C 1-6 alkyl group which may be substituted; An optionally substituted C 6-10 aryl group or an optionally substituted heterocyclic group, R 8 and R 9 are each independently a hydrogen atom or a C 1-4 alkyl group, and R 7 is A linear or branched C 1 which may have a substituent A -15 alkyl group or an optionally substituted C 3-6 cycloalkyl group;
  • two Rs are groups bonded to each other to form a 1,2-ethylene group or a 1,3-propylene group
  • L 2 is a group of a divalent group represented by NH-
  • L 3 is an optionally substituted straight or branched C 1-6 alkylene group
  • R 1, R 2 and R 3 are each independently
  • R 4 is an optionally substituted linear or branched C 1-6 alkyl group, optionally substituted C 6- 10 aryl group or an optionally substituted heterocyclic group
  • R 8 and R 9 are each independently a hydrogen atom or a C 1-4 alkyl group
  • R 7 has a substituent.
  • two Rs are a group bonded to each other to form a 1,3-propylene group
  • L 2 is represented by a single bond or —NH—.
  • a divalent amino group L 3 is a single bond or an optionally substituted linear or branched C 1-6 alkylene group
  • R 1 , R 2 and R 3 are each independently
  • R 4 is an optionally substituted linear or branched C 1-4 alkyl group
  • R 4 is an optionally substituted linear or branched C 1-6 alkyl group, optionally substituted C 6-10.
  • R 8 and R 9 are each independently a hydrogen atom or a C 1-4 alkyl group, and R 7 has a substituent.
  • two Rs are groups that are bonded to each other to form a 1,3-propylene group
  • L 2 is 2 represented by —NH—.
  • L 3 is a linear or branched C 1-6 alkylene group which may be substituted
  • R 1 , R 2 and R 3 may each independently be substituted.
  • a linear or branched C 1-4 alkyl group, and R 4 is an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 6-10 aryl group, or a substituted group.
  • R 8 and R 9 are each independently a hydrogen atom or a C 1-4 alkyl group, and R 7 is a linear or branched group optionally having a substituent. C 1-15 alkyl group or substituted A good C 3-6 cycloalkyl group.
  • the compound according to the present embodiment or a pharmacologically acceptable salt thereof is a compound selected from the following compound group or a pharmacologically acceptable salt thereof.
  • the compound according to the present embodiment or a pharmacologically acceptable salt thereof may be a single optically active substance or a mixture of a plurality of optically active substances.
  • the “pharmacologically acceptable salt” is not particularly limited as long as it is a pharmaceutically acceptable salt, and includes hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Salts with inorganic acids acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, lactic acid, trifluoroacetic acid and other organic carboxylic acids; methanesulfonic acid, trifluoromethanesulfonic acid, benzene Salts with organic sulfonic acids such as sulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid; salts with alkali metals such as lithium, sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonia and morpholine , Glucosamine, ethylenediamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, diethanolamine Quaternary ammonium salts such as piperazine and the like.
  • the compound according to this embodiment or a pharmacologically acceptable salt thereof can form a hydrate or a solvate, and each or a mixture thereof is included in the present invention.
  • the compound according to this embodiment may contain an unnatural proportion of atomic isotopes at one or more of the constituent atoms.
  • atomic isotope for example, deuterium ( 2 H), tritium ( 3 H), carbon-14 ( 14 C), fluorine-18 ( 18 F), sulfur-35 ( 35 S), or iodine-125 ( 125 I).
  • these compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotopic variations of the compounds according to this embodiment are encompassed by the present invention, whether radioactive or not.
  • the compound according to the present embodiment or a pharmacologically acceptable salt thereof may be an excipient, a lubricant, a binder, a disintegrant, a coating agent, a stabilizer, an isotonic agent, a buffer, if necessary.
  • a pH regulator, solubilizer, thickener, preservative, antioxidant, sweetener, colorant, fragrance and the like can be added and used as a pharmaceutical composition.
  • the pharmaceutical composition can be appropriately prepared according to the purpose by a known method described in, for example, the 16th revised Japanese Pharmacopoeia, General Rules for Preparations.
  • the content of the compound according to the present embodiment or a pharmacologically acceptable salt thereof in the pharmaceutical composition can be appropriately adjusted.
  • the pharmaceutical composition is, for example, a preparation for oral administration such as tablets, capsules, granules, powders, injections (for example, intravenous administration, subcutaneous administration, intramuscular administration, intraperitoneal administration), eye drops, nasal drops. , Suppositories, ointments, lotions, creams, gels, sprays, patches, inhalants, preparations for parenteral administration such as transdermal preparations, etc., as described in the 16th revised Japanese Pharmacopoeia It can be a dosage form.
  • Excipients include, for example, lactose, mannitol, starch, crystalline cellulose, light anhydrous silicic acid, calcium carbonate and calcium hydrogen phosphate, and lubricants include, for example, stearic acid, magnesium stearate and talc.
  • lubricants include, for example, stearic acid, magnesium stearate and talc.
  • the binder include starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone
  • examples of the disintegrant include carboxymethylcellulose, low-substituted hydroxypropylmethylcellulose, and calcium citrate.
  • the coating agent include hydroxypropyl methylcellulose, macrogol and silicone resin, and examples of the stabilizer include ethyl paraoxybenzoate and benzyl alcohol.
  • isotonic agents include glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol and the like
  • buffering agents include boric acid, borate, phosphoric acid, phosphate, citric acid, Examples thereof include citrate, acetic acid, acetate, ⁇ -aminocaproic acid, trometamol and the like
  • pH adjusters include hydrochloric acid, citric acid, phosphoric acid, glacial acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, Examples thereof include sodium hydrogen carbonate.
  • solubilizer examples include polysorbate 80, polyoxyethylene hydrogenated castor oil 60, macrogol 4000, purified soybean lecithin, polyoxyethylene (160) polyoxypropylene (30) glycol, and the like.
  • examples thereof include cellulose polymers such as hydroxypropylmethylcellulose and hydroxypropylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone.
  • examples of the stabilizer include edetic acid, sodium edetate, and the like, and examples of the preservative include sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl paraoxybenzoate, propyl paraoxybenzoate. And chlorobutanol.
  • Ingredients that may be contained in the pharmaceutical composition for transdermal administration such as ointments, lotions, creams, gels, patches, and sprays include, for example, lauryl alcohol, myristyl alcohol, ethylene glycol salicylate, Absorption accelerators such as pyrothiodecane; fatty acid esters such as diisopropyl adipate, isopropyl myristate, cetyl lactate, myristyl lactate, isopropyl palmitate, diethyl sebacate, hexyl ralphosphate, cetyl isooctanoate; cetyl alcohol, stearyl alcohol, oleyl alcohol, Aliphatic alcohols such as hexadecyl alcohol and behenyl alcohol; glycols such as propylene glycol, propylene diol, polyethylene glycol and dipropylene glycol; sorbitan fat Surfactants such as ester, glycerin fatty acid ester, polyoxyethylene
  • the dose of the compound according to the present embodiment or a pharmacologically acceptable salt thereof can be appropriately changed depending on symptoms, age, dosage form and the like.
  • 0.01 to 2000 mg, preferably 1 to 500 mg per day can be administered once or divided into several times.
  • lotions, creams, or gels it is usually 0.00001% (w / v) to 10% (w / v), preferably 0.001% (w / v) to 5% ( One having a concentration of w / v) can be administered once or divided into several times.
  • the compound which concerns on this invention, or its pharmacologically acceptable salt is not limited to the compound manufactured by the following manufacturing methods, or its pharmacologically acceptable salt.
  • a partial structure for example, a hydroxy group, an amino group, a carbonyl group, a carboxyl group, an amide group, or a thiol group
  • the desired product can be obtained by introducing a protecting group into the partial structure to perform a desired reaction, and then removing the protecting group.
  • Compound (I) can be produced using compound (A) as a starting material by the following production methods 1 to 4, for example. In addition, the manufacturing method of a compound (A) is mentioned later.
  • Production method 1 is a method for producing compound (I) through steps 1 to 3 using compound (A) as a starting material.
  • Production method 1 is a preferred production method when L 2 is a divalent amino group represented by an oxygen atom or —NH—.
  • R, R 1 , R 2 , R 3 , R 4 , R 5 , L 2 and L 3 are defined in the same manner as in formula (I).
  • the P 1 group represents an amino-protecting group, and X represents a leaving group.
  • the P 1 group only needs to replace the acidic proton of pyrazole in the 4,6-dihydropyrrolo [3,4-c] pyrazole skeleton.
  • the P 1 group may be substituted at the 1-position of the 4,6-dihydropyrrolo [3,4-c] pyrazole skeleton or may be substituted at the 2-position.
  • the compound (A) will be described using a chemical formula substituted at the 1-position of the 4,6-dihydropyrrolo [3,4-c] pyrazole skeleton.
  • the P 1 group is not particularly limited as long as it is a substituent known to those skilled in the art as an amino-protecting group.
  • Examples of the P 1 group include an optionally substituted C 7-11 aralkyl group such as benzyl group, p-methoxyphenylmethyl group, o-nitrophenylmethyl group; acetyl group, trifluoroacetyl group, benzoyl group, etc.
  • An optionally substituted acyl group methoxycarbonyl group, ethoxycarbonyl group, Boc group (tert-butoxycarbonyl group), Cbz group (benzyloxycarbonyl group), Fmoc group (fluorenylmethyloxycarbonyl group), Teoc
  • C 1-6 alkoxycarbonyl group such as a trimethylsilylethyloxycarbonyl group; an alkenyloxycarbonyl group such as an Alloc group (allyloxycarbonyl group); an alkylsulfonyl group such as a methanesulfonyl group; C 6- such as toluenesulfonyl group A 10 arylsulfonyl group.
  • the X group is not particularly limited as long as it is a substituent known to those skilled in the art as a leaving group.
  • Examples of X include a halogen atom; an imidazolyl group; an aminooxy group such as a succinyl-N-oxy group and a benzotriazolyl-N-oxy group; and an acyloxy group such as a pivaloyloxy group and a benzoyloxy group.
  • X may be a hydroxyl group.
  • Step 1 is a step of obtaining compound (B) by reacting compound (A) with an acylating agent.
  • acylating agent for example, phosgene, diphosgene, triphosgene, carbonyldiimidazole (CDI), N, N′-disuccinimidyl carbonate, carbonate ester and the like can be used.
  • the amount of the acylating agent to be used is preferably 0.4 to 3.0 mol, more preferably 0.7 to 1.5 mol, per 1 mol of compound (A).
  • Step 1 may be performed in a solvent or without a solvent.
  • a solvent there is no limitation as long as the solvent does not affect the reaction, and an organic solvent is preferable.
  • the organic solvent include dichloromethane, 1,2-dichloroethane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran (THF), N, N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).
  • Step 1 can further add a base to promote the reaction.
  • a base examples include triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo [4.3.0] nonene (DBN), 1,8-diazabicyclo [5.4.0] undecene (DBU), pyridine, And organic amines such as 4-dimethylaminopyridine (DMAP).
  • the amount of the base to be added is preferably 1 to 10 mol, more preferably 3 to 6 mol, relative to 1 mol of the compound (A).
  • the reaction temperature in step 1 can be appropriately set by those skilled in the art.
  • the reaction temperature is usually ⁇ 100 to ⁇ 20 ° C., preferably ⁇ 80 to ⁇ 60 ° C.
  • Step 2 is a step in which compound (B) and compound (C) are reacted to obtain compound (D).
  • the L 2 group is an oxygen atom or a divalent amino group represented by —NH—. That is, the compound (C) is an alcohol or an amine.
  • the amount of compound (C) to be used is preferably 1 to 20 mol, more preferably 2 to 5 mol, per 1 mol of compound (B).
  • Compound (C) and compound (B) may be dissolved in an organic solvent and added to the reaction solution.
  • Step 2 may be performed in a solvent or without a solvent.
  • a solvent there is no limitation as long as the solvent does not affect the reaction, and an organic solvent is preferable.
  • the organic solvent include dichloromethane, 1,2-dichloroethane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran (THF), 1,4-dioxane, N, N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).
  • THF tetrahydrofuran
  • DMF 1,4-dioxane
  • N, N-dimethylformamide (DMF) dimethyl sulfoxide
  • DMSO dimethyl sulfoxide
  • Step 2 can further add a base to promote the reaction.
  • a base examples include triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo [4.3.0] nonene (DBN), 1,8-diazabicyclo [5.4.0] undecene (DBU), pyridine, Organic amines such as 4-dimethylaminopyridine (DMAP); inorganic bases such as potassium carbonate and sodium carbonate.
  • DIPEA diisopropylethylamine
  • DBN 1,5-diazabicyclo [4.3.0] nonene
  • DBU 1,8-diazabicyclo [5.4.0] undecene
  • pyridine Organic amines such as 4-dimethylaminopyridine (DMAP); inorganic bases such as potassium carbonate and sodium carbonate.
  • the amount of the base to be added is preferably 1 to 20 mol, more preferably 2 to 5 mol, per 1 mol of the compound (A).
  • the reaction temperature in step 2 can be appropriately set by those skilled in the art.
  • the reaction temperature is usually 0 to 120 ° C., preferably 25 to 100 ° C.
  • Step 3 is a step for producing compound (I) by removing P 1 group of compound (D).
  • the reaction conditions in step 3 can be appropriately selected by those skilled in the art depending on the type of P 1 group used.
  • the P 1 group when it is an aralkyl group, it may be carried out by hydrogenolysis or using a protonic acid or a Lewis acid.
  • the P 1 group is a Boc group, the treatment can be performed by treatment with a proton acid or a Lewis acid.
  • the P 1 group is a Cbz group, the treatment can be performed by hydrogenolysis or treatment with a base.
  • a reagent that generates fluoride ions such as tetrabutylammonium fluoride can be used.
  • the P 1 group is an alkoxycarbonyl group such as a methoxycarbonyl group or an ethoxycarbonyl group
  • an organic amine such as triethylamine or diisopropylethylamine (DIPEA) or an inorganic base such as potassium carbonate or sodium carbonate
  • DIPEA diisopropylethylamine
  • an inorganic base such as potassium carbonate or sodium carbonate
  • Compound (I) obtained by Step 3 can be converted into a pharmacologically acceptable salt thereof by a method well known to those skilled in the art.
  • Production method 2 is a method in which compound (C) is used as a starting material, compound (D) is obtained through steps 4 and 5, and then converted into compound (I) according to step 3 of production method 1 above.
  • Production method 2 is a preferred production method when L 2 is a divalent amino group represented by an oxygen atom or —NH—.
  • R, R 1 , R 2 , R 3 , R 4 , R 5 , L 2 , L 3 , P 1 and X are defined in the same manner as in Production Method 1 above.
  • Step 4 is a step of obtaining compound (E) by reacting compound (C) with an acylating agent.
  • the L 2 group is a divalent amino group represented by an oxygen atom or —NH—. That is, the compound (C) is an alcohol or an amine.
  • acylating agent for example, phosgene, diphosgene, triphosgene, carbonyldiimidazole (CDI), N, N′-disuccinimidyl carbonate, carbonate ester and the like can be used.
  • the amount of the acylating agent to be used is preferably 1 to 5 mol, more preferably 1 to 2 mol, per 1 mol of compound (C).
  • Step 4 may be performed in a solvent or without a solvent.
  • a solvent there is no limitation as long as the solvent does not affect the reaction, and an organic solvent is preferable.
  • the organic solvent include acetonitrile, dichloromethane, diethyl ether, tetrahydrofuran (THF), N, N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).
  • Step 4 can further add a base to promote the reaction.
  • a base examples include triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo [4.3.0] nonene (DBN), 1,8-diazabicyclo [5.4.0] undecene (DBU), pyridine, And organic amines such as 4-dimethylaminopyridine (DMAP).
  • the amount of the base to be added is preferably 1 to 5 mol, more preferably 1 to 2 mol, relative to 1 mol of the compound (C).
  • the reaction temperature in step 4 can be appropriately set by those skilled in the art.
  • the reaction temperature is usually 0 to 100 ° C., preferably 20 to 40 ° C.
  • Step 5 is a step of obtaining compound (D) by reacting compound (E) with compound (A).
  • the amount of compound (E) to be used is preferably 1 to 5 mol, more preferably 1 to 2 mol, per 1 mol of compound (A).
  • Compound (E) and compound (A) may be dissolved in an organic solvent and added to the reaction solution.
  • Step 5 may be performed in a solvent or without a solvent.
  • a solvent there is no limitation as long as the solvent does not affect the reaction, and an organic solvent is preferable.
  • the organic solvent include dichloromethane, diethyl ether, tetrahydrofuran (THF), N, N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).
  • Step 5 can further add a base to promote the reaction.
  • a base examples include triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo [4.3.0] nonene (DBN), 1,8-diazabicyclo [5.4.0] undecene (DBU), pyridine, And organic amines such as 4-dimethylaminopyridine (DMAP).
  • the amount of the base to be added is preferably 1 to 10 mol, more preferably 1 to 5 mol, relative to 1 mol of the compound (A).
  • the reaction temperature in step 5 can be appropriately set by those skilled in the art.
  • the reaction temperature is usually 0 to 100 ° C., preferably 20 to 40 ° C.
  • Production method 3 is a method in which compound (A) and compound (F) are reacted to obtain compound (D), and then converted to compound (I) according to step 3 of production method 1 described above.
  • Production method 3 is a preferred production method when L 2 is a single bond.
  • R, R 1 , R 2 , R 3 , R 4 , R 5 , L 2 , L 3 and P 1 are defined in the same manner as in Production Method 1 above.
  • Step 6 is a step of condensing compound (A) and compound (F) to obtain compound (D).
  • the compound (F) is converted into an acid halide, carboxylic acid anhydride, acid azide, or active ester using a reagent used in the amide bond forming reaction, and then reacted with the compound (A).
  • the reagent used for the amide bond forming reaction is not particularly limited as long as it is known to those skilled in the art as a reagent used for the amide bond forming reaction.
  • the amount of compound (F) to be used is preferably 1 to 10 mol, more preferably 1 to 5 mol, per 1 mol of compound (A).
  • Compound (F) may be dissolved in an organic solvent and added to the reaction solution.
  • Step 6 may be performed in a solvent or without a solvent.
  • a solvent there is no limitation as long as the solvent does not affect the reaction, and an organic solvent is preferable.
  • the organic solvent include dichloromethane, 1,2-dichloroethane, diethyl ether, tetrahydrofuran (THF), N, N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).
  • Step 6 can further add a base to promote the reaction.
  • a base examples include triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo [4.3.0] nonene (DBN), 1,8-diazabicyclo [5.4.0] undecene (DBU), pyridine, And organic amines such as 4-dimethylaminopyridine (DMAP).
  • the amount of the base to be added is preferably 1 to 10 mol, more preferably 1 to 5 mol, relative to 1 mol of the compound (A).
  • the reaction temperature in step 6 can be appropriately set by those skilled in the art.
  • the reaction temperature is usually 0 to 100 ° C., preferably 20 to 40 ° C.
  • Production method 4 is a method in which compound (H) is used as a starting material, compound (D) is obtained through steps 7 and 8, and then converted into compound (I) according to step 3 of production method 1 above. is there.
  • R, R 1 , R 2 , R 3 , R 4 , L 2 and L 3 are defined in the same manner as in formula (I).
  • the P 1 group represents an amino-protecting group
  • P 2 represents a hydroxyl-protecting group.
  • P 1 group is defined similarly to the production method 1.
  • the P 2 group is not particularly limited as long as it is a substituent known to those skilled in the art as a hydroxyl-protecting group.
  • Examples of the P 2 group include an optionally substituted C 7-11 aralkyl group such as benzyl group, p-methoxyphenylmethyl group, o-nitrophenylmethyl group; acetyl group, trifluoroacetyl group, benzoyl group, etc.
  • a substituted silyl group such as trimethylsilyl group, tert-butyldimethylsilyl group, triethylsilyl group, triisopropylsilyl group, tert-butyldiphenylsilyl group, and the like.
  • Step 7 is a step in which compound (H) is deprotected to obtain compound (J).
  • the removal reaction of the P 2 group can also be carried out by methods well known to those skilled in the art (for example, Protective Groups in Organic Synthesis 4th edition, TW Greene, PGM M. Wuts, John Wiley & Sons Inc. (Method described in 2006)).
  • Step 8 is a step of obtaining compound (D) by reacting compound (J) with an acid halide, acid anhydride, or alkyl halide.
  • the amount of acid halide, acid anhydride, or alkyl halide to be used is preferably 1 to 10 mol, more preferably 1 to 2 mol, per 1 mol of compound (J).
  • Step 8 may be performed in a solvent or without a solvent.
  • a solvent there is no limitation as long as the solvent does not affect the reaction, and an organic solvent is preferable.
  • the organic solvent include dichloromethane, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, N, N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).
  • Step 8 can further add a base to promote the reaction.
  • a base examples include triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo [4.3.0] nonene (DBN), 1,8-diazabicyclo [5.4.0] undecene (DBU), pyridine, And organic amines such as 4-dimethylaminopyridine (DMAP).
  • the amount of the base to be added is preferably 1 to 20 mol, more preferably 1 to 5 mol, relative to 1 mol of the compound (J).
  • the reaction temperature in step 8 can be appropriately set by those skilled in the art.
  • the reaction temperature is usually ⁇ 20 to 120 ° C., preferably 15 to 100 ° C.
  • Compound (A) can be produced, for example, using compound (A1) as a starting material by the following method.
  • Compound (A1) can be produced, for example, with reference to WO2007 / 72153 or through the following steps 11 to 15.
  • the compound (A1) is 3-amino-6,6-dimethyl-4,6-dihydropyrrolo [3,4-c] pyrazole, the nitrogen atom on the pyrazole skeleton is P 1 group, and the nitrogen atom at the 5-position May be substituted with a P 3 group.
  • the P 1 group only needs to replace the acidic proton of pyrazole in the 4,6-dihydropyrrolo [3,4-c] pyrazole skeleton. Therefore, the P 1 group may be substituted at the 1-position of the 4,6-dihydropyrrolo [3,4-c] pyrazole skeleton or may be substituted at the 2-position.
  • the compounds (A1) and (A2) will be described using chemical formulas substituted at the 1-position of the 4,6-dihydropyrrolo [3,4-c] pyrazole skeleton.
  • P 1 has the same definition as in the compound (A).
  • the P 3 group is not particularly limited as long as it is a substituent known to those skilled in the art as an amino-protecting group.
  • Examples of the P 3 group include C 7-11 aralkyl groups which may be substituted such as benzyl group, p-methoxyphenylmethyl group and o-nitrophenylmethyl group; substituted acetyl groups and trifluoroacetyl groups.
  • Optionally substituted C 1-6 alkylcarbonyl group optionally substituted C 6-10 arylcarbonyl group such as benzoyl group; methoxycarbonyl group, ethoxycarbonyl group, Boc group (tert-butoxycarbonyl group), Cbz group (Benzyloxycarbonyl group), Fmoc group (fluorenylmethyloxycarbonyl group), Teoc group (trimethylsilylethyloxycarbonyl group) and other optionally substituted C1-6 alkoxycarbonyl groups; Alloc group (allyloxycarbonyl group) Alkenyloxycarbonyl group such as An alkylsulfonyl group such as an arylsulfonyl group; an optionally substituted C 6-10 arylsulfonyl group such as a p-toluenesulfonyl group.
  • benzoyl group methoxycarbonyl group, ethoxycarbonyl group, Boc group (tert-butoxycarbonyl
  • R, R 1 , R 2 and R 3 have the same definitions as in compound (I).
  • the X group is not particularly limited as long as it is a substituent known to those skilled in the art as a leaving group.
  • Examples of X include a halogen atom; an imidazolyl group; an aminooxy group such as a succinyl-N-oxy group and a benzotriazolyl-N-oxy group; and an acyloxy group such as a pivaloyloxy group and a benzoyloxy group.
  • X may be a hydroxyl group.
  • the compound (A2) is a carboxylic acid (that is, X is a hydroxyl group)
  • it may be reacted with the compound (A1) after being converted to an acid anhydride by a method well known to those skilled in the art.
  • You may react with a compound (A1) using the reagent known as a condensing agent used for.
  • Step 9 is a step in which compound (A1) and compound (A2) are reacted to obtain compound (A3).
  • the amount of compound (A2) to be used is preferably 1 to 10 mol, more preferably 1 to 3 mol, per 1 mol of compound (A1).
  • Step 9 may be performed in a solvent or without a solvent.
  • a solvent there is no limitation as long as the solvent does not affect the reaction, and an organic solvent is preferable.
  • the organic solvent include dichloromethane, diethyl ether, tetrahydrofuran (THF), N, N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).
  • a base can be further added to accelerate the reaction.
  • the base include triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo [4.3.0] nonene (DBN), 1,8-diazabicyclo [5.4.0] undecene (DBU), pyridine, And organic amines such as 4-dimethylaminopyridine (DMAP).
  • the amount of the base to be added is preferably 1 to 20 mol, more preferably 1 to 5 mol, relative to 1 mol of the compound (A1).
  • the reaction temperature in step 9 can be appropriately set by those skilled in the art.
  • the reaction temperature is usually ⁇ 40 to 100 ° C., preferably ⁇ 20 to 20 ° C.
  • Step 10 is a step of obtaining compound (A) by carrying out deprotection reaction of compound (A3).
  • the removal reaction of the P 3 group can also be performed by a method well known to those skilled in the art (for example, Protective Groups in Organic Synthesis 4th edition, TW Greene, PMGM Wuts, John Wiley & Sons Inc. (Method described in 2006)).
  • P 3 has the same definition as in compound (A1).
  • Step 11 is a step of obtaining compound (A5) by reacting compound (A4) with acrylonitrile.
  • the amount of acrylonitrile to be used is preferably 1 to 10 mol, more preferably 1 to 3 mol, per 1 mol of compound (A4).
  • Step 11 is not limited as long as it is a solvent that does not affect the reaction, and is preferably an aqueous solvent.
  • Step 11 can further add a base to promote the reaction.
  • the base include inorganic bases such as potassium hydroxide.
  • the amount of the base to be added is preferably 0.8 to 2 mol with respect to 1 mol of the compound (A1).
  • the reaction temperature in step 11 can be appropriately set by those skilled in the art.
  • the reaction temperature is usually 0 to 100 ° C., preferably 50 to 90 ° C.
  • Step 12 is a step of obtaining compound (A6) by protecting the amino group of compound (A5) with P 3 group.
  • the protection reaction of the amino group with the P 3 group can be performed by a method well known to those skilled in the art (for example, Protective Groups in Organic Synthesis 4th edition, TW Greene, PGM Wuts, John Wiley). & Sons Inc. (2006) etc.).
  • Step 13 is a step of obtaining a compound (A7) by carrying out a cyclization reaction of the compound (A6).
  • Step 13 may be performed in a solvent or without a solvent.
  • a solvent there is no limitation as long as the solvent does not affect the reaction, and an organic solvent is preferable.
  • the organic solvent include diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, N, N-dimethylformamide (DMF) toluene and the like.
  • Step 13 can further add a base to accelerate the reaction.
  • the base include sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, n-butyl lithium, tert-butoxy potassium and the like.
  • the amount of the base to be added is preferably 1 to 3 mol with respect to 1 mol of compound (A6).
  • the reaction temperature in step 13 can be appropriately set by those skilled in the art.
  • the reaction temperature is usually 20 to 150 ° C., preferably 50 to 100 ° C.
  • Step 14 is a step in which compound (A7) and hydrazine are reacted to obtain compound (A8).
  • Step 14 may be performed in a solvent or without a solvent.
  • a solvent there is no limitation as long as the solvent does not affect the reaction, and an organic solvent is preferable. Examples of the organic solvent include ethanol, n-propanol, n-butanol and the like.
  • an acid can be further added to accelerate the reaction. Examples of the acid include acetic acid, hydrochloric acid, sulfuric acid and the like.
  • the amount of the acid to be added is preferably 1 to 10 mol with respect to 1 mol of the compound (A7).
  • the reaction temperature in step 14 can be appropriately set by those skilled in the art.
  • the reaction temperature is usually 20 to 150 ° C., preferably 50 to 120 ° C.
  • Step 15 is a step of obtaining compound (A1) by protecting the amino group of compound (A7) with P 1 group.
  • the protection reaction of the amino group with the P 1 group can be carried out by methods well known to those skilled in the art (for example, Protective Groups in Organic Synthesis 4th edition, TW Greene, PGM Wuts, John Wiley). & Sons Inc. (2006) etc.).
  • DIOL silica gel in silica gel column chromatography refers to CHROMATOREX (trade name) DIOL MB 100-40 / 75 manufactured by Fuji Silysia Chemical Ltd.
  • DNH silica gel in silica gel column chromatography refers to CHROMATOREX (trade name) DNH MB 100-40 / 75 manufactured by Fuji Silysia Chemical Ltd.
  • the mass spectrum ionization mode DUIS is a mixed mode of ESI and APCI.
  • 1 H-NMR is expressed as a chemical shift ( ⁇ ) with tetramethylsilane as an internal standard (0 ppm), and the coupling constant (J value) is expressed in Hz.
  • the abbreviations of the splitting pattern of each peak have the following meanings. s: singlet, d: doublet, t: triplet, q: quartet, br: broad.
  • reaction solution was diluted with dichloromethane and then washed with a saturated aqueous sodium hydrogen carbonate solution. After separating the organic layer and the aqueous layer, the aqueous layer was extracted twice with dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The operation of adding 25 ml of toluene to the obtained concentrated residue and concentrating it under reduced pressure was repeated three times, followed by drying under reduced pressure to obtain a concentrated residue.
  • the obtained concentrated residue was crystallized from ethyl acetate / n-hexane, and the precipitated solid was collected by filtration, washed with n-hexane, and dried under reduced pressure to give 22.7 mg (yield 9). % [2 steps]) as a white solid. Further, the filtrate was concentrated under reduced pressure and dried under reduced pressure to obtain 178 mg (yield 70% [2 steps]) of the title compound as a white foam.
  • the aqueous layer was extracted twice with 50 ml of dichloromethane, and the obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the obtained concentrated residue was crystallized from ethyl acetate / diisopropyl ether, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 173 mg (yield 73%) of the title compound as a white solid.
  • DIPEA 0.24 ml (1.4 mmol) was added to a solution of 138 mg (0.684 mmol) in dehydrated 1,4-dioxane 2 ml under an argon atmosphere at room temperature, and the mixture was stirred at 100 ° C. for 3 hours.
  • 1 ml of triethylamine and 1 ml of ethanol were added to the reaction solution, and the mixture was heated and stirred at 80 ° C. for 5 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • reaction mixture was concentrated under reduced pressure, 4 ml of methanol and 1 ml of triethylamine were added to the resulting concentrated residue, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate, water, and a saturated aqueous sodium chloride solution were added to the resulting concentrated residue, followed by liquid separation. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was concentrated under reduced pressure.
  • the resulting concentrated residue was crystallized from dichloromethane / diethyl ether / n-hexane, and the precipitated solid was collected by filtration.
  • reaction mixture was concentrated under reduced pressure, 4 ml of methanol and 1 ml of triethylamine were added to the resulting residue, and the mixture was stirred at room temperature for 18 hours.
  • reaction solution was concentrated under reduced pressure, ethyl acetate was added to the resulting concentrated residue, and then washed successively with 10% aqueous potassium dihydrogen phosphate, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure.
  • concentration under reduced pressure and drying under reduced pressure 139 mg (yield 63%) of the title compound was obtained as a pale yellow foam.
  • the reaction solution was concentrated under reduced pressure, and ethyl acetate, water and a saturated aqueous sodium chloride solution were added to the concentrated residue, followed by liquid separation.
  • the aqueous layer was extracted with ethyl acetate, and the entire organic layer obtained was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was concentrated under reduced pressure.
  • the obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
  • DIOL silica gel, elution solvent; ethyl acetate: methanol 100: 0 to 99: 1 (V / V)
  • the fraction containing was concentrated under reduced pressure.
  • the aqueous layer was extracted twice with 10 ml of dichloromethane, and the entire organic layer obtained was washed successively with 10 ml of water, 10 ml of saturated aqueous sodium hydrogen carbonate solution and 10 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. went.
  • the reaction solution was concentrated under reduced pressure, and 8 ml of ethyl acetate, 0.4 ml of water, and 8 ml of a saturated aqueous sodium chloride solution were added to the resulting concentrated residue for liquid separation.
  • the aqueous layer was extracted twice with 10 ml of dichloromethane, and the entire organic layer obtained was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.
  • the fraction containing was concentrated under reduced pressure to obtain a concentrated residue.
  • the reaction solution was concentrated under reduced pressure, 4 ml of methanol and 1 ml of triethylamine were added to the resulting concentrated residue, and the mixture was subjected to a microwave reaction apparatus and reacted at 80 ° C. for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the resulting concentrated residue. After washing sequentially with 10% aqueous potassium dihydrogen phosphate solution, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, the organic layer was dehydrated. After drying over magnesium sulfate and filtration, the filtrate was concentrated under reduced pressure.
  • reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, washed successively with 10% aqueous potassium dihydrogen phosphate solution, saturated aqueous sodium hydrogen carbonate solution, saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • reaction solution was concentrated under reduced pressure, added with ethyl acetate, washed successively with 10% aqueous potassium dihydrogen phosphate, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, and the organic layer was dried over anhydrous magnesium sulfate, After filtration, the filtrate was concentrated under reduced pressure.
  • reaction solution was concentrated under reduced pressure, 2 ml of methanol and 0.5 ml of triethylamine were sequentially added at room temperature, and the mixture was stirred at 80 ° C. for 1 hour in a microwave reactor. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The concentrated residue was dissolved in 5 ml of ethyl acetate, washed twice with 5% aqueous potassium dihydrogen phosphate solution, and then the organic layer was washed with 5 ml of saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.
  • the inside of the reaction vessel was replaced with a nitrogen atmosphere under reduced pressure, and then 68.3 mg of 20% palladium hydroxide / carbon [containing 50 wt% water] was added at room temperature, and then replaced with a hydrogen atmosphere under reduced pressure again. Stir for 5 hours. After completion of the reaction, the inside of the reaction vessel was replaced with a nitrogen atmosphere under reduced pressure. The reaction solution was filtered using a Celite filter, and the removed solid was washed with ethanol, and then the filtrate was concentrated under reduced pressure.
  • the obtained concentrated residue was dissolved in ethyl acetate, then n-hexane was added and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 104 mg of the title compound (yield 55 % [2 steps]) as a white solid.
  • the inside of the reaction vessel was replaced with a nitrogen atmosphere under reduced pressure.
  • the reaction solution was filtered using a celite filter, and the removed solid was washed with ethyl acetate, and then the filtrate was concentrated under reduced pressure.
  • the reaction solution diluted with dichloromethane was washed with 5% aqueous potassium hydrogen sulfate solution, and then separated.
  • the aqueous layer was extracted twice with dichloromethane, and then the entire organic layer obtained was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.
  • the containing fraction was concentrated under reduced pressure to distill off acetonitrile.
  • the fraction was concentrated under reduced pressure to distill off acetonitrile.
  • the inside of the reaction vessel was replaced with a nitrogen atmosphere under reduced pressure.
  • the reaction solution was filtered using a celite filter, and the removed solid was washed with ethyl acetate, and then the filtrate was concentrated under reduced pressure.
  • the organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
  • the obtained concentrated residue was dissolved in ethyl acetate, then n-hexane was added and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 115 mg of the title compound (yield 82 %) As a white solid.
  • the obtained concentrated residue was dissolved in ethyl acetate, then n-hexane was added and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 135 mg of the title compound (yield 83 %) As a white solid.
  • the obtained concentrated residue was dissolved in ethyl acetate, then added to n-hexane and the precipitated solid was collected by filtration and dried under reduced pressure to give 97.6 mg (yield 48%) of the title compound as a white solid. Obtained. Mass spectrum (CI, m / z): 509 [M + 1] + .
  • the obtained concentrated residue was dissolved in ethyl acetate, and n-hexane was added, and the precipitated solid was collected by filtration, washed with n-hexane and then dried under reduced pressure to give 144 mg of the title compound (yield 80%). %) As a white solid.
  • the obtained concentrated residue was dissolved in dichloromethane, 5% aqueous potassium hydrogen sulfate solution was added, and the mixture was stirred and separated.
  • the obtained organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the obtained concentrated residue was dissolved in methanol, and the solid precipitated by adding to water was collected by filtration and dried under reduced pressure to obtain 187 mg (yield 75%) of the title compound as a white solid.
  • the obtained concentrated residue was dissolved in methanol, and then the resulting solid added to water was collected by filtration and dried under reduced pressure to obtain 164 mg (yield 66%) of the title compound as a white solid.
  • the obtained concentrated residue was dissolved in methanol, and the solid precipitated by adding to water was collected by filtration and dried under reduced pressure to obtain 62 mg (yield 42%) of the title compound as a white solid.
  • the obtained concentrated residue was dissolved in ethyl acetate, n-hexane was added and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to obtain 187 mg of a white solid.
  • Phenyl) -2-methylbutan-2-ol 134 mg, including impurities
  • DIPEA 0.602 ml, 3.40 mmol
  • 0.318 ml (3.40 mmol) of N, N-dimethylethane-1,2-diamine was added at room temperature, and the mixture was stirred at that temperature for 2 hours.
  • 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • the obtained organic layer was washed successively with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
  • reaction solution was allowed to cool to room temperature, and 0.738 ml (6.78 mmol) of N, N-dimethylethane-1,2-diamine was added dropwise at room temperature, followed by stirring at room temperature for 4 hours.
  • 5% aqueous potassium hydrogen sulfate solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
  • the concentrated residue was dissolved in 60 ml of ethyl acetate and washed 3 times with 10 ml of 5% aqueous potassium hydrogen sulfate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
  • the obtained concentrated residue was dissolved in ethyl acetate, then n-hexane was added and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 107 mg of the title compound (yield: 52 %) As a white solid.
  • the obtained concentrated residue was dissolved in ethyl acetate, then n-hexane was added and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 96 mg of the title compound (yield 62 % [2 steps]) as a white solid.
  • Mass spectrum (CI, m / z): 498 [M + 1] + .
  • the obtained concentrated residue was dissolved in a mixed solvent of ethyl acetate / ethanol, then added with n-hexane, and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 802 mg of a white solid.
  • the fraction containing the optically active substance eluted in was concentrated under reduced pressure.
  • the obtained concentrated residue was dissolved in a small amount of ethyl acetate, and n-hexane was added to precipitate a solid.
  • the solid was collected by filtration, washed with n-hexane, and dried under reduced pressure at 50 ° C. to obtain 62 mg (yield 54%) of the title compound as a white solid.
  • the fraction containing -trifluoro-N- (3-hydroxy-3-methyl-1-phenylbutyl) acetamide was concentrated under reduced pressure to obtain a concentrated residue.
  • sodium borohydride 64.6 mg (1.71 mmol) was added in several portions at room temperature, and the mixture was stirred at room temperature for 14 hours.
  • the reaction solution was allowed to cool to room temperature and concentrated under reduced pressure.
  • Water and ethyl acetate were added to the resulting concentrated residue, and the mixture was extracted with ethyl acetate.
  • the obtained organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
  • the reaction solution was filtered through Celite.
  • the solid on celite was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure.
  • 0.19 g of 20% palladium hydroxide / carbon (containing 50 wt% water) was added at room temperature under an argon atmosphere, and the atmosphere was replaced with a hydrogen atmosphere under reduced pressure. Stir for 5 hours.
  • the reaction solution was filtered through Celite after replacing with an argon atmosphere.
  • the solid on celite was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure.
  • To a solution of the concentrated residue obtained in 100 ml of ethyl acetate was added 60.0 ml (240 mmol) of 4N hydrogen chloride / ethyl acetate at room temperature in a nitrogen atmosphere, followed by stirring at the same temperature for 5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure.
  • the obtained concentrated residue was suspended in diisopropyl ether, and the suspension was stirred at room temperature.
  • the insoluble material was collected by filtration, and the obtained solid was washed with diisopropyl ether.
  • the obtained solid was dissolved in water, saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added, and the mixture was stirred at room temperature for 5 min. After liquid separation, the aqueous layer was extracted twice with dichloromethane. The whole organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and dried under reduced pressure to obtain 8.27 g (yield 73% [2 steps]) of the title compound as a slightly orange solid. It was.
  • reaction solution was poured into 2N hydrochloric acid and stirred.
  • the aqueous layer and the organic layer were separated, and the organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then the filtrate was concentrated under reduced pressure.
  • the mixture was extracted twice with 100 ml of ethyl acetate, and all the organic layers were combined and washed successively with 100 ml of water and 100 ml of a saturated aqueous sodium chloride solution. After drying with magnesium sulfate, filtration and concentration under reduced pressure were performed to distill off half of the solvent. 12 g of activated carbon was added to the resulting solution, and the mixture was stirred at room temperature for 30 minutes, filtered and concentrated under reduced pressure. The resulting concentrated residue was diluted with 10 ml of diisopropyl ether, 50 ml of n-hexane was added thereto, the precipitated solid was crushed, and stirred at room temperature for 30 minutes.
  • reaction solution was diluted with ethyl acetate, added with celite, and filtered.
  • a sodium bicarbonate aqueous solution was added to the filtrate and stirred to neutralize. This was extracted twice with ethyl acetate. All organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.
  • reaction solution was poured into 1000 ml of a saturated aqueous sodium hydrogen carbonate solution, stirred at room temperature, and then separated. The aqueous layer was extracted twice with 500 ml of ethyl acetate, and then the entire organic layer obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
  • the title compound (1.03 g, yield 91%) was obtained as a colorless oil.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

This pharmaceutical composition for treatment or prevention of atopic dermatitis contains a compound represented by general expression (I) (In the formula, the two Rs independently represent a C1-3 alkyl group, or represent groups that, bonded together, form a C2-5 alkylene group. L2 represents a single bond, etc., L3 represents a single bond, etc., R1, R2 and R3 independently represent an optionally substituted linear or branched C1-4 alkyl group, etc., R4 represents an optionally substituted linear or branched C1-6 alkyl group, etc., and R5 represents a hydrogen atom, etc.), or a pharmacologically acceptable salt thereof.

Description

アトピー性皮膚炎の治療または予防のための医薬組成物Pharmaceutical composition for the treatment or prevention of atopic dermatitis
　本発明は、置換ジヒドロピロロピラゾール化合物もしくはその薬理上許容される塩、またはそのプロドラッグを含む、アトピー性皮膚炎の治療および／または予防に有用な医薬組成物に関する。 The present invention relates to a pharmaceutical composition useful for the treatment and / or prevention of atopic dermatitis, comprising a substituted dihydropyrrolopyrazole compound or a pharmacologically acceptable salt thereof, or a prodrug thereof.
　気管支喘息、アトピー性皮膚炎、花粉症、アレルギー性鼻炎、食物アレルギー等のアレルギー性疾患の患者は年々増加しており、近年、日本では総人口の約１／３がアレルギー性疾患に罹患していると考えられている（非特許文献１参照）。 The number of patients with allergic diseases such as bronchial asthma, atopic dermatitis, hay fever, allergic rhinitis, and food allergies is increasing year by year. In recent years, about 1/3 of the total population in Japan suffers from allergic diseases. (See Non-Patent Document 1).
　アトピー性皮膚炎は、アトピー素因と呼ばれるアレルギー体質、例えばアレルギー喘息、アレルギー性鼻炎、皮膚炎の蕁麻疹を起こしやすい体質の上に、様々な刺激が加わって生じる痒みを伴う慢性の皮膚疾患である。一般には、広範囲にわたって慢性湿疹の症状を呈し、強い痒みを伴う。また、患者によっては、赤い湿疹、結節などができ、激しい痒みを伴い、湿潤した局面から組織液が浸出して、激しい痛みを伴う。 Atopic dermatitis is a chronic skin disease with itching caused by various stimuli on allergic constitution called atopic predisposition, such as allergic asthma, allergic rhinitis, dermatitis urticaria . In general, it presents symptoms of chronic eczema over a wide area, with strong itching. In addition, some patients have red eczema, nodules, etc., accompanied by severe itching, and tissue fluid oozes from the moistened phase, causing severe pain.
　アトピー性皮膚炎の症状が重篤な場合は、症状の増悪阻止、一時的な治癒等を目的として、ステロイド外用剤、非ステロイド系消炎外用剤等の使用、抗アレルギー剤、抗ヒスタミン剤、ステロイド剤等の内服、更には、減感作療法、アレルゲン除去食療法、スキンケア・生活環境の改善等、様々な試みがなされている。しかし、これらの方法では、一時的に異常のない皮膚状態まで改善させることはできても、短期間のうちに症状が再発することが多く、長期にわたる治療期間を必要とすることが多い。また、長期間の投薬により、治療費が嵩む、副作用が懸念される等の問題もある。例えば、抗ヒスタミン剤はある程度の止痒効果はあるものの持続性に欠け、服用後に倦怠感や眠気を生じるものがあり、日常生活に支障を来す場合がある。また、ステロイド剤は皮膚症状の改善に高い効果を示すものの、大量使用による副腎皮質機能不全などの強い副作用があり、使用にあたっては医師の管理による十分な注意が必要で、長期連用は困難であった。従って、十分に安全性が確立され、より有効なアトピー性皮膚炎の治療薬が望まれている。 If the symptoms of atopic dermatitis are severe, use of steroids, non-steroidal anti-inflammatory agents, etc., antiallergic agents, antihistamines, steroids, etc. for the purpose of preventing exacerbations and temporary healing Various attempts have been made, such as internal use, desensitization therapy, allergen-removing diet, skin care and improvement of living environment. However, in these methods, although the skin condition can be temporarily improved without any abnormality, symptoms often recur in a short period of time, and a long treatment period is often required. In addition, there are problems such as increased treatment costs and concerns about side effects due to long-term medication. For example, although antihistamines have a certain level of antipruritic effect, they are not durable and may cause fatigue and drowsiness after administration, which may interfere with daily life. In addition, although steroids are highly effective in improving skin symptoms, they have strong side effects such as adrenal cortical dysfunction due to large-scale use. It was. Therefore, safety is sufficiently established, and a more effective therapeutic drug for atopic dermatitis is desired.
　一方、ＣＤＫ７（サイクリン依存性キナーゼ７）は当初、出芽酵母におけるｍＲＮＡ転写制御因子として同定され、その後、細胞周期制御とｍＲＮＡ転写制御の二つの役割を果たすことが明らかとなった。（非特許文献２参照）。ＣＤＫ７を含むＣＤＫファミリー（ＣＤＫｓ）は、炎症性細胞・免疫細胞の増殖、アポトーシスの制御、炎症性メディエーターの転写制御等を介して炎症反応に関わることが知られており、その阻害はこれらに起因する疾患に対して有望と考えられている（非特許文献３参照）。事実、ＣＤＫｓを阻害する化合物が、アトピー性皮膚疾患の病態形成に重要な好酸球に対して、アポトーシス等を介して好酸球数の抑制を示すこと（非特許文献４参照）、アトピー性皮膚炎と関連の深いＴｈ１７の分化を抑制する（非特許文献５及び６参照）こと等が報告されている。 On the other hand, CDK7 (cyclin-dependent kinase 7) was initially identified as an mRNA transcription factor in Saccharomyces cerevisiae, and subsequently became clear to play two roles, cell cycle control and mRNA transcription control. (Refer nonpatent literature 2). CDK family including CDK7 (CDKs) is known to be involved in inflammatory reaction through proliferation of inflammatory cells and immune cells, regulation of apoptosis, transcriptional regulation of inflammatory mediators, etc. It is considered promising for the disease to be performed (see Non-Patent Document 3). In fact, a compound that inhibits CDKs shows suppression of the number of eosinophils via apoptosis or the like with respect to eosinophils important for the pathogenesis of atopic skin diseases (see Non-Patent Document 4), atopicity It has been reported that Th17 differentiation deeply associated with dermatitis is suppressed (see Non-Patent Documents 5 and 6).
　しかし、これまでにＣＤＫ７を特異的に阻害する化合物がアトピー性皮膚炎に有用であることを具体的に示した報告はない。 However, there is no report that specifically shows that a compound that specifically inhibits CDK7 is useful for atopic dermatitis.
国際公開第２００２／０１２２４２号International Publication No. 2002/012242 国際公開第２００４／０５６８２７号International Publication No. 2004/056827 国際公開第２００４／０８０４５７号International Publication No. 2004/080457 国際公開第２００７／０６８６３７号International Publication No. 2007/068637 国際公開第２００７／０７２１５３号International Publication No. 2007/072153 国際公開第２００７／０９９１７１号International Publication No. 2007/099171 国際公開第２００８／０４３７４５号International Publication No. 2008/043745 国際公開第２００８／１２５９４５号International Publication No. 2008/125945 国際公開第２０１１／０４４２６４号International Publication No. 2011/044264 国際公開第２００８／１５１３０４号International Publication No. 2008/151304 国際公開第２０１３／１２８０２８号International Publication No. 2013/128028 国際公開第２０１３／１２８０２９号International Publication No. 2013/128029 国際公開第２０１４／０６３０６８号International Publication No. 2014/063068 国際公開第２０１５／０５８１２６号International Publication No. 2015/058126 国際公開第２０１５／０５８１４０号International Publication No. 2015/058140 国際公開第２０１５／０５８１６３号International Publication No. 2015/058163 国際公開第２０１５／１２４９４１号International Publication No. 2015/124941 国際公開第２０１５／１５４０２２号International Publication No. 2015/154022 国際公開第２０１５／１５４０３８号International Publication No. 2015/154038 国際公開第２０１５／１５４０３９号International Publication No. 2015/154039
　本発明者等は、アトピー性皮膚炎の治療および／または予防に有用な、優れたＣＤＫ７阻害剤の開発を目指して鋭意研究を行った。その結果、特定の構造を有する新規な置換ジヒドロピロロピラゾール化合物もしくはその薬理上許容される塩が、優れたＣＤＫ７阻害活性を有し、当該化合物もしくはその薬理上許容される塩を含む医薬組成物がアトピー性皮膚炎の治療薬および／または予防薬（好ましくは、治療薬）として有用であることを見出し、さらに当該化合物のプロドラッグとなり得る化合物をも見出し、本発明を完成させた。 The inventors of the present invention have conducted intensive research aimed at developing an excellent CDK7 inhibitor useful for the treatment and / or prevention of atopic dermatitis. As a result, a novel substituted dihydropyrrolopyrazole compound having a specific structure or a pharmacologically acceptable salt thereof has excellent CDK7 inhibitory activity, and a pharmaceutical composition comprising the compound or a pharmacologically acceptable salt thereof is provided. The inventors have found that it is useful as a therapeutic agent and / or preventive agent (preferably a therapeutic agent) for atopic dermatitis, and has also found a compound that can be a prodrug of the compound, thereby completing the present invention.
　なお、特許文献１乃至９、および、非特許文献８乃至１０には、６，６－ジメチル－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール骨格を有する化合物が記載されているが、本発明に係る化合物またはその薬理上許容される塩は開示されていない。 Patent Documents 1 to 9 and Non-Patent Documents 8 to 10 describe compounds having a 6,6-dimethyl-4,6-dihydropyrrolo [3,4-c] pyrazole skeleton. The compound according to the present invention or a pharmacologically acceptable salt thereof is not disclosed.
　また、ＣＤＫ７を阻害する化合物としては、特許文献１０にピラゾロピリミジン誘導体が、特許文献１１、１２にピラゾロトリアジン誘導体が、特許文献１３、および、非特許文献７にフェニル誘導体が、特許文献１４乃至２０に複素環化合物が開示されているが、４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール骨格を有する化合物は開示されていない。 Further, as compounds that inhibit CDK7, Patent Document 10 discloses pyrazolopyrimidine derivatives, Patent Documents 11 and 12, pyrazolotriazine derivatives, Patent Document 13 and Non-Patent Document 7, phenyl derivatives, Patent Document 14 Although heterocyclic compounds are disclosed in -20 to 20, a compound having a 4,6-dihydropyrrolo [3,4-c] pyrazole skeleton is not disclosed.
　本発明は、優れたＣＤＫ７阻害活性を有する新規な置換ジヒドロピロロピラゾール化合物もしくはその薬理上許容される塩、またはそのプロドラッグを含む、アトピー性皮膚炎の治療もしくは予防のための医薬組成物；
アトピー性皮膚炎の治療もしくは予防（好適には、治療）のための医薬組成物製造のための置換ジヒドロピロロピラゾール化合物もしくはその薬理上許容される塩、またはそのプロドラッグの使用；および
置換ジヒドロピロロピラゾール化合物もしくはその薬理上許容される塩、またはそのプロドラッグの薬剤的な有効量を温血動物（好適には、ヒト）に投与することによるアトピー性皮膚炎の治療もしくは予防（好適には、治療）のための方法を提供する。 The present invention relates to a pharmaceutical composition for treating or preventing atopic dermatitis, comprising a novel substituted dihydropyrrolopyrazole compound having excellent CDK7 inhibitory activity or a pharmacologically acceptable salt thereof, or a prodrug thereof;
Use of a substituted dihydropyrrolopyrazole compound or a pharmacologically acceptable salt thereof, or a prodrug thereof for the manufacture of a pharmaceutical composition for the treatment or prevention (preferably treatment) of atopic dermatitis; and substituted dihydropyrrolo Treatment or prevention of atopic dermatitis by administration of a pharmaceutically effective amount of a pyrazole compound or a pharmacologically acceptable salt thereof or a prodrug thereof to a warm-blooded animal (preferably a human) (preferably, A method for treatment).
　本発明は、一つの側面から以下の［１］～［３７］を提供する。
［１］一般式（Ｉ）：
Figure JPOXMLDOC01-appb-C000006
 ［式中、
　２つのＲは、それぞれ独立にＣ１－３アルキル基を示す、または、互いに結合してＣ２－５アルキレン基を形成している基を示し、
　Ｌ２は、単結合、酸素原子、または、－ＮＨ－で表される２価のアミノ基を示し、
　Ｌ３は、単結合、または、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基を示し、
　Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ１－４アルキル基を示し、
　Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示し、
　Ｒ５は、水素原子、置換されていてもよい直鎖もしくは分岐Ｃ１－１６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示す］
で表される化合物またはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［２］一般式（ＩＩ）：
Figure JPOXMLDOC01-appb-C000007
 ［式中、
　Ｌ２は、単結合、酸素原子、または、－ＮＨ－で表される２価のアミノ基を示し、
　Ｌ３は、単結合、または、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基を示し、
　Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ１－４アルキル基を示し、
　Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示し、
　Ｒ５は、水素原子、置換されていてもよい直鎖もしくは分岐Ｃ１－１６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示す］
で表される化合物またはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［３］Ｌ２およびＬ３が、単結合を示す、［２］記載の医薬組成物。
［４］Ｌ２が、－ＮＨ－で表される２価のアミノ基を示し、Ｌ３が、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基を示す、［２］記載の医薬組成物。
［５］一般式（ＩＩＩ）：
Figure JPOXMLDOC01-appb-C000008
 ［式中、
　Ｌ２は、単結合、酸素原子、または、－ＮＨ－で表される２価のアミノ基を示し、
　Ｌ３は、単結合、または、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基を示し、
　Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ１－４アルキル基を示し、
　Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示し、
　Ｒ５は、水素原子、置換されていてもよい直鎖もしくは分岐Ｃ１－１６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示す］
で表される化合物またはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［６］Ｌ２およびＬ３が、単結合を示す、［５］記載の医薬組成物。
［７］Ｌ２が、－ＮＨ－で表される２価のアミノ基を示し、Ｌ３が、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基を示す、［５］記載の医薬組成物。
［８］一般式（ＩＶ）：
Figure JPOXMLDOC01-appb-C000009
 ［式中、
　Ｌ２は、単結合、酸素原子、または、－ＮＨ－で表される２価のアミノ基を示し、
　Ｌ３は、単結合、または、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基を示し、
　Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ１－４アルキル基を示し、
　Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示し、
　Ｒ５は、水素原子、置換されていてもよい直鎖もしくは分岐Ｃ１－１６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示す］
で表される化合物またはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［９］Ｌ２およびＬ３が、単結合を示す、［８］記載の医薬組成物。
［１０］Ｌ２が、－ＮＨ－で表される２価のアミノ基を示し、Ｌ３が、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基を示す、［８］記載の医薬組成物。
［１１］一般式（Ｖ）もしくは（ＶＩ）：
Figure JPOXMLDOC01-appb-C000010
 ［式中、
　２つのＲは、それぞれ独立にＣ１－３アルキル基を示す、または、互いに結合してＣ２－５アルキレン基を形成している基を示し、
　Ｌ２は、単結合、酸素原子、または、－ＮＨ－で表される２価のアミノ基を示し、
　Ｌ３は、単結合、または、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基を示し、
　Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ１－４アルキル基を示し、
　Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示し、
　Ｒ６は、水素原子、置換されていてもよい直鎖もしくは分岐Ｃ１－１６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ１－６アルコキシ基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示し、
　Ｒ７は、置換されていてもよい直鎖もしくは分岐Ｃ１－１６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示し、
　Ｒ８およびＲ９は、それぞれ独立に、水素原子またはＣ１－４アルキル基を示す］
で表される化合物またはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［１２］Ｌ２が、－ＮＨ－で表される２価のアミノ基を示し、Ｌ３が、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基を示す、［１１］記載の医薬組成物。
［１３］（Ｓ）－Ｎ－（２－ヒドロキシ－１－フェニルエチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－（２－ヒドロキシ－１－フェニルエチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－（２－ヒドロキシ－１－フェニルエチル）－６，６－ジメチル－３－［２－メチル－２－（トリメチルシリル）プロパンアミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－３－［１－（エチルジメチルシリル）シクロブタンカルボキサミド］－Ｎ－（２－ヒドロキシ－１－フェニルエチル）－６，６－ジメチル－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－３－［２－（エチルジメチルシリル）－２－メチルプロパンアミド］－Ｎ－（２－ヒドロキシ－１－フェニルエチル）－６，６－ジメチル－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－２－［（２－メトキシプロパン－２－イル）オキシ］－１－フェニルエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキシラート、
（Ｓ）－２－ヒドロキシ－１－フェニルエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキシラート、
２－メトキシ－１－フェニルエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキシラート、
（Ｒ）－Ｎ－（３－ヒドロキシ－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－（３－ヒドロキシ－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－（４－ヒドロキシ－１－フェニルブチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－（５－ヒドロキシ－１－フェニルペンチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－（２－ヒドロキシ－２－メチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－（２－ヒドロキシ－２－メチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
Ｎ－（３－ヒドロキシ－２，２－ジメチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－（３－ヒドロキシ－３－メチル－１－フェニルブチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－（２－メトキシ－１－フェニルエチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－［２－（ジフルオロメトキシ）－１－フェニルエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－（２－エトキシ－１－フェニルエチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－（３－メトキシ－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４．５．６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニル酢酸ナトリウム、
Ｎ－［１－（２－フルオロフェニル）－２－ヒドロキシエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－［１－（３－フルオロフェニル）－２－ヒドロキシエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－［１－（４－フルオロフェニル）－２－ヒドロキシエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
Ｎ－［２－ヒドロキシ－１－（ピリジン－２－イル）エチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
Ｎ－［２－ヒドロキシ－１－（ピリジン－３－イル）エチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－（１－シクロヘキシル－２－ヒドロキシエチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－（１－ヒドロキシ－３－メチルブタン－２－イル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－（１－ヒドロキシプロパン－２－イル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　アセタート、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　プロピオナート、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　ブタノアート、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　ペンタノアート、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　オクタノアート、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　ドデカノアート、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　パルミタート、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　イソブタノアート、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　ピバラート、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　３－メチルブタノアート、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　ベンゾアート、
（Ｓ）－４－（２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエトキシ）－４－オキソブタン酸ナトリウム、
（Ｓ）－（２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエトキシ）メチル　ピバラート、
（Ｓ）－２－アセトキシ－１－フェニルエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキシラート、
（Ｓ）－ベンジル　２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルアセタート、
（Ｓ）－メチル　２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルアセタート、
Ｎ－（２，２－ジフルオロ－３－ヒドロキシ－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－［１－（２－クロロフェニル）－２－ヒドロキシエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－［２－ヒドロキシ－１－（ｏ－トリル）エチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－（１－ヒドロキシ－３－フェニルプロパン－２－イル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
Ｎ－［５－（３－ヒドロキシ－２－フェニルプロパノイル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
（Ｓ）－Ｎ－［５－（３－ヒドロキシ－２－フェニルプロパノイル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
（Ｒ）－Ｎ－［５－（２－メトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
（Ｓ）－Ｎ－［５－（２－メトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
Ｎ－［５－（３－メトキシ－２－フェニルプロパノイル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
Ｎ－［５－（４－メトキシ－２－フェニルブタノイル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
（Ｓ）－Ｎ－［５－（３－ヒドロキシ－２－フェニルプロパノイル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロプロパンカルボキサミド、
（Ｒ）－Ｎ－［５－（２－メトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロプロパンカルボキサミド、
（Ｒ）－Ｎ－｛５－［２－（ジフルオロメトキシ）－２－フェニルアセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
（Ｒ）－Ｎ－［５－（２－エトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
（Ｒ）－１－（エチルジメチルシリル）－Ｎ－［５－（２－メトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］シクロブタンカルボキサミド、
（Ｒ）－Ｎ－［５－（２－シクロプロポキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
（Ｒ）－Ｎ－［５－（２－イソプロポキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
（Ｒ）－Ｎ－｛６，６－ジメチル－５－［２－フェニル－２－（トリフルオロメトキシ）アセチル］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
（Ｒ）－Ｎ－［６，６－ジメチル－５－（２－フェニル－２－プロポキシアセチル）－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
Ｎ－｛５－［２－（４－フルオロフェニル）－２－メトキシアセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
Ｎ－｛５－［２－（３－フルオロフェニル）－２－メトキシアセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
（Ｒ）－Ｎ－｛５－［２－（２－フルオロフェニル）－２－メトキシアセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
Ｎ－｛５－［２－メトキシ－２－（チオフェン－２－イル）アセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
（－）－Ｎ－｛５－［２－メトキシ－２－（チオフェン－２－イル）アセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
（＋）－Ｎ－｛５－［２－メトキシ－２－（チオフェン－２－イル）アセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
Ｎ－｛［１－（ヒドロキシメチル）シクロブチル］（フェニル）メチル｝－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－［２－（１－ヒドロキシシクロプロピル）－１－フェニルエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－（３－エチル－３－ヒドロキシ－１－フェニルペンチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－［１－（４－フルオロフェニル）－３－ヒドロキシ－３－メチルブチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－［１－（３－フルオロフェニル）－３－ヒドロキシ－３－メチルブチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－［１－（２－フルオロフェニル）－３－ヒドロキシ－３－メチルブチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－（５－ヒドロキシ－２，５－ジメチルヘキサン－３－イル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
Ｎ－［１－（４－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
Ｎ－［１－（３－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（－）－Ｎ－［１－（３－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（＋）－Ｎ－［１－（３－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
Ｎ－［１－（２－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
Ｎ－（１－ヒドロキシ－２，２，４－トリメチルペンタン－３－イル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－（３－ヒドロキシ－３－メチル－１－フェニルブチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
Ｎ－（３－ヒドロキシ－２，２－ジメチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（－）－Ｎ－（３－ヒドロキシ－２，２－ジメチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（＋）－Ｎ－（３－ヒドロキシ－２，２－ジメチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－［５－（２－ブトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、および
Ｎ－（３－メトキシ－２，２－ジメチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド
からなる化合物群から選択される化合物またはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［１４］（Ｒ）－Ｎ－［１－（４－フルオロフェニル）－３－ヒドロキシ－３－メチルブチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［１５］（－）－Ｎ－（３－ヒドロキシ－２，２－ジメチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパン－１－カルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［１６］（Ｒ）－Ｎ－［５－（２－メトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［１７］（Ｒ）－Ｎ－［６，６－ジメチル－５－（２－フェニル－２－プロポキシアセチル）－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［１８］（Ｒ）－Ｎ－｛５－［２－（２－フルオロフェニル）－２－メトキシアセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［１９］（Ｒ）－Ｎ－［５－（２－エトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［２０］（Ｒ）－Ｎ－［５－（２－シクロプロポキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［２１］（Ｒ）－Ｎ－［５－（２－イソプロポキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［２２］（＋）－Ｎ－｛５－［２－メトキシ－２－（チオフェン－２－イル）アセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［２３］（－）－Ｎ－［１－（３－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［２４］Ｎ－｛５－［２－（３－フルオロフェニル）－２－メトキシアセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［２５］Ｎ－［１－（４－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［２６］（Ｒ）－Ｎ－［１－（３－フルオロフェニル）－３－ヒドロキシ－３－メチルブチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［２７］（Ｒ）－Ｎ－｛６，６－ジメチル－５－［２－フェニル－２－（トリフルオロメトキシ）アセチル］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［２８］（Ｒ）－Ｎ－［２－（１－ヒドロキシシクロプロピル）－１－フェニルエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［２９］（Ｒ）－Ｎ－（３－ヒドロキシ－３－メチル－１－フェニルブチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［３０］（Ｒ）－Ｎ－［５－（２－メトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロプロパンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［３１］（Ｒ）－Ｎ－｛５－［２－（ジフルオロメトキシ）－２－フェニルアセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［３２］（Ｒ）－１－（エチルジメチルシリル）－Ｎ－［５－（２－メトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］シクロブタンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［３３］Ｎ－｛［１－（ヒドロキシメチル）シクロブチル］（フェニル）メチル｝－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。
［３４］［１］乃至［３３］のいずれかに記載の化合物、または、その薬理上許容される塩を、それを必要とする対象に投与することを含む、アトピー性皮膚炎の治療または予防方法。
［３５］アトピー性皮膚炎の治療剤または予防剤である医薬組成物の製造のための、［１］乃至［３３］のいずれかに記載の化合物、または、その薬理上許容される塩の使用。
［３６］アトピー性皮膚炎を治療または予防するための、［１］乃至［３３］のいずれかに記載の化合物、または、その薬理上許容される塩の使用。
［３７］アトピー性皮膚炎の治療または予防に使用するための、［１］乃至［３３］のいずれかに記載の化合物、または、その薬理上許容される塩。 The present invention provides the following [1] to [37] from one aspect.
[1] General formula (I):
Figure JPOXMLDOC01-appb-C000006
 [Where:
Two R's each independently represent a C 1-3 alkyl group, or a group bonded to each other to form a C 2-5 alkylene group;
L 2 represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—,
L 3 represents a single bond or a linear or branched C 1-6 alkylene group which may be substituted,
R 1 , R 2 and R 3 each independently represents an optionally substituted linear or branched C 1-4 alkyl group;
R 4 is an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-10 aryl group, or And represents an optionally substituted heterocyclic group,
R 5 represents a hydrogen atom, an optionally substituted linear or branched C 1-16 alkyl group, an optionally substituted C 3-6 cycloalkyl group, or an optionally substituted C 6-10 aryl group. Or a heterocyclic group which may be substituted]
A pharmaceutical composition for treating or preventing atopic dermatitis, comprising a compound represented by the formula: or a pharmacologically acceptable salt thereof.
[2] General formula (II):
Figure JPOXMLDOC01-appb-C000007
 [Where:
L 2 represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—,
L 3 represents a single bond or a linear or branched C 1-6 alkylene group which may be substituted,
R 1 , R 2 and R 3 each independently represents an optionally substituted linear or branched C 1-4 alkyl group;
R 4 is an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-10 aryl group, or And represents an optionally substituted heterocyclic group,
R 5 represents a hydrogen atom, an optionally substituted linear or branched C 1-16 alkyl group, an optionally substituted C 3-6 cycloalkyl group, or an optionally substituted C 6-10 aryl group. Or a heterocyclic group which may be substituted]
A pharmaceutical composition for treating or preventing atopic dermatitis, comprising a compound represented by the formula: or a pharmacologically acceptable salt thereof.
[3] The pharmaceutical composition according to [2], wherein L 2 and L 3 represent a single bond.
[4] L 2 is a divalent group represented by -NH-, L 3 indicates a straight chain may be substituted or branched C 1-6 alkylene group, [2] according Pharmaceutical composition.
[5] General formula (III):
Figure JPOXMLDOC01-appb-C000008
 [Where:
L 2 represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—,
L 3 represents a single bond or a linear or branched C 1-6 alkylene group which may be substituted,
R 1 , R 2 and R 3 each independently represents an optionally substituted linear or branched C 1-4 alkyl group;
R 4 is an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-10 aryl group, or And represents an optionally substituted heterocyclic group,
R 5 represents a hydrogen atom, an optionally substituted linear or branched C 1-16 alkyl group, an optionally substituted C 3-6 cycloalkyl group, or an optionally substituted C 6-10 aryl group. Or a heterocyclic group which may be substituted]
A pharmaceutical composition for treating or preventing atopic dermatitis, comprising a compound represented by the formula: or a pharmacologically acceptable salt thereof.
[6] The pharmaceutical composition according to [5], wherein L 2 and L 3 represent a single bond.
[7] L 2 is a divalent group represented by -NH-, L 3 indicates a straight chain may be substituted or branched C 1-6 alkylene group, [5] according Pharmaceutical composition.
[8] General formula (IV):
Figure JPOXMLDOC01-appb-C000009
 [Where:
L 2 represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—,
L 3 represents a single bond or a linear or branched C 1-6 alkylene group which may be substituted,
R 1 , R 2 and R 3 each independently represents an optionally substituted linear or branched C 1-4 alkyl group;
R 4 is an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-10 aryl group, or And represents an optionally substituted heterocyclic group,
R 5 represents a hydrogen atom, an optionally substituted linear or branched C 1-16 alkyl group, an optionally substituted C 3-6 cycloalkyl group, or an optionally substituted C 6-10 aryl group. Or a heterocyclic group which may be substituted]
A pharmaceutical composition for treating or preventing atopic dermatitis, comprising a compound represented by the formula: or a pharmacologically acceptable salt thereof.
[9] The pharmaceutical composition according to [8], wherein L 2 and L 3 represent a single bond.
[10] L 2 is a divalent group represented by -NH-, L 3 indicates a straight chain may be substituted or branched C 1-6 alkylene group, [8] described Pharmaceutical composition.
[11] General formula (V) or (VI):
Figure JPOXMLDOC01-appb-C000010
 [Where:
Two R's each independently represent a C 1-3 alkyl group, or a group bonded to each other to form a C 2-5 alkylene group;
L 2 represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—,
L 3 represents a single bond or a linear or branched C 1-6 alkylene group which may be substituted,
R 1 , R 2 and R 3 each independently represents an optionally substituted linear or branched C 1-4 alkyl group;
R 4 is an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-10 aryl group, or And represents an optionally substituted heterocyclic group,
R 6 is a hydrogen atom, an optionally substituted linear or branched C 1-16 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 1-6 alkoxy group , An optionally substituted C 6-10 aryl group or an optionally substituted heterocyclic group;
R 7 is an optionally substituted linear or branched C 1-16 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-10 aryl group, or And represents an optionally substituted heterocyclic group,
R 8 and R 9 each independently represents a hydrogen atom or a C 1-4 alkyl group]
A pharmaceutical composition for treating or preventing atopic dermatitis, comprising a compound represented by the formula: or a pharmacologically acceptable salt thereof.
[12] L 2 is a divalent group represented by -NH-, L 3 indicates a straight chain may be substituted or branched C 1-6 alkylene group, [11] according Pharmaceutical composition.
[13] (S) -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c Pyrazole-5 (1H) -carboxamide,
(S) -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide,
(S) -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-3- [2-methyl-2- (trimethylsilyl) propanamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
(S) -3- [1- (Ethyldimethylsilyl) cyclobutanecarboxamide] -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
(S) -3- [2- (Ethyldimethylsilyl) -2-methylpropanamide] -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-4,6-dihydropyrrolo [3 4-c] pyrazole-5 (1H) -carboxamide,
(S) -2-[(2-Methoxypropan-2-yl) oxy] -1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxylate,
(S) -2-Hydroxy-1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H)- Carboxylate,
2-methoxy-1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxylate,
(R) -N- (3-hydroxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(R) -N- (3-hydroxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide,
(R) -N- (4-hydroxy-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(R) -N- (5-hydroxy-1-phenylpentyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(S) -N- (2-hydroxy-2-methyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
(S) -N- (2-hydroxy-2-methyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide,
N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
(R) -N- (3-hydroxy-3-methyl-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
(S) -N- (2-methoxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(S) -N- [2- (Difluoromethoxy) -1-phenylethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c Pyrazole-5 (1H) -carboxamide,
(S) —N- (2-Ethoxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(R) -N- (3-methoxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4.5.6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Sodium phenylacetate,
N- [1- (2-Fluorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide,
(S) -N- [1- (3-Fluorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide,
(S) -N- [1- (4-Fluorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide,
N- [2-hydroxy-1- (pyridin-2-yl) ethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
N- [2-hydroxy-1- (pyridin-3-yl) ethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
(S) -N- (1-cyclohexyl-2-hydroxyethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(S) -N- (1-Hydroxy-3-methylbutan-2-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c Pyrazole-5 (1H) -carboxamide,
(S) -N- (1-hydroxypropan-2-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl acetate,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl propionate,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl butanoate,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl pentanoate,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl octanoate,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl dodecanoate,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl palmitate,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl isobutanoate,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl pivalate,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl 3-methylbutanoate,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl benzoate,
(S) -4- (2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide } -2-Phenylethoxy) -4-oxobutanoic acid sodium,
(S)-(2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide}- 2-phenylethoxy) methyl pivalate,
(S) -2-Acetoxy-1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H)- Carboxylate,
(S) -Benzyl 2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide}- 2-phenyl acetate,
(S) -Methyl 2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide}- 2-phenyl acetate,
N- (2,2-difluoro-3-hydroxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
(S) —N- [1- (2-chlorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
(S) -N- [2-hydroxy-1- (o-tolyl) ethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
(S) -N- (1-hydroxy-3-phenylpropan-2-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
N- [5- (3-Hydroxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- ( Trimethylsilyl) cyclobutanecarboxamide,
(S) -N- [5- (3-Hydroxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide,
(S) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide,
N- [5- (3-Methoxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- ( Trimethylsilyl) cyclobutanecarboxamide,
N- [5- (4-Methoxy-2-phenylbutanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- ( Trimethylsilyl) cyclobutanecarboxamide,
(S) -N- [5- (3-Hydroxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclopropanecarboxamide,
(R) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclopropanecarboxamide,
(R) -N- {5- [2- (Difluoromethoxy) -2-phenylacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3- Yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- [5- (2-Ethoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -1- (Ethyldimethylsilyl) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c ] Pyrazol-3-yl] cyclobutanecarboxamide,
(R) -N- [5- (2-Cyclopropoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- [5- (2-Isopropoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- {6,6-dimethyl-5- [2-phenyl-2- (trifluoromethoxy) acetyl] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3 -Yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- [6,6-Dimethyl-5- (2-phenyl-2-propoxyacetyl) -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide,
N- {5- [2- (4-Fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
N- {5- [2- (3-Fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- {5- [2- (2-Fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole- 3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl } -1- (Trimethylsilyl) cyclobutanecarboxamide,
(-)-N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole -3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
(+)-N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole -3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
N-{[1- (hydroxymethyl) cyclobutyl] (phenyl) methyl} -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide,
(R) -N- [2- (1-hydroxycyclopropyl) -1-phenylethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 4-c] pyrazole-5 (1H) -carboxamide,
(R) -N- (3-Ethyl-3-hydroxy-1-phenylpentyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
(R) -N- [1- (4-Fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [ 3,4-c] pyrazole-5 (1H) -carboxamide,
(R) -N- [1- (3-Fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [ 3,4-c] pyrazole-5 (1H) -carboxamide,
(R) -N- [1- (2-Fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [ 3,4-c] pyrazole-5 (1H) -carboxamide,
(R) -N- (5-hydroxy-2,5-dimethylhexane-3-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 4-c] pyrazole-5 (1H) -carboxamide,
N- [1- (4-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxamide,
N- [1- (3-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxamide,
(−) — N- [1- (3-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- Dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide,
(+)-N- [1- (3-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- Dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide,
N- [1- (2-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxamide,
N- (1-hydroxy-2,2,4-trimethylpentan-3-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
(R) -N- (3-hydroxy-3-methyl-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide,
N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c Pyrazole-5 (1H) -carboxamide,
(−) — N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3, 4-c] pyrazole-5 (1H) -carboxamide,
(+)-N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 4-c] pyrazole-5 (1H) -carboxamide,
(R) -N- [5- (2-Butoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide and N- (3-methoxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- A pharmaceutical composition for treating or preventing atopic dermatitis, comprising a compound selected from the group consisting of dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof object.
[14] (R) -N- [1- (4-Fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- A pharmaceutical composition for treating or preventing atopic dermatitis, comprising dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof.
[15] (-)-N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropane-1-carboxamide] -4, A pharmaceutical composition for treating or preventing atopic dermatitis, comprising 6-dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof.
[16] (R) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3- IL] -1- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof, a pharmaceutical composition for treating or preventing atopic dermatitis.
[17] (R) -N- [6,6-Dimethyl-5- (2-phenyl-2-propoxyacetyl) -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3- IL] -1- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof, a pharmaceutical composition for treating or preventing atopic dermatitis.
[18] (R) -N- {5- [2- (2-Fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c ] A pharmaceutical composition for treating or preventing atopic dermatitis, comprising pyrazol-3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.
[19] (R) -N- [5- (2-Ethoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3- IL] -1- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof, a pharmaceutical composition for treating or preventing atopic dermatitis.
[20] (R) -N- [5- (2-Cyclopropoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3 -Yl] -1- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof, a pharmaceutical composition for treating or preventing atopic dermatitis.
[21] (R) -N- [5- (2-Isopropoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3 -Yl] -1- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof, a pharmaceutical composition for treating or preventing atopic dermatitis.
[22] (+)-N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4 c] A pharmaceutical composition for treating or preventing atopic dermatitis, comprising pyrazol-3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide or a pharmaceutically acceptable salt thereof.
[23] (−)-N- [1- (3-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4 , 6-dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof, a pharmaceutical composition for treating or preventing atopic dermatitis.
[24] N- {5- [2- (3-Fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3 -Il} -1- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof, a pharmaceutical composition for treating or preventing atopic dermatitis.
[25] N- [1- (4-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydro A pharmaceutical composition for treating or preventing atopic dermatitis, comprising pyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof.
[26] (R) -N- [1- (3-Fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- A pharmaceutical composition for treating or preventing atopic dermatitis, comprising dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof.
[27] (R) -N- {6,6-dimethyl-5- [2-phenyl-2- (trifluoromethoxy) acetyl] -1,4,5,6-tetrahydropyrrolo [3,4-c] A pharmaceutical composition for treating or preventing atopic dermatitis, comprising pyrazol-3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.
[28] (R) -N- [2- (1-hydroxycyclopropyl) -1-phenylethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo A pharmaceutical composition for treating or preventing atopic dermatitis, comprising [3,4-c] pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof.
[29] (R) -N- (3-hydroxy-3-methyl-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof, a pharmaceutical composition for treating or preventing atopic dermatitis.
[30] (R) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3- IL] -1- (trimethylsilyl) cyclopropanecarboxamide or a pharmacologically acceptable salt thereof, a pharmaceutical composition for treating or preventing atopic dermatitis.
[31] (R) -N- {5- [2- (Difluoromethoxy) -2-phenylacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole A pharmaceutical composition for treating or preventing atopic dermatitis, comprising -3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide or a pharmaceutically acceptable salt thereof.
[32] (R) -1- (Ethyldimethylsilyl) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3 4-c] pyrazol-3-yl] cyclobutanecarboxamide or a pharmacologically acceptable salt thereof, a pharmaceutical composition for treating or preventing atopic dermatitis.
[33] N-{[1- (hydroxymethyl) cyclobutyl] (phenyl) methyl} -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] A pharmaceutical composition for treating or preventing atopic dermatitis, comprising pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof.
[34] Treatment or prevention of atopic dermatitis, comprising administering the compound according to any one of [1] to [33] or a pharmacologically acceptable salt thereof to a subject in need thereof. Method.
[35] Use of the compound according to any one of [1] to [33] or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition which is a therapeutic or preventive agent for atopic dermatitis. .
[36] Use of the compound according to any one of [1] to [33] or a pharmacologically acceptable salt thereof for treating or preventing atopic dermatitis.
[37] The compound according to any one of [1] to [33] or a pharmacologically acceptable salt thereof for use in the treatment or prevention of atopic dermatitis.
　本発明の一般式（Ｉ）で表される化合物の具体例としては、例えば、下記表１乃至２０に示すような化合物を挙げることができる。なお、下記表１乃至２０中、Ｍｅはメチル基を示し、Ｅｔはエチル基を示し、ｎＰｒはｎ－プロピル基を示し、ｉＰｒはイソプロピル基を示し、ｃＰｒはシクロプロピル基を示し、ｎＢｕはｎ－ブチル基を示し、ｉＢｕはイソブチル基を示し、ｔＢｕはｔｅｒｔ－ブチル基を示し、ｃＨｅｘはシクロヘキシル基を示し、Ｐｈはフェニル基を示し、２－Ｆ－Ｐｈは２－フルオロフェニル基を示し、３－Ｆ－Ｐｈは３－フルオロフェニル基を示し、４－Ｆ－Ｐｈは４－フルオロフェニル基を示し、２－Ｃｌ－Ｐｈは２－クロロフェニル基を示し、３－Ｃｌ－Ｐｈは３－クロロフェニル基を示し、４－Ｃｌ－Ｐｈは４－クロロフェニル基を示し、２－Ｍｅ－Ｐｈは２－メチルフェニル基を示し、３－Ｍｅ－Ｐｈは３－メチルフェニル基を示し、４－Ｍｅ－Ｐｈは４－メチルフェニル基を示し、２－Ｐｙは２－ピリジル基を示し、３－Ｐｙは３－ピリジル基を示し、４－Ｐｙは４－ピリジル基を示し、Ｂｎはベンジル基を示し、－は単結合を示し、「（Ｒ）－」、及び、「（Ｓ）－」は、下記の一般式（ＩＩ）、（ＩＩＩ）、（ＩＶ）、（Ｖａ）、（Ｖｂ）、（Ｖｃ）、（ＶＩａ）、（ＶＩｂ）、および、（ＶＩｃ）中の「＊」を付した炭素原子の立体配置を示し、「ｒａｃｅｍｉｃ」はラセミ体であることを示し、「（＋）」は右旋性の光学活性体であること示し、「（－）」は左旋性の光学活性体であることを示す。また、表中、Ｌ３として記載された各化学構造は、対応する一般式において、「＊」を付した炭素原子に当該化学構造の左側に位置する原子が結合するものとする。例えば、化合物番号ＩＩ－１１の化合物の場合、Ｌ３に相当するＣＨ２（ＣＭｅ）２は、メチレン炭素原子（ＣＨ２）が「＊」を付した炭素原子に結合し、ジメチルメチレン炭素原子（ＣＭｅ）２がＲ５に隣接する酸素原子と結合することを意味する。 Specific examples of the compound represented by the general formula (I) of the present invention include compounds shown in Tables 1 to 20 below. In Tables 1 to 20, Me represents a methyl group, Et represents an ethyl group, nPr represents an n-propyl group, iPr represents an isopropyl group, cPr represents a cyclopropyl group, and nBu represents n -Butyl group, iBu represents isobutyl group, tBu represents tert-butyl group, cHex represents cyclohexyl group, Ph represents phenyl group, 2-F-Ph represents 2-fluorophenyl group, 3-F-Ph represents 3-fluorophenyl group, 4-F-Ph represents 4-fluorophenyl group, 2-Cl-Ph represents 2-chlorophenyl group, 3-Cl-Ph represents 3-chlorophenyl group 4-Cl-Ph represents a 4-chlorophenyl group, 2-Me-Ph represents a 2-methylphenyl group, 3-Me-Ph represents a 3-methylphenyl group, e-Ph represents a 4-methylphenyl group, 2-Py represents a 2-pyridyl group, 3-Py represents a 3-pyridyl group, 4-Py represents a 4-pyridyl group, and Bn represents a benzyl group. -Represents a single bond, and "(R)-" and "(S)-" represent the following general formulas (II), (III), (IV), (Va), (Vb), In (Vc), (VIa), (VIb), and (VIc), the configuration of carbon atoms marked with “*” is shown, “racetic” indicates a racemate, and “(+)” Indicates a dextrorotatory optically active substance, and “(−)” indicates a levorotatory optically active substance. In the table, each chemical structure described as L 3 is assumed to have an atom located on the left side of the chemical structure bonded to a carbon atom marked with “*” in the corresponding general formula. For example, in the case of the compound of Compound No. II-11, CH 2 (CMe) 2 corresponding to L 3 is bonded to a carbon atom to which a methylene carbon atom (CH 2 ) is marked with “*”, and a dimethylmethylene carbon atom ( CMe) 2 means bonded to the oxygen atom adjacent to R 5 .
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000030
　本発明の一般式（Ｉ）で表される特定の構造を有する新規な置換ジヒドロピロロピラゾール化合物またはその薬理上許容される塩は、その化合物自身またはその代謝物が優れたＣＤＫ７阻害活性、キナーゼ阻害作用に関する高い選択性、および、優れた安全性を有している。従って、一般式（Ｉ）で表される化合物またはその薬理上許容される塩を含む医薬組成物は、アトピー性皮膚炎の治療薬および／または予防薬として有用である。 The novel substituted dihydropyrrolopyrazole compound having a specific structure represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has excellent CDK7 inhibitory activity, kinase inhibition, when the compound itself or its metabolite is excellent. High selectivity for action and excellent safety. Therefore, the pharmaceutical composition containing the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof is useful as a therapeutic and / or prophylactic agent for atopic dermatitis.
　本発明の一実施形態について、以下に説明する。なお、本明細書中、「一般式（Ｉ）で表される化合物」等を便宜上、それぞれ「化合物（Ｉ）」等ともいう。以下に定義または例示される各種の置換基は、任意に選択して組み合わせることができる。 An embodiment of the present invention will be described below. In the present specification, “a compound represented by the general formula (I)” and the like are also referred to as “compound (I)” and the like for convenience. The various substituents defined or exemplified below can be arbitrarily selected and combined.
　本明細書中、「プロドラッグ」とは、動物体内に投与されることにより、代謝反応を受け、ＣＤＫ７阻害作用を有する化合物を生成する化合物またはその塩のことを意味する。 In the present specification, the “prodrug” means a compound or a salt thereof that undergoes a metabolic reaction to produce a compound having a CDK7 inhibitory action when administered into an animal body.
　本発明の一実施形態は、一般式（Ｉ）で表される化合物またはその薬学上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物である。
Figure JPOXMLDOC01-appb-C000031
 One embodiment of the present invention is a pharmaceutical composition for treating or preventing atopic dermatitis comprising a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000031
　一般式（Ｉ）において、
　２つのＲは、それぞれ独立にＣ１－３アルキル基を示す、または、互いに結合してＣ２－５アルキレン基を形成している基を示し、
　Ｌ２は、単結合、酸素原子、または、－ＮＨ－で表される２価のアミノ基を示し、
　Ｌ３は、単結合、または、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基を示し、
　Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ１－４アルキル基を示し、
　Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示し、
　Ｒ５は、水素原子、置換されていてもよい直鎖もしくは分岐Ｃ１－１６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示す。 In general formula (I):
Two R's each independently represent a C 1-3 alkyl group, or a group bonded to each other to form a C 2-5 alkylene group;
L 2 represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—,
L 3 represents a single bond or a linear or branched C 1-6 alkylene group which may be substituted,
R 1 , R 2 and R 3 each independently represents an optionally substituted linear or branched C 1-4 alkyl group;
R 4 is an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-10 aryl group, or And represents an optionally substituted heterocyclic group,
R 5 represents a hydrogen atom, an optionally substituted linear or branched C 1-16 alkyl group, an optionally substituted C 3-6 cycloalkyl group, or an optionally substituted C 6-10 aryl group. Or an optionally substituted heterocyclic group.
　本明細書中、「置換されていてもよい」との語は、当該基が無置換のものであってもよく、置換基でさらに置換されたものであってもよいことを意味する。 In the present specification, the term “may be substituted” means that the group may be unsubstituted or further substituted with a substituent.
　上記置換基は、１価の基を意味し、例えば、直鎖もしくは分岐Ｃ１－６アルキル基、Ｃ３－６シクロアルキル基、直鎖もしくは分岐Ｃ２－６アルケニル基、Ｃ３－６シクロアルケニル基、直鎖もしくは分岐Ｃ２－６アルキニル基、Ｃ１－６アルコキシ基、ハロゲン原子、水酸基、シアノ基、オキソ基（＝Ｏ）、アミノ基、Ｃ１－６アルキルアミノ基、ニトロ基、カルボキシ基（－ＣＯＯＨ）、カルバモイル基（－ＣＯＮＨ２）、Ｎ－モノＣ１－６アルキルカルバモイル基、Ｎ，Ｎ－ジＣ１－６アルキルカルバモイル基、Ｃ１－６アルカノイルオキシ基（－ＯＣＯＲ、ＲはＣ１－６アルキル基）、Ｃ６－１０アリール基、複素環基、Ｃ６－１０アリールオキシ基、Ｃ７－１２アラルキル基、および、Ｃ７－１２アラルキルオキシ基が挙げられる。上記置換基は、さらにハロゲン原子、水酸基、アミノ基、シアノ基、オキソ基（＝Ｏ）、直鎖もしくは分岐Ｃ１－６アルキル基等で置換されていてもよい。置換基がアミノ基またはカルボキシ基の場合には、その塩の形態であってもよい。 The above substituent means a monovalent group, for example, a linear or branched C 1-6 alkyl group, a C 3-6 cycloalkyl group, a linear or branched C 2-6 alkenyl group, a C 3-6 cyclo An alkenyl group, a linear or branched C 2-6 alkynyl group, a C 1-6 alkoxy group, a halogen atom, a hydroxyl group, a cyano group, an oxo group (═O), an amino group, a C 1-6 alkylamino group, a nitro group, Carboxy group (—COOH), carbamoyl group (—CONH 2 ), N-mono C 1-6 alkylcarbamoyl group, N, N-diC 1-6 alkylcarbamoyl group, C 1-6 alkanoyloxy group (—OCOR, R is C 1-6 alkyl group), C 6-10 aryl group, a heterocyclic group, C 6-10 aryloxy group, C 7-12 aralkyl groups, and, C 7-12 aralkyloxy group And the like. The above substituents may be further substituted with a halogen atom, a hydroxyl group, an amino group, a cyano group, an oxo group (═O), a linear or branched C 1-6 alkyl group, and the like. When the substituent is an amino group or a carboxy group, it may be in the form of a salt thereof.
　当該基が置換基を２つ以上有する場合には、２つの置換基が互いに結合して環状構造を形成してもよい。２つの置換基が互いに結合して環状構造を形成する場合としては、例えば、シクロプロピル基、シクロブチル基、メチレンジオキシ基が挙げられる。具体的には、ベンゼン環にメチレンジオキシ基が結合した場合、当該置換基は１，３－ベンゾジオキソール基となり、１，２－エチレン基の同じ炭素原子に２つのメチル基を有して、互いに結合した場合、当該基は下記式（Ｍ－１）または（Ｍ－２）で表される基となり、１，２－エチレン基の同じ炭素原子にメチル基とエチル基を有して、エチル基の２位とメチル基が結合した場合、当該基は下記式（Ｎ－１）または（Ｎ－２）で表される基となる。
Figure JPOXMLDOC01-appb-C000032
 When the group has two or more substituents, the two substituents may be bonded to each other to form a cyclic structure. Examples of the case where two substituents are bonded to each other to form a cyclic structure include a cyclopropyl group, a cyclobutyl group, and a methylenedioxy group. Specifically, when a methylenedioxy group is bonded to the benzene ring, the substituent is a 1,3-benzodioxole group, which has two methyl groups on the same carbon atom of the 1,2-ethylene group. When bonded to each other, the group becomes a group represented by the following formula (M-1) or (M-2), and has a methyl group and an ethyl group on the same carbon atom of the 1,2-ethylene group. When the 2-position of the ethyl group is bonded to the methyl group, the group is a group represented by the following formula (N-1) or (N-2).
Figure JPOXMLDOC01-appb-C000032
　本明細書記載の直鎖もしくは分岐Ｃ１－６アルキル基とは、炭素数１乃至６の直鎖もしくは分岐アルキル基を意味する。直鎖もしくは分岐Ｃ１－６アルキル基としては、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、ペンチル基、イソペンチル基、ネオペンチル基、ｔｅｒｔ－ペンチル基、１－エチルプロピル基、１－メチルブチル基、２－メチルブチル基、１，２－ジメチルプロピル基、ヘキシル基、１－メチルペンチル基、２－メチルペンチル基、３－メチルペンチル基、４－メチルペンチル基、１－エチルブチル基、２－エチルブチル基、１，１－ジメチルブチル基、２，２－ジメチルブチル基、３，３－ジメチルブチル基、１，２－ジメチルブチル基、１，３－ジメチルブチル基、または、２，３－ジメチルブチル基のようなＣ１－６アルキル基が挙げられる、上記置換基は、好ましくは、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基である。 The linear or branched C 1-6 alkyl group described in the present specification means a linear or branched alkyl group having 1 to 6 carbon atoms. Examples of linear or branched C 1-6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, and neopentyl. Group, tert-pentyl group, 1-ethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl Group, 4-methylpentyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, or include C 1-6 alkyl groups such as 2,3-dimethylbutyl group, the Substituent is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, butyl group, isobutyl group, sec- butyl group, a tert- butyl group.
　ハロゲン原子で置換されたＣ１－６アルキル基としては、例えば、クロロメチル基、ブロモメチル基、ヨードメチル基、ジフルオロメチル基、ジクロロメチル基、ジブロモメチル基、ジヨードメチル基、トリフルオロメチル基、トリクロロメチル基、１－フルオロエチル基、２－フルオロエチル基、２－クロロエチル基、２－ブロモエチル基、２，２－ジフルオロエチル基、２，２，２－トリフルオロエチル基、ペンタフルオロエチル基、２，２－ジクロロエチル基、２，２，２－トリクロロエチル基、１－フルオロプロピル基、２－フルオロプロピル基、３－フルオロプロピル基、３，３，３－トリフルオロプロピル基、パーフルオロプロピル基、１－フルオロメチルエチル基、１－ジフルオロメチルエチル基、１－トリフルオロメチルエチル基、１－フルオロ－１－メチルエチル基、４－フルオロブチル基、パーフルオロブチル基、５－フルオロペンチル基、パーフルオロペンチル基、６－フルオロヘキシル基、または、パーフルオロヘキシル基が挙げられる。 Examples of the C 1-6 alkyl group substituted with a halogen atom include a chloromethyl group, a bromomethyl group, an iodomethyl group, a difluoromethyl group, a dichloromethyl group, a dibromomethyl group, a diiodomethyl group, a trifluoromethyl group, and a trichloromethyl group. 1-fluoroethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 2,2 -Dichloroethyl group, 2,2,2-trichloroethyl group, 1-fluoropropyl group, 2-fluoropropyl group, 3-fluoropropyl group, 3,3,3-trifluoropropyl group, perfluoropropyl group, 1 -Fluoromethylethyl group, 1-difluoromethylethyl group, 1-trifluoromethyl group Examples include a til group, 1-fluoro-1-methylethyl group, 4-fluorobutyl group, perfluorobutyl group, 5-fluoropentyl group, perfluoropentyl group, 6-fluorohexyl group, or perfluorohexyl group. .
　アリール基で置換されたＣ１－６アルキル基は、例えばＣ７―１１アラルキル基であってもよい。Ｃ７―１１アラルキル基は、合計炭素数７～１１の、アリール基を有するアルキル基を意味し、例えば、ベンジル基、フェニルエチル基およびナフチルメチル基が挙げられる。 The C 1-6 alkyl group substituted with an aryl group may be, for example, a C 7-11 aralkyl group. The C 7-11 aralkyl group means an alkyl group having an aryl group having a total carbon number of 7 to 11, and examples thereof include a benzyl group, a phenylethyl group, and a naphthylmethyl group.
　本明細書記載のＣ３－６シクロアルキル基とは、炭素数３乃至６の環状アルキル基を意味する。Ｃ３－６シクロアルキル基としては、例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基等の単環；ビシクロ［３．１．０］ヘキシル基等の縮合環；スピロ［２．３］ヘキシル基等のスピロ環が挙げられる。上記置換基は、好ましくは、シクロプロピル基、シクロブチル基である。 The C 3-6 cycloalkyl group described in the present specification means a cyclic alkyl group having 3 to 6 carbon atoms. Examples of the C 3-6 cycloalkyl group include monocyclic rings such as cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group; condensed rings such as bicyclo [3.1.0] hexyl group; spiro [2.3] Spiro rings such as a hexyl group can be mentioned. The substituent is preferably a cyclopropyl group or a cyclobutyl group.
　本明細書記載の直鎖もしくは分岐Ｃ２－６アルケニル基とは、炭素数２乃至６の直鎖もしくは分岐アルケニル基を意味する。直鎖もしくは分岐Ｃ２－６アルケニル基としては、例えば、ビニル基、プロペン－１－イル基、プロペン－２－イル基、１－ブテニル基、２－ブテニル基、３－ブテニル基、１－メチル－１－プロペニル基、２－メチル－１－プロペニル基、１－ペンテニル基、２－ペンテニル基、３－ペンテニル基、４－ペンテニル基、５－ペンテニル基、１－メチル－１－ブテニル基、２－メチル－１－ブテニル基、３－メチル－１－ブテニル基、４－メチル－１－ブテニル基、１－メチル－２－ブテニル基、２－メチル－２－ブテニル基、３－メチル－２－ブテニル基、４－メチル－２－ブテニル基、１－メチル－３－ブテニル基、２－メチル－３－ブテニル基、３－メチル－３－ブテニル基、４－メチル－３－ブテニル基、１，２－ジメチル－１－プロペニル基、１－ヘキセニル基、２－ヘキセニル基、３－ヘキセニル基、４－ヘキセニル基、５－ヘキセニル基、６－ヘキセニル基およびこれらの構造異性体のようなアルケニル基が挙げられる。 The linear or branched C 2-6 alkenyl group described herein means a linear or branched alkenyl group having 2 to 6 carbon atoms. Examples of the linear or branched C 2-6 alkenyl group include a vinyl group, a propen-1-yl group, a propen-2-yl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, and 1-methyl. -1-propenyl group, 2-methyl-1-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 5-pentenyl group, 1-methyl-1-butenyl group, 2 -Methyl-1-butenyl group, 3-methyl-1-butenyl group, 4-methyl-1-butenyl group, 1-methyl-2-butenyl group, 2-methyl-2-butenyl group, 3-methyl-2- Butenyl group, 4-methyl-2-butenyl group, 1-methyl-3-butenyl group, 2-methyl-3-butenyl group, 3-methyl-3-butenyl group, 4-methyl-3-butenyl group, 1, 2-dimethyl-1-p Examples include an alkenyl group such as a lopenyl group, a 1-hexenyl group, a 2-hexenyl group, a 3-hexenyl group, a 4-hexenyl group, a 5-hexenyl group, a 6-hexenyl group, and structural isomers thereof.
　本明細書記載のＣ３－６シクロアルケニル基とは、炭素数３乃至６のシクロアルケニル基を意味する。Ｃ３－６シクロアルケニル基としては、例えば、シクロプロペニル基、シクロブテニル基、シクロペンテニル基およびシクロヘキセニル基が挙げられる。 The C 3-6 cycloalkenyl group described herein means a cycloalkenyl group having 3 to 6 carbon atoms. Examples of the C 3-6 cycloalkenyl group include a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, and a cyclohexenyl group.
　本明細書記載のＣ２－６アルキニル基とは、炭素数２乃至６のアルキニル基を意味する。Ｃ２－６アルキニル基としては、例えば、エチニル基、プロパルギル基、ブチニル基、ペンチニル基、ヘキシニル基が挙げられる。 The C 2-6 alkynyl group described herein means an alkynyl group having 2 to 6 carbon atoms. Examples of the C 2-6 alkynyl group include an ethynyl group, a propargyl group, a butynyl group, a pentynyl group, and a hexynyl group.
　本明細書記載のＣ１－６アルコキシ基とは、オキシ基（－Ｏ－）と、当該オキシ基に結合した直鎖もしくは分岐Ｃ１－６アルキル基、または、Ｃ３－６シクロアルキル基からなる基を意味する。Ｃ１－６アルコキシ基としては、例えば、メトキシ基、エトキシ基、プロピルオキシ基、イソプロピルオキシ基、シクロプロピルオキシ基、ブトキシ基、シクロブチルオキシ基、ペンチルオキシ基、シクロペンチルオキシ基、ヘキシルオキシ基、シクロヘキシルオキシ基が挙げられる。 The C 1-6 alkoxy group described herein includes an oxy group (—O—) and a linear or branched C 1-6 alkyl group bonded to the oxy group, or a C 3-6 cycloalkyl group. Means the group Examples of the C 1-6 alkoxy group include a methoxy group, ethoxy group, propyloxy group, isopropyloxy group, cyclopropyloxy group, butoxy group, cyclobutyloxy group, pentyloxy group, cyclopentyloxy group, hexyloxy group, A cyclohexyloxy group is mentioned.
　本明細書記載のＣ１－６アルキルアミノ基とは、１個もしくは独立して選択される２個の上記直鎖もしくは分岐Ｃ１－６アルキル基、または、Ｃ３－６シクロアルキル基で置換されたアミノ基を意味する。Ｃ１－６アルキルアミノ基としては、例えば、メチルアミノ基、エチルアミノ基、プロピルアミノ基、イソプロピルアミノ基、シクロプロピルアミノ基、ブトキシ基、シクロブチルアミノ基、ペンチルアミノ基、シクロペンチルアミノ基、ヘキシルアミノ基、シクロヘキシルアミノ基、ジメチルアミノ基、ジエチルアミノ基、エチルメチルアミノ基、イソプロピルメチルアミノ基、シクロプロピルメチルアミノ基が挙げられる。 The C 1-6 alkylamino group described herein is substituted with one or two independently selected linear or branched C 1-6 alkyl groups or C 3-6 cycloalkyl groups. Means an amino group formed. Examples of the C 1-6 alkylamino group include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a cyclopropylamino group, a butoxy group, a cyclobutylamino group, a pentylamino group, a cyclopentylamino group, and hexyl. Examples thereof include an amino group, a cyclohexylamino group, a dimethylamino group, a diethylamino group, an ethylmethylamino group, an isopropylmethylamino group, and a cyclopropylmethylamino group.
　本明細書記載のハロゲン原子とは、フッ素原子、塩素原子、臭素原子またはヨウ素原子を意味する。 The halogen atom described in this specification means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
　本明細書記載のＣ６－１０アリール基とは、炭素数６乃至１０のアリール基を意味する。Ｃ６－１０アリール基としては、例えば、フェニル基、ナフチル基等が挙げられる。 The C 6-10 aryl group described in the present specification means an aryl group having 6 to 10 carbon atoms. Examples of the C 6-10 aryl group include a phenyl group and a naphthyl group.
　本明細書記載の複素環基とは、窒素原子、酸素原子または硫黄原子を少なくとも１つ有する環状基を意味し、芳香族複素環基であってもよく、非芳香族複素環基であってもよい。芳香族複素環基としては、例えば、ピリジン基、ピリミジン基、ピリダジン基、ピラジン基、トリアジン基、ピロール基、イミダゾール基、ピラゾール基、インドール基、インダゾール基、フラン基、ベンゾフラン基、チオフェン基、ベンゾチオフェン基、チアゾール基、イソチアゾール基、オキサゾール基、イソキサゾール基およびオキサジアゾール基が挙げられる。非芳香族複素環基としては、例えば、ピロリジニル基、ピペリジニル基、ピペラジニル基、モルホリニル基およびチオモルホリニル基が挙げられる。 The heterocyclic group described in the present specification means a cyclic group having at least one nitrogen atom, oxygen atom or sulfur atom, which may be an aromatic heterocyclic group or a non-aromatic heterocyclic group. Also good. Examples of aromatic heterocyclic groups include pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyrrole, imidazole, pyrazole, indole, indazole, furan, benzofuran, thiophene, benzo Examples include thiophene group, thiazole group, isothiazole group, oxazole group, isoxazole group and oxadiazole group. Examples of the non-aromatic heterocyclic group include a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, and a thiomorpholinyl group.
　本明細書記載のＣ６－１０アリールオキシ基とは、オキシ基（－Ｏ－）と、当該オキシ基に結合した上記Ｃ６－１０アリール基からなる基を意味する。Ｃ６－１０アリールオキシ基としては、フェニルオキシ基、１－ナフチルオキシ基、２－ナフチルオキシ基等が挙げられる。 The C 6-10 aryloxy group described herein means a group consisting of an oxy group (—O—) and the above C 6-10 aryl group bonded to the oxy group. Examples of the C 6-10 aryloxy group include phenyloxy group, 1-naphthyloxy group, 2-naphthyloxy group and the like.
　本明細書記載のＣ７－１２アラルキル基とは、上記Ｃ６－１０アリール基に置換された上記Ｃ１－６アルキル基を意味する。Ｃ７－１２アラルキル基としては、ベンジル基、フェニルエチル基、ナフチルメチル基、ナフチルエチル基等が挙げられる。 The C 7-12 aralkyl group described in the present specification means the above C 1-6 alkyl group substituted by the above C 6-10 aryl group. Examples of the C 7-12 aralkyl group include a benzyl group, a phenylethyl group, a naphthylmethyl group, and a naphthylethyl group.
　本明細書記載のＣ７－１２アラルキルオキシ基とは、オキシ基（－Ｏ－）と、当該オキシ基に結合した上記Ｃ７－１２アラルキル基からなる基を意味する。Ｃ７－１２アラルキルオキシ基としては、ベンジルオキシ基、フェニルエチルオキシ基、ナフチルメチルオキシ基、ナフチルエチルオキシ基等が挙げられる。 The C 7-12 aralkyloxy group described herein means a group consisting of an oxy group (—O—) and the C 7-12 aralkyl group bonded to the oxy group. Examples of the C 7-12 aralkyloxy group include a benzyloxy group, a phenylethyloxy group, a naphthylmethyloxy group, and a naphthylethyloxy group.
　ＲとしてのＣ１－３アルキル基は、炭素数１乃至３のアルキル基であり、上記Ｃ１－６アルキル基のうち、炭素数１乃至３のものに相当する。Ｃ１－３アルキル基としては、メチル基、エチル基、プロピル基、イソプロピル基が挙げられる。 The C 1-3 alkyl group as R is an alkyl group having 1 to 3 carbon atoms, and corresponds to one having 1 to 3 carbon atoms among the above C 1-6 alkyl groups. Examples of the C 1-3 alkyl group include a methyl group, an ethyl group, a propyl group, and an isopropyl group.
　２つのＲが互いに結合してＣ２－５アルキレン基を形成している基とは、上記Ｃ１－６アルキル基のうち、炭素数２乃至５のものに相当するＣ２－５アルキル基から、さらに１つの水素原子を除いてなる２価の基を意味する。Ｃ２－５アルキレン基としては、１，２－エチレン基、１，２－プロピレン基、１，３－プロピレン基、１，２－ブチレン基、１，３－ブチレン基、１，４－ブチレン基、２，３－ブチレン基、１，２－ペンチレン基、１，３－ペンチレン基、１，４－ペンチレン基、１，５－ペンチレン基、２，３－ペンチレン基、２，４－ペンチレン基が挙げられる。 C 2 bind two R each other - 5 The groups form an alkylene group of the C 1-6 alkyl group, a C 2-5 alkyl group corresponds to that of 2 to 5 carbon atoms Further, it means a divalent group formed by removing one hydrogen atom. C 2-5 alkylene group includes 1,2-ethylene group, 1,2-propylene group, 1,3-propylene group, 1,2-butylene group, 1,3-butylene group, 1,4-butylene group 2,3-butylene group, 1,2-pentylene group, 1,3-pentylene group, 1,4-pentylene group, 1,5-pentylene group, 2,3-pentylene group, 2,4-pentylene group Can be mentioned.
　Ｌ３としての直鎖もしくは分岐Ｃ１－６アルキレン基とは、上記Ｃ１－６アルキル基からさらに１つの水素原子を除いてなる２価の基を意味する。Ｃ１－６アルキレン基としては、例えば、メチレン基、１，１－エチレン基、１，２－エチレン基、１，１－プロピレン基、１，２－プロピレン基、２，２－プロピレン基、１，３－プロピレン基が挙げられる。 The straight chain or branched C 1-6 alkylene group as L 3 means a divalent group obtained by removing one hydrogen atom from the C 1-6 alkyl group. Examples of the C 1-6 alkylene group include a methylene group, 1,1-ethylene group, 1,2-ethylene group, 1,1-propylene group, 1,2-propylene group, 2,2-propylene group, , 3-propylene group.
　Ｒ１、Ｒ２またはＲ３としての直鎖もしくは分岐Ｃ１－４アルキル基は、炭素数１乃至４の直鎖もしくは分岐アルキル基であり、上記Ｃ１－６アルキル基のうち、炭素数１乃至４のものに相当する。 Straight or branched C 1-4 alkyl group as R 1, R 2 or R 3 is a linear or branched alkyl group having 1 to 4 carbon atoms, among the above C 1-6 alkyl group, carbon number 1 It corresponds to the thing of thru | or 4.
　Ｒ４としての直鎖もしくは分岐Ｃ１－６アルキル基、Ｃ３－６シクロアルキル基、Ｃ６－１０アリール基、および、複素環基は、上記置換基と同様に定義される。 The linear or branched C 1-6 alkyl group, C 3-6 cycloalkyl group, C 6-10 aryl group and heterocyclic group as R 4 are defined in the same manner as the above substituents.
　Ｒ５としての、直鎖もしくは分岐Ｃ１－１６アルキル基とは、炭素数１乃至１６のアルキル基を意味する。直鎖もしくは分岐Ｃ１－１６アルキル基としては、例えば、メチル基、エチル基、プロピル基、ブチル基、イソブチル基、ペンチル基、イソペンチル基、ネオペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基、ウンデシル基、ドデシル基、トリデシル基、テトラデシル基、ペンタデシル基、ヘキサデシル基等のＣ１－１６アルキル基が挙げられる。 The linear or branched C 1-16 alkyl group as R 5 means an alkyl group having 1 to 16 carbon atoms. Examples of the linear or branched C 1-16 alkyl group include a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a pentyl group, an isopentyl group, a neopentyl group, a hexyl group, a heptyl group, an octyl group, and a nonyl group. C 1-16 alkyl groups such as decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group and the like.
　Ｒ５としてのＣ３－６シクロアルキル基、Ｃ６－１０アリール基、および、複素環基は、上記置換基と同様に定義される。 The C 3-6 cycloalkyl group, C 6-10 aryl group and heterocyclic group as R 5 are defined in the same manner as the above substituents.
　本実施形態に係る化合物は、一般式（ＩＩ）、一般式（ＩＩＩ）、または、一般式（ＩＶ）のいずれかの化学式で表される化合物であってもよい。 The compound according to this embodiment may be a compound represented by any one of the general formula (II), general formula (III), or general formula (IV).
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
　一般式（ＩＩ）、一般式（ＩＩＩ）、および、一般式（ＩＶ）において、Ｌ２、Ｌ３、Ｒ１、Ｒ２、Ｒ３、Ｒ４およびＲ５は、一般式（Ｉ）と同様に定義される。 In general formula (II), general formula (III), and general formula (IV), L 2 , L 3 , R 1 , R 2 , R 3 , R 4 and R 5 are the same as in general formula (I). Defined in
　一般式（Ｉ）乃至（ＩＶ）において、Ｌ２は、酸素原子、または－ＮＨ－で表される２価のアミノ基であってもよい。Ｌ３は、単結合、または置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基であってもよい。 In the general formula (I) to (IV), L 2 may be a divalent amino group represented by an oxygen atom or -NH-,. L 3 may be a single bond or an optionally substituted linear or branched C 1-6 alkylene group.
　一般式（Ｉ）乃至（ＩＶ）におけるＬ２およびＬ３として、好ましくは、Ｌ２およびＬ３が単結合であるか、またはＬ２が、－ＮＨ－で表される２価のアミノ基であり、Ｌ３が、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基である。 As L 2 and L 3 in the general formulas (I) to (IV), preferably, L 2 and L 3 are a single bond, or L 2 is a divalent amino group represented by —NH—. And L 3 is a linear or branched C 1-6 alkylene group which may be substituted.
　一般式（Ｉ）乃至（ＩＶ）において、Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ１－４アルキル基であってもよい。Ｒ４は、水素原子、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基または置換されていてもよい複素環基であってもよい。Ｒ５は、水素原子、置換されていてもよい直鎖もしくは分岐Ｃ１－１６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基であってもよい。 In the general formulas (I) to (IV), R 1 , R 2 and R 3 may each independently be a linear or branched C 1-4 alkyl group which may be substituted. R 4 represents a hydrogen atom, an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-10 aryl group Alternatively, it may be an optionally substituted heterocyclic group. R 5 represents a hydrogen atom, an optionally substituted linear or branched C 1-16 alkyl group, an optionally substituted C 3-6 cycloalkyl group, or an optionally substituted C 6-10 aryl group. Or a heterocyclic group which may be substituted.
　一般式（Ｉ）乃至（ＩＶ）において、好ましくは、Ｌ２は、単結合、または－ＮＨ－で表される２価のアミノ基であり、Ｌ３は、単結合、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基であり、Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ１－４アルキル基であり、Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ６－１０アリール基または置換されていてもよい複素環基であり、Ｒ５は、水素原子、置換されていてもよい直鎖もしくは分岐Ｃ１－１６アルキル基、または置換されていてもよいＣ３－６シクロアルキル基である。 In the general formulas (I) to (IV), preferably, L 2 is a single bond or a divalent amino group represented by —NH—, and L 3 may be a single bond or substituted. A linear or branched C 1-6 alkylene group, R 1 , R 2 and R 3 are each independently an optionally substituted linear or branched C 1-4 alkyl group, and R 4 is An optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 6-10 aryl group or an optionally substituted heterocyclic group, R 5 is a hydrogen atom, substituted A linear or branched C 1-16 alkyl group which may be substituted, or a C 3-6 cycloalkyl group which may be substituted.
　一般式（Ｉ）乃至（ＩＶ）において、別の態様として好ましくは、Ｌ２およびＬ３は、単結合であり、Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ１－４アルキル基であり、Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ６－１０アリール基または置換されていてもよい複素環基であり、Ｒ５は、水素原子、置換されていてもよい直鎖もしくは分岐Ｃ１－１６アルキル基、または置換されていてもよいＣ３－６シクロアルキル基である。 In the general formulas (I) to (IV), as another aspect, preferably L 2 and L 3 are a single bond, and R 1 , R 2 and R 3 may each independently be substituted. A linear or branched C 1-4 alkyl group, and R 4 is an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 6-10 aryl group, or a substituted And R 5 is a hydrogen atom, an optionally substituted linear or branched C 1-16 alkyl group, or an optionally substituted C 3-6 cycloalkyl group.
　一般式（Ｉ）乃至（ＩＶ）において、更に別の態様として好ましくは、Ｌ２は、－ＮＨ－で表される２価のアミノ基であり、Ｌ３は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基であり、Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ１－４アルキル基であり、Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ６－１０アリール基または置換されていてもよい複素環基であり、Ｒ５は、水素原子、置換されていてもよい直鎖もしくは分岐Ｃ１－１６アルキル基、または置換されていてもよいＣ３－６シクロアルキル基である。 In the general formulas (I) to (IV), preferably, as another embodiment, L 2 is a divalent amino group represented by —NH—, and L 3 is a linear chain which may be substituted. Or a branched C 1-6 alkylene group, R 1 , R 2 and R 3 are each independently a linear or branched C 1-4 alkyl group which may be substituted, and R 4 is a substituted A linear or branched C 1-6 alkyl group which may be substituted, a C 6-10 aryl group which may be substituted or a heterocyclic group which may be substituted; R 5 is a hydrogen atom, substituted It may be a linear or branched C 1-16 alkyl group, or an optionally substituted C 3-6 cycloalkyl group.
　一般式（Ｉ）乃至（ＩＶ）において、より好ましくは、Ｌ２は、単結合、または－ＮＨ－で表される２価のアミノ基であり、Ｌ３は、単結合、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基であり、Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、直鎖もしくは分岐Ｃ１－４アルキル基であり、Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ６－１０アリール基または置換されていてもよい複素環基であり、Ｒ５は、水素原子、直鎖もしくは分岐Ｃ１－１６アルキル基、ハロゲン原子、オキソ基、または、直鎖もしくは分岐Ｃ１－６アルキル基で置換された直鎖もしくは分岐Ｃ１－１６アルキル基、または、ハロゲン原子で置換されていてもよいＣ３－６シクロアルキル基である。 In the general formulas (I) to (IV), more preferably, L 2 is a single bond or a divalent amino group represented by —NH—, and L 3 may be a single bond or a substituted group. Good linear or branched C 1-6 alkylene group, R 1 , R 2 and R 3 are each independently a linear or branched C 1-4 alkyl group, and R 4 may be substituted A good linear or branched C 1-6 alkyl group, an optionally substituted C 6-10 aryl group or an optionally substituted heterocyclic group, and R 5 is a hydrogen atom, linear or branched C 1 A -16 alkyl group, a halogen atom, an oxo group, or a linear or branched C 1-16 alkyl group substituted with a linear or branched C 1-6 alkyl group, or C optionally substituted with a halogen atom 3-6 cycloalkyl It is a group.
　一般式（Ｉ）乃至（ＩＶ）において、別の態様としてより好ましくは、Ｌ２およびＬ３は、単結合であり、Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、直鎖もしくは分岐Ｃ１－４アルキル基であり、Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ６－１０アリール基または置換されていてもよい複素環基であり、Ｒ５は、水素原子、直鎖もしくは分岐Ｃ１－１６アルキル基、ハロゲン原子、オキソ基、または、直鎖もしくは分岐Ｃ１－６アルキル基で置換された直鎖もしくは分岐Ｃ１－１６アルキル基、または、ハロゲン原子で置換されていてもよいＣ３－６シクロアルキル基である。 In the general formulas (I) to (IV), as another embodiment, L 2 and L 3 are preferably a single bond, and R 1 , R 2 and R 3 are each independently a straight-chain or branched C 1-4 alkyl group, and R 4 is an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 6-10 aryl group, or an optionally substituted heterocyclic ring R 5 represents a linear or branched C 1 substituted with a hydrogen atom, a linear or branched C 1-16 alkyl group, a halogen atom, an oxo group, or a linear or branched C 1-6 alkyl group. A -16 alkyl group or a C 3-6 cycloalkyl group optionally substituted with a halogen atom;
　一般式（Ｉ）乃至（ＩＶ）において、更に別の態様としてより好ましくは、Ｌ２は、－ＮＨ－で表される２価のアミノ基であり、Ｌ３は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基であり、Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、直鎖もしくは分岐Ｃ１－４アルキル基であり、Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ６－１０アリール基または置換されていてもよい複素環基であり、Ｒ５は、水素原子、直鎖もしくは分岐Ｃ１－１６アルキル基、ハロゲン原子、オキソ基、または、直鎖もしくは分岐Ｃ１－６アルキル基で置換された直鎖もしくは分岐Ｃ１－１６アルキル基、または、ハロゲン原子で置換されていてもよいＣ３－６シクロアルキル基である。 In the general formulas (I) to (IV), more preferably as another embodiment, L 2 is a divalent amino group represented by —NH—, and L 3 is an optionally substituted amino group. A chain or branched C 1-6 alkylene group, R 1 , R 2 and R 3 are each independently a straight chain or branched C 1-4 alkyl group, and R 4 is an optionally substituted A chain or branched C 1-6 alkyl group, an optionally substituted C 6-10 aryl group or an optionally substituted heterocyclic group, and R 5 is a hydrogen atom, linear or branched C 1-16 An alkyl group, a halogen atom, an oxo group, or a linear or branched C 1-16 alkyl group substituted with a linear or branched C 1-6 alkyl group, or a C 3- optionally substituted with a halogen atom With 6 cycloalkyl groups is there.
　一般式（Ｉ）乃至（ＩＶ）において、特に好ましくは、Ｌ２は、単結合、または、－ＮＨ－で表される２価のアミノ基であり、Ｌ３は、単結合、または、下記式（Ｏ－１）、（Ｏ－２）、（Ｍ－２）もしくは（Ｎ－１）で表される基であり、Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、直鎖もしくは分岐Ｃ１－４アルキル基であり、Ｒ４は、置換されていてもよいフェニル基、または、チエニル基であり、Ｒ５は、水素原子、直鎖もしくは分岐Ｃ１－１６アルキル基、ハロゲン原子で置換された直鎖もしくは分岐Ｃ１－１６アルキル基、または、Ｃ３－６シクロアルキル基である。なお、本明細書中、式（Ｏ－１）で表される化学構造を「Ｃ（Ｍｅ）２ＣＨ２」ともいい、式（Ｏ－２）で表される化学構造を「ＣＨ２Ｃ（Ｍｅ）２」ともいい、式（Ｍ－２）で表される化学構造を「ＣＨ２－１，１－シクロプロピレン」ともいい、式（Ｎ－１）で表される化学構造を「１，１－シクロブチレン－ＣＨ２」ともいう。 In the general formula (I) to (IV), particularly preferably, L 2 represents a single bond or a divalent group represented by -NH-, L 3 represents a single bond, or the following formula A group represented by (O-1), (O-2), (M-2) or (N-1), wherein R 1 , R 2 and R 3 are each independently a linear or branched C 1-4 alkyl group, R 4 is an optionally substituted phenyl group or thienyl group, R 5 is a hydrogen atom, a linear or branched C 1-16 alkyl group, substituted with a halogen atom Straight chain or branched C 1-16 alkyl group or C 3-6 cycloalkyl group. In this specification, the chemical structure represented by the formula (O-1) is also referred to as “C (Me) 2 CH 2 ”, and the chemical structure represented by the formula (O-2) is represented by “CH 2 C ( Me) 2 ”, the chemical structure represented by the formula (M-2) is also referred to as“ CH 2 -1,1-cyclopropylene ”, and the chemical structure represented by the formula (N-1) is“ 1, ” Also referred to as “1-cyclobutylene-CH 2 ”.
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
　一般式（Ｉ）乃至（ＩＶ）において、別の態様として特に好ましくは、Ｌ２は、－ＮＨ－で表される２価のアミノ基であり、Ｌ３は、上記式（Ｏ－１）、（Ｏ－２）、（Ｍ－２）もしくは（Ｎ－１）で表される基であり、Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、直鎖もしくは分岐Ｃ１－４アルキル基であり、Ｒ４は、置換されていてもよいフェニル基、または、チエニル基であり、Ｒ５は、水素原子、直鎖もしくは分岐Ｃ１－１６アルキル基、ハロゲン原子で置換された直鎖もしくは分岐Ｃ１－１６アルキル基、または、Ｃ３－６シクロアルキル基である。 In the general formulas (I) to (IV), as another embodiment, L 2 is particularly preferably a divalent amino group represented by —NH—, and L 3 represents the above formula (O-1), A group represented by (O-2), (M-2) or (N-1), wherein R 1 , R 2 and R 3 are each independently a linear or branched C 1-4 alkyl group; R 4 is an optionally substituted phenyl group or thienyl group, and R 5 is a hydrogen atom, a linear or branched C 1-16 alkyl group, a linear or branched group substituted with a halogen atom A C 1-16 alkyl group or a C 3-6 cycloalkyl group;
　本実施形態に係る化合物（Ｉ）またはその薬理上許容される塩の中でも、一般式（Ｖ）で表されるように、Ｒ５がオキソ基で置換されており、該オキソ基とＲ５が結合する酸素原子とがエステル結合を形成する化合物、または、一般式（ＶＩ）で表されるように、Ｒ５が酸素原子を含む置換基によって置換されたアルキレン基で、該酸素原子とＲ５が結合する酸素原子とを含むアセタール基が形成されている化合物は、プロドラッグとして作用する化合物であり得る。化合物（Ｖ）または化合物（ＶＩ）は、経口吸収性および皮膚透過性により優れる傾向があり、かつ、代謝により化合物（Ｉ）（ただし、Ｒ５が水素原子である）を生じ得る。 Among the compounds (I) or pharmacologically acceptable salts thereof according to this embodiment, as represented by the general formula (V), R 5 is substituted with an oxo group, and the oxo group and R 5 are A compound in which an oxygen atom to be bonded forms an ester bond or an alkylene group in which R 5 is substituted with a substituent containing an oxygen atom as represented by the general formula (VI), and the oxygen atom and R 5 A compound in which an acetal group containing an oxygen atom to which is bonded can be a compound that acts as a prodrug. Compound (V) or Compound (VI) tends to be superior in oral absorption and skin permeability, and can yield Compound (I) (wherein R 5 is a hydrogen atom) by metabolism.
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
　一般式（Ｖ）および一般式（ＶＩ）において、Ｒ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｌ２およびＬ３は、一般式（Ｉ）と同様に定義される。Ｒ６は、水素原子、置換されていてもよい直鎖もしくは分岐Ｃ１－１５アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ１－６アルコキシ基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示し、Ｒ８およびＲ９は、それぞれ独立に、水素原子またはＣ１－４アルキル基を示す。Ｒ７は、置換基を有してもよい直鎖もしくは分岐Ｃ１－１５アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示す。Ｒ６またはＲ７としての直鎖もしくは分岐Ｃ１－１５アルキル基、Ｃ３－６シクロアルキル基、Ｃ６－１０アリール基、および、複素環基、ならびにこれらを置換する置換基は、一般式（Ｉ）乃至（ＩＶ）中の基と同様に定義される。 In the general formula (V) and the general formula (VI), R, R 1 , R 2 , R 3 , R 4 , L 2 and L 3 are defined in the same manner as in the general formula (I). R 6 represents a hydrogen atom, an optionally substituted linear or branched C 1-15 alkyl group, an optionally substituted C 3-6 cycloalkyl group, or an optionally substituted C 1-6 alkoxy group. Represents an optionally substituted C 6-10 aryl group or an optionally substituted heterocyclic group, and R 8 and R 9 each independently represents a hydrogen atom or a C 1-4 alkyl group. . R 7 is a linear or branched C 1-15 alkyl group which may have a substituent, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-10 aryl group, Or the heterocyclic group which may be substituted is shown. The linear or branched C 1-15 alkyl group, the C 3-6 cycloalkyl group, the C 6-10 aryl group, and the heterocyclic group as R 6 or R 7 , and the substituents that replace them are represented by the general formula Defined similarly to the groups in (I) to (IV).
　Ｒ６は、置換されていてもよい直鎖もしくは分岐Ｃ１－１５アルキル基、または、置換されていてもよいＣ６－１０アリール基であってもよい。Ｒ７は、置換されていてもよい直鎖もしくは分岐Ｃ１－１６アルキル基であってもよい。 R 6 may be a linear or branched C 1-15 alkyl group which may be substituted, or a C 6-10 aryl group which may be substituted. R 7 may be an optionally substituted straight chain or branched C 1-16 alkyl group.
　一般式（Ｖ）および一般式（ＶＩ）におけるＬ２およびＬ３として、好ましくは、Ｌ２が、－ＮＨ－で表される２価のアミノ基であり、Ｌ３が、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基である。 As L 2 and L 3 in the general formula (V) and the general formula (VI), preferably L 2 is a divalent amino group represented by —NH—, and L 3 may be substituted. Good linear or branched C 1-6 alkylene group.
　一般式（Ｖ）において、好ましくは、２つのＲは、互いに結合して１，２－エチレン基または１，３－プロピレン基を形成している基であり、Ｌ２は、単結合、または、－ＮＨ－で表される２価のアミノ基であり、Ｌ３は、単結合、または、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基であり、Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ１－４アルキル基であり、Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基であり、Ｒ６は、置換されていてもよい直鎖もしくは分岐Ｃ１－１５アルキル基である。 In the general formula (V), preferably, two Rs are groups bonded to each other to form a 1,2-ethylene group or a 1,3-propylene group, and L 2 is a single bond, or A divalent amino group represented by —NH—, L 3 is a single bond or a linear or branched C 1-6 alkylene group which may be substituted, and R 1 , R 2 and R 3 is each independently a linear or branched C 1-4 alkyl group which may be substituted; R 4 is a linear or branched C 1-6 alkyl group which may be substituted; An optionally substituted C 6-10 aryl group or an optionally substituted heterocyclic group, and R 6 is an optionally substituted linear or branched C 1-15 alkyl group.
　一般式（Ｖ）において、別の態様として好ましくは、２つのＲは、互いに結合して１，２－エチレン基または１，３－プロピレン基を形成している基であり、Ｌ２は、－ＮＨ－で表される２価のアミノ基であり、Ｌ３は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基であり、Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ１－４アルキル基であり、Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基であり、Ｒ６は、置換されていてもよい直鎖もしくは分岐Ｃ１－１５アルキル基である。 In the general formula (V), preferably, as another embodiment, two Rs are a group bonded to each other to form a 1,2-ethylene group or a 1,3-propylene group, and L 2 is a group represented by — A divalent amino group represented by NH—, L 3 is an optionally substituted linear or branched C 1-6 alkylene group, and R 1 , R 2 and R 3 are each independently , An optionally substituted linear or branched C 1-4 alkyl group, and R 4 is an optionally substituted linear or branched C 1-6 alkyl group, optionally substituted C 6- A 10 aryl group or an optionally substituted heterocyclic group, and R 6 is an optionally substituted linear or branched C 1-15 alkyl group.
　一般式（Ｖ）において、好ましくは、２つのＲは、互いに結合して１，３－プロピレン基を形成している基であり、Ｌ２は、単結合、または、－ＮＨ－で表される２価のアミノ基であり、Ｌ３は、単結合、または、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基であり、Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ１－４アルキル基であり、Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基であり、Ｒ６は、置換されていてもよい直鎖もしくは分岐Ｃ１－１５アルキル基である。 In the general formula (V), preferably, two Rs are groups bonded to each other to form a 1,3-propylene group, and L 2 is represented by a single bond or —NH—. A divalent amino group, L 3 is a single bond or an optionally substituted linear or branched C 1-6 alkylene group, and R 1 , R 2 and R 3 are each independently R 4 is an optionally substituted linear or branched C 1-4 alkyl group, R 4 is an optionally substituted linear or branched C 1-6 alkyl group, optionally substituted C 6-10. An aryl group or an optionally substituted heterocyclic group, and R 6 is an optionally substituted linear or branched C 1-15 alkyl group.
　一般式（Ｖ）において、別の態様として好ましくは、２つのＲは、互いに結合して１，３－プロピレン基を形成している基であり、Ｌ２は、－ＮＨ－で表される２価のアミノ基であり、Ｌ３は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基であり、Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ１－４アルキル基であり、Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基であり、Ｒ６は、置換されていてもよい直鎖もしくは分岐Ｃ１－１５アルキル基である。 In the general formula (V), preferably, as another embodiment, two Rs are groups that are bonded to each other to form a 1,3-propylene group, and L 2 is a group represented by —NH—. A monovalent amino group, L 3 is a linear or branched C 1-6 alkylene group which may be substituted, and R 1 , R 2 and R 3 may each independently be substituted. A linear or branched C 1-4 alkyl group, and R 4 is an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 6-10 aryl group, or a substituted group. An optionally substituted heterocyclic group, and R 6 is an optionally substituted linear or branched C 1-15 alkyl group.
　一般式（ＶＩ）において、好ましくは、２つのＲは、互いに結合して１，２－エチレン基または１，３－プロピレン基を形成している基であり、Ｌ２は、単結合、または、－ＮＨ－で表される２価のアミノ基であり、Ｌ３は、単結合、または、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基であり、Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ１－４アルキル基であり、Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基であり、Ｒ８およびＲ９は、それぞれ独立に、水素原子またはＣ１－４アルキル基であり、Ｒ７は、置換基を有してもよい直鎖もしくは分岐Ｃ１－１５アルキル基、または、置換されていてもよいＣ３－６シクロアルキル基である。 In the general formula (VI), preferably, two Rs are groups that are bonded to each other to form a 1,2-ethylene group or a 1,3-propylene group, and L 2 is a single bond, or A divalent amino group represented by —NH—, L 3 is a single bond or a linear or branched C 1-6 alkylene group which may be substituted, and R 1 , R 2 and R 3 is each independently a linear or branched C 1-4 alkyl group which may be substituted; R 4 is a linear or branched C 1-6 alkyl group which may be substituted; An optionally substituted C 6-10 aryl group or an optionally substituted heterocyclic group, R 8 and R 9 are each independently a hydrogen atom or a C 1-4 alkyl group, and R 7 is A linear or branched C 1 which may have a substituent A -15 alkyl group or an optionally substituted C 3-6 cycloalkyl group;
　一般式（ＶＩ）において、別の態様として好ましくは、２つのＲは、互いに結合して１，２－エチレン基または１，３－プロピレン基を形成している基であり、Ｌ２は、－ＮＨ－で表される２価のアミノ基であり、Ｌ３は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基であり、Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ１－４アルキル基であり、Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基であり、Ｒ８およびＲ９は、それぞれ独立に、水素原子またはＣ１－４アルキル基であり、Ｒ７は、置換基を有してもよい直鎖もしくは分岐Ｃ１－１５アルキル基、または、置換されていてもよいＣ３－６シクロアルキル基である。 In the general formula (VI), preferably, as another embodiment, two Rs are groups bonded to each other to form a 1,2-ethylene group or a 1,3-propylene group, and L 2 is a group of a divalent group represented by NH-, L 3 is an optionally substituted straight or branched C 1-6 alkylene group, R 1, R 2 and R 3 are each independently , An optionally substituted linear or branched C 1-4 alkyl group, and R 4 is an optionally substituted linear or branched C 1-6 alkyl group, optionally substituted C 6- 10 aryl group or an optionally substituted heterocyclic group, R 8 and R 9 are each independently a hydrogen atom or a C 1-4 alkyl group, and R 7 has a substituent. A linear or branched C 1-15 alkyl group, Alternatively, it is an optionally substituted C 3-6 cycloalkyl group.
　一般式（ＶＩ）において、好ましくは、２つのＲは、互いに結合して１，３－プロピレン基を形成している基であり、Ｌ２は、単結合、または、－ＮＨ－で表される２価のアミノ基であり、Ｌ３は、単結合、または、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基であり、Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ１－４アルキル基であり、Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基であり、Ｒ８およびＲ９は、それぞれ独立に、水素原子またはＣ１－４アルキル基であり、Ｒ７は、置換基を有してもよい直鎖もしくは分岐Ｃ１－１５アルキル基、または、置換されていてもよいＣ３－６シクロアルキル基である。 In the general formula (VI), preferably, two Rs are a group bonded to each other to form a 1,3-propylene group, and L 2 is represented by a single bond or —NH—. A divalent amino group, L 3 is a single bond or an optionally substituted linear or branched C 1-6 alkylene group, and R 1 , R 2 and R 3 are each independently R 4 is an optionally substituted linear or branched C 1-4 alkyl group, R 4 is an optionally substituted linear or branched C 1-6 alkyl group, optionally substituted C 6-10. An aryl group or an optionally substituted heterocyclic group, R 8 and R 9 are each independently a hydrogen atom or a C 1-4 alkyl group, and R 7 has a substituent. A linear or branched C 1-15 alkyl group, or , An optionally substituted C 3-6 cycloalkyl group.
　一般式（ＶＩ）において、別の態様として好ましくは、２つのＲは、互いに結合して１，３－プロピレン基を形成している基であり、Ｌ２は、－ＮＨ－で表される２価のアミノ基であり、Ｌ３は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基であり、Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ１－４アルキル基であり、Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基であり、Ｒ８およびＲ９は、それぞれ独立に、水素原子またはＣ１－４アルキル基であり、Ｒ７は、置換基を有してもよい直鎖もしくは分岐Ｃ１－１５アルキル基、または、置換されていてもよいＣ３－６シクロアルキル基である。 In the general formula (VI), preferably, as another embodiment, two Rs are groups that are bonded to each other to form a 1,3-propylene group, and L 2 is 2 represented by —NH—. A monovalent amino group, L 3 is a linear or branched C 1-6 alkylene group which may be substituted, and R 1 , R 2 and R 3 may each independently be substituted. A linear or branched C 1-4 alkyl group, and R 4 is an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 6-10 aryl group, or a substituted group. R 8 and R 9 are each independently a hydrogen atom or a C 1-4 alkyl group, and R 7 is a linear or branched group optionally having a substituent. C 1-15 alkyl group or substituted A good C 3-6 cycloalkyl group.
　本実施形態に係る化合物またはその薬理上許容される塩としては、具体的には、以下に示す化合物群から選択される化合物またはその薬理上許容される塩である。
（Ｓ）－Ｎ－（２－ヒドロキシ－１－フェニルエチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－（２－ヒドロキシ－１－フェニルエチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－（２－ヒドロキシ－１－フェニルエチル）－６，６－ジメチル－３－［２－メチル－２－（トリメチルシリル）プロパンアミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－３－［１－（エチルジメチルシリル）シクロブタンカルボキサミド］－Ｎ－（２－ヒドロキシ－１－フェニルエチル）－６，６－ジメチル－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－３－［２－（エチルジメチルシリル）－２－メチルプロパンアミド］－Ｎ－（２－ヒドロキシ－１－フェニルエチル）－６，６－ジメチル－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－２－［（２－メトキシプロパン－２－イル）オキシ］－１－フェニルエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキシラート、
（Ｓ）－２－ヒドロキシ－１－フェニルエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキシラート、
２－メトキシ－１－フェニルエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキシラート、
（Ｒ）－Ｎ－（３－ヒドロキシ－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－（３－ヒドロキシ－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－（４－ヒドロキシ－１－フェニルブチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－（５－ヒドロキシ－１－フェニルペンチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－（２－ヒドロキシ－２－メチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－（２－ヒドロキシ－２－メチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
Ｎ－（３－ヒドロキシ－２，２－ジメチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－（３－ヒドロキシ－３－メチル－１－フェニルブチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－（２－メトキシ－１－フェニルエチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－［２－（ジフルオロメトキシ）－１－フェニルエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－（２－エトキシ－１－フェニルエチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－（３－メトキシ－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４．５．６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニル酢酸ナトリウム、
Ｎ－［１－（２－フルオロフェニル）－２－ヒドロキシエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－［１－（３－フルオロフェニル）－２－ヒドロキシエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－［１－（４－フルオロフェニル）－２－ヒドロキシエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
Ｎ－［２－ヒドロキシ－１－（ピリジン－２－イル）エチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
Ｎ－［２－ヒドロキシ－１－（ピリジン－３－イル）エチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－（１－シクロヘキシル－２－ヒドロキシエチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－（１－ヒドロキシ－３－メチルブタン－２－イル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－（１－ヒドロキシプロパン－２－イル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　アセタート、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　プロピオナート、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　ブタノアート、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　ペンタノアート、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　オクタノアート、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　ドデカノアート、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　パルミタート、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　イソブタノアート、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　ピバラート、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　３－メチルブタノアート、
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　ベンゾアート、
（Ｓ）－４－（２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエトキシ）－４－オキソブタン酸ナトリウム、
（Ｓ）－（２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエトキシ）メチル　ピバラート、
（Ｓ）－２－アセトキシ－１－フェニルエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキシラート、
（Ｓ）－ベンジル　２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルアセタート、
（Ｓ）－メチル　２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルアセタート、
Ｎ－（２，２－ジフルオロ－３－ヒドロキシ－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－［１－（２－クロロフェニル）－２－ヒドロキシエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－［２－ヒドロキシ－１－（ｏ－トリル）エチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｓ）－Ｎ－（１－ヒドロキシ－３－フェニルプロパン－２－イル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
Ｎ－［５－（３－ヒドロキシ－２－フェニルプロパノイル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
（Ｓ）－Ｎ－［５－（３－ヒドロキシ－２－フェニルプロパノイル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
（Ｒ）－Ｎ－［５－（２－メトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
（Ｓ）－Ｎ－［５－（２－メトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
Ｎ－［５－（３－メトキシ－２－フェニルプロパノイル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
Ｎ－［５－（４－メトキシ－２－フェニルブタノイル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
（Ｓ）－Ｎ－［５－（３－ヒドロキシ－２－フェニルプロパノイル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロプロパンカルボキサミド、
（Ｒ）－Ｎ－［５－（２－メトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロプロパンカルボキサミド、
（Ｒ）－Ｎ－｛５－［２－（ジフルオロメトキシ）－２－フェニルアセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
（Ｒ）－Ｎ－［５－（２－エトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
（Ｒ）－１－（エチルジメチルシリル）－Ｎ－［５－（２－メトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］シクロブタンカルボキサミド、
（Ｒ）－Ｎ－［５－（２－シクロプロポキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
（Ｒ）－Ｎ－［５－（２－イソプロポキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
（Ｒ）－Ｎ－｛６，６－ジメチル－５－［２－フェニル－２－（トリフルオロメトキシ）アセチル］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
（Ｒ）－Ｎ－［６，６－ジメチル－５－（２－フェニル－２－プロポキシアセチル）－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
Ｎ－｛５－［２－（４－フルオロフェニル）－２－メトキシアセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
Ｎ－｛５－［２－（３－フルオロフェニル）－２－メトキシアセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
（Ｒ）－Ｎ－｛５－［２－（２－フルオロフェニル）－２－メトキシアセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
Ｎ－｛５－［２－メトキシ－２－（チオフェン－２－イル）アセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
（－）－Ｎ－｛５－［２－メトキシ－２－（チオフェン－２－イル）アセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
（＋）－Ｎ－｛５－［２－メトキシ－２－（チオフェン－２－イル）アセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
Ｎ－｛［１－（ヒドロキシメチル）シクロブチル］（フェニル）メチル｝－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－［２－（１－ヒドロキシシクロプロピル）－１－フェニルエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－（３－エチル－３－ヒドロキシ－１－フェニルペンチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－［１－（４－フルオロフェニル）－３－ヒドロキシ－３－メチルブチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－［１－（３－フルオロフェニル）－３－ヒドロキシ－３－メチルブチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－［１－（２－フルオロフェニル）－３－ヒドロキシ－３－メチルブチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－（５－ヒドロキシ－２，５－ジメチルヘキサン－３－イル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
Ｎ－［１－（４－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
Ｎ－［１－（３－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（－）－Ｎ－［１－（３－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（＋）－Ｎ－［１－（３－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
Ｎ－［１－（２－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
Ｎ－（１－ヒドロキシ－２，２，４－トリメチルペンタン－３－イル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－（３－ヒドロキシ－３－メチル－１－フェニルブチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
Ｎ－（３－ヒドロキシ－２，２－ジメチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（－）－Ｎ－（３－ヒドロキシ－２，２－ジメチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（＋）－Ｎ－（３－ヒドロキシ－２，２－ジメチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
（Ｒ）－Ｎ－［５－（２－ブトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、および
Ｎ－（３－メトキシ－２，２－ジメチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド Specifically, the compound according to the present embodiment or a pharmacologically acceptable salt thereof is a compound selected from the following compound group or a pharmacologically acceptable salt thereof.
(S) -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(S) -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide,
(S) -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-3- [2-methyl-2- (trimethylsilyl) propanamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
(S) -3- [1- (Ethyldimethylsilyl) cyclobutanecarboxamide] -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
(S) -3- [2- (Ethyldimethylsilyl) -2-methylpropanamide] -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-4,6-dihydropyrrolo [3 4-c] pyrazole-5 (1H) -carboxamide,
(S) -2-[(2-Methoxypropan-2-yl) oxy] -1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxylate,
(S) -2-Hydroxy-1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H)- Carboxylate,
2-methoxy-1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxylate,
(R) -N- (3-hydroxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(R) -N- (3-hydroxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide,
(R) -N- (4-hydroxy-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(R) -N- (5-hydroxy-1-phenylpentyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(S) -N- (2-hydroxy-2-methyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
(S) -N- (2-hydroxy-2-methyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide,
N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
(R) -N- (3-hydroxy-3-methyl-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
(S) -N- (2-methoxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(S) -N- [2- (Difluoromethoxy) -1-phenylethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c Pyrazole-5 (1H) -carboxamide,
(S) —N- (2-Ethoxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(R) -N- (3-methoxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4.5.6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Sodium phenylacetate,
N- [1- (2-Fluorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide,
(S) -N- [1- (3-Fluorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide,
(S) -N- [1- (4-Fluorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide,
N- [2-hydroxy-1- (pyridin-2-yl) ethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
N- [2-hydroxy-1- (pyridin-3-yl) ethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
(S) -N- (1-cyclohexyl-2-hydroxyethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(S) -N- (1-Hydroxy-3-methylbutan-2-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c Pyrazole-5 (1H) -carboxamide,
(S) -N- (1-hydroxypropan-2-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl acetate,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl propionate,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl butanoate,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl pentanoate,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl octanoate,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl dodecanoate,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl palmitate,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl isobutanoate,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl pivalate,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl 3-methylbutanoate,
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl benzoate,
(S) -4- (2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide } -2-Phenylethoxy) -4-oxobutanoic acid sodium,
(S)-(2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide}- 2-phenylethoxy) methyl pivalate,
(S) -2-Acetoxy-1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H)- Carboxylate,
(S) -Benzyl 2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide}- 2-phenyl acetate,
(S) -Methyl 2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide}- 2-phenyl acetate,
N- (2,2-difluoro-3-hydroxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
(S) —N- [1- (2-chlorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
(S) -N- [2-hydroxy-1- (o-tolyl) ethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
(S) -N- (1-hydroxy-3-phenylpropan-2-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
N- [5- (3-Hydroxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- ( Trimethylsilyl) cyclobutanecarboxamide,
(S) -N- [5- (3-Hydroxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide,
(S) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide,
N- [5- (3-Methoxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- ( Trimethylsilyl) cyclobutanecarboxamide,
N- [5- (4-Methoxy-2-phenylbutanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- ( Trimethylsilyl) cyclobutanecarboxamide,
(S) -N- [5- (3-Hydroxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclopropanecarboxamide,
(R) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclopropanecarboxamide,
(R) -N- {5- [2- (Difluoromethoxy) -2-phenylacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3- Yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- [5- (2-Ethoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -1- (Ethyldimethylsilyl) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c ] Pyrazol-3-yl] cyclobutanecarboxamide,
(R) -N- [5- (2-Cyclopropoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- [5- (2-Isopropoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- {6,6-dimethyl-5- [2-phenyl-2- (trifluoromethoxy) acetyl] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3 -Yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- [6,6-Dimethyl-5- (2-phenyl-2-propoxyacetyl) -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide,
N- {5- [2- (4-Fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
N- {5- [2- (3-Fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- {5- [2- (2-Fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole- 3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl } -1- (Trimethylsilyl) cyclobutanecarboxamide,
(-)-N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole -3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
(+)-N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole -3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
N-{[1- (hydroxymethyl) cyclobutyl] (phenyl) methyl} -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide,
(R) -N- [2- (1-hydroxycyclopropyl) -1-phenylethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 4-c] pyrazole-5 (1H) -carboxamide,
(R) -N- (3-Ethyl-3-hydroxy-1-phenylpentyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
(R) -N- [1- (4-Fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [ 3,4-c] pyrazole-5 (1H) -carboxamide,
(R) -N- [1- (3-Fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [ 3,4-c] pyrazole-5 (1H) -carboxamide,
(R) -N- [1- (2-Fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [ 3,4-c] pyrazole-5 (1H) -carboxamide,
(R) -N- (5-hydroxy-2,5-dimethylhexane-3-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 4-c] pyrazole-5 (1H) -carboxamide,
N- [1- (4-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxamide,
N- [1- (3-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxamide,
(−) — N- [1- (3-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- Dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide,
(+)-N- [1- (3-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- Dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide,
N- [1- (2-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxamide,
N- (1-hydroxy-2,2,4-trimethylpentan-3-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
(R) -N- (3-hydroxy-3-methyl-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide,
N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c Pyrazole-5 (1H) -carboxamide,
(−) — N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3, 4-c] pyrazole-5 (1H) -carboxamide,
(+)-N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 4-c] pyrazole-5 (1H) -carboxamide,
(R) -N- [5- (2-Butoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide and N- (3-methoxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- Dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide
　本実施形態に係る化合物またはその薬理上許容される塩は、単一の光学活性体であってもよく、複数の光学活性体の混合物であってもよい。 The compound according to the present embodiment or a pharmacologically acceptable salt thereof may be a single optically active substance or a mixture of a plurality of optically active substances.
　本実施形態に係る化合物に幾何異性体又は回転異性体が存在する場合、それらの異性体も本発明の範囲に含まれ、また、プロトン互変異性が存在する場合には、それらの互変異性体も本発明に包含される。 When geometrical isomers or rotational isomers are present in the compound according to this embodiment, these isomers are also included in the scope of the present invention, and when tautomerism exists, their tautomerism is included. The body is also encompassed by the present invention.
　本実施形態に係る「薬理上許容される塩」とは、医薬として許容される塩であれば、特に制限はなく、塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、リン酸等の無機酸との塩；酢酸、フマル酸、マレイン酸、コハク酸、クエン酸、酒石酸、アジピン酸、乳酸、トリフルオロ酢酸等の有機カルボン酸との塩；メタンスルホン酸、トリフルオロメタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、ナフタレンスルホン酸等の有機スルホン酸との塩；リチウム、ナトリウム、カリウム等のアルカリ金属との塩；カルシウム、マグネシウム等のアルカリ土類金属との塩；アンモニア、モルホリン、グルコサミン、エチレンジアミン、グアニジン、ジエチルアミン、トリエチルアミン、ジシクロヘキシルアミン、ジエタノールアミン、ピペラジン等との四級アンモニウム塩等が挙げられる。 The “pharmacologically acceptable salt” according to the present embodiment is not particularly limited as long as it is a pharmaceutically acceptable salt, and includes hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Salts with inorganic acids; acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, lactic acid, trifluoroacetic acid and other organic carboxylic acids; methanesulfonic acid, trifluoromethanesulfonic acid, benzene Salts with organic sulfonic acids such as sulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid; salts with alkali metals such as lithium, sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonia and morpholine , Glucosamine, ethylenediamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, diethanolamine Quaternary ammonium salts such as piperazine and the like.
　本実施形態に係る化合物またはその薬理上許容される塩は、水和物、または、溶媒和物を形成することができ、その各々またはそれらの混合物は、本発明に包含される。 The compound according to this embodiment or a pharmacologically acceptable salt thereof can form a hydrate or a solvate, and each or a mixture thereof is included in the present invention.
　本実施形態に係る化合物は、構成する原子の一つまたは複数で非天然の比率の原子同位体を含むこともある。原子同位体としては、例えば、重水素（２Ｈ）、トリチウム（３Ｈ）、炭素－１４（１４Ｃ）、フッ素－１８（１８Ｆ）、硫黄－３５（３５Ｓ）、または、ヨウ素－１２５（１２５Ｉ）などが挙げられる。これらの化合物は、治療または予防剤、研究試薬、例えば、アッセイ試薬、及び診断剤、例えば、インビボ画像診断剤として有用である。本実施形態に係る化合物のすべての同位体変種は、放射性であるかどうかにかかわらず、本発明に包含される。 The compound according to this embodiment may contain an unnatural proportion of atomic isotopes at one or more of the constituent atoms. As the atomic isotope, for example, deuterium ( 2 H), tritium ( 3 H), carbon-14 ( 14 C), fluorine-18 ( 18 F), sulfur-35 ( 35 S), or iodine-125 ( 125 I). These compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotopic variations of the compounds according to this embodiment are encompassed by the present invention, whether radioactive or not.
　本実施形態に係る化合物またはその薬理上許容される塩は、必要に応じて、賦形剤、滑沢剤、結合剤、崩壊剤、コーティング剤、安定化剤、等張化剤、緩衝剤、ｐＨ調節剤、可溶化剤、増粘剤、保存剤、抗酸化剤、甘味料、着色剤、香料等を添加して、医薬組成物として使用することができる。医薬組成物は、例えば、第十六改正日本薬局方　製剤総則等に記載の公知の方法により、目的に合わせて適宜調製することができる。 The compound according to the present embodiment or a pharmacologically acceptable salt thereof may be an excipient, a lubricant, a binder, a disintegrant, a coating agent, a stabilizer, an isotonic agent, a buffer, if necessary. A pH regulator, solubilizer, thickener, preservative, antioxidant, sweetener, colorant, fragrance and the like can be added and used as a pharmaceutical composition. The pharmaceutical composition can be appropriately prepared according to the purpose by a known method described in, for example, the 16th revised Japanese Pharmacopoeia, General Rules for Preparations.
　医薬組成物における、本実施形態に係る化合物またはその薬理上許容される塩の含有量は、適宜調整することができる。 The content of the compound according to the present embodiment or a pharmacologically acceptable salt thereof in the pharmaceutical composition can be appropriately adjusted.
　医薬組成物は、例えば、錠剤、カプセル剤、顆粒剤、散剤等の経口投与用製剤、注射剤（例えば、静脈内投与、皮下投与、筋肉内投与、腹腔内投与）、点眼剤、点鼻剤、座剤、軟膏剤、ローション剤、クリーム剤、ゲル剤、スプレー剤、貼付剤、吸入剤、経皮吸収製剤等の非経口投与用製剤等、第十六改正日本薬局方　製剤総則に記載の剤形とすることができる。 The pharmaceutical composition is, for example, a preparation for oral administration such as tablets, capsules, granules, powders, injections (for example, intravenous administration, subcutaneous administration, intramuscular administration, intraperitoneal administration), eye drops, nasal drops. , Suppositories, ointments, lotions, creams, gels, sprays, patches, inhalants, preparations for parenteral administration such as transdermal preparations, etc., as described in the 16th revised Japanese Pharmacopoeia It can be a dosage form.
　賦形剤としては、例えば、乳糖、マンニトール、デンプン、結晶セルロース、軽質無水ケイ酸、炭酸カルシウムおよびリン酸水素カルシウムが挙げられ、滑沢剤としては、例えば、ステアリン酸、ステアリン酸マグネシウムおよびタルクが挙げられる。結合剤としては、例えば、デンプン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロースおよびポリビニルピロリドンが挙げられ、崩壊剤としては、例えば、カルボキシメチルセルロース、低置換度ヒドロキシプロピルメチルセルロースおよびクエン酸カルシウムが挙げられる。コーティング剤としては、例えば、ヒドロキシプロピルメチルセルロース、マクロゴールおよびシリコーン樹脂が挙げられ、安定化剤としては、例えば、パラオキシ安息香酸エチルおよびベンジルアルコールが挙げられる。 Excipients include, for example, lactose, mannitol, starch, crystalline cellulose, light anhydrous silicic acid, calcium carbonate and calcium hydrogen phosphate, and lubricants include, for example, stearic acid, magnesium stearate and talc. Can be mentioned. Examples of the binder include starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone, and examples of the disintegrant include carboxymethylcellulose, low-substituted hydroxypropylmethylcellulose, and calcium citrate. Examples of the coating agent include hydroxypropyl methylcellulose, macrogol and silicone resin, and examples of the stabilizer include ethyl paraoxybenzoate and benzyl alcohol.
　等張化剤としては、例えば、グリセリン、プロピレングリコール、塩化ナトリウム、塩化カリウム、ソルビトール、マンニトール等が挙げられ、緩衝剤としては、ホウ酸、ホウ酸塩、リン酸、リン酸塩、クエン酸、クエン酸塩、酢酸、酢酸塩、ε－アミノカプロン酸、トロメタモール等が挙げられ、ｐＨ調節剤としては、例えば、塩酸、クエン酸、リン酸、氷酢酸、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられる。また、可溶化剤としては、例えば、ポリソルベート８０、ポリオキシエチレン硬化ヒマシ油６０、マクロゴール４０００、精製大豆レシチン、ポリオキシエチレン（１６０）ポリオキシプロピレン（３０）グリコール等が挙げられ、増粘剤としては、例えば、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース等のセルロース系高分子、ポリビニルアルコール、ポリビニルピロリドン等が挙げられる。安定化剤としては、例えば、エデト酸、エデト酸ナトリウム等が挙げられ、保存剤としては、例えば、ソルビン酸、ソルビン酸カリウム、塩化ベンザルコニウム、塩化ベンゼトニウム、パラオキシ安息香酸メチル、パラオキシ安息香酸プロピル、クロロブタノール等が挙げられる。 Examples of isotonic agents include glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol and the like, and buffering agents include boric acid, borate, phosphoric acid, phosphate, citric acid, Examples thereof include citrate, acetic acid, acetate, ε-aminocaproic acid, trometamol and the like. Examples of pH adjusters include hydrochloric acid, citric acid, phosphoric acid, glacial acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, Examples thereof include sodium hydrogen carbonate. Examples of the solubilizer include polysorbate 80, polyoxyethylene hydrogenated castor oil 60, macrogol 4000, purified soybean lecithin, polyoxyethylene (160) polyoxypropylene (30) glycol, and the like. Examples thereof include cellulose polymers such as hydroxypropylmethylcellulose and hydroxypropylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone. Examples of the stabilizer include edetic acid, sodium edetate, and the like, and examples of the preservative include sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl paraoxybenzoate, propyl paraoxybenzoate. And chlorobutanol.
　軟膏剤、ローション剤、クリーム剤、ゲル剤、貼付剤、および、スプレー剤等の経皮投与用医薬組成物が含んでいてもよい成分としては、例えば、ラウリルアルコール、ミリスチルアルコール、サリチル酸エチレングリコール、ピロチオデカン等の吸収促進剤；アジピン酸ジイソプロピル、ミリスチン酸イソプロピル、乳酸セチル、乳酸ミリスチル、パルミチン酸イソプロピル、セバシン酸ジエチル、ラルリン酸ヘキシル、イソオクタン酸セチル等の脂肪酸エステル；セチルアルコール、ステアリルアルコール、オレイルアルコール、ヘキサデシルアルコール、ベヘニルアルコール等の脂肪族アルコール；プロピレングリコール、プロピレンジオール、ポリエチレングリコール、ジプロピレングリコール等のグリコール類；ソルビタン脂肪酸エステル、グリセリン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレングリセリン脂肪酸エステル、ポリエチレングリコール脂肪酸エステル、ポリオキシエチレンアルキルエーテル、ポリオキシエチレンヒマシ油、ポリオキシエチレン硬化ヒマシ油等の界面活性剤等が挙げられる。 Ingredients that may be contained in the pharmaceutical composition for transdermal administration such as ointments, lotions, creams, gels, patches, and sprays include, for example, lauryl alcohol, myristyl alcohol, ethylene glycol salicylate, Absorption accelerators such as pyrothiodecane; fatty acid esters such as diisopropyl adipate, isopropyl myristate, cetyl lactate, myristyl lactate, isopropyl palmitate, diethyl sebacate, hexyl ralphosphate, cetyl isooctanoate; cetyl alcohol, stearyl alcohol, oleyl alcohol, Aliphatic alcohols such as hexadecyl alcohol and behenyl alcohol; glycols such as propylene glycol, propylene diol, polyethylene glycol and dipropylene glycol; sorbitan fat Surfactants such as ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, etc. Can be mentioned.
　本実施形態に係る化合物またはその薬理上許容される塩の投与量は、症状、年齢、剤型等により適宜変更することができる。例えば、経口投与の場合、通常１日当たり０．０１乃至２０００ｍｇ、好ましくは１乃至５００ｍｇを１回又は数回に分けて投与することができる。 The dose of the compound according to the present embodiment or a pharmacologically acceptable salt thereof can be appropriately changed depending on symptoms, age, dosage form and the like. For example, in the case of oral administration, 0.01 to 2000 mg, preferably 1 to 500 mg per day can be administered once or divided into several times.
　軟膏剤、ローション剤、クリーム剤、または、ゲル剤であれば通常０．００００１％（ｗ／ｖ）乃至１０％（ｗ／ｖ）、好ましくは０．００１％（ｗ／ｖ）乃至５％（ｗ／ｖ）の濃度のものを１回又は数回に分けて投与することができる。 For ointments, lotions, creams, or gels, it is usually 0.00001% (w / v) to 10% (w / v), preferably 0.001% (w / v) to 5% ( One having a concentration of w / v) can be administered once or divided into several times.
　次に、本実施形態に係る化合物またはその薬理上許容される塩の製造方法について、説明する。なお、本発明に係る化合物またはその薬理上許容される塩は、以下の製造方法によって製造された化合物またはその薬理上許容される塩に限定されるものではない。 Next, a method for producing the compound according to this embodiment or a pharmacologically acceptable salt thereof will be described. In addition, the compound which concerns on this invention, or its pharmacologically acceptable salt is not limited to the compound manufactured by the following manufacturing methods, or its pharmacologically acceptable salt.
　以下に示す製造法において、化合物中に所望の反応を阻害するか、あるいは副反応を受ける部分構造（例えば、ヒドロキシ基、アミノ基、カルボニル基、カルボキシル基、アミド基、又は、チオール基等）が存在する場合、それらの部分構造に保護基を導入して所望の反応を行い、その後に当該保護基を除去することによって目的物を得ることができる。 In the production method shown below, a partial structure (for example, a hydroxy group, an amino group, a carbonyl group, a carboxyl group, an amide group, or a thiol group) that inhibits a desired reaction or undergoes a side reaction is present in a compound. When present, the desired product can be obtained by introducing a protecting group into the partial structure to perform a desired reaction, and then removing the protecting group.
　保護基の導入反応および除去反応は有機合成化学で常用される方法（例えば、Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ　第４版、Ｔ．Ｗ．Ｇｒｅｅｎｅ、Ｐ．Ｇ．Ｍ．Ｗｕｔｓ著、Ｊｏｈｎ　Ｗｉｌｅｙ　＆　Ｓｏｎｓ　Ｉｎｃ．（２００６年）等に記載の方法）に準じて実施できる。 Protective group introduction and removal reactions are commonly used in organic synthetic chemistry (for example, Protective Groups in Organic Synthesis 4th Edition, TW Greene, PGM Wuts, John Wiley & Sons Inc.). (2006), etc.).
　本発明化合物の個々の具体的な製造方法については、後述の実施例で詳細に説明する。 Specific production methods of the compound of the present invention will be described in detail in the examples described later.
　化合物（Ｉ）は、例えば、以下の製造方法１乃至４の方法により、化合物（Ａ）を出発原料として製造することができる。なお、化合物（Ａ）の製造方法については、後述する。 Compound (I) can be produced using compound (A) as a starting material by the following production methods 1 to 4, for example. In addition, the manufacturing method of a compound (A) is mentioned later.
＜化合物（Ｉ）の製造方法１＞
　製造方法１は、化合物（Ａ）を出発原料として、工程１乃至３を経て化合物（Ｉ）を製造する方法である。製造方法１は、Ｌ２が酸素原子または－ＮＨ－で表される２価のアミノ基である場合に、好適な製造方法である。製造方法１において、Ｒ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｌ２およびＬ３は、一般式（Ｉ）と同様に定義される。Ｐ１基は、アミノ基の保護基を示し、Ｘは、脱離基を示す。なお、Ｐ１基は４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール骨格におけるピラゾールの酸性プロトンを置換することができればよい。したがって、Ｐ１基は４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール骨格の１位に置換していてもよく、２位に置換していてもよい。便宜上、化合物（Ａ）として、４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール骨格の１位に置換した化学式を用いて説明する。 <Production Method 1 of Compound (I)>
Production method 1 is a method for producing compound (I) through steps 1 to 3 using compound (A) as a starting material. Production method 1 is a preferred production method when L 2 is a divalent amino group represented by an oxygen atom or —NH—. In production method 1, R, R 1 , R 2 , R 3 , R 4 , R 5 , L 2 and L 3 are defined in the same manner as in formula (I). The P 1 group represents an amino-protecting group, and X represents a leaving group. The P 1 group only needs to replace the acidic proton of pyrazole in the 4,6-dihydropyrrolo [3,4-c] pyrazole skeleton. Therefore, the P 1 group may be substituted at the 1-position of the 4,6-dihydropyrrolo [3,4-c] pyrazole skeleton or may be substituted at the 2-position. For convenience, the compound (A) will be described using a chemical formula substituted at the 1-position of the 4,6-dihydropyrrolo [3,4-c] pyrazole skeleton.
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
　Ｐ１基は、当業者にアミノ基の保護基として知られる置換基であれば、特に制限はない。Ｐ１基としては、例えば、ベンジル基、ｐ－メトキシフェニルメチル基、ｏ－ニトロフェニルメチル基等の置換されていてもよいＣ７―１１アラルキル基；アセチル基、トリフルオロアセチル基、ベンゾイル基等の置換されていてもよいアシル基；メトキシカルボニル基、エトキシカルボニル基、Ｂｏｃ基（ｔｅｒｔ－ブトキシカルボニル基）、Ｃｂｚ基（ベンジルオキシカルボニル基）、Ｆｍｏｃ基（フルオレニルメチルオキシカルボニル基）、Ｔｅｏｃ基（トリメチルシリルエチルオキシカルボニル基）等の置換されていてもよいＣ１－６アルコキシカルボニル基；Ａｌｌｏｃ基（アリルオキシカルボニル基）等のアルケニルオキシカルボニル基；メタンスルホニル基等のアルキルスルホニル基；ｐ－トルエンスルホニル基等のＣ６－１０アリールスルホニル基が挙げられる。 The P 1 group is not particularly limited as long as it is a substituent known to those skilled in the art as an amino-protecting group. Examples of the P 1 group include an optionally substituted C 7-11 aralkyl group such as benzyl group, p-methoxyphenylmethyl group, o-nitrophenylmethyl group; acetyl group, trifluoroacetyl group, benzoyl group, etc. An optionally substituted acyl group; methoxycarbonyl group, ethoxycarbonyl group, Boc group (tert-butoxycarbonyl group), Cbz group (benzyloxycarbonyl group), Fmoc group (fluorenylmethyloxycarbonyl group), Teoc An optionally substituted C 1-6 alkoxycarbonyl group such as a trimethylsilylethyloxycarbonyl group; an alkenyloxycarbonyl group such as an Alloc group (allyloxycarbonyl group); an alkylsulfonyl group such as a methanesulfonyl group; C 6- such as toluenesulfonyl group A 10 arylsulfonyl group.
　Ｘ基は、当業者に脱離基として知られる置換基であれば、特に制限はない。Ｘとしては、例えば、ハロゲン原子；イミダゾリル基；スクシニル－Ｎ－オキシ基、ベンゾトリアゾリル－Ｎ－オキシ基等のアミノオキシ基；ピバロイルオキシ基、ベンゾイルオキシ基等のアシルオキシ基が挙げられる。また、Ｘは、水酸基であってもよい。 The X group is not particularly limited as long as it is a substituent known to those skilled in the art as a leaving group. Examples of X include a halogen atom; an imidazolyl group; an aminooxy group such as a succinyl-N-oxy group and a benzotriazolyl-N-oxy group; and an acyloxy group such as a pivaloyloxy group and a benzoyloxy group. X may be a hydroxyl group.
（工程１）
　工程１は、化合物（Ａ）とアシル化剤を反応させて、化合物（Ｂ）を得る工程である。 (Process 1)
Step 1 is a step of obtaining compound (B) by reacting compound (A) with an acylating agent.
　アシル化剤としては、例えば、ホスゲン、ジホスゲン、トリホスゲン、カルボニルジイミダゾール（ＣＤＩ）、Ｎ，Ｎ’－ジスクシンイミジル　カルボナート、炭酸エステル等を使用することができる。 As the acylating agent, for example, phosgene, diphosgene, triphosgene, carbonyldiimidazole (CDI), N, N′-disuccinimidyl carbonate, carbonate ester and the like can be used.
　アシル化剤の使用量は、化合物（Ａ）１モルに対して、好ましくは、０．４乃至３．０モルであり、より好ましくは、０．７乃至１．５モルである。 The amount of the acylating agent to be used is preferably 0.4 to 3.0 mol, more preferably 0.7 to 1.5 mol, per 1 mol of compound (A).
　工程１は、反応を溶媒中で行ってもよく、無溶媒で行ってもよい。溶媒を用いる場合には、反応に影響を与えない溶媒であれば限定は無く、好ましくは、有機溶媒である。有機溶媒としては、ジクロロメタン、１，２－ジクロロエタン、ジエチルエーテル、１，２－ジメトキシエタン、テトラヒドロフラン（ＴＨＦ）、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、ジメチルスルホキシド（ＤＭＳＯ）が挙げられる。 Step 1 may be performed in a solvent or without a solvent. When a solvent is used, there is no limitation as long as the solvent does not affect the reaction, and an organic solvent is preferable. Examples of the organic solvent include dichloromethane, 1,2-dichloroethane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran (THF), N, N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).
　工程１は、反応を促進するために、さらに塩基を添加することができる。塩基としては、例えば、トリエチルアミン、ジイソプロピルエチルアミン（ＤＩＰＥＡ）、１，５－ジアザビシクロ［４．３．０］ノネン（ＤＢＮ）、１，８－ジアザビシクロ［５．４．０］ウンデセン（ＤＢＵ）、ピリジン、４－ジメチルアミノピリジン（ＤＭＡＰ）等の有機アミンが挙げられる。 Step 1 can further add a base to promote the reaction. Examples of the base include triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo [4.3.0] nonene (DBN), 1,8-diazabicyclo [5.4.0] undecene (DBU), pyridine, And organic amines such as 4-dimethylaminopyridine (DMAP).
　添加する塩基の量は、化合物（Ａ）１モルに対して、好ましくは、１乃至１０モルであり、より好ましくは、３乃至６モルである。 The amount of the base to be added is preferably 1 to 10 mol, more preferably 3 to 6 mol, relative to 1 mol of the compound (A).
　工程１の反応温度は、当業者が適宜設定することができる。反応温度としては、通常、－１００乃至－２０℃であり、好ましくは－８０乃至－６０℃である。 The reaction temperature in step 1 can be appropriately set by those skilled in the art. The reaction temperature is usually −100 to −20 ° C., preferably −80 to −60 ° C.
（工程２）
　工程２は、化合物（Ｂ）と化合物（Ｃ）を反応させて、化合物（Ｄ）を得る工程である。 (Process 2)
Step 2 is a step in which compound (B) and compound (C) are reacted to obtain compound (D).
　工程２において、Ｌ２基は酸素原子または－ＮＨ－で表される２価のアミノ基である。すなわち、化合物（Ｃ）は、アルコールまたはアミンである。 In step 2, the L 2 group is an oxygen atom or a divalent amino group represented by —NH—. That is, the compound (C) is an alcohol or an amine.
　化合物（Ｃ）の使用量は、化合物（Ｂ）１モルに対して、好ましくは、１乃至２０モルであり、より好ましくは、２乃至５モルである。化合物（Ｃ）および化合物（Ｂ）は、有機溶媒に溶解させて反応液に加えてもよい。 The amount of compound (C) to be used is preferably 1 to 20 mol, more preferably 2 to 5 mol, per 1 mol of compound (B). Compound (C) and compound (B) may be dissolved in an organic solvent and added to the reaction solution.
　工程２は、反応を溶媒中で行ってもよく、無溶媒で行ってもよい。溶媒を用いる場合には、反応に影響を与えない溶媒であれば限定は無く、好ましくは、有機溶媒である。有機溶媒としては、ジクロロメタン、１，２－ジクロロエタン、ジエチルエーテル、１，２－ジメトキシエタン、テトラヒドロフラン（ＴＨＦ）、１，４－ジオキサン、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、ジメチルスルホキシド（ＤＭＳＯ）が挙げられる。 Step 2 may be performed in a solvent or without a solvent. When a solvent is used, there is no limitation as long as the solvent does not affect the reaction, and an organic solvent is preferable. Examples of the organic solvent include dichloromethane, 1,2-dichloroethane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran (THF), 1,4-dioxane, N, N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO). Can be mentioned.
　工程２は、反応を促進するために、さらに塩基を添加することができる。塩基としては、例えば、トリエチルアミン、ジイソプロピルエチルアミン（ＤＩＰＥＡ）、１，５－ジアザビシクロ［４．３．０］ノネン（ＤＢＮ）、１，８－ジアザビシクロ［５．４．０］ウンデセン（ＤＢＵ）、ピリジン、４－ジメチルアミノピリジン（ＤＭＡＰ）等の有機アミン；炭酸カリウム、炭酸ナトリウム等の無機塩基が挙げられる。 Step 2 can further add a base to promote the reaction. Examples of the base include triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo [4.3.0] nonene (DBN), 1,8-diazabicyclo [5.4.0] undecene (DBU), pyridine, Organic amines such as 4-dimethylaminopyridine (DMAP); inorganic bases such as potassium carbonate and sodium carbonate.
　添加する塩基の量は、化合物（Ａ）１モルに対して、好ましくは、１乃至２０モルであり、より好ましくは、２乃至５モルである。 The amount of the base to be added is preferably 1 to 20 mol, more preferably 2 to 5 mol, per 1 mol of the compound (A).
　工程２の反応温度は、当業者が適宜設定することができる。反応温度としては、通常、０乃至１２０℃であり、好ましくは２５乃至１００℃である。 The reaction temperature in step 2 can be appropriately set by those skilled in the art. The reaction temperature is usually 0 to 120 ° C., preferably 25 to 100 ° C.
（工程３）
　工程３は、化合物（Ｄ）のＰ１基を除去させて、化合物（Ｉ）を製造する工程である。 (Process 3)
Step 3 is a step for producing compound (I) by removing P 1 group of compound (D).
　工程３の反応条件は、使用するＰ１基の種類によって、当業者が適宜選択することができる。例えば、Ｐ１基がアラルキル基の場合には、加水素分解によって行ってもよく、プロトン酸またはルイス酸を用いて行ってもよい。また、Ｐ１基がＢｏｃ基の場合には、プロトン酸またはルイス酸で処理することによって行うことができ、Ｐ１基がＣｂｚ基の場合には、加水素分解または塩基で処理することによって行うことができ、Ｐ１基がＴｅｏｃ基の場合には、テトラブチルアンモニウム　フルオリド等のフッ化物イオンを生じる試薬を用いることができる。また、Ｐ１基がメトキシカルボニル基やエトキシカルボニル基等のアルコキシカルボニル基の場合には、トリエチルアミン、ジイソプロピルエチルアミン（ＤＩＰＥＡ）等の有機アミン、または、炭酸カリウム、炭酸ナトリウム等の無機塩基の存在下、加熱することによって行ってもよい。 The reaction conditions in step 3 can be appropriately selected by those skilled in the art depending on the type of P 1 group used. For example, when the P 1 group is an aralkyl group, it may be carried out by hydrogenolysis or using a protonic acid or a Lewis acid. When the P 1 group is a Boc group, the treatment can be performed by treatment with a proton acid or a Lewis acid. When the P 1 group is a Cbz group, the treatment can be performed by hydrogenolysis or treatment with a base. In the case where the P 1 group is a Teoc group, a reagent that generates fluoride ions such as tetrabutylammonium fluoride can be used. When the P 1 group is an alkoxycarbonyl group such as a methoxycarbonyl group or an ethoxycarbonyl group, in the presence of an organic amine such as triethylamine or diisopropylethylamine (DIPEA) or an inorganic base such as potassium carbonate or sodium carbonate, You may carry out by heating.
　工程３によって得られる化合物（Ｉ）は、当業者に周知の方法により、その薬理上許容可能な塩へと変換することができる。 Compound (I) obtained by Step 3 can be converted into a pharmacologically acceptable salt thereof by a method well known to those skilled in the art.
＜化合物（Ｉ）の製造方法２＞
　製造方法２は、化合物（Ｃ）を出発原料として、工程４および５を経て化合物（Ｄ）を得た後、上記製造方法１の工程３にしたがい、化合物（Ｉ）へと変換する方法である。製造方法２は、Ｌ２が酸素原子または－ＮＨ－で表される２価のアミノ基である場合に、好適な製造方法である。製造方法２において、Ｒ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｌ２、Ｌ３、Ｐ１およびＸは、上記製造方法１と同様に定義される。 <Production Method 2 of Compound (I)>
Production method 2 is a method in which compound (C) is used as a starting material, compound (D) is obtained through steps 4 and 5, and then converted into compound (I) according to step 3 of production method 1 above. . Production method 2 is a preferred production method when L 2 is a divalent amino group represented by an oxygen atom or —NH—. In Production Method 2, R, R 1 , R 2 , R 3 , R 4 , R 5 , L 2 , L 3 , P 1 and X are defined in the same manner as in Production Method 1 above.
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
（工程４）
　工程４は、化合物（Ｃ）とアシル化剤を反応させて、化合物（Ｅ）を得る工程である。 (Process 4)
Step 4 is a step of obtaining compound (E) by reacting compound (C) with an acylating agent.
　工程４において、Ｌ２基は酸素原子または－ＮＨ－で表される２価のアミノ基である。すなわち、化合物（Ｃ）は、アルコールまたはアミンである。 In Step 4, the L 2 group is a divalent amino group represented by an oxygen atom or —NH—. That is, the compound (C) is an alcohol or an amine.
　アシル化剤としては、例えば、ホスゲン、ジホスゲン、トリホスゲン、カルボニルジイミダゾール（ＣＤＩ）、Ｎ，Ｎ’－ジスクシンイミジル　カルボナート、炭酸エステル等を使用することができる。 As the acylating agent, for example, phosgene, diphosgene, triphosgene, carbonyldiimidazole (CDI), N, N′-disuccinimidyl carbonate, carbonate ester and the like can be used.
　アシル化剤の使用量は、化合物（Ｃ）１モルに対して、好ましくは、１乃至５モルであり、より好ましくは、１乃至２モルである。 The amount of the acylating agent to be used is preferably 1 to 5 mol, more preferably 1 to 2 mol, per 1 mol of compound (C).
　工程４は、反応を溶媒中で行ってもよく、無溶媒で行ってもよい。溶媒を用いる場合には、反応に影響を与えない溶媒であれば限定は無く、好ましくは、有機溶媒である。有機溶媒としては、アセトニトリル、ジクロロメタン、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、ジメチルスルホキシド（ＤＭＳＯ）が挙げられる。 Step 4 may be performed in a solvent or without a solvent. When a solvent is used, there is no limitation as long as the solvent does not affect the reaction, and an organic solvent is preferable. Examples of the organic solvent include acetonitrile, dichloromethane, diethyl ether, tetrahydrofuran (THF), N, N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).
　工程４は、反応を促進するために、さらに塩基を添加することができる。塩基としては、例えば、トリエチルアミン、ジイソプロピルエチルアミン（ＤＩＰＥＡ）、１，５－ジアザビシクロ［４．３．０］ノネン（ＤＢＮ）、１，８－ジアザビシクロ［５．４．０］ウンデセン（ＤＢＵ）、ピリジン、４－ジメチルアミノピリジン（ＤＭＡＰ）等の有機アミンが挙げられる。 Step 4 can further add a base to promote the reaction. Examples of the base include triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo [4.3.0] nonene (DBN), 1,8-diazabicyclo [5.4.0] undecene (DBU), pyridine, And organic amines such as 4-dimethylaminopyridine (DMAP).
　添加する塩基の量は、化合物（Ｃ）１モルに対して、好ましくは、１乃至５モルであり、より好ましくは、１乃至２モルである。 The amount of the base to be added is preferably 1 to 5 mol, more preferably 1 to 2 mol, relative to 1 mol of the compound (C).
　工程４の反応温度は、当業者が適宜設定することができる。反応温度としては、通常、０乃至１００℃であり、好ましくは２０乃至４０℃である。 The reaction temperature in step 4 can be appropriately set by those skilled in the art. The reaction temperature is usually 0 to 100 ° C., preferably 20 to 40 ° C.
（工程５）
　工程５は、化合物（Ｅ）と化合物（Ａ）を反応させて、化合物（Ｄ）を得る工程である。 (Process 5)
Step 5 is a step of obtaining compound (D) by reacting compound (E) with compound (A).
　化合物（Ｅ）の使用量は、化合物（Ａ）１モルに対して、好ましくは、１乃至５モルであり、より好ましくは、１乃至２モルである。化合物（Ｅ）および化合物（Ａ）は、有機溶媒に溶解させて反応液に加えてもよい。 The amount of compound (E) to be used is preferably 1 to 5 mol, more preferably 1 to 2 mol, per 1 mol of compound (A). Compound (E) and compound (A) may be dissolved in an organic solvent and added to the reaction solution.
　工程５は、反応を溶媒中で行ってもよく、無溶媒で行ってもよい。溶媒を用いる場合には、反応に影響を与えない溶媒であれば限定は無く、好ましくは、有機溶媒である。有機溶媒としては、ジクロロメタン、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、ジメチルスルホキシド（ＤＭＳＯ）が挙げられる。 Step 5 may be performed in a solvent or without a solvent. When a solvent is used, there is no limitation as long as the solvent does not affect the reaction, and an organic solvent is preferable. Examples of the organic solvent include dichloromethane, diethyl ether, tetrahydrofuran (THF), N, N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).
　工程５は、反応を促進するために、さらに塩基を添加することができる。塩基としては、例えば、トリエチルアミン、ジイソプロピルエチルアミン（ＤＩＰＥＡ）、１，５－ジアザビシクロ［４．３．０］ノネン（ＤＢＮ）、１，８－ジアザビシクロ［５．４．０］ウンデセン（ＤＢＵ）、ピリジン、４－ジメチルアミノピリジン（ＤＭＡＰ）等の有機アミンが挙げられる。 Step 5 can further add a base to promote the reaction. Examples of the base include triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo [4.3.0] nonene (DBN), 1,8-diazabicyclo [5.4.0] undecene (DBU), pyridine, And organic amines such as 4-dimethylaminopyridine (DMAP).
　添加する塩基の量は、化合物（Ａ）１モルに対して、好ましくは、１乃至１０モルであり、より好ましくは、１乃至５モルである。 The amount of the base to be added is preferably 1 to 10 mol, more preferably 1 to 5 mol, relative to 1 mol of the compound (A).
　工程５の反応温度は、当業者が適宜設定することができる。反応温度としては、通常、０乃至１００℃であり、好ましくは２０乃至４０℃である。 The reaction temperature in step 5 can be appropriately set by those skilled in the art. The reaction temperature is usually 0 to 100 ° C., preferably 20 to 40 ° C.
＜化合物（Ｉ）の製造方法３＞
　製造方法３は、化合物（Ａ）と化合物（Ｆ）とを反応させて化合物（Ｄ）を得た後、上記製造方法１の工程３にしたがい、化合物（Ｉ）へと変換する方法である。製造方法３は、Ｌ２が単結合である場合に、好適な製造方法である。製造方法３において、Ｒ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｌ２、Ｌ３およびＰ１は、上記製造方法１と同様に定義される。 <Production Method 3 of Compound (I)>
Production method 3 is a method in which compound (A) and compound (F) are reacted to obtain compound (D), and then converted to compound (I) according to step 3 of production method 1 described above. Production method 3 is a preferred production method when L 2 is a single bond. In Production Method 3, R, R 1 , R 2 , R 3 , R 4 , R 5 , L 2 , L 3 and P 1 are defined in the same manner as in Production Method 1 above.
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
（工程６）
　工程６は、化合物（Ａ）と化合物（Ｆ）を縮合させて、化合物（Ｄ）を得る工程である。上記縮合反応は、アミド結合形成反応に用いる試薬を用いて、化合物（Ｆ）を酸ハライド、カルボン酸無水物、酸アジド、または、活性エステルに変換した後に化合物（Ａ）と反応させる。なお、上記アミド結合形成反応に用いる試薬は、当業者にアミド結合形成反応に用いる試薬として知られる試薬であれば、特に制限は無い。 (Step 6)
Step 6 is a step of condensing compound (A) and compound (F) to obtain compound (D). In the condensation reaction, the compound (F) is converted into an acid halide, carboxylic acid anhydride, acid azide, or active ester using a reagent used in the amide bond forming reaction, and then reacted with the compound (A). The reagent used for the amide bond forming reaction is not particularly limited as long as it is known to those skilled in the art as a reagent used for the amide bond forming reaction.
　化合物（Ｆ）の使用量は、化合物（Ａ）１モルに対して、好ましくは、１乃至１０モルであり、より好ましくは、１乃至５モルである。化合物（Ｆ）は、有機溶媒に溶解させて反応液に加えてもよい。 The amount of compound (F) to be used is preferably 1 to 10 mol, more preferably 1 to 5 mol, per 1 mol of compound (A). Compound (F) may be dissolved in an organic solvent and added to the reaction solution.
　工程６は、反応を溶媒中で行ってもよく、無溶媒で行ってもよい。溶媒を用いる場合には、反応に影響を与えない溶媒であれば限定は無く、好ましくは、有機溶媒である。有機溶媒としては、ジクロロメタン、１，２－ジクロロエタン、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、ジメチルスルホキシド（ＤＭＳＯ）が挙げられる。 Step 6 may be performed in a solvent or without a solvent. When a solvent is used, there is no limitation as long as the solvent does not affect the reaction, and an organic solvent is preferable. Examples of the organic solvent include dichloromethane, 1,2-dichloroethane, diethyl ether, tetrahydrofuran (THF), N, N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).
　工程６は、反応を促進するために、さらに塩基を添加することができる。塩基としては、例えば、トリエチルアミン、ジイソプロピルエチルアミン（ＤＩＰＥＡ）、１，５－ジアザビシクロ［４．３．０］ノネン（ＤＢＮ）、１，８－ジアザビシクロ［５．４．０］ウンデセン（ＤＢＵ）、ピリジン、４－ジメチルアミノピリジン（ＤＭＡＰ）等の有機アミンが挙げられる。 Step 6 can further add a base to promote the reaction. Examples of the base include triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo [4.3.0] nonene (DBN), 1,8-diazabicyclo [5.4.0] undecene (DBU), pyridine, And organic amines such as 4-dimethylaminopyridine (DMAP).
　添加する塩基の量は、化合物（Ａ）１モルに対して、好ましくは、１乃至１０モルであり、より好ましくは、１乃至５モルである。 The amount of the base to be added is preferably 1 to 10 mol, more preferably 1 to 5 mol, relative to 1 mol of the compound (A).
　工程６の反応温度は、当業者が適宜設定することができる。反応温度としては、通常、０乃至１００℃であり、好ましくは２０乃至４０℃である。 The reaction temperature in step 6 can be appropriately set by those skilled in the art. The reaction temperature is usually 0 to 100 ° C., preferably 20 to 40 ° C.
＜化合物（Ｉ）の製造方法４＞
　製造方法４は、化合物（Ｈ）を出発原料として、工程７および工程８を経て化合物（Ｄ）を得た後、上記製造方法１の工程３にしたがい、化合物（Ｉ）へと変換する方法である。製造方法４において、Ｒ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｌ２およびＬ３は、一般式（Ｉ）と同様に定義される。Ｐ１基は、アミノ基の保護基を示し、Ｐ２は、水酸基の保護基を示す。なお、Ｐ１基は上記製造方法１と同様に定義される。 <Production Method 4 of Compound (I)>
Production method 4 is a method in which compound (H) is used as a starting material, compound (D) is obtained through steps 7 and 8, and then converted into compound (I) according to step 3 of production method 1 above. is there. In production method 4, R, R 1 , R 2 , R 3 , R 4 , L 2 and L 3 are defined in the same manner as in formula (I). The P 1 group represents an amino-protecting group, and P 2 represents a hydroxyl-protecting group. Incidentally, P 1 group is defined similarly to the production method 1.
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
　Ｐ２基は、当業者に水酸基の保護基として知られる置換基であれば、特に制限はない。Ｐ２基としては、例えば、ベンジル基、ｐ－メトキシフェニルメチル基、ｏ－ニトロフェニルメチル基等の置換されていてもよいＣ７―１１アラルキル基；アセチル基、トリフルオロアセチル基、ベンゾイル基等の置換されていてもよいアシル基；トリメチルシリル基、ｔｅｒｔ－ブチルジメチルシリル基、トリエチルシリル基、トリイソプロピルシリル基、ｔｅｒｔ－ブチルジフェニルシリル基等の置換シリル基が挙げられる。 The P 2 group is not particularly limited as long as it is a substituent known to those skilled in the art as a hydroxyl-protecting group. Examples of the P 2 group include an optionally substituted C 7-11 aralkyl group such as benzyl group, p-methoxyphenylmethyl group, o-nitrophenylmethyl group; acetyl group, trifluoroacetyl group, benzoyl group, etc. A substituted silyl group such as trimethylsilyl group, tert-butyldimethylsilyl group, triethylsilyl group, triisopropylsilyl group, tert-butyldiphenylsilyl group, and the like.
（工程７）
　工程７は、化合物（Ｈ）の脱保護反応を行い、化合物（Ｊ）を得る工程である。Ｐ２基の除去反応は当業者に周知の方法で行うこともできる（例えば、Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ　第４版、Ｔ．Ｗ．Ｇｒｅｅｎｅ、Ｐ．Ｇ．Ｍ．Ｗｕｔｓ著、Ｊｏｈｎ　Ｗｉｌｅｙ　＆　Ｓｏｎｓ　Ｉｎｃ．（２００６年）等に記載の方法）。 (Step 7)
Step 7 is a step in which compound (H) is deprotected to obtain compound (J). The removal reaction of the P 2 group can also be carried out by methods well known to those skilled in the art (for example, Protective Groups in Organic Synthesis 4th edition, TW Greene, PGM M. Wuts, John Wiley & Sons Inc. (Method described in 2006)).
（工程８）
　工程８は、化合物（Ｊ）と酸ハライド、酸無水物、または、アルキルハライドを反応させて、化合物（Ｄ）を得る工程である。 (Process 8)
Step 8 is a step of obtaining compound (D) by reacting compound (J) with an acid halide, acid anhydride, or alkyl halide.
　酸ハライド、酸無水物、または、アルキルハライドの使用量は、化合物（Ｊ）１モルに対して、好ましくは、１乃至１０モルであり、より好ましくは、１乃至２モルである。 The amount of acid halide, acid anhydride, or alkyl halide to be used is preferably 1 to 10 mol, more preferably 1 to 2 mol, per 1 mol of compound (J).
　工程８は、反応を溶媒中で行ってもよく、無溶媒で行ってもよい。溶媒を用いる場合には、反応に影響を与えない溶媒であれば限定は無く、好ましくは、有機溶媒である。有機溶媒としては、ジクロロメタン、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４－ジオキサン、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、ジメチルスルホキシド（ＤＭＳＯ）が挙げられる。 Step 8 may be performed in a solvent or without a solvent. When a solvent is used, there is no limitation as long as the solvent does not affect the reaction, and an organic solvent is preferable. Examples of the organic solvent include dichloromethane, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, N, N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).
　工程８は、反応を促進するために、さらに塩基を添加することができる。塩基としては、例えば、トリエチルアミン、ジイソプロピルエチルアミン（ＤＩＰＥＡ）、１，５－ジアザビシクロ［４．３．０］ノネン（ＤＢＮ）、１，８－ジアザビシクロ［５．４．０］ウンデセン（ＤＢＵ）、ピリジン、４－ジメチルアミノピリジン（ＤＭＡＰ）等の有機アミンが挙げられる。 Step 8 can further add a base to promote the reaction. Examples of the base include triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo [4.3.0] nonene (DBN), 1,8-diazabicyclo [5.4.0] undecene (DBU), pyridine, And organic amines such as 4-dimethylaminopyridine (DMAP).
　添加する塩基の量は、化合物（Ｊ）１モルに対して、好ましくは、１乃至２０モルであり、より好ましくは、１乃至５モルである。 The amount of the base to be added is preferably 1 to 20 mol, more preferably 1 to 5 mol, relative to 1 mol of the compound (J).
　工程８の反応温度は、当業者が適宜設定することができる。反応温度としては、通常、－２０乃至１２０℃であり、好ましくは１５乃至１００℃である。 The reaction temperature in step 8 can be appropriately set by those skilled in the art. The reaction temperature is usually −20 to 120 ° C., preferably 15 to 100 ° C.
＜化合物（Ａ）の製造方法＞
　化合物（Ａ）は、例えば、以下の方法により化合物（Ａ１）を出発原料として製造することができる。化合物（Ａ１）は、例えば、ＷＯ２００７／７２１５３を参考にする、若しくは、下記工程１１乃至１５を経て製造することができる。 <Method for Producing Compound (A)>
Compound (A) can be produced, for example, using compound (A1) as a starting material by the following method. Compound (A1) can be produced, for example, with reference to WO2007 / 72153 or through the following steps 11 to 15.
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
　化合物（Ａ１）は、３－アミノ－６，６－ジメチル－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾールであり、ピラゾール骨格上の窒素原子がＰ１基で、５位の窒素原子がＰ３基で置換されていてもよい。なお、Ｐ１基は４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール骨格におけるピラゾールの酸性プロトンを置換することができればよい。したがって、Ｐ１基は４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール骨格の１位に置換していてもよく、２位に置換していてもよい。便宜上、化合物（Ａ１）および化合物（Ａ２）として、４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール骨格の１位に置換した化学式を用いて説明する。 The compound (A1) is 3-amino-6,6-dimethyl-4,6-dihydropyrrolo [3,4-c] pyrazole, the nitrogen atom on the pyrazole skeleton is P 1 group, and the nitrogen atom at the 5-position May be substituted with a P 3 group. The P 1 group only needs to replace the acidic proton of pyrazole in the 4,6-dihydropyrrolo [3,4-c] pyrazole skeleton. Therefore, the P 1 group may be substituted at the 1-position of the 4,6-dihydropyrrolo [3,4-c] pyrazole skeleton or may be substituted at the 2-position. For convenience, the compounds (A1) and (A2) will be described using chemical formulas substituted at the 1-position of the 4,6-dihydropyrrolo [3,4-c] pyrazole skeleton.
　化合物（Ａ１）において、Ｐ１は、化合物（Ａ）における定義と同義である。Ｐ３基は、当業者にアミノ基の保護基として知られる置換基であれば、特に制限はない。Ｐ３基としては、例えば、ベンジル基、ｐ－メトキシフェニルメチル基、ｏ－ニトロフェニルメチル基等の置換されていてもよいＣ７―１１アラルキル基；アセチル基、トリフルオロアセチル基等の置換されていてもよいＣ１－６アルキルカルボニル基、ベンゾイル基等の置換されていてもよいＣ６－１０アリールカルボニル基；メトキシカルボニル基、エトキシカルボニル基、Ｂｏｃ基（ｔｅｒｔ－ブトキシカルボニル基）、Ｃｂｚ基（ベンジルオキシカルボニル基）、Ｆｍｏｃ基（フルオレニルメチルオキシカルボニル基）、Ｔｅｏｃ基（トリメチルシリルエチルオキシカルボニル基）等の置換されていてもよいＣ１－６アルコキシカルボニル基；Ａｌｌｏｃ基（アリルオキシカルボニル基）等のアルケニルオキシカルボニル基；メタンスルホニル基等のアルキルスルホニル基；ｐ－トルエンスルホニル基等の置換されていてもよいＣ６－１０アリールスルホニル基が挙げられる。 In the compound (A1), P 1 has the same definition as in the compound (A). The P 3 group is not particularly limited as long as it is a substituent known to those skilled in the art as an amino-protecting group. Examples of the P 3 group include C 7-11 aralkyl groups which may be substituted such as benzyl group, p-methoxyphenylmethyl group and o-nitrophenylmethyl group; substituted acetyl groups and trifluoroacetyl groups. Optionally substituted C 1-6 alkylcarbonyl group, optionally substituted C 6-10 arylcarbonyl group such as benzoyl group; methoxycarbonyl group, ethoxycarbonyl group, Boc group (tert-butoxycarbonyl group), Cbz group (Benzyloxycarbonyl group), Fmoc group (fluorenylmethyloxycarbonyl group), Teoc group (trimethylsilylethyloxycarbonyl group) and other optionally substituted C1-6 alkoxycarbonyl groups; Alloc group (allyloxycarbonyl group) Alkenyloxycarbonyl group such as An alkylsulfonyl group such as an arylsulfonyl group; an optionally substituted C 6-10 arylsulfonyl group such as a p-toluenesulfonyl group.
　式（Ａ２）および（Ａ３）において、Ｒ、Ｒ１、Ｒ２およびＲ３は、化合物（Ｉ）における定義と同義である。Ｘ基は、当業者に脱離基として知られる置換基であれば、特に制限はない。Ｘとしては、例えば、ハロゲン原子；イミダゾリル基；スクシニル－Ｎ－オキシ基、ベンゾトリアゾリル－Ｎ－オキシ基等のアミノオキシ基；ピバロイルオキシ基、ベンゾイルオキシ基等のアシルオキシ基が挙げられる。また、Ｘは、水酸基であってもよい。
　化合物（Ａ２）がカルボン酸（すなわち、Ｘが水酸基）である場合、当業者に周知の方法で酸無水物に変換した後に化合物（Ａ１）と反応してもよく、当業者にアミド結合形成反応に用いる縮合剤として知られる試薬を用いて、化合物（Ａ１）と反応してもよい。 In formulas (A2) and (A3), R, R 1 , R 2 and R 3 have the same definitions as in compound (I). The X group is not particularly limited as long as it is a substituent known to those skilled in the art as a leaving group. Examples of X include a halogen atom; an imidazolyl group; an aminooxy group such as a succinyl-N-oxy group and a benzotriazolyl-N-oxy group; and an acyloxy group such as a pivaloyloxy group and a benzoyloxy group. X may be a hydroxyl group.
When the compound (A2) is a carboxylic acid (that is, X is a hydroxyl group), it may be reacted with the compound (A1) after being converted to an acid anhydride by a method well known to those skilled in the art. You may react with a compound (A1) using the reagent known as a condensing agent used for.
（工程９）
　工程９は、化合物（Ａ１）と化合物（Ａ２）を反応させて、化合物（Ａ３）を得る工程である。 (Step 9)
Step 9 is a step in which compound (A1) and compound (A2) are reacted to obtain compound (A3).
　化合物（Ａ２）の使用量は、化合物（Ａ１）１モルに対して、好ましくは、１乃至１０モルであり、より好ましくは、１乃至３モルである。 The amount of compound (A2) to be used is preferably 1 to 10 mol, more preferably 1 to 3 mol, per 1 mol of compound (A1).
　工程９は、反応を溶媒中で行ってもよく、無溶媒で行ってもよい。溶媒を用いる場合には、反応に影響を与えない溶媒であれば限定は無く、好ましくは、有機溶媒である。有機溶媒としては、ジクロロメタン、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、ジメチルスルホキシド（ＤＭＳＯ）が挙げられる。 Step 9 may be performed in a solvent or without a solvent. When a solvent is used, there is no limitation as long as the solvent does not affect the reaction, and an organic solvent is preferable. Examples of the organic solvent include dichloromethane, diethyl ether, tetrahydrofuran (THF), N, N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).
　工程９は、反応を促進するために、さらに塩基を添加することができる。塩基としては、例えば、トリエチルアミン、ジイソプロピルエチルアミン（ＤＩＰＥＡ）、１，５－ジアザビシクロ［４．３．０］ノネン（ＤＢＮ）、１，８－ジアザビシクロ［５．４．０］ウンデセン（ＤＢＵ）、ピリジン、４－ジメチルアミノピリジン（ＤＭＡＰ）等の有機アミンが挙げられる。 In step 9, a base can be further added to accelerate the reaction. Examples of the base include triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo [4.3.0] nonene (DBN), 1,8-diazabicyclo [5.4.0] undecene (DBU), pyridine, And organic amines such as 4-dimethylaminopyridine (DMAP).
　添加する塩基の量は、化合物（Ａ１）１モルに対して、好ましくは、１乃至２０モルであり、より好ましくは、１乃至５モルである。 The amount of the base to be added is preferably 1 to 20 mol, more preferably 1 to 5 mol, relative to 1 mol of the compound (A1).
　工程９の反応温度は、当業者が適宜設定することができる。反応温度としては、通常、－４０乃至１００℃であり、好ましくは－２０乃至２０℃である。 The reaction temperature in step 9 can be appropriately set by those skilled in the art. The reaction temperature is usually −40 to 100 ° C., preferably −20 to 20 ° C.
（工程１０）
　工程１０は、化合物（Ａ３）の脱保護反応を行い、化合物（Ａ）を得る工程である。Ｐ３基の除去反応は当業者に周知の方法で行うこともできる（例えば、Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ　第４版、Ｔ．Ｗ．Ｇｒｅｅｎｅ、Ｐ．Ｇ．Ｍ．Ｗｕｔｓ著、Ｊｏｈｎ　Ｗｉｌｅｙ　＆　Ｓｏｎｓ　Ｉｎｃ．（２００６年）等に記載の方法）。 (Process 10)
Step 10 is a step of obtaining compound (A) by carrying out deprotection reaction of compound (A3). The removal reaction of the P 3 group can also be performed by a method well known to those skilled in the art (for example, Protective Groups in Organic Synthesis 4th edition, TW Greene, PMGM Wuts, John Wiley & Sons Inc. (Method described in 2006)).
＜化合物（Ａ１）の製造方法＞ <Method for producing compound (A1)>
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
　式（Ａ６）、（Ａ７）および（Ａ８）において、Ｐ３は、化合物（Ａ１）における定義と同義である。 In formulas (A6), (A7) and (A8), P 3 has the same definition as in compound (A1).
（工程１１）
　工程１１は、化合物（Ａ４）とアクリロニトリルを反応させて、化合物（Ａ５）を得る工程である。 (Step 11)
Step 11 is a step of obtaining compound (A5) by reacting compound (A4) with acrylonitrile.
　アクリロニトリルの使用量は、化合物（Ａ４）１モルに対して、好ましくは、１乃至１０モルであり、より好ましくは、１乃至３モルである。 The amount of acrylonitrile to be used is preferably 1 to 10 mol, more preferably 1 to 3 mol, per 1 mol of compound (A4).
　工程１１は、反応に影響を与えない溶媒であれば限定は無く、好ましくは、水溶媒である。 Step 11 is not limited as long as it is a solvent that does not affect the reaction, and is preferably an aqueous solvent.
　工程１１は、反応を促進するために、さらに塩基を添加することができる。塩基としては水酸化カリウム等の無機塩基が挙げられる。添加する塩基の量は、化合物（Ａ１）１モルに対して、好ましくは、０．８乃至２モルである。 Step 11 can further add a base to promote the reaction. Examples of the base include inorganic bases such as potassium hydroxide. The amount of the base to be added is preferably 0.8 to 2 mol with respect to 1 mol of the compound (A1).
　工程１１の反応温度は、当業者が適宜設定することができる。反応温度としては、通常、０乃至１００℃であり、好ましくは５０乃至９０℃である。 The reaction temperature in step 11 can be appropriately set by those skilled in the art. The reaction temperature is usually 0 to 100 ° C., preferably 50 to 90 ° C.
（工程１２）
　工程１２は、化合物（Ａ５）のアミノ基をＰ３基で保護して、化合物（Ａ６）を得る工程である。アミノ基のＰ３基による保護反応は当業者に周知の方法で行うことができる（例えば、Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ　第４版、Ｔ．Ｗ．Ｇｒｅｅｎｅ、Ｐ．Ｇ．Ｍ．Ｗｕｔｓ著、Ｊｏｈｎ　Ｗｉｌｅｙ　＆　Ｓｏｎｓ　Ｉｎｃ．（２００６年）等に記載の方法）。 (Step 12)
Step 12 is a step of obtaining compound (A6) by protecting the amino group of compound (A5) with P 3 group. The protection reaction of the amino group with the P 3 group can be performed by a method well known to those skilled in the art (for example, Protective Groups in Organic Synthesis 4th edition, TW Greene, PGM Wuts, John Wiley). & Sons Inc. (2006) etc.).
（工程１３）
　工程１３は、化合物（Ａ６）の環化反応を行い、化合物（Ａ７）を得る工程である。 (Step 13)
Step 13 is a step of obtaining a compound (A7) by carrying out a cyclization reaction of the compound (A6).
　工程１３は、反応を溶媒中で行ってもよく、無溶媒で行ってもよい。溶媒を用いる場合には、反応に影響を与えない溶媒であれば限定は無く、好ましくは、有機溶媒である。有機溶媒としては、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４－ジオキサン、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）トルエン等が挙げられる。 Step 13 may be performed in a solvent or without a solvent. When a solvent is used, there is no limitation as long as the solvent does not affect the reaction, and an organic solvent is preferable. Examples of the organic solvent include diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, N, N-dimethylformamide (DMF) toluene and the like.
　工程１３は、反応を促進するために、さらに塩基を添加することができる。塩基としては、例えば、水素化ナトリウム、水素化カリウム、ナトリウム　メトキシド、ナトリウム　エトキシド、ｎ－ブチルリチウム、ｔｅｒｔ－ブトキシカリウム等が挙げられる。添加する塩基の量は、化合物（Ａ６）１モルに対して、好ましくは、１乃至３モルである。 Step 13 can further add a base to accelerate the reaction. Examples of the base include sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, n-butyl lithium, tert-butoxy potassium and the like. The amount of the base to be added is preferably 1 to 3 mol with respect to 1 mol of compound (A6).
　工程１３の反応温度は、当業者が適宜設定することができる。反応温度としては、通常２０乃至１５０℃であり、好ましくは５０乃至１００℃である。 The reaction temperature in step 13 can be appropriately set by those skilled in the art. The reaction temperature is usually 20 to 150 ° C., preferably 50 to 100 ° C.
（工程１４）
　工程１４は、化合物（Ａ７）とヒドラジンを反応させ、化合物（Ａ８）を得る工程である。
　工程１４は、反応を溶媒中で行ってもよく、無溶媒で行ってもよい。溶媒を用いる場合には、反応に影響を与えない溶媒であれば限定は無く、好ましくは、有機溶媒である。有機溶媒としては、エタノール、ｎ－プロパノール、ｎ－ブタノール等が挙げられる。
　工程１４は、反応を促進するために、さらに酸を添加することができる。酸としては、例えば、酢酸、塩酸、硫酸等が挙げられる。添加する酸の量は、化合物（Ａ７）１モルに対して、好ましくは、１乃至１０モルである。
　工程１４の反応温度は、当業者が適宜設定することができる。反応温度としては、通常２０乃至１５０℃であり、好ましくは５０乃至１２０℃である。 (Step 14)
Step 14 is a step in which compound (A7) and hydrazine are reacted to obtain compound (A8).
Step 14 may be performed in a solvent or without a solvent. When a solvent is used, there is no limitation as long as the solvent does not affect the reaction, and an organic solvent is preferable. Examples of the organic solvent include ethanol, n-propanol, n-butanol and the like.
In step 14, an acid can be further added to accelerate the reaction. Examples of the acid include acetic acid, hydrochloric acid, sulfuric acid and the like. The amount of the acid to be added is preferably 1 to 10 mol with respect to 1 mol of the compound (A7).
The reaction temperature in step 14 can be appropriately set by those skilled in the art. The reaction temperature is usually 20 to 150 ° C., preferably 50 to 120 ° C.
（工程１５）
　工程１５は、化合物（Ａ７）のアミノ基をＰ１基で保護して、化合物（Ａ１）を得る工程である。アミノ基のＰ１基による保護反応は当業者に周知の方法で行うことができる（例えば、Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ　第４版、Ｔ．Ｗ．Ｇｒｅｅｎｅ、Ｐ．Ｇ．Ｍ．Ｗｕｔｓ著、Ｊｏｈｎ　Ｗｉｌｅｙ　＆　Ｓｏｎｓ　Ｉｎｃ．（２００６年）等に記載の方法）。 (Step 15)
Step 15 is a step of obtaining compound (A1) by protecting the amino group of compound (A7) with P 1 group. The protection reaction of the amino group with the P 1 group can be carried out by methods well known to those skilled in the art (for example, Protective Groups in Organic Synthesis 4th edition, TW Greene, PGM Wuts, John Wiley). & Sons Inc. (2006) etc.).
　以下に、本実施形態に係る化合物またはその薬学上許容される塩について、実施例（実施例１乃至８９）、参考例（参考例１乃至１０８）、および、試験例（試験例１乃至６）を示して本発明を更に詳細に説明するが、これらの例示は本発明をよりよく理解するためのものであり、本発明の範囲を限定するものではない。 Hereinafter, with respect to the compounds according to the present embodiment or pharmaceutically acceptable salts thereof, Examples (Examples 1 to 89), Reference Examples (Reference Examples 1 to 108), and Test Examples (Test Examples 1 to 6) The present invention will be described in more detail with reference to the following examples, but these examples are for better understanding of the present invention and are not intended to limit the scope of the present invention.
　シリカゲルカラムクロマトグラフィーにおけるＤＩＯＬシリカゲルとは、富士シリシア化学社製ＣＨＲＯＭＡＴＯＲＥＸ（商品名）ＤＩＯＬ　ＭＢ　１００－４０／７５を示す。 DIOL silica gel in silica gel column chromatography refers to CHROMATOREX (trade name) DIOL MB 100-40 / 75 manufactured by Fuji Silysia Chemical Ltd.
　シリカゲルカラムクロマトグラフィーにおけるＤＮＨシリカゲルとは、富士シリシア化学社製ＣＨＲＯＭＡＴＯＲＥＸ（商品名）ＤＮＨ　ＭＢ　１００－４０／７５を示す。 DNH silica gel in silica gel column chromatography refers to CHROMATOREX (trade name) DNH MB 100-40 / 75 manufactured by Fuji Silysia Chemical Ltd.
　同位体の存在によりマススペクトルの値が複数観測される場合は、ｍ／ｚが最小のもののみ記載した。マススペクトルのイオン化モードのＤＵＩＳとは、ＥＳＩとＡＰＣＩのミックスモードである。 When multiple mass spectrum values were observed due to the presence of isotopes, only those with the smallest m / z were listed. The mass spectrum ionization mode DUIS is a mixed mode of ESI and APCI.
　１Ｈ－ＮＭＲは、特記しない限り、テトラメチルシランを内部標準（０ｐｐｍ）とする化学シフト（δ）で表示され、カップリング定数（Ｊ値）はＨｚ単位で表記する。また、各ピークの分裂パターンの略号は、次のとおりの意味である。ｓ：シングレット、ｄ：ダブレット、ｔ：トリプレット、ｑ：カルテット、ｂｒ：ブロード。 Unless otherwise stated, 1 H-NMR is expressed as a chemical shift (δ) with tetramethylsilane as an internal standard (0 ppm), and the coupling constant (J value) is expressed in Hz. Moreover, the abbreviations of the splitting pattern of each peak have the following meanings. s: singlet, d: doublet, t: triplet, q: quartet, br: broad.
　実施例及び参考例中に記載される略号は、通常、有機化学、薬学の分野で一般的に使用される意味で使用される。各略号は、具体的には、以下のように当業者に理解されるものである。
ＡＴＰ：アデノシン三リン酸
Ｂｏｃ：ｔｅｒｔ－ブチルオキシカルボニル
Ｃｂｚ：ベンジルオキシカルボニル
ＤＩＰＥＡ：Ｎ，Ｎ－ジイソプロピルエチルアミン
ＤＭＦ：Ｎ，Ｎ－ジメチルホルムアミド
ＤＭＳＯ：ジメチルスルホキシド
ＤＴＴ：ジチオスレイトール
Ｅｔ：エチル
ＦＢＳ：ウシ胎児血清
ＨＥＰＥＳ：Ｎ－２－ヒドロキシエチルピペラジン－Ｎ’－２－エタンスルホン酸
ＭＢＰ：ミエリン塩基タンパク
ｎ－：ノルマル
ＮＡＤＰＨ：ニコチンアミドアデニンジヌクレオチドリン酸
ＰＢＭＣ：末梢血単核球
ＰＢＳ：リン酸緩衝塩化ナトリウム水溶液
ＴＢＭＥ：ｔｅｒｔ－ブチルメチルエーテル
ＴＢＳ：ｔｅｒｔ－ブチルジメチルシリル
ｔｅｒｔ－：ターシャリー
ＴＨＦ：テトラヒドロフラン
Ｔｒｉｓ：トリスヒドロキシアミノメタン Abbreviations described in Examples and Reference Examples are usually used in the meaning commonly used in the fields of organic chemistry and pharmacy. Each abbreviation is specifically understood by those skilled in the art as follows.
ATP: adenosine triphosphate Boc: tert-butyloxycarbonyl Cbz: benzyloxycarbonyl DIPEA: N, N-diisopropylethylamine DMF: N, N-dimethylformamide DMSO: dimethyl sulfoxide DTT: dithiothreitol Et: ethyl FBS: fetal bovine Serum HEPES: N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid MBP: myelin base protein n-: normal NADPH: nicotinamide adenine dinucleotide phosphate PBMC: peripheral blood mononuclear cells PBS: phosphate buffered chloride Sodium aqueous solution TBME: tert-butyl methyl ether TBS: tert-butyldimethylsilyl tert-: tertiary THF: tetrahydrofuran Tris: trishydroxyaminomethane
（実施例１）
（Ｓ）－Ｎ－（２－ヒドロキシ－１－フェニルエチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－１８）
Figure JPOXMLDOC01-appb-C000042
 Example 1
(S) -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide (Compound No. IV-18)
Figure JPOXMLDOC01-appb-C000042
　参考例３と同様に合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート３０８ｍｇ（０．６９８ｍｍｏｌ）のＴＨＦ６ｍｌ溶液に、ＤＩＰＥＡ０．２３ｍｌ（１．４ｍｍｏｌ）、（Ｓ）－（＋）－２－フェニルグリシノール４７２ｍｇ（３．４４ｍｍｏｌ）を室温で加えた後、マイクロウエーブ反応装置に供し、８０℃で１時間反応させた。次いで、反応液にメタノール２．７ｍｌ（６７ｍｍｏｌ）、トリエチルアミン２．７ｍｌ（１９ｍｍｏｌ）を加えた後、マイクロウエーブ反応装置に供し、８０℃で０．５時間反応した。
　反応終了後、反応液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～９８：２（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣に対し酢酸エチル／ジエチルエーテルで晶析を行い、得られた固体を濾取した。得られた固体に水２０ｍｌを加え撹拌後、不溶物を濾取、減圧乾燥することにより、標記化合物１５２ｍｇ（収率４６％）を白色固体として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：４７０［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.20 & 11.65 (br s, total 1H), 9.66 - 9.46 (m, 1H), 7.41 - 7.25 (m, 4H), 7.22- 7.15 (m, 1H), 6.18 & 6.06 (d, J = 7.7 Hz, total 1H), 4.88 (t, J = 5.9 Hz,1H), 4.83 - 4.71 (m, 1H), 4.62 - 4.41 (m, 2H), 3.69 - 3.52 (m, 2H), 2.49 - 2.41(m, 2H), 2.30 - 2.12 (m, 2H), 1.93 - 1.73 (m, 2H), 1.68 - 1.44 (m, 6H), 0.17 -0.04 (m, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 synthesized as in Reference Example 3 To a solution of (4H) -carboxylate 308 mg (0.698 mmol) in THF 6 ml, DIPEA 0.23 ml (1.4 mmol) and (S)-(+)-2-phenylglycinol 472 mg (3.44 mmol) were added at room temperature. Then, it was used in a microwave reactor and reacted at 80 ° C. for 1 hour. Next, 2.7 ml (67 mmol) of methanol and 2.7 ml (19 mmol) of triethylamine were added to the reaction solution, which was then subjected to a microwave reactor and reacted at 80 ° C. for 0.5 hour.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 98: 2 (V / V)), and the fraction containing the desired product was reduced in pressure. Concentrated. The resulting concentrated residue was crystallized from ethyl acetate / diethyl ether, and the resulting solid was collected by filtration. After adding 20 ml of water to the obtained solid and stirring, the insoluble matter was collected by filtration and dried under reduced pressure to obtain 152 mg (yield 46%) of the title compound as a white solid.
Mass spectrum (DUIS, m / z): 470 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.20 & 11.65 (br s, total 1H), 9.66-9.46 (m, 1H), 7.41-7.25 (m, 4H), 7.22- 7.15 (m, 1H), 6.18 & 6.06 (d, J = 7.7 Hz, total 1H), 4.88 (t, J = 5.9 Hz, 1H), 4.83-4.71 (m, 1H), 4.62-4.41 (m, 2H), 3.69- 3.52 (m, 2H), 2.49-2.41 (m, 2H), 2.30-2.12 (m, 2H), 1.93-1.73 (m, 2H), 1.68-1.44 (m, 6H), 0.17 -0.04 (m, 9H ).
（実施例２）
（Ｓ）－Ｎ－（２－ヒドロキシ－１－フェニルエチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＩＩ－１１）
Figure JPOXMLDOC01-appb-C000043
 (Example 2)
(S) -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide (Compound No. III-11)
Figure JPOXMLDOC01-appb-C000043
　参考例７と同様にして合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート　塩酸塩４３３ｍｇ（１．０８ｍｍｏｌ）の脱水ジクロロメタン７．５ｍｌ溶液に、窒素雰囲気下、ＤＩＰＥＡ０．９０ｍｌ（５．２ｍｍｏｌ）を室温で加えた後、ビス（トリクロロメチル）カルボナート２７５ｍｇ（０．９２８ｍｍｏｌ）の脱水ジクロロメタン２．５ｍｌ溶液を－７８℃で滴下しながら加え、同温度で２．５時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液１０ｍｌを加え、成り行きで室温まで昇温させながら撹拌した。有機層と水層を分けた後、水層をジクロロメタンで２回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９０：１０～８０：２０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥して濃縮残渣を得た。
　得られた濃縮残渣４５７ｍｇの脱水ＴＨＦ４ｍｌ溶液に、窒素雰囲気下、ＤＩＰＥＡ０．４０ｍｌ（２．２ｍｍｏｌ）、（Ｓ）－（＋）－２－フェニルグリシノール５２８ｍｇ（３．８５ｍｍｏｌ）を室温で加えた後、加熱還流させながら３．７５時間撹拌した。次いで、反応液にトリエチルアミン０．９０ｍｌ（６．５ｍｍｏｌ）、メタノール０．９０ｍｌ（２２ｍｍｏｌ）を加えた後、加熱還流させながら１時間撹拌した。
　反応終了後、反応液に水を加え、ジクロロメタンで３回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＮＨシリカゲル，溶出溶媒；ジクロロメタン：メタノール＝１００：０～９７：３（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣に対し酢酸エチル／ジイソプロピルエーテル／ｎ－ヘキサンで晶析を行い、析出した固体を濾取し、ｎ－ヘキサンで掛け洗いした後、減圧乾燥することにより標記化合物３８８ｍｇ（収率７９％［２工程］）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４５６［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.02 & 11.54 (br s, total 1H), 9.44 & 9.25 (br s, total1H), 7.40 - 7.33 (m, 2H), 7.33 - 7.24 (m, 2H), 7.23 - 7.16 (m, 1H), 5.88 - 5.69(m, 1H), 4.86 - 4.79 (m, 1H), 4.61 (t, J = 5.6 Hz, 1H), 4.55 - 4.37 (m, 2H), 3.71 - 3.64 (m, 2H), 1.63 (s,3H), 1.57 (s, 3H), 1.08 - 1.01 (m, 2H), 0.83 - 0.60 (m, 2H), 0.07 (s, 9H)。 Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxy synthesized as in Reference Example 7 To a solution of 433 mg (1.08 mmol) of Lato hydrochloride in 7.5 ml of dehydrated dichloromethane was added DIPEA (0.90 ml, 5.2 mmol) at room temperature under a nitrogen atmosphere, and then 275 mg (0.928 mmol) of bis (trichloromethyl) carbonate was added. A 2.5 ml solution of dehydrated dichloromethane was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 2.5 hours.
After completion of the reaction, 10 ml of a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, followed by stirring while raising the temperature to room temperature. After separating the organic layer and the aqueous layer, the aqueous layer was extracted twice with dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 80:20 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure. To obtain a concentrated residue.
After adding 0.40 ml (2.2 mmol) of DIPEA and 528 mg (3.85 mmol) of (S)-(+)-2-phenylglycinol to a solution of the obtained concentrated residue 457 mg in dehydrated THF 4 ml under a nitrogen atmosphere at room temperature. The mixture was stirred for 3.75 hours while being heated to reflux. Next, after adding 0.90 ml (6.5 mmol) of triethylamine and 0.90 ml (22 mmol) of methanol to the reaction solution, the mixture was stirred for 1 hour while being heated to reflux.
After completion of the reaction, water was added to the reaction solution and extracted three times with dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DNH silica gel, elution solvent; dichloromethane: methanol = 100: 0 to 97: 3 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The concentrated residue thus obtained was crystallized from ethyl acetate / diisopropyl ether / n-hexane, and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 388 mg (yield) 79% [2 steps]) was obtained as a white solid.
Mass spectrum (CI, m / z): 456 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.02 & 11.54 (br s, total 1H), 9.44 & 9.25 (br s, total 1H), 7.40-7.33 (m, 2H), 7.33-7.24 (m , 2H), 7.23-7.16 (m, 1H), 5.88-5.69 (m, 1H), 4.86-4.79 (m, 1H), 4.61 (t, J = 5.6 Hz, 1H), 4.55-4.37 (m, 2H ), 3.71-3.64 (m, 2H), 1.63 (s, 3H), 1.57 (s, 3H), 1.08-1.01 (m, 2H), 0.83-0.60 (m, 2H), 0.07 (s, 9H).
（実施例３）
（Ｓ）－Ｎ－（２－ヒドロキシ－１－フェニルエチル）－６，６－ジメチル－３－［２－メチル－２－（トリメチルシリル）プロパンアミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＩ－１３）
Figure JPOXMLDOC01-appb-C000044
 (Example 3)
(S) -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-3- [2-methyl-2- (trimethylsilyl) propanamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide (Compound No. II-13)
Figure JPOXMLDOC01-appb-C000044
　参考例９と同様にして合成した５－ｔｅｒｔ－ブチル　１－エチル　６，６－ジメチル－３－［２－メチル－２－（トリメチルシリル）プロパンアミド］ピロロ［３，４－ｃ］ピラゾール－１，５（４Ｈ，６Ｈ）－ジカルボキシラート３３７ｍｇ（０．７１４ｍｍｏｌ）の脱水ジクロロメタン３ｍｌ溶液に、窒素雰囲気下、２，６－ルチジン０．２５ｍｌ（２．２ｍｍｏｌ）、トリメチルシリル　トリフルオロメタンスルホナート０．３９ｍｌ（２．２ｍｍｏｌ）を０℃で順次加え、同温度で１．５時間撹拌した。
　反応終了後、反応液をジクロロメタンで希釈し、次いで飽和炭酸水素ナトリウム水溶液で洗浄した。有機層と水層を分けた後、水層をジクロロメタンで２回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣にトルエン２５ｍｌを加え、それを減圧濃縮する操作を３回繰り返した後、減圧乾燥して濃縮残渣を得た。
　得られた濃縮残渣２９２ｍｇの脱水ジクロロメタン５ｍｌ溶液に、窒素雰囲気下、ＤＩＰＥＡ０．３８ｍｌ（２．２ｍｍｏｌ）を室温で加えた後、ビス（トリクロロメチル）カルボナート１４９ｍｇ（０．５０２ｍｍｏｌ）を－７８℃で加え、同温度で２．５時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液７ｍｌを加え、成り行きで室温まで昇温させながら撹拌した。有機層と水層を分けた後、水層をジクロロメタンで１回抽出した。全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９０：１０～８５：１５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥して濃縮残渣を得た。
　得られた濃縮残渣２６２ｍｇの脱水ＴＨＦ３ｍｌ溶液に、窒素雰囲気下、ＤＩＰＥＡ０．２７ｍｌ（１．６ｍｍｏｌ）、（Ｓ）－（＋）－２－フェニルグリシノール２５５ｍｇ（１．８６ｍｍｏｌ）を室温で加えた後、加熱還流させながら２．５時間撹拌した。次いで、反応液にトリエチルアミン１．０ｍｌ（７．２ｍｍｏｌ）、メタノール１．０ｍｌ（２５ｍｍｏｌ）を加えた後、加熱還流させながら５．５時間撹拌した。
　反応終了後、反応液に水を加え、ジクロロメタンで３回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣に酢酸０．１０ｍｌを加えた後、シリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ジクロロメタン：メタノール＝１００：０～９７：３（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣に対し酢酸エチル／ｎ－ヘキサンで晶析を行い、得られた固体を濾取し、ｎ－ヘキサンで掛け洗いした後、減圧乾燥することにより標記化合物２０６ｍｇ（収率６３％［３工程］）を微黄色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４５８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.25 & 11.64 (br s, total 1H), 9.42 - 9.11 (m, 1H), 7.38 -7.25 (m, 4H), 7.23 - 7.15 (m, 1H), 6.21 - 6.05 (m, 1H), 4.87 (t, J = 5.9 Hz, 1H), 4.81 - 4.73 (m, 1H), 4.57 -4.41 (m, 2H), 3.70 - 3.54 (m, 2H), 1.66 - 1.47 (m, 6H), 1.25 (s, 6H), 0.04 (s,9H)。 5-tert-butyl 1-ethyl 6,6-dimethyl-3- [2-methyl-2- (trimethylsilyl) propanamide] pyrrolo [3,4-c] pyrazole-1, synthesized in the same manner as in Reference Example 9. To a solution of 337 mg (0.714 mmol) of 5 (4H, 6H) -dicarboxylate in 3 ml of dehydrated dichloromethane was added 0.25 ml (2.2 mmol) of 2,6-lutidine, 0.39 ml of trimethylsilyl trifluoromethanesulfonate under a nitrogen atmosphere ( 2.2 mmol) was added sequentially at 0 ° C., and the mixture was stirred at the same temperature for 1.5 hours.
After completion of the reaction, the reaction solution was diluted with dichloromethane and then washed with a saturated aqueous sodium hydrogen carbonate solution. After separating the organic layer and the aqueous layer, the aqueous layer was extracted twice with dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The operation of adding 25 ml of toluene to the obtained concentrated residue and concentrating it under reduced pressure was repeated three times, followed by drying under reduced pressure to obtain a concentrated residue.
To a solution of 292 mg of the concentrated residue in 5 ml of dehydrated dichloromethane, 0.38 ml (2.2 mmol) of DIPEA was added at room temperature under a nitrogen atmosphere, and then 149 mg (0.502 mmol) of bis (trichloromethyl) carbonate was added at −78 ° C. The mixture was stirred at the same temperature for 2.5 hours.
After completion of the reaction, 7 ml of a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, followed by stirring while raising the temperature to room temperature. After separating the organic layer and the aqueous layer, the aqueous layer was extracted once with dichloromethane. All organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 85:15 (V / V)), and the fraction containing the target product was concentrated under reduced pressure and dried under reduced pressure. To obtain a concentrated residue.
To a solution of 262 mg of the obtained concentrated residue in 3 ml of dehydrated THF, 0.27 ml (1.6 mmol) of DIPEA and 255 mg (1.86 mmol) of (S)-(+)-2-phenylglycinol were added at room temperature under a nitrogen atmosphere. The mixture was stirred for 2.5 hours while being heated to reflux. Next, 1.0 ml (7.2 mmol) of triethylamine and 1.0 ml (25 mmol) of methanol were added to the reaction solution, and then stirred for 5.5 hours while heating to reflux.
After completion of the reaction, water was added to the reaction solution and extracted three times with dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After adding 0.10 ml of acetic acid to the obtained concentrated residue, silica gel column chromatography (DIOL silica gel, elution solvent; dichloromethane: methanol = 100: 0 to 97: 3 (V / V)) was applied to obtain the target product. Containing fractions were concentrated under reduced pressure. The concentrated residue thus obtained was crystallized from ethyl acetate / n-hexane, and the resulting solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 206 mg (yield 63%) of the title compound. [3 steps]) was obtained as a slightly yellow solid.
Mass spectrum (CI, m / z): 458 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.25 & 11.64 (br s, total 1H), 9.42-9.11 (m, 1H), 7.38 -7.25 (m, 4H), 7.23-7.15 (m, 1H), 6.21-6.05 (m, 1H), 4.87 (t, J = 5.9 Hz, 1H), 4.81-4.73 (m, 1H), 4.57 -4.41 (m, 2H), 3.70-3.54 (m, 2H) , 1.66-1.47 (m, 6H), 1.25 (s, 6H), 0.04 (s, 9H).
（実施例４）
（Ｓ）－３－［１－（エチルジメチルシリル）シクロブタンカルボキサミド］－Ｎ－（２－ヒドロキシ－１－フェニルエチル）－６，６－ジメチル－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－２０）
Figure JPOXMLDOC01-appb-C000045
 Example 4
(S) -3- [1- (Ethyldimethylsilyl) cyclobutanecarboxamide] -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide (Compound No. IV-20)
Figure JPOXMLDOC01-appb-C000045
　参考例１３と同様にして合成したエチル　５－（クロロカルボニル）－３－［１－（エチルジメチルシリル）シクロブタンカルボキサミド］－６，６－ジメチル－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート４５４ｍｇ（０．９９７ｍｍｏｌ）の脱水ＴＨＦ１０ｍｌ溶液に、アルゴン雰囲気下、（Ｓ）－（＋）－２－フェニルグリシノール７００ｍｇ（５．１０ｍｍｏｌ）、ＤＩＰＥＡ０．３５ｍｌ（２．０ｍｍｏｌ）を室温で加えた後、６０℃で４時間撹拌した。次いで、反応液にメタノール６ｍｌ、トリエチルアミン２ｍｌを加え、６０℃で２時間撹拌した。
　反応終了後、反応液を減圧濃縮し、得られた濃縮残渣に飽和炭酸水素ナトリウム水溶液を加え、その混合液をジクロロメタンで３回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥し、濾過後、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～９８：２（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。濃縮残渣に対しジクロロメタン／ジイソプロピルエーテルで晶析を行い、析出した固体を濾取し、次いで減圧乾燥することにより、標記化合物４０４ｍｇ（収率８４％）を白色固体として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：４８４［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.20 & 11.66 (br s, total 1H), 9.64 - 9.47 (m, 1H), 7.40 -7.14 (m, 5H), 6.26 - 6.01 (m, 1H), 4.88 (t, J = 5.8 Hz, 1H), 4.83 - 4.71 (m,1H), 4.60 - 4.43 (m, 2H), 3.66 - 3.54 (m, 2H), 2.48 - 2.42 (m, 2H), 2.33 - 2.14(m, 2H), 1.93 - 1.72 (m, 2H), 1.67 - 1.45 (m, 6H), 0.92 (t, J = 7.9 Hz, 3H),0.60 (q, J = 7.9 Hz, 2H), 0.08 (s, 6H)。 Ethyl 5- (chlorocarbonyl) -3- [1- (ethyldimethylsilyl) cyclobutanecarboxamide] -6,6-dimethyl-5,6-dihydropyrrolo [3,4-c] synthesized as in Reference Example 13 To a solution of 454 mg (0.997 mmol) of pyrazole-2 (4H) -carboxylate in 10 ml of dehydrated THF, argon (S)-(+)-2-phenylglycinol 700 mg (5.10 mmol), DIPEA 0.35 ml (2 0.0 mmol) was added at room temperature, followed by stirring at 60 ° C. for 4 hours. Next, 6 ml of methanol and 2 ml of triethylamine were added to the reaction solution, and the mixture was stirred at 60 ° C. for 2 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the resulting concentrated residue, and the mixture was extracted three times with dichloromethane. The obtained all organic layers were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 98: 2 (V / V)), and the fraction containing the desired product was reduced in pressure. Concentrated. The concentrated residue was crystallized from dichloromethane / diisopropyl ether, and the precipitated solid was collected by filtration and then dried under reduced pressure to obtain 404 mg (yield 84%) of the title compound as a white solid.
Mass spectrum (DUIS, m / z): 484 [M + 1] + .
1 H-NMR spectrum (400MHz, DMSO-d 6) δ: 12.20 & 11.66 (br s, total 1H), 9.64 - 9.47 (m, 1H), 7.40 -7.14 (m, 5H), 6.26 - 6.01 (m, 1H), 4.88 (t, J = 5.8 Hz, 1H), 4.83-4.71 (m, 1H), 4.60-4.43 (m, 2H), 3.66-3.54 (m, 2H), 2.48-2.42 (m, 2H) , 2.33-2.14 (m, 2H), 1.93-1.72 (m, 2H), 1.67-1.45 (m, 6H), 0.92 (t, J = 7.9 Hz, 3H), 0.60 (q, J = 7.9 Hz, 2H ), 0.08 (s, 6H).
（実施例５）
（Ｓ）－３－［２－（エチルジメチルシリル）－２－メチルプロパンアミド］－Ｎ－（２－ヒドロキシ－１－フェニルエチル）－６，６－ジメチル－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＩ－１４）
Figure JPOXMLDOC01-appb-C000046
 (Example 5)
(S) -3- [2- (Ethyldimethylsilyl) -2-methylpropanamide] -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-4,6-dihydropyrrolo [3 4-c] pyrazole-5 (1H) -carboxamide (Compound No. II-14)
Figure JPOXMLDOC01-appb-C000046
　参考例１６と同様にして合成したエチル　３－［２－（エチルジメチルシリル）－２－メチルプロパンアミド］－６，６－ジメチル－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－１（４Ｈ）－カルボキシラート２．４４ｇ（６．４１ｍｍｏｌ）の脱水ジクロロメタン３０ｍｌ溶液に、窒素雰囲気下、ＤＩＰＥＡ５．６ｍｌ（３２ｍｍｏｌ）、ビス（トリクロロメチル）カルボナート１．３３ｇ（４．４８ｍｍｏｌ）の脱水ジクロロメタン１０ｍｌ溶液を－７８℃で順次加え、同温度で１時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加え、攪拌しながら成り行きで室温まで昇温した。分液後、水層をジクロロメタンで抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９５：５～７０：３０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、濃縮残渣２．５１ｇを得た。
　得られた濃縮残渣４７４ｍｇの脱水ＴＨＦ１０ｍｌ溶液に、アルゴン雰囲気下、（Ｓ）－２－アミノ－２－フェニルエタノール７００ｍｇ（５．１０ｍｍｏｌ）、ＤＩＰＥＡ０．３５ｍｌ（２．０ｍｍｏｌ）を室温で加えた後、マイクロウエーブ反応装置に供し、１００℃で２時間反応した。放冷後、メタノール６ｍｌ、トリエチルアミン２ｍｌを加え、マイクロウエーブ反応装置に供し、８０℃で３時間反応した。
　反応終了後、反応液を減圧濃縮し、得られた濃縮残渣に飽和炭酸水素ナトリウム水溶液を加え、その混合液をジクロロメタンで３回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～９８：２（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。濃縮残渣に対しジクロロメタン／ジイソプロピルエーテルで晶析を行い、析出した固体を濾取し、次いで減圧乾燥することにより、標記化合物３２１ｍｇ（収率５６％［２工程］）を白色固体として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：４７２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.26 & 11.67 (br s, total 1H), 9.42 - 9.16 (m, 1H), 7.38 - 7.25(m, 4H), 7.25 - 7.14 (m, 1H), 6.20 - 6.04 (m, 1H), 4.88 (t, J = 5.8 Hz, 1H),4.82 - 4.72 (m, 1H), 4.55 - 4.42 (m, 2H), 3.66 - 3.55 (m, 2H), 1.64 - 1.48 (m,6H), 1.26 (s, 6H), 0.90 (t, J = 7.9 Hz, 3H), 0.56 (q, J = 7.9 Hz, 2H), 0.02 (s,6H)。 Ethyl 3- [2- (ethyldimethylsilyl) -2-methylpropanamide] -6,6-dimethyl-5,6-dihydropyrrolo [3,4-c] pyrazole-1 synthesized in the same manner as in Reference Example 16 A solution of 2.44 g (6.41 mmol) of (4H) -carboxylate in 30 ml of dehydrated dichloromethane and 10 ml of dehydrated dichloromethane of 5.6 ml (32 mmol) of DIPEA and 1.33 g (4.48 mmol) of bis (trichloromethyl) carbonate in a nitrogen atmosphere. The solution was added sequentially at −78 ° C. and stirred at the same temperature for 1 hour.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the temperature was increased to room temperature while stirring. After separation, the aqueous layer was extracted with dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 95: 5 to 70:30 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. 2.51 g of concentrated residue was obtained.
(S) -2-Amino-2-phenylethanol 700 mg (5.10 mmol) and DIPEA 0.35 ml (2.0 mmol) were added to a solution of the obtained concentrated residue 474 mg in dehydrated THF 10 ml under an argon atmosphere at room temperature. It was used in a microwave reactor and reacted at 100 ° C. for 2 hours. After allowing to cool, 6 ml of methanol and 2 ml of triethylamine were added, and the mixture was subjected to a microwave reactor and reacted at 80 ° C. for 3 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the resulting concentrated residue, and the mixture was extracted three times with dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 98: 2 (V / V)), and the fraction containing the desired product was reduced in pressure. Concentrated. The concentrated residue was crystallized from dichloromethane / diisopropyl ether, and the precipitated solid was collected by filtration and then dried under reduced pressure to obtain 321 mg (yield 56% [2 steps]) of the title compound as a white solid.
Mass spectrum (DUIS, m / z): 472 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.26 & 11.67 (br s, total 1H), 9.42-9.16 (m, 1H), 7.38-7.25 (m, 4H), 7.25-7.14 (m, 1H), 6.20-6.04 (m, 1H), 4.88 (t, J = 5.8 Hz, 1H), 4.82-4.72 (m, 1H), 4.55-4.42 (m, 2H), 3.66-3.55 (m, 2H) , 1.64-1.48 (m, 6H), 1.26 (s, 6H), 0.90 (t, J = 7.9 Hz, 3H), 0.56 (q, J = 7.9 Hz, 2H), 0.02 (s, 6H).
（実施例６）
（Ｓ）－２－［（２－メトキシプロパン－２－イル）オキシ］－１－フェニルエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキシラート（化合物番号ＶＩ－１００）
Figure JPOXMLDOC01-appb-C000047
 (Example 6)
(S) -2-[(2-Methoxypropan-2-yl) oxy] -1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxylate (Compound No. VI-100)
Figure JPOXMLDOC01-appb-C000047
　参考例４と同様にして合成した５－ｔｅｒｔ－ブチル　１－エチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］ピロロ［３，４－ｃ］ピラゾール－１，５（４Ｈ，６Ｈ）－ジカルボキシラート２２５ｍｇ（０．４７０ｍｍｏｌ）より参考例５と同様の反応を行い得た粗エチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－１（４Ｈ）－カルボキシラート２０５ｍｇ［不純物を含む］に、窒素雰囲気下、参考例１８と同様にして合成した（Ｓ）－２，５－ジオキソピロリジン－１－イル　｛２－［（２－メトキシプロパン－２－イル）オキシ］－１－フェニルエチル｝カルボナート１８７ｍｇ（０．５３３ｍｍｏｌ）のＴＨＦ３ｍｌ溶液、ＤＩＰＥＡ０．２８ｍｌ（１．６ｍｍｏｌ）を室温で加え、同温度で１５時間撹拌した。次いで、反応液にトリエチルアミン１．０ｍｌ（７．２ｍｍｏｌ）、メタノール０．７０ｍｌ（１７ｍｍｏｌ）を加え、室温で４．５時間、加熱還流させながら２時間撹拌した後、反応液に（Ｓ）－２－アミノ－２－フェニルエタノール２４７ｍｇ（１．８０ｍｍｏｌ）を加え、加熱還流させながら４．５時間撹拌した。
　反応終了後、反応液に水を加え、ジクロロメタンで３回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝８０：２０～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣に対し酢酸エチル／ｎ－ヘキサンで晶析を行い、析出した固体を濾取し、ｎ－ヘキサンで掛け洗いした後、減圧乾燥することにより標記化合物２２．７ｍｇ（収率９％［２工程］）を白色固体として得た。更に濾液を減圧濃縮、減圧乾燥することにより標記化合物１７８ｍｇ（収率７０％［２工程］）を白色泡状物として得た。
マススペクトル（ＥＳＩ，ｍ／ｚ）：５６５［Ｍ＋２３（Ｎａ）］＋，５４１［Ｍ－１］－。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.35 - 12.19 & 11.96 - 11.80 (m, total 1H), 9.85 - 9.44 (m,1H), 7.45 - 7.26 (m, 5H), 5.81 - 5.68 (m, 1H), 4.63 - 4.18 (m, 2H), 3.72 - 3.50(m, 2H), 3.08 - 2.94 (m, 3H), 2.56 - 2.38 (m, 2H), 2.30 - 2.10 (m, 2H), 1.94 -1.75 (m, 2H), 1.73 - 1.45 (m, 6H), 1.32 - 1.18 (m, 6H), 0.13 - 0.02 (m, 9H)。 5-tert-butyl 1-ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] pyrrolo [3,4-c] pyrazole-1,5 (4H, synthesized in the same manner as in Reference Example 4 6H) -Dicarboxylate 225 mg (0.470 mmol) of crude ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo obtained by the same reaction as in Reference Example 5 (S) -2,5-dioxopyrrolidine-1 synthesized in the same manner as in Reference Example 18 under nitrogen atmosphere with 205 mg of [3,4-c] pyrazole-1 (4H) -carboxylate [containing impurities] -Yl {2-[(2-methoxypropan-2-yl) oxy] -1-phenylethyl} carbonate 187 mg (0.533 mmol) l) in THF (3 ml) and DIPEA (0.28 ml, 1.6 mmol) were added at room temperature, and the mixture was stirred at the same temperature for 15 hours. Next, 1.0 ml (7.2 mmol) of triethylamine and 0.70 ml (17 mmol) of methanol were added to the reaction solution, and the mixture was stirred at room temperature for 4.5 hours with heating under reflux for 2 hours. -Amino-2-phenylethanol (247 mg, 1.80 mmol) was added, and the mixture was stirred for 4.5 hours while heating to reflux.
After completion of the reaction, water was added to the reaction solution and extracted three times with dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 80: 20 to 50:50 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The obtained concentrated residue was crystallized from ethyl acetate / n-hexane, and the precipitated solid was collected by filtration, washed with n-hexane, and dried under reduced pressure to give 22.7 mg (yield 9). % [2 steps]) as a white solid. Further, the filtrate was concentrated under reduced pressure and dried under reduced pressure to obtain 178 mg (yield 70% [2 steps]) of the title compound as a white foam.
Mass spectrum (ESI, m / z): 565 [M + 23 (Na)] + , 541 [M−1] − .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.35-12.19 & 11.96-11.80 (m, total 1H), 9.85-9.44 (m, 1H), 7.45-7.26 (m, 5H), 5.81-5.68 (m, 1H), 4.63-4.18 (m, 2H), 3.72-3.50 (m, 2H), 3.08-2.94 (m, 3H), 2.56-2.38 (m, 2H), 2.30-2.10 (m, 2H) , 1.94 -1.75 (m, 2H), 1.73-1.45 (m, 6H), 1.32-1.18 (m, 6H), 0.13-0.02 (m, 9H).
（実施例７）
（Ｓ）－２－ヒドロキシ－１－フェニルエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキシラート（化合物番号ＩＶ－１）
Figure JPOXMLDOC01-appb-C000048
 (Example 7)
(S) -2-Hydroxy-1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H)- Carboxylate (Compound No. IV-1)
Figure JPOXMLDOC01-appb-C000048
　実施例６と同様にして合成した（Ｓ）－２－［（２－メトキシプロパン－２－イル）オキシ］－１－フェニルエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキシラート１７５ｍｇ（０．３２２ｍｍｏｌ）のメタノール２．５ｍｌ溶液に、窒素雰囲気下、ピリジニウム　ｐ－トルエンスルホナート９．６ｍｇ（０．０３８ｍｍｏｌ）を０℃で加え、同温度で７０分間撹拌した。
　反応終了後、反応液にトリエチルアミン０．１ｍｌを加えた後に減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝６５：３５～２５：７５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣に対し酢酸エチル／ｎ－ヘキサンで晶析を行い、析出した固体を濾取し、ｎ－ヘキサンで掛け洗いした後、減圧乾燥することにより標記化合物１２４ｍｇ（収率８２％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４７１［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.35 - 12.11 & 11.97 - 11.79 (m, total 1H), 9.84 - 9.46 (m,1H), 7.46 - 7.20 (m, 5H), 5.71 - 5.58 (m, 1H), 5.12 - 4.95 (m, 1H), 4.72 - 4.18(m, 2H), 3.80 - 3.54 (m, 2H), 2.60 - 2.38 (m, 2H), 2.30 - 2.10 (m, 2H), 1.93 -1.74 (m, 2H), 1.74 - 1.43 (m, 6H), 0.16 - 0.02 (m, 9H)。 (S) -2-[(2-methoxypropan-2-yl) oxy] -1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] synthesized in the same manner as in Example 6. 9.6 mg of pyridinium p-toluenesulfonate in a 2.5 ml methanol solution of 175 mg (0.322 mmol) of -4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxylate under a nitrogen atmosphere (0.038 mmol) was added at 0 ° C., and the mixture was stirred at the same temperature for 70 minutes.
After completion of the reaction, 0.1 ml of triethylamine was added to the reaction solution, followed by concentration under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 65: 35 to 25:75 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The resulting concentrated residue was crystallized from ethyl acetate / n-hexane, and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 124 mg of the title compound (yield 82%). Was obtained as a white solid.
Mass spectrum (CI, m / z): 471 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.35-12.11 & 11.97-11.79 (m, total 1H), 9.84-9.46 (m, 1H), 7.46-7.20 (m, 5H), 5.71-5.58 (m, 1H), 5.12-4.95 (m, 1H), 4.72-4.18 (m, 2H), 3.80-3.54 (m, 2H), 2.60-2.38 (m, 2H), 2.30-2.10 (m, 2H) , 1.93 -1.74 (m, 2H), 1.74-1.43 (m, 6H), 0.16-0.02 (m, 9H).
（実施例８）
２－メトキシ－１－フェニルエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキシラート（化合物番号ＩＩＩ－３）
Figure JPOXMLDOC01-appb-C000049
 (Example 8)
2-methoxy-1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxylate ( Compound No. III-3)
Figure JPOXMLDOC01-appb-C000049
　参考例７と同様にして合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート　塩酸塩２．１５ｇ（５．３６ｍｍｏｌ）の脱水ジクロロメタン７２ｍｌ溶液に、ＤＩＰＥＡ３．６ｍｌ（２１ｍｍｏｌ）を室温で加え、次いでドライアイス／アセトン冷媒中で冷却した後、ビス（トリクロロメチル）カルボナート１．１７ｇ（３．９４ｍｍｏｌ）の脱水ジクロロメタン１２ｍｌ溶液を３０分かけて滴下し、同温度で６時間撹拌した。この際、反応の途中でＤＩＰＥＡ３．６ｍｌ（２１ｍｍｏｌ）を４回、ＤＩＰＥＡ（１．０ｍｌ，５．７ｍｍｏｌ）を１回、を順次追加した。
　反応終了後、－７８℃で飽和炭酸水素ナトリウム水溶液４６ｍｌを加えた後、成り行きで室温まで昇温した。反応液を分液後、水層をジクロロメタン５０ｍｌで２回抽出し、得られた全有機層を無水硫酸マグネシウムで乾燥し、濾過後、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７８：２２～５７：４３（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。濃縮残渣にｎ－ヘキサン２０ｍｌを加え、氷冷後、析出した固体を濾取、減圧乾燥することにより、白色固体１．９６ｇを得た。
　得られた白色固体４０．４ｍｇ（０．０９４６ｍｍｏｌ）に２－メトキシ－１－フェニルエタノール［国際公開第２０１２／１３８６４８号公報に記載の方法に準じて合成］２２４ｍｇ（１．４８ｍｍｏｌ）、炭酸カリウム２６．０ｍｇ（０．１８８ｍｍｏｌ）、１，２－ジメトキシエタン０．８ｍｌ、モレキュラーシーブ４Ａ（粉末）８０ｍｇを室温で加えた後、８０℃で２６時間攪拌した。
　反応終了後、不溶物を濾過し、濾液に酢酸エチル１０ｍｌ、水５ｍｌ、飽和塩化ナトリウム水溶液５ｍｌを加えた後、分液した。得られた有機層を無水硫酸マグネシウムで乾燥し、濾過後、濾液を減圧濃縮した。得られた濃縮残渣を４回のシリカゲルカラムクロマトグラフィー（シリカゲル（１回目）、溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～９３：７（Ｖ／Ｖ）：シリカゲル（２回目）、溶出溶媒；酢酸エチル：メタノール＝９８：２～９５：５（Ｖ／Ｖ）：シリカゲル（３回目），溶出溶媒；１，２－ジクロロエタン：メタノール＝９８：２～９５：５（Ｖ／Ｖ）：ＤＮＨシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝９８：２～９５：５（Ｖ／Ｖ））、及び、分取ＨＰＬＣ（カラム；Ｘ－Ｂｒｉｄｇｅ（商品名）ＯＤＳ，溶出溶媒；０．１％ギ酸水溶液：０．１％ギ酸：アセトニトリル＝５０：５０～５：９５（Ｖ／Ｖ）））に付し、目的物を含む画分を希アンモニア水で中和後、減圧濃縮した。得られた濃縮残渣をアセトニトリルと水を加えて溶解した後に凍結乾燥することにより、標記化合物４．１ｍｇ（収率８％［２工程］）を白色泡状物として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：４７１［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.40 - 11.86 (m, 1H), 10.11 - 9.61 (m, 1H),7.49 - 7.22 (m, 5H), 5.90 - 5.71 (m, 1H), 4.63 - 4.14 (m, 2H), 3.77 - 3.51 (m,2H), 3.30 - 3.29 (m, 3H), 1.78 - 1.40 (m, 6H), 1.11 - 0.92 (m, 2H), 0.81 - 0.59(m, 2H), 0.11 - -0.04 (m, 9H)。 Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxy synthesized as in Reference Example 7 To a solution of 2.15 g (5.36 mmol) of the hydrochloride salt in 72 ml of dehydrated dichloromethane, 3.6 ml (21 mmol) of DIPEA was added at room temperature, and after cooling in a dry ice / acetone refrigerant, 1.17 g of bis (trichloromethyl) carbonate was added. A solution of (3.94 mmol) in 12 ml of dehydrated dichloromethane was added dropwise over 30 minutes, and the mixture was stirred at the same temperature for 6 hours. During the reaction, 3.6 ml (21 mmol) of DIPEA and 4 times of DIPEA (1.0 ml, 5.7 mmol) were sequentially added during the reaction.
After completion of the reaction, 46 ml of a saturated aqueous sodium hydrogen carbonate solution was added at −78 ° C., and then the temperature was raised to room temperature. After separation of the reaction solution, the aqueous layer was extracted twice with 50 ml of dichloromethane, and the obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 78: 22 to 57:43 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. 20 ml of n-hexane was added to the concentrated residue, and after cooling with ice, the precipitated solid was collected by filtration and dried under reduced pressure to obtain 1.96 g of a white solid.
To 40.4 mg (0.0946 mmol) of the obtained white solid, 2-methoxy-1-phenylethanol [synthesized according to the method described in International Publication No. 2012/138648], 224 mg (1.48 mmol), potassium carbonate 26 0.0 mg (0.188 mmol), 1,2-dimethoxyethane 0.8 ml, and molecular sieve 4A (powder) 80 mg were added at room temperature, followed by stirring at 80 ° C. for 26 hours.
After completion of the reaction, insoluble matters were filtered, and 10 ml of ethyl acetate, 5 ml of water, and 5 ml of a saturated sodium chloride aqueous solution were added to the filtrate, followed by liquid separation. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography four times (silica gel (first time), elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 93: 7 (V / V): silica gel (second time), Elution solvent; ethyl acetate: methanol = 98: 2 to 95: 5 (V / V): silica gel (third time), elution solvent; 1,2-dichloroethane: methanol = 98: 2 to 95: 5 (V / V) : DNH silica gel, elution solvent; 1,2-dichloroethane: methanol = 98: 2-95: 5 (V / V)), and preparative HPLC (column; X-Bridge (trade name) ODS, elution solvent: 0 1% formic acid aqueous solution: 0.1% formic acid: acetonitrile = 50: 50 to 5:95 (V / V))), and the fraction containing the desired product was neutralized with dilute aqueous ammonia and concentrated under reduced pressure. . The resulting concentrated residue was dissolved by adding acetonitrile and water and then freeze-dried to obtain 4.1 mg (yield: 8% [2 steps]) of the title compound as a white foam.
Mass spectrum (DUIS, m / z): 471 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.40-11.86 (m, 1H), 10.11-9.61 (m, 1H), 7.49-7.22 (m, 5H), 5.90-5.71 (m, 1H) , 4.63-4.14 (m, 2H), 3.77-3.51 (m, 2H), 3.30-3.29 (m, 3H), 1.78-1.40 (m, 6H), 1.11-0.92 (m, 2H), 0.81-0.59 ( m, 2H), 0.11--0.04 (m, 9H).
（実施例９）
（Ｒ）－Ｎ－（３－ヒドロキシ－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－４９）
Figure JPOXMLDOC01-appb-C000050
 Example 9
(R) -N- (3-hydroxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide (Compound No. IV-49)
Figure JPOXMLDOC01-appb-C000050
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート２１６ｍｇ（０．４８９ｍｍｏｌ）の１，４－ジオキサン４．５ｍｌ溶液に、アルゴン雰囲気下、（Ｒ）－３－アミノ－３－フェニルプロパン－１－オール［Ａｒｋ　Ｐｈａｒｍ，Ｉｎｃ．から購入］３７９ｍｇ（２．５１ｍｍｏｌ）、ＤＩＰＥＡ０．１７ｍｌ（０．９９ｍｍｏｌ）を室温で加えた後、マイクロウエーブ反応装置に供し、１００℃で１時間反応した。放冷後、メタノール１．０ｍｌ及びトリエチルアミン０．５ｍｌを加え、マイクロウエーブ反応装置に供し、８０℃で１時間反応させた。
　反応終了後、反応液を減圧濃縮し、酢酸エチル、水及び飽和塩化ナトリウム水溶液を加え、分液した。有機層を無水硫酸マグネシウムで乾燥し、濾過後、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝９９：１～９６：４（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣に対し酢酸エチル／ジイソプロピルエーテルで晶析を行い、析出した固体を濾取、減圧乾燥することにより、標記化合物１７３ｍｇ（収率７３％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４８４［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.19 & 11.66 (s, total 1H), 9.61 -9.47 (m, 1H), 7.39 - 7.13 (m, 5H), 6.46 & 6.38 (d, J= 8.0 Hz, total 1H), 4.92 - 4.83 (m, 1H), 4.66 - 4.33(m, 3H), 3.46 - 3.34 (m, 2H), 2.50 - 2.41 (m, 2H), 2.26 - 2.13 (m, 2H), 2.01 -1.72 (m, 4H), 1.65 - 1.47 (m, 6H), 0.12 - 0.06 (m, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 (R) -3-Amino-3-phenylpropan-1-ol [Ark Pharm, Inc.] was added to a solution of 216 mg (0.489 mmol) of 2 (4H) -carboxylate in 4.5 ml of 1,4-dioxane under an argon atmosphere. . Purchased from] After adding 379 mg (2.51 mmol) and DIPEA 0.17 ml (0.99 mmol) at room temperature, it was subjected to a microwave reactor and reacted at 100 ° C. for 1 hour. After allowing to cool, 1.0 ml of methanol and 0.5 ml of triethylamine were added, and the mixture was used in a microwave reactor and reacted at 80 ° C. for 1 hour.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and ethyl acetate, water and a saturated aqueous sodium chloride solution were added to separate the layers. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 99: 1 to 96: 4 (V / V)), and the fraction containing the desired product was reduced in pressure. Concentrated. The obtained concentrated residue was crystallized from ethyl acetate / diisopropyl ether, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 173 mg (yield 73%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 484 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.19 & 11.66 (s, total 1H), 9.61 -9.47 (m, 1H), 7.39-7.13 (m, 5H), 6.46 & 6.38 (d, J = 8.0 Hz, total 1H), 4.92-4.83 (m, 1H), 4.66-4.33 (m, 3H), 3.46-3.34 (m, 2H), 2.50-2.41 (m, 2H), 2.26-2.13 (m, 2H), 2.01 -1.72 (m, 4H), 1.65-1.47 (m, 6H), 0.12-0.06 (m, 9H).
（実施例１０）
（Ｒ）－Ｎ－（３－ヒドロキシ－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＩＩ－１７）
Figure JPOXMLDOC01-appb-C000051
 (Example 10)
(R) -N- (3-hydroxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide (Compound No. III-17)
Figure JPOXMLDOC01-appb-C000051
　参考例７と同様にして合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート　塩酸塩４６８ｍｇ（１．１７ｍｍｏｌ）の脱水ジクロロメタン１０ｍｌ溶液に、窒素雰囲気下、ＤＩＰＥＡ０．７２ｍｌ（４．１ｍｍｏｌ）を室温で加えた後、ビス（トリクロロメチル）カルボナート２３５ｍｇ（０．７９１ｍｍｏｌ）を－７８℃で加え、同温度で３時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液２０ｍｌを加え、成り行きで室温まで昇温させながら撹拌した。有機層と水層を分けた後、水層をジクロロメタンで２回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９０：１０～７５：２５（Ｖ／Ｖ））に付し、エチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラートを含む画分を減圧濃縮、減圧乾燥することにより濃縮残渣４９０ｍｇを得た。
　得られた濃縮残渣１１３ｍｇの脱水ＴＨＦ２ｍｌ溶液に、窒素雰囲気下、ＤＩＰＥＡ０．１４ｍｌ（０．８０ｍｍｏｌ）、（Ｒ）－３－アミノ－３－フェニルプロパン－１－オール［Ａｒｋ　Ｐｈａｒｍ，Ｉｎｃ．から購入］１０５ｍｇ（０．６９２ｍｍｏｌ）を室温で加えた後、加熱還流させながら２．５時間撹拌した。次いで、２－アミノエタノール０．１０ｍｌ（１．７ｍｍｏｌ）を加えた後、加熱還流させながら２時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで３回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣に酢酸０．１ｍｌを加えた後、シリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝５０：５０～１５：８５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を再度シリカゲルカラムクロマトグラフィー（溶出溶媒；ジクロロメタン：メタノール＝９９：１～９５：５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣に対し酢酸エチル／ｎ－ヘキサンで晶析を行い、析出した固体を濾取し、ｎ－ヘキサンで掛け洗いした後、減圧乾燥することにより、標記化合物４９ｍｇ（収率３９％［２工程］）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４７０［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.22 & 11.84 (br s, total 1H), 9.91 - 9.66 (m, 1H), 7.37 -7.26 (m, 4H), 7.21 - 7.14 (m, 1H), 6.50 - 6.28 (m, 1H), 4.92 - 4.80 (m, 1H), 4.65- 4.52 (m, 1H), 4.49 - 4.31 (m,2H), 3.44 - 3.36 (m, 2H), 2.00 - 1.77 (m, 2H), 1.59 (br s, 3H), 1.51 (br s,3H), 1.06 - 0.93 (m, 2H), 0.81 - 0.61 (m, 2H), 0.03 (s, 9H)。 Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxy synthesized as in Reference Example 7 To a solution of 468 mg (1.17 mmol) of Lato hydrochloride in 10 ml of dehydrated dichloromethane was added 0.72 ml (4.1 mmol) of DIPEA at room temperature under a nitrogen atmosphere, and then 235 mg (0.791 mmol) of bis (trichloromethyl) carbonate was added to -78. The mixture was added at 0 ° C. and stirred at the same temperature for 3 hours.
After completion of the reaction, 20 ml of a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, followed by stirring while raising the temperature to room temperature. After separating the organic layer and the aqueous layer, the aqueous layer was extracted twice with dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 75:25 (V / V)) to obtain ethyl 5- (chlorocarbonyl) -6,6- A fraction containing dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate was concentrated under reduced pressure and dried under reduced pressure. A concentrated residue 490 mg was obtained.
To a solution of 113 mg of the obtained concentrated residue in 2 ml of dehydrated THF, 0.14 ml (0.80 mmol) of DIPEA, (R) -3-amino-3-phenylpropan-1-ol [Ark Pharm, Inc. Purchased from] After adding 105 mg (0.692 mmol) at room temperature, the mixture was stirred for 2.5 hours with heating under reflux. Subsequently, 0.10 ml (1.7 mmol) of 2-aminoethanol was added, and the mixture was stirred for 2 hours while being heated to reflux.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Acetic acid (0.1 ml) was added to the resulting concentrated residue, followed by silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 50: 50 to 15:85 (V / V)), Fractions containing the desired product were concentrated under reduced pressure. The obtained concentrated residue was again subjected to silica gel column chromatography (elution solvent; dichloromethane: methanol = 99: 1 to 95: 5 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The resulting concentrated residue was crystallized from ethyl acetate / n-hexane, and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 49 mg of the title compound (yield 39%). [2 steps]) was obtained as a white solid.
Mass spectrum (CI, m / z): 470 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.22 & 11.84 (br s, total 1H), 9.91-9.66 (m, 1H), 7.37 -7.26 (m, 4H), 7.21-7.14 (m, 1H), 6.50-6.28 (m, 1H), 4.92-4.80 (m, 1H), 4.65- 4.52 (m, 1H), 4.49-4.31 (m, 2H), 3.44-3.36 (m, 2H), 2.00- 1.77 (m, 2H), 1.59 (br s, 3H), 1.51 (br s, 3H), 1.06-0.93 (m, 2H), 0.81-0.61 (m, 2H), 0.03 (s, 9H).
（実施例１１）
（Ｒ）－Ｎ－（４－ヒドロキシ－１－フェニルブチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－６４）
Figure JPOXMLDOC01-appb-C000052
 (Example 11)
(R) -N- (4-hydroxy-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide (Compound No. IV-64)
Figure JPOXMLDOC01-appb-C000052
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１００ｍｇ（０．２２７ｍｍｏｌ）、（Ｒ）－４－アミノ－４－フェニルブタン－１－オール　塩酸塩［ＮｅｔＣｈｅｍ，　Ｉｎｃ．より購入］１３８ｍｇ（０．６８４ｍｍｏｌ）の脱水１，４－ジオキサン２ｍｌ溶液に、アルゴン雰囲気下、ＤＩＰＥＡ０．２４ｍｌ（１．４ｍｍｏｌ）を室温で加え、１００℃で３時間攪拌した。次いで、反応液へトリエチルアミン１ｍｌ、エタノール１ｍｌを加え、８０℃で５時間加熱攪拌した。
　反応終了後、反応液に水を加え、その混合液から酢酸エチルで抽出した。得られた有機層は飽和塩化ナトリウム水溶液で洗浄、無水硫酸ナトリウムを加えて乾燥し、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルクロマトグラフィー（ＤＩＯＬシリカゲル、溶出溶媒；ｎ－ヘキサン：酢酸エチル＝５０：５０～０：１００（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物９１．３ｍｇ（収率８１％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４９８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.18 & 11.73 (s, total 1H), 9.66 - 9.40 (m,1H), 7.38 - 7.33 (m, 2H), 7.33 - 7.26 (m, 2H), 7.21 - 7.13 (m, 1H), 6.43 - 6.16(m, 1H), 4.75 - 4.66 (m, 1H), 4.47 (br s, 2H), 4.38 (t, J = 5.2 Hz, 1H), 3.45 - 3.35 (m, 2H), 2.49 - 2.42(m, 2H), 2.25 - 2.14 (m, 2H), 1.88 - 1.64 (m, 4H), 1.60 (br s, 3H), 1.55 -1.28 (m, 5H), 0.09 (s, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 2 (4H) -carboxylate 100 mg (0.227 mmol), (R) -4-amino-4-phenylbutan-1-ol hydrochloride [NetChem, Inc. Purchased] DIPEA 0.24 ml (1.4 mmol) was added to a solution of 138 mg (0.684 mmol) in dehydrated 1,4-dioxane 2 ml under an argon atmosphere at room temperature, and the mixture was stirred at 100 ° C. for 3 hours. Next, 1 ml of triethylamine and 1 ml of ethanol were added to the reaction solution, and the mixture was heated and stirred at 80 ° C. for 5 hours.
After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 50: 50 to 0: 100 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. By drying under reduced pressure, 91.3 mg (yield 81%) of the title compound was obtained as a white solid.
Mass spectrum (CI, m / z): 498 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.18 & 11.73 (s, total 1H), 9.66-9.40 (m, 1H), 7.38-7.33 (m, 2H), 7.33-7.26 (m, 2H ), 7.21-7.13 (m, 1H), 6.43-6.16 (m, 1H), 4.75-4.66 (m, 1H), 4.47 (br s, 2H), 4.38 (t, J = 5.2 Hz, 1H), 3.45 -3.35 (m, 2H), 2.49-2.42 (m, 2H), 2.25-2.14 (m, 2H), 1.88-1.64 (m, 4H), 1.60 (br s, 3H), 1.55 -1.28 (m, 5H ), 0.09 (s, 9H).
（実施例１２）
（Ｒ）－Ｎ－（５－ヒドロキシ－１－フェニルペンチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－６７）
Figure JPOXMLDOC01-appb-C000053
 Example 12
(R) -N- (5-hydroxy-1-phenylpentyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide (Compound No. IV-67)
Figure JPOXMLDOC01-appb-C000053
　１Ｍ水素化アルミニウムリチウム／ＴＨＦ溶液９．５０ｍｌ（９．５０ｍｍｏｌ）の脱水ＴＨＦ４０ｍｌ溶液に、アルゴン雰囲気下で攪拌しながら（Ｒ）－エチル　５－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－５－フェニルペンタノアート［Ｔｅｔｒａｈｅｄｒｏｎ　Ｌｅｔｔ．，１９９８，３９，５９５１－５９５４．に記載の方法に準じて合成］２．０２ｇ（６．２８ｍｍｏｌ）の脱水ＴＨＦ２０ｍｌ溶液を０℃で滴下し、同温度で２時間攪拌した。
　反応終了後、ＴＨＦ５０ｍｌを加えた後、水０．４ｍｌ、１Ｎ水酸化ナトリウム水溶液１．６ｍｌ（１．６ｍｍｏｌ）を加え、同温度で３０分攪拌した。析出した固体をセライトフィルターを用いて濾過し、固体を酢酸エチルで洗浄した。得られた濾液を減圧濃縮、減圧乾燥することにより、濃縮残渣を得た。
　得られた濃縮残渣１．６８ｇのジクロロメタン２０ｍｌ溶液に、アルゴン雰囲気下、トリフルオロ酢酸２ｍｌを室温で加え、同温度で２時間攪拌した。
　反応終了後、反応液を減圧濃縮、減圧乾燥することにより、濃縮残渣１．３５ｇを得た。
　得られた濃縮残渣９０５ｍｇの脱水ＴＨＦ３ｍｌ溶液に、アルゴン雰囲気下で攪拌しながらＤＩＰＥＡ０．６０ｍｌ（３．４ｍｍｏｌ）加えた後、参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート２０５ｍｇ（０．４６５ｍｍｏｌ）を室温で加え、６０℃で４時間攪拌した。次いで、反応液へトリエチルアミン０．５ｍｌ、メタノール１ｍｌを加え、６０℃で３時間加熱攪拌し、次いで室温で１５時間攪拌した。
　反応終了後、反応液を減圧濃縮した。得られた濃縮残渣をシリカゲルクロマトグラフィー（ＤＩＯＬシリカゲル、溶出溶媒；ジクロロメタン：メタノール＝１００：０～９０：１０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥した。得られた濃縮残渣を更にシリカゲルクロマトグラフィー（ＤＮＨシリカゲル、溶出溶媒；ジクロロメタン：メタノール＝１００：０～９３：７（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥した。得られた濃縮残渣をシリカゲルクロマトグラフィー（ＤＩＯＬシリカゲル、溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７０：３０～０：１００（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１３１ｍｇ（収率５５％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５１２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.18 & 11.64 (br s, total 1H), 9.58 -9.47 (m, 1H), 7.38 - 7.33 (m, 2H), 7.32 - 7.25 (m, 2H), 7.21 - 7.14 (m, 1H),6.38 - 6.15 (m, 1H), 4.75 - 4.65 (m, 1H), 4.52 - 4.38 (m, 2H), 4.33 (t, J = 5.2Hz, 1H), 3.39 - 3.33 (m, 2H), 2.49 - 2.42 (m, 2H), 2.26 - 2.14 (m, 2H), 1.88 -1.72 (m, 3H), 1.72 - 1.30 (m, 10H), 1.27 - 1.14 (m, 1H), 0.13 - 0.06 (m, 9H)。 To a solution of 9.50 ml (9.50 mmol) of 1M lithium aluminum hydride / THF in 40 ml of dehydrated THF, (R) -ethyl 5-[(tert-butoxycarbonyl) amino] -5-phenylpenta with stirring under an argon atmosphere. Noart [Tetrahedron Lett. 1998, 39, 5951-5594. Synthesis according to the method described in 1] A solution of 2.02 g (6.28 mmol) in 20 ml of dehydrated THF was added dropwise at 0 ° C. and stirred at the same temperature for 2 hours.
After completion of the reaction, 50 ml of THF was added, 0.4 ml of water and 1.6 ml (1.6 mmol) of 1N sodium hydroxide aqueous solution were added, and the mixture was stirred at the same temperature for 30 minutes. The precipitated solid was filtered using a celite filter, and the solid was washed with ethyl acetate. The obtained filtrate was concentrated under reduced pressure and dried under reduced pressure to obtain a concentrated residue.
To a solution of 1.68 g of the concentrated residue in 20 ml of dichloromethane was added 2 ml of trifluoroacetic acid at room temperature under an argon atmosphere, and the mixture was stirred at the same temperature for 2 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure and dried under reduced pressure to obtain 1.35 g of a concentrated residue.
To a solution of 905 mg of the concentrated residue obtained in 3 ml of dehydrated THF, 0.60 ml (3.4 mmol) of DIPEA was added with stirring under an argon atmosphere. 6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate 205 mg (0.465 mmol) was added at room temperature, Stir at 4 ° C. for 4 hours. Next, 0.5 ml of triethylamine and 1 ml of methanol were added to the reaction solution, and the mixture was heated and stirred at 60 ° C. for 3 hours, and then stirred at room temperature for 15 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel chromatography (DIOL silica gel, elution solvent; dichloromethane: methanol = 100: 0 to 90:10 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure. . The obtained concentrated residue was further subjected to silica gel chromatography (DNH silica gel, elution solvent; dichloromethane: methanol = 100: 0 to 93: 7 (V / V)), and the fraction containing the target product was concentrated under reduced pressure and dried under reduced pressure. did. The obtained concentrated residue was subjected to silica gel chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30 to 0: 100 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. By drying under reduced pressure, 131 mg (55% yield) of the title compound was obtained as a white solid.
Mass spectrum (CI, m / z): 512 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.18 & 11.64 (br s, total 1H), 9.58 -9.47 (m, 1H), 7.38-7.33 (m, 2H), 7.32-7.25 (m, 2H), 7.21-7.14 (m, 1H), 6.38-6.15 (m, 1H), 4.75-4.65 (m, 1H), 4.52-4.38 (m, 2H), 4.33 (t, J = 5.2Hz, 1H) , 3.39-3.33 (m, 2H), 2.49-2.42 (m, 2H), 2.26-2.14 (m, 2H), 1.88 -1.72 (m, 3H), 1.72-1.30 (m, 10H), 1.27-1.14 ( m, 1H), 0.13-0.06 (m, 9H).
（実施例１３）
（Ｓ）－Ｎ－（２－ヒドロキシ－２－メチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－３４）
Figure JPOXMLDOC01-appb-C000054
 (Example 13)
(S) -N- (2-hydroxy-2-methyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide (Compound No. IV-34)
Figure JPOXMLDOC01-appb-C000054
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート２００ｍｇ（０．４５４ｍｍｏｌ）の脱水ＴＨＦ３ｍｌ溶液に、アルゴン雰囲気下、ＤＩＰＥＡ０．１６ｍｌ（０．９２ｍｍｏｌ）、（Ｓ）－１－アミノ－２－メチル－１－フェニルプロパン－２－オール［ＩＳ　Ｃｈｅｍｉｃａｌ　Ｔｅｃｈｎｏｌｏｇｙより購入］３８５ｍｇ（２．３３ｍｍｏｌ）を室温で加え、６０℃で４時間攪拌した。次いでメタノール１ｍｌ、トリエチルアミン１ｍｌを室温で加え、同温度で１５時間攪拌した。
　反応終了後、反応液に水を加え、その混合液から酢酸エチルで抽出した。得られた有機層は飽和塩化ナトリウム水溶液で洗浄、無水硫酸ナトリウムを加えて乾燥し、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ジクロロメタン：メタノール＝１００：０～９０：１０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥した。得られた濃縮残渣を再度シリカゲルクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ジクロロメタン：メタノール＝１００：０～９０：１０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１８２ｍｇ（収率８１％）を白色固体として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：４９８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.22 & 11.78 (br s, total 1H), 9.74 -9.49 (m, 1H), 7.38 - 7.16 (m, 5H), 5.90 - 5.74 (m, 1H), 4.85 (s, 1H), 4.65 -4.35 (m, 3H), 2.49 - 2.41 (m, 2H), 2.28 - 2.15 (m, 2H), 1.91 - 1.73 (m, 2H),1.67 - 1.44 (m, 6H), 1.22 (s, 3H), 0.91 (s, 3H), 0.09 (s, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 2 (4H) -carboxylate (200 mg, 0.454 mmol) in dehydrated THF (3 ml) under an argon atmosphere, DIPEA (0.16 ml, 0.92 mmol), (S) -1-amino-2-methyl-1-phenylpropane-2 -All [purchased from IS Chemical Technology] 385 mg (2.33 mmol) was added at room temperature, followed by stirring at 60 ° C for 4 hours. Next, 1 ml of methanol and 1 ml of triethylamine were added at room temperature, and the mixture was stirred at the same temperature for 15 hours.
After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel chromatography (DIOL silica gel, elution solvent; dichloromethane: methanol = 100: 0 to 90:10 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure. . The obtained concentrated residue was again subjected to silica gel chromatography (DIOL silica gel, elution solvent; dichloromethane: methanol = 100: 0 to 90:10 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure. This gave 182 mg (81% yield) of the title compound as a white solid.
Mass spectrum (DUIS, m / z): 498 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.22 & 11.78 (br s, total 1H), 9.74 -9.49 (m, 1H), 7.38-7.16 (m, 5H), 5.90-5.74 (m, 1H), 4.85 (s, 1H), 4.65 -4.35 (m, 3H), 2.49-2.41 (m, 2H), 2.28-2.15 (m, 2H), 1.91-1.73 (m, 2H), 1.67-1.44 ( m, 6H), 1.22 (s, 3H), 0.91 (s, 3H), 0.09 (s, 9H).
（実施例１４）
（Ｓ）－Ｎ－（２－ヒドロキシ－２－メチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＩＩ－１４）
Figure JPOXMLDOC01-appb-C000055
 (Example 14)
(S) -N- (2-hydroxy-2-methyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide (Compound No. III-14)
Figure JPOXMLDOC01-appb-C000055
　参考例７と同様にして合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート　塩酸塩４６８ｍｇ（１．１７ｍｍｏｌ）の脱水ジクロロメタン１０ｍｌ溶液に、窒素雰囲気下、ＤＩＰＥＡ０．７２ｍｌ（４．１ｍｍｏｌ）を室温で加えた後、ビス（トリクロロメチル）カルボナート２３５ｍｇ（０．７９１ｍｍｏｌ）を－７８℃で加え、同温度で３時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液２０ｍｌを加え、成り行きで室温まで昇温させながら撹拌した。有機層と水層を分けた後、水層をジクロロメタンで２回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９０：１０～７５：２５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより濃縮残渣４９０ｍｇを得た。
　得られた濃縮残渣１１２ｍｇの脱水ＴＨＦ２ｍｌ溶液に、窒素雰囲気下、ＤＩＰＥＡ０．１４ｍｌ（０．８０ｍｍｏｌ）、（Ｓ）－１－アミノ－２－メチル－１－フェニルプロパン－２－オール［ＩＳ　Ｃｈｅｍｉｃａｌ　Ｔｅｃｈｎｏｌｏｇｙより購入］１０９ｍｇ（０．６６０ｍｍｏｌ）を室温で順次加えた後、加熱還流させながら３時間撹拌した。次いで、２－アミノエタノール０．１０ｍｌ（１．７ｍｍｏｌ）を加えた後、加熱還流させながら２．５時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで３回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣に酢酸０．１ｍｌを加えた後、シリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝５０：５０～２０：８０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣に対し酢酸エチル／ｎ－ヘキサンで晶析を行い、析出した固体を濾取し、ｎ－ヘキサンで掛け洗いした後、減圧乾燥することにより標記化合物１００ｍｇ（収率７７％［２工程］）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４８４［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.24 & 11.90 (br s, total 1H), 10.02 - 9.68 (m, 1H), 7.38 -7.16 (m, 5H), 5.89 - 5.71 (m, 1H), 4.82 (s, 1H), 4.59 (d, J = 8.4 Hz, 1H), 4.56 - 4.31 (m, 2H), 1.66 -1.43 (m, 6H), 1.21 (s, 3H), 1.06 - 0.97 (m, 2H), 0.91 (s, 3H), 0.81 - 0.61 (m,2H), 0.04 (s, 9H)。 Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxy synthesized as in Reference Example 7 To a solution of 468 mg (1.17 mmol) of Lato hydrochloride in 10 ml of dehydrated dichloromethane was added 0.72 ml (4.1 mmol) of DIPEA at room temperature under a nitrogen atmosphere, and then 235 mg (0.791 mmol) of bis (trichloromethyl) carbonate was added to -78. The mixture was added at ° C and stirred at the same temperature for 3 hours.
After completion of the reaction, 20 ml of a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, followed by stirring while raising the temperature to room temperature. After separating the organic layer and the aqueous layer, the aqueous layer was extracted twice with dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 75:25 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure. As a result, 490 mg of concentrated residue was obtained.
To a solution of 112 mg of the resulting concentrated residue in 2 ml of dehydrated THF, under a nitrogen atmosphere, 0.14 ml (0.80 mmol) of DIPEA, (S) -1-amino-2-methyl-1-phenylpropan-2-ol [from IS Chemical Technology Purchase] 109 mg (0.660 mmol) was sequentially added at room temperature, followed by stirring for 3 hours while heating to reflux. Subsequently, 0.10 ml (1.7 mmol) of 2-aminoethanol was added, and the mixture was stirred for 2.5 hours while being heated to reflux.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Acetic acid 0.1 ml was added to the obtained concentrated residue, followed by silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 50: 50 to 20:80 (V / V)), Fractions containing the desired product were concentrated under reduced pressure. The obtained concentrated residue was crystallized from ethyl acetate / n-hexane, and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 100 mg of the title compound (yield 77% [yield 77% [yield]). Two steps]) were obtained as a white solid.
Mass spectrum (CI, m / z): 484 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.24 & 11.90 (br s, total 1H), 10.02-9.68 (m, 1H), 7.38 -7.16 (m, 5H), 5.89-5.71 (m, 1H), 4.82 (s, 1H), 4.59 (d, J = 8.4 Hz, 1H), 4.56-4.31 (m, 2H), 1.66 -1.43 (m, 6H), 1.21 (s, 3H), 1.06-0.97 (m, 2H), 0.91 (s, 3H), 0.81-0.61 (m, 2H), 0.04 (s, 9H).
（実施例１５）
Ｎ－（３－ヒドロキシ－２，２－ジメチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－８５）
Figure JPOXMLDOC01-appb-C000056
 (Example 15)
N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide (Compound No. IV-85)
Figure JPOXMLDOC01-appb-C000056
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１５２ｍｇ（０．３４６ｍｍｏｌ）、３－アミノ－２，２－ジメチル－３－フェニルプロパン－１－オール［Ｓｙｎｔｈｅｔｉｃ　Ｃｏｍｍｕｎｉｃａｔｉｏｎｓ　１９９４，２４（７），８９９－９０６．に記載の方法に準じて合成］２０１ｍｇ（１．１２ｍｍｏｌ）の１，４－ジオキサン４ｍｌ溶液に、アルゴン雰囲気下、ＤＩＰＥＡ０．１８ｍｌ（１．０ｍｍｏｌ）を室温で加えた後、マイクロウエーブ反応装置に供し、１００℃で１時間反応した。放冷後、反応液を減圧濃縮し、得られた濃縮残渣にメタノール４ｍｌ及びトリエチルアミン１ｍｌを加え、室温で１５時間攪拌した。
　反応終了後、反応液を減圧濃縮し、得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；酢酸エチル：メタノール＝９９：１～９７：３（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を再度シリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝９９：１～９２：８（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣に対しジクロロメタン／ｎ－ヘキサンで晶析を行い、析出した固体を濾取、減圧乾燥することにより、標記化合物５５ｍｇ（収率３１％）を白色固体として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：５１２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.21 & 11.95 (br s, total 1H), 9.89 - 9.36 (m, 1H), 7.36 -7.17 (m, 5H), 6.85 (d, J = 8.1 Hz, 1H), 5.50 - 5.39 (m, 1H), 4.64 (d, J = 8.1 Hz, 1H), 4.47 - 4.28 (m, 2H), 3.30 -3.22 (m, 1H), 3.03 (dd, J = 4.1, 10.4 Hz, 1H), 2.49 - 2.40 (m, 2H), 2.28 - 2.13(m, 2H), 1.92 - 1.71 (m, 2H), 1.60 (br s, 3H), 1.53 (s, 3H), 1.06 (s, 3H),0.64 (s, 3H), 0.09 (s, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 152 mg (0.346 mmol) of 2 (4H) -carboxylate, 3-amino-2,2-dimethyl-3-phenylpropan-1-ol [Synthetic Communications 1994, 24 (7), 899-906. Synthesis in accordance with the method described in 1) DIPEA (0.18 ml, 1.0 mmol) was added to a 4 ml solution of 201 mg (1.12 mmol) in 1,4-dioxane at room temperature under an argon atmosphere, and the mixture was then used in a microwave reactor. , Reacted at 100 ° C. for 1 hour. After allowing to cool, the reaction mixture was concentrated under reduced pressure, 4 ml of methanol and 1 ml of triethylamine were added to the resulting concentrated residue, and the mixture was stirred at room temperature for 15 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; ethyl acetate: methanol = 99: 1 to 97: 3 (V / V)), Fractions containing the desired product were concentrated under reduced pressure. The obtained concentrated residue is again subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 99: 1 to 92: 8 (V / V)), and the fraction containing the target product is obtained. Concentrated under reduced pressure. The obtained concentrated residue was crystallized from dichloromethane / n-hexane, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 55 mg (yield 31%) of the title compound as a white solid.
Mass spectrum (DUIS, m / z): 512 [M + 1] + .
1 H-NMR spectrum (400MHz, DMSO-d 6) δ: 12.21 & 11.95 (br s, total 1H), 9.89 - 9.36 (m, 1H), 7.36 -7.17 (m, 5H), 6.85 (d, J = 8.1 Hz, 1H), 5.50-5.39 (m, 1H), 4.64 (d, J = 8.1 Hz, 1H), 4.47-4.28 (m, 2H), 3.30 -3.22 (m, 1H), 3.03 (dd, J = 4.1, 10.4 Hz, 1H), 2.49-2.40 (m, 2H), 2.28-2.13 (m, 2H), 1.92-1.71 (m, 2H), 1.60 (br s, 3H), 1.53 (s, 3H) , 1.06 (s, 3H), 0.64 (s, 3H), 0.09 (s, 9H).
（実施例１６）
（Ｒ）－Ｎ－（３－ヒドロキシ－３－メチル－１－フェニルブチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－７０）
Figure JPOXMLDOC01-appb-C000057
 (Example 16)
(R) -N- (3-hydroxy-3-methyl-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide (Compound No. IV-70)
Figure JPOXMLDOC01-appb-C000057
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１３２ｍｇ（０．３００ｍｍｏｌ）、参考例２１と同様にして合成した（Ｒ）－４－アミノ－２－メチル－４－フェニルブタン－２－オール１５５ｍｇ（０．８６５ｍｍｏｌ）の１，４－ジオキサン４ｍｌ溶液に、アルゴン雰囲気下、ＤＩＰＥＡ０．１５ｍｌ（０．８６ｍｍｏｌ）を室温で加えた後、１００℃で２時間攪拌した。放冷後、反応液を減圧濃縮し、得られた濃縮残渣にメタノール４ｍｌ及びトリエチルアミン１ｍｌを加え、室温で１８時間攪拌した。
　反応終了後、反応液を減圧濃縮し、得られた濃縮残渣に酢酸エチル、水、飽和塩化ナトリウム水溶液を加えた後、分液した。得られた有機層を無水硫酸マグネシウムで乾燥し、濾過後、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝９８：２～９１：９（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮に対しジクロロメタン／ジエチルエーテル／ｎ－ヘキサンで晶析を行い、析出した固体を濾取、減圧乾燥することにより、標記化合物１０４ｍｇ（収率６８％）を白色固体として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：５１２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.20 & 11.73 (br s, 1H), 9.66 - 9.40 (m, 1H), 7.37 - 7.25 (m, 4H), 7.19 - 7.13 (m, 1H), 6.54 (d, J =5.3 Hz, 1H), 4.95 - 4.84 (m, 1H), 4.75 - 4.57 (m, 1H), 4.45 (br s, 2H), 2.47 - 2.42 (m, 2H), 2.25 - 2.14(m, 2H), 2.02 - 1.74 (m, 3H), 1.65 (dd, J = 3.3, 14.3 Hz, 1H), 1.58 (s, 3H),1.53 (s, 3H), 1.16 (s, 3H), 1.13 (s, 3H), 0.09 (s, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 132 mg (0.300 mmol) of 2 (4H) -carboxylate, 155 mg (0.865 mmol) of (R) -4-amino-2-methyl-4-phenylbutan-2-ol synthesized in the same manner as in Reference Example 21 To a 4 ml solution of 1,4-dioxane, 0.15 ml (0.86 mmol) of DIPEA was added at room temperature under an argon atmosphere, followed by stirring at 100 ° C. for 2 hours. After allowing to cool, the reaction mixture was concentrated under reduced pressure, 4 ml of methanol and 1 ml of triethylamine were added to the resulting concentrated residue, and the mixture was stirred at room temperature for 18 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate, water, and a saturated aqueous sodium chloride solution were added to the resulting concentrated residue, followed by liquid separation. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane: methanol = 98: 2 to 91: 9 (V / V)), and the fraction containing the desired product was reduced in pressure. Concentrated. The resulting concentration was crystallized from dichloromethane / diethyl ether / n-hexane, and the precipitated solid was collected by filtration and dried under reduced pressure to give 104 mg (yield 68%) of the title compound as a white solid.
Mass spectrum (DUIS, m / z): 512 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.20 & 11.73 (br s, 1H), 9.66-9.40 (m, 1H), 7.37-7.25 (m, 4H), 7.19-7.13 (m, 1H ), 6.54 (d, J = 5.3 Hz, 1H), 4.95-4.84 (m, 1H), 4.75-4.57 (m, 1H), 4.45 (br s, 2H), 2.47-2.42 (m, 2H), 2.25 -2.14 (m, 2H), 2.02-1.74 (m, 3H), 1.65 (dd, J = 3.3, 14.3 Hz, 1H), 1.58 (s, 3H), 1.53 (s, 3H), 1.16 (s, 3H ), 1.13 (s, 3H), 0.09 (s, 9H).
（実施例１７）
（Ｓ）－Ｎ－（２－メトキシ－１－フェニルエチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－２１）
Figure JPOXMLDOC01-appb-C000058
 (Example 17)
(S) -N- (2-methoxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide (Compound No. IV-21)
Figure JPOXMLDOC01-appb-C000058
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート２０１ｍｇ（０．４５６ｍｍｏｌ）の１，４－ジオキサン４．５ｍｌ溶液に、ＤＩＰＥＡ０．１６ｍｌ（０．９１ｍｍｏｌ）、（Ｓ）－２－メトキシ－１－フェニルアミン［Ｊ．Ｃｈｅｍ．Ｓｏｃ．，Ｐｅｒｋｉｎ　Ｔｒａｎｓａｃｔｉｏｎｓ　１, ２００２，２０，２２３７－２２４２．に記載の方法に準じて合成］２１３ｍｇ（１．４１ｍｍｏｌ）を室温で加えた後、マイクロウエーブ反応装置に供し、１００℃で１時間反応させた。次いで、メタノール１ｍｌ及びトリエチルアミン０．５ｍｌを加えた後、再びマイクロウエーブ反応装置にて、８０℃で１時間反応させた。
　反応終了後、反応液に酢酸エチル８ｍｌ、水０．４ｍｌ、飽和塩化ナトリウム水溶液８ｍｌを加えてから分液し、水層をジクロロメタン１０ｍｌで抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥後、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～９５：５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣にジエチルエーテルを加え超音波処理した後、析出した不溶物を濾取し、減圧乾燥することにより、標記化合物１８０ｍｇ（収率８２％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４８４［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.20 & 11.67 (br s, total 1H), 9.68 - 9.41 (m, 1H), 7.41 - 7.35 (m, 2H), 7.34 - 7.27 (m, 2H), 7.25 - 7.17(m, 1H), 6.44 - 6.13 (m, 1H), 5.02 - 4.92 (m, 1H), 4.57 - 4.39 (m, 2H), 3.63(dd, J = 7.9, 9.9 Hz, 1H), 3.50 (dd, J = 6.0, 9.9 Hz, 1H), 3.26 (s, 3H), 2.49 -2.42 (m, 2H), 2.26 - 2.15 (m, 2H), 1.92 - 1.73 (m, 2H), 1.60 (br s, 3H), 1.53(br s, 3H), 0.09 (s, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 To a solution of 201 mg (0.456 mmol) of 2 (4H) -carboxylate in 4.5 ml of 1,4-dioxane, 0.16 ml (0.91 mmol) of DIPEA, (S) -2-methoxy-1-phenylamine [J. Chem. Soc. Perkin Transactions 1, 2002, 20, 2237-2242. Synthesis according to the method described in 1.] After adding 213 mg (1.41 mmol) at room temperature, it was subjected to a microwave reactor and reacted at 100 ° C. for 1 hour. Next, 1 ml of methanol and 0.5 ml of triethylamine were added, and the mixture was reacted again at 80 ° C. for 1 hour in a microwave reactor.
After completion of the reaction, 8 ml of ethyl acetate, 0.4 ml of water and 8 ml of a saturated sodium chloride aqueous solution were added to the reaction solution, followed by liquid separation, and the aqueous layer was extracted with 10 ml of dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired product was reduced in pressure. Concentrated. Diethyl ether was added to the obtained concentrated residue and subjected to ultrasonic treatment, and the precipitated insoluble matter was collected by filtration and dried under reduced pressure to obtain 180 mg (yield 82%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 484 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.20 & 11.67 (br s, total 1H), 9.68-9.41 (m, 1H), 7.41-7.35 (m, 2H), 7.34-7.27 (m, 2H), 7.25-7.17 (m, 1H), 6.44-6.13 (m, 1H), 5.02-4.92 (m, 1H), 4.57-4.39 (m, 2H), 3.63 (dd, J = 7.9, 9.9 Hz, 1H), 3.50 (dd, J = 6.0, 9.9 Hz, 1H), 3.26 (s, 3H), 2.49 -2.42 (m, 2H), 2.26-2.15 (m, 2H), 1.92-1.73 (m, 2H) , 1.60 (br s, 3H), 1.53 (br s, 3H), 0.09 (s, 9H).
（実施例１８）
（Ｓ）－Ｎ－［２－（ジフルオロメトキシ）－１－フェニルエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－２３）
Figure JPOXMLDOC01-appb-C000059
 (Example 18)
(S) -N- [2- (Difluoromethoxy) -1-phenylethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c Pyrazole-5 (1H) -carboxamide (Compound No. IV-23)
Figure JPOXMLDOC01-appb-C000059
　参考例２３と同様にして合成した（Ｓ）－２－（ジフルオロメトキシ）－１－フェニルエタンアミン　トリフルオロ酢酸塩２１０ｍｇ（０．６９７ｍｍｏｌ）、ＤＩＰＥＡ０．４２５ｍｌ（２．４３ｍｍｏｌ）の脱水１，４－ジオキサン３ｍｌ溶液に、アルゴン雰囲気下、参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１０７ｍｇ（０．２４３ｍｍｏｌ）を室温で加え、１００℃で１時間加熱攪拌した。次いで、反応液へトリエチルアミン１ｍｌ、メタノール１ｍｌを加え、８０℃で１時間加熱攪拌した。
　反応終了後、反応液に水を加え、その混合液から酢酸エチルで抽出した。得られた有機層を飽和塩化ナトリウム水溶液で洗浄、無水硫酸ナトリウムを加えて乾燥し、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルクロマトグラフィー（ＤＩＯＬシリカゲル、溶出溶媒；ｎ－ヘキサン：酢酸エチル＝５０：５０～０：１００（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物４０．５ｍｇ（収率３２％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５２０［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.20 (br s, 1H), 10.12 - 9.41 (m, 1H), 7.43 -7.38 (m, 2H), 7.38 - 7.32 (m, 2H), 7.28 - 7.23 (m, 1H), 6.70 (t, J = 76.0Hz, 1H), 6.59 - 6.46 (m, 1H), 5.10 - 5.01 (m, 1H), 4.52 - 4.43 (m, 2H), 4.13(dd, J = 8.3, 10.4 Hz, 1H), 4.05 - 3.99 (m, 1H), 2.48 - 2.42 (m,2H), 2.24 - 2.15 (m, 2H), 1.88 - 1.75 (m, 2H), 1.60 (s, 3H), 1.53 (s, 3H), 0.09(s, 9H)。 (S) -2- (Difluoromethoxy) -1-phenylethanamine trifluoroacetate 210 mg (0.697 mmol), DIPEA 0.425 ml (2.43 mmol) dehydrated 1,4-synthesized in the same manner as in Reference Example 23 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo synthesized in the same manner as in Reference Example 3 under an argon atmosphere in a 3 ml solution of dioxane. 107 mg (0.243 mmol) of [3,4-c] pyrazole-2 (4H) -carboxylate was added at room temperature, and the mixture was heated and stirred at 100 ° C. for 1 hour. Next, 1 ml of triethylamine and 1 ml of methanol were added to the reaction solution, and the mixture was heated and stirred at 80 ° C. for 1 hour.
After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 50: 50 to 0: 100 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. By drying under reduced pressure, 40.5 mg (yield 32%) of the title compound was obtained as a white solid.
Mass spectrum (CI, m / z): 520 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.20 (br s, 1H), 10.12-9.41 (m, 1H), 7.43 -7.38 (m, 2H), 7.38-7.32 (m, 2H), 7.28-7.23 (m, 1H), 6.70 (t, J = 76.0Hz, 1H), 6.59-6.46 (m, 1H), 5.10-5.01 (m, 1H), 4.52-4.43 (m, 2H), 4.13 ( dd, J = 8.3, 10.4 Hz, 1H), 4.05-3.99 (m, 1H), 2.48-2.42 (m, 2H), 2.24-2.15 (m, 2H), 1.88-1.75 (m, 2H), 1.60 ( s, 3H), 1.53 (s, 3H), 0.09 (s, 9H).
（実施例１９）
（Ｓ）－Ｎ－（２－エトキシ－１－フェニルエチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－２５）
Figure JPOXMLDOC01-appb-C000060
 (Example 19)
(S) —N- (2-Ethoxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide (Compound No. IV-25)
Figure JPOXMLDOC01-appb-C000060
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１３６ｍｇ（０．３０８ｍｍｏｌ）、参考例２４と同様にして合成した（Ｓ）－２－エトキシ－１－フェニルエタンアミン１６２ｍｇ（０．９７９ｍｍｏｌ）の１，４－ジオキサン４ｍｌ溶液に、アルゴン雰囲気下、ＤＩＰＥＡ０．１６ｍｌ（０．９２ｍｍｏｌ）を室温で加えた後、１００℃で２時間攪拌した。放冷後、反応液を減圧濃縮して得られた濃縮残渣にメタノール４ｍｌ及びトリエチルアミン１ｍｌを加え、マイクロウエーブ反応装置に供し、８０℃で１時間反応させた。
　反応終了後、反応液を減圧濃縮し、得られた濃縮残渣に酢酸エチルを加えた後、１０％リン酸二水素カリウム水溶液、飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄し、得られた有機層を無水硫酸マグネシウムで乾燥、濾過後、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝９８：２～９１：９（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣に対しジクロロメタン／ジエチルエーテル／ｎ－ヘキサンで晶析を行い、析出した固体を濾取した。得られた固体を再度シリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～９３：７（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を再々度シリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：酢酸エチル＝１００：０～６７：３３（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣にジエチルエーテル及びｎ－ヘキサンを加え、超音波処理後、析出した固体を濾取し、減圧乾燥することにより、標記化合物８１ｍｇ（収率５３％）を白色固体として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：４９８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.20 & 11.71 (br s, total 1H), 9.67 - 9.47 (m, 1H), 7.41 - 7.34 (m,2H), 7.34 - 7.27 (m, 2H), 7.25 - 7.17 (m, 1H), 6.38 - 6.11 (m, 1H), 4.99 - 4.91(m, 1H), 4.56 - 4.38 (m, 2H), 3.65 (dd, J = 8.0, 9.9 Hz, 1H), 3.54 (dd, J = 6.0,9.9 Hz, 1H), 3.51 - 3.41 (m, 2H), 2.49 - 2.41 (m, 2H), 2.28 - 2.14 (m, 2H),1.91 - 1.71 (m, 2H), 1.61 (br s, 3H), 1.54 (br s, 3H), 1.08 (t, J = 7.0 Hz,3H), 0.09 (s, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 136 mg (0.308 mmol) of 2 (4H) -carboxylate and a solution of 162 mg (0.979 mmol) of (S) -2-ethoxy-1-phenylethanamine synthesized in the same manner as in Reference Example 24 in 4 ml of 1,4-dioxane In an argon atmosphere, 0.16 ml (0.92 mmol) of DIPEA was added at room temperature, followed by stirring at 100 ° C. for 2 hours. After allowing to cool, 4 ml of methanol and 1 ml of triethylamine were added to the concentrated residue obtained by concentrating the reaction solution under reduced pressure, and the mixture was subjected to a reaction at 80 ° C. for 1 hour.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the resulting concentrated residue, and then washed successively with 10% aqueous potassium dihydrogen phosphate, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 98: 2 to 91: 9 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The resulting concentrated residue was crystallized from dichloromethane / diethyl ether / n-hexane, and the precipitated solid was collected by filtration. The obtained solid was again subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 93: 7 (V / V)), and the fraction containing the desired product was reduced in pressure. Concentrated. The obtained concentrated residue was subjected again to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: ethyl acetate = 100: 0 to 67:33 (V / V)), and the fraction containing the target product was obtained. The minute was concentrated under reduced pressure. Diethyl ether and n-hexane were added to the obtained concentrated residue, and after ultrasonication, the precipitated solid was collected by filtration and dried under reduced pressure to obtain 81 mg (yield 53%) of the title compound as a white solid.
Mass spectrum (DUIS, m / z): 498 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.20 & 11.71 (br s, total 1H), 9.67-9.47 (m, 1H), 7.41-7.34 (m, 2H), 7.34-7.27 (m, 2H), 7.25-7.17 (m, 1H), 6.38-6.11 (m, 1H), 4.99-4.91 (m, 1H), 4.56-4.38 (m, 2H), 3.65 (dd, J = 8.0, 9.9 Hz, 1H), 3.54 (dd, J = 6.0,9.9 Hz, 1H), 3.51-3.41 (m, 2H), 2.49-2.41 (m, 2H), 2.28-2.14 (m, 2H), 1.91-1.71 (m, 2H), 1.61 (br s, 3H), 1.54 (br s, 3H), 1.08 (t, J = 7.0 Hz, 3H), 0.09 (s, 9H).
（実施例２０）
（Ｒ）－Ｎ－（３－メトキシ－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－５１）
Figure JPOXMLDOC01-appb-C000061
 (Example 20)
(R) -N- (3-methoxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide (Compound No. IV-51)
Figure JPOXMLDOC01-appb-C000061
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１３８ｍｇ（０．３１４ｍｍｏｌ）、参考例２５と同様にして合成した（Ｒ）－３－メトキシ－１－フェニルプロパン－１－アミン１６３ｍｇ（０．９８７ｍｍｏｌ）の１，４－ジオキサン４ｍｌ溶液に、アルゴン雰囲気下、ＤＩＰＥＡ０．１６ｍｌ（０．９２ｍｍｏｌ）を室温で加えた後、１００℃で２時間攪拌した。放冷後、反応液を減圧濃縮し、得られた残渣にメタノール４ｍｌ及びトリエチルアミン１ｍｌを加え、室温で１８時間攪拌した。
　反応終了後、反応液を減圧濃縮し、得られた濃縮残渣に酢酸エチルを加えた後、１０％リン酸二水素カリウム水溶液、飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄し、得られた有機層を無水硫酸マグネシウムで乾燥、濾過後、濾液を減圧濃縮した。得られた残渣はシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝９５：５～８８：１２（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣にジエチルエーテル及びｎ－ヘキサンを加え、超音波処理した後、析出した固体を濾取、減圧乾燥することにより、標記化合物８８ｍｇ（収率５６％）を白色固体として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：４９８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.18 & 11.73 (br s, total 1H), 9.54 (br s, 1H), 7.35 - 7.28(m, 4H), 7.22 - 7.16 (m, 1H), 6.41 (br s, 1H), 4.91 - 4.79 (m, 1H), 4.53 -4.40 (m, 2H), 3.32 - 3.27 (m, 2H), 3.23 (s, 3H), 2.50 - 2.42 (m, 2H), 2.26 -2.15 (m, 2H), 2.08 - 1.70 (m, 4H), 1.60 (s, 3H), 1.52 (s, 3H), 0.09 (s, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 138 mg (0.314 mmol) of 2 (4H) -carboxylate, 163 mg (0.987 mmol) of 1,4- (R) -3-methoxy-1-phenylpropan-1-amine synthesized in the same manner as in Reference Example 25 To a 4 ml solution of dioxane, 0.16 ml (0.92 mmol) of DIPEA was added at room temperature under an argon atmosphere, and the mixture was stirred at 100 ° C. for 2 hours. After allowing to cool, the reaction mixture was concentrated under reduced pressure, 4 ml of methanol and 1 ml of triethylamine were added to the resulting residue, and the mixture was stirred at room temperature for 18 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the resulting concentrated residue, and then washed successively with 10% aqueous potassium dihydrogen phosphate, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 95: 5 to 88:12 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. Diethyl ether and n-hexane were added to the resulting concentrated residue, followed by sonication. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 88 mg (yield 56%) of the title compound as a white solid.
Mass spectrum (DUIS, m / z): 498 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.18 & 11.73 (br s, total 1H), 9.54 (br s, 1H), 7.35-7.28 (m, 4H), 7.22-7.16 (m, 1H ), 6.41 (br s, 1H), 4.91-4.79 (m, 1H), 4.53 -4.40 (m, 2H), 3.32-3.27 (m, 2H), 3.23 (s, 3H), 2.50-2.42 (m, 2H), 2.26 -2.15 (m, 2H), 2.08-1.70 (m, 4H), 1.60 (s, 3H), 1.52 (s, 3H), 0.09 (s, 9H).
（実施例２１）
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４．５．６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニル酢酸ナトリウム（化合物番号ＩＶ－９５のナトリウム塩）
Figure JPOXMLDOC01-appb-C000062
 (Example 21)
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4.5.6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Sodium phenylacetate (sodium salt of compound no. IV-95)
Figure JPOXMLDOC01-appb-C000062
　実施例４４と同様にして合成した（Ｓ）－ベンジル　２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルアセタート９８．０ｍｇ（０．１７１ｍｍｏｌ）のエタノール１５ｍｌ溶液に、窒素雰囲気下、パラジウム／炭素［ＡＳＣＡ２（商品名），Ｎ．Ｅ．ＣＨＥＭＣＡＴ社製，５２％含水］１９．９ｍｇを加えた後、減圧下水素雰囲気へと置換し、室温で５０分撹拌した。
　反応終了後、アルゴン雰囲気へ置換を行い、反応液をセライト濾過した。得られた濾液に炭酸水素ナトリウム１４．８ｍｇ（０．１７６ｍｍｏｌ）を加え、減圧濃縮した。得られた濃縮残渣に精製水、ジエチルエーテルを加えた後、減圧乾固することにより、標記化合物８２ｍｇ（収率９５％）を白色固体として得た。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.41 (br s, 1H), 9.95 (br. s, 1H), 7.38 - 7.30 (m, 2H), 7.24 -7.17 (m, 2H), 7.14 - 7.08 (m, 1H), 6.42 (d, J = 4.6 Hz, 1H), 4.68 (d, J = 4.6Hz, 1H), 4.48 (d, J = 11.3 Hz, 1H), 4.45 (d, J = 11.3 Hz, 1H), 2.51 - 2.41 (m,2H), 2.28 - 2.14 (m, 2H), 1.90 - 1.74 (m, 2H), 1.59 (s, 3H), 1.55 (s, 3H), 0.08(s, 9H)。 (S) -Benzyl 2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4] synthesized in the same manner as in Example 44 c] Pyrazole-5-carboxamide} -2-phenylacetate in a solution of 98.0 mg (0.171 mmol) in ethanol under a nitrogen atmosphere, palladium / carbon [ASCA2 (trade name), N.I. E. After adding 19.9 mg of CHEMCAT, 52% water content], the mixture was replaced with a hydrogen atmosphere under reduced pressure, and stirred at room temperature for 50 minutes.
After completion of the reaction, the atmosphere was replaced with an argon atmosphere, and the reaction solution was filtered through celite. To the obtained filtrate was added 14.8 mg (0.176 mmol) of sodium hydrogen carbonate, and the mixture was concentrated under reduced pressure. Purified water and diethyl ether were added to the resulting concentrated residue, followed by drying under reduced pressure to obtain 82 mg (yield 95%) of the title compound as a white solid.
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.41 (br s, 1H), 9.95 (br. S, 1H), 7.38-7.30 (m, 2H), 7.24 -7.17 (m, 2H), 7.14-7.08 (m, 1H), 6.42 (d, J = 4.6 Hz, 1H), 4.68 (d, J = 4.6Hz, 1H), 4.48 (d, J = 11.3 Hz, 1H), 4.45 (d, J = 11.3 Hz, 1H), 2.51-2.41 (m, 2H), 2.28-2.14 (m, 2H), 1.90-1.74 (m, 2H), 1.59 (s, 3H), 1.55 (s, 3H), 0.08 ( s, 9H).
（実施例２２）
Ｎ－［１－（２－フルオロフェニル）－２－ヒドロキシエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－１０７）
Figure JPOXMLDOC01-appb-C000063
 (Example 22)
N- [1- (2-Fluorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide (Compound No. IV-107)
Figure JPOXMLDOC01-appb-C000063
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート２０１ｍｇ（０．４５６ｍｍｏｌ）の１，４－ジオキサン５ｍｌ溶液に、アルゴン雰囲気下，ＤＩＰＥＡ０．２３ｍｌ（１．４ｍｍｏｌ）、２－アミノ－２－（２－フルオロフェニル）エタノール［Ａｍａｔｅｋ　Ｃｈｅｍｉｃａｌより購入］２１２ｍｇ（１．３７ｍｍｏｌ）を室温で加えた後、１００℃で１時間反応させた。反応液を減圧濃縮した後、濃縮残渣にメタノール４ｍｌ、トリエチルアミン１ｍｌを加え、６５℃で４．５時間、さらに７０℃で１．５時間反応させた。
　反応終了後、反応液を減圧濃縮し、得られた濃縮残渣を酢酸エチル５ｍｌに溶解させ、５％硫酸水素カリウム水溶液１０ｍｌで２回洗浄した。得られた全有機層を飽和炭酸水素ナトリウム水溶液１０ｍｌで洗浄後、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～９８：２（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１３１ｍｇ（収率５９％）を白色泡状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４８８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.41 - 11.66 (m, 1H), 9.94 - 9.30 (m, 1H), 7.51 - 7.42 (m, 1H),7.31 - 7.06 (m, 3H), 6.19 (br s, 1H), 5.15 - 5.04 (m, 1H), 4.98 (t, J = 6.0Hz, 1H), 4.54 (br s, 2H), 3.64 - 3.54 (m, 2H), 2.49 - 2.42 (m, 2H), 2.26 - 2.15 (m, 2H), 1.87 - 1.76(m, 2H), 1.60 (s, 3H), 1.51 (s, 3H), 0.10 (s, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 To a solution of 201 mg (0.456 mmol) of 2 (4H) -carboxylate in 5 ml of 1,4-dioxane, 0.23 ml (1.4 mmol) of DIPEA, 2-amino-2- (2-fluorophenyl) ethanol in an argon atmosphere [ Purchased from Amatek Chemical] 212 mg (1.37 mmol) was added at room temperature, followed by reaction at 100 ° C. for 1 hour. After the reaction solution was concentrated under reduced pressure, 4 ml of methanol and 1 ml of triethylamine were added to the concentrated residue, and the mixture was reacted at 65 ° C. for 4.5 hours and further at 70 ° C. for 1.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting concentrated residue was dissolved in 5 ml of ethyl acetate and washed twice with 10 ml of 5% aqueous potassium hydrogen sulfate solution. The obtained all organic layer was washed with 10 ml of saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 98: 2 (V / V)), and the fraction containing the desired product was reduced in pressure. Concentration and drying under reduced pressure gave 131 mg (59% yield) of the title compound as a white foam.
Mass spectrum (CI, m / z): 488 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.41-11.66 (m, 1H), 9.94-9.30 (m, 1H), 7.51-7.42 (m, 1H), 7.31-7.06 (m, 3H) , 6.19 (br s, 1H), 5.15-5.04 (m, 1H), 4.98 (t, J = 6.0Hz, 1H), 4.54 (br s, 2H), 3.64-3.54 (m, 2H), 2.49-2.42 (m, 2H), 2.26-2.15 (m, 2H), 1.87-1.76 (m, 2H), 1.60 (s, 3H), 1.51 (s, 3H), 0.10 (s, 9H).
（実施例２３）
（Ｓ）－Ｎ－［１－（３－フルオロフェニル）－２－ヒドロキシエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－１１１）
Figure JPOXMLDOC01-appb-C000064
 (Example 23)
(S) -N- [1- (3-Fluorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide (Compound No. IV-111)
Figure JPOXMLDOC01-appb-C000064
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート２０１ｍｇ（０．４５６ｍｍｏｌ）の１，４－ジオキサン５．０ｍｌ溶液に、アルゴン雰囲気下、ＤＩＰＥＡ０．２３ｍｌ（１．４ｍｍｏｌ）、（Ｓ）－２－アミノ－２－（３－フルオロフェニル）エタノール［Ａｍａｔｅｋ　Ｃｈｅｍｉｃａｌより購入］２１２ｍｇ（１．３７ｍｍｏｌ）を室温で加えた後、１００℃で１時間反応させた。反応液を減圧濃縮した後、濃縮残渣にメタノール４ｍｌ、トリエチルアミン１ｍｌを加え、室温で１７時間反応させた。
　反応終了後、反応液を減圧濃縮し、得られた濃縮残渣を酢酸エチル５ｍｌに溶解させ、５％リン酸二水素カリウム水溶液１０ｍｌで２回、飽和炭酸水素ナトリウム水溶液１０ｍｌで１回洗浄後、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～９８：２（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１２８ｍｇ（収率５８％）を白色泡状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４８８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.35 - 11.70 (m, 1H), 9.84 - 9.41 (m, 1H), 7.38 - 7.29 (m, 1H),7.21 - 7.15 (m, 2H), 7.05 - 6.98 (m, 1H), 6.21 (br s, 1H), 4.92 (t, J = 5.8Hz, 1H), 4.83 - 4.74 (m, 1H), 4.58 - 4.45 (m, 2H), 3.67 - 3.55 (m, 2H), 2.49 - 2.42 (m,  2H), 2.26 - 2.15 (m, 2H), 1.89 - 1.73 (m, 2H), 1.60 (s, 3H), 1.53 (s, 3H), 0.09 (s,9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 To a 5.0 ml 1,4-dioxane solution of 201 mg (0.456 mmol) of 2 (4H) -carboxylate, 0.23 ml (1.4 mmol), (S) -2-amino-2- (3 -Fluorophenyl) ethanol [purchased from Amatek Chemical] 212 mg (1.37 mmol) was added at room temperature, followed by reaction at 100 ° C. for 1 hour. After concentrating the reaction solution under reduced pressure, 4 ml of methanol and 1 ml of triethylamine were added to the concentrated residue and reacted at room temperature for 17 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting concentrated residue was dissolved in 5 ml of ethyl acetate, washed twice with 10 ml of 5% aqueous potassium dihydrogen phosphate solution and once with 10 ml of saturated aqueous sodium bicarbonate solution, and then anhydrous. The extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 98: 2 (V / V)), and the fraction containing the desired product was reduced in pressure. Concentration and drying under reduced pressure gave 128 mg (yield 58%) of the title compound as a white foam.
Mass spectrum (CI, m / z): 488 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.35-11.70 (m, 1H), 9.84-9.41 (m, 1H), 7.38-7.29 (m, 1H), 7.21-7.15 (m, 2H) , 7.05-6.98 (m, 1H), 6.21 (br s, 1H), 4.92 (t, J = 5.8Hz, 1H), 4.83-4.74 (m, 1H), 4.58-4.45 (m, 2H), 3.67- 3.55 (m, 2H), 2.49-2.42 (m, 2H), 2.26-2.15 (m, 2H), 1.89-1.73 (m, 2H), 1.60 (s, 3H), 1.53 (s, 3H), 0.09 ( s, 9H).
（実施例２４）
（Ｓ）－Ｎ－［１－（４－フルオロフェニル）－２－ヒドロキシエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－１１３）
Figure JPOXMLDOC01-appb-C000065
 (Example 24)
(S) -N- [1- (4-Fluorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide (Compound No. IV-113)
Figure JPOXMLDOC01-appb-C000065
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート２０１ｍｇ（０．４５６ｍｍｏｌ）の１，４－ジオキサン５．０ｍｌ溶液に、アルゴン雰囲気下、ＤＩＰＥＡ０．２３ｍｌ（１．４ｍｍｏｌ）、（Ｓ）－２－アミノ－２－（４－フルオロフェニル）エタノール［Ａｍａｔｅｋ　Ｃｈｅｍｉｃａｌより購入］２１２ｍｇ（１．３７ｍｍｏｌ）を室温で加えた後、１００℃で１時間反応させた。反応液を減圧濃縮した後、濃縮残渣にメタノール４ｍｌ、トリエチルアミン１ｍｌを加え、室温で１５時間反応させた。
　反応終了後、反応液を減圧濃縮し、得られた濃縮残渣を酢酸エチル５ｍｌに溶解させ、５％リン酸二水素カリウム水溶液１０ｍｌで２回、飽和炭酸水素ナトリウム水溶液１０ｍｌで１回洗浄後、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～９８：２（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を再度シリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～９８：２（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１３９ｍｇ（収率６３％）を淡黄色泡状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４８８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.20 & 11.71 (br s, total 1H), 9.75 - 9.43 (m, 1H), 7.42 -7.33 (m, 2H), 7.15 - 7.06 (m, 2H), 6.28 - 6.02 (m, 1H), 4.89 (t, J = 5.8 Hz,1H), 4.81 -4.72 (m, 1H), 4.51 (br s, 2H), 3.66 - 3.53 (m, 2H), 2.49 - 2.42 (m, 2H), 2.26- 2.15 (m, 2H), 1.90 - 1.74 (m, 2H), 1.60 (br s, 3H), 1.53 (br s, 3H), 0.09(s, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 To a 5.0 ml 1,4-dioxane solution of 201 mg (0.456 mmol) of 2 (4H) -carboxylate, 0.23 ml (1.4 mmol) DIPEA, (S) -2-amino-2- (4 -Fluorophenyl) ethanol [purchased from Amatek Chemical] 212 mg (1.37 mmol) was added at room temperature, followed by reaction at 100 ° C. for 1 hour. After concentrating the reaction solution under reduced pressure, 4 ml of methanol and 1 ml of triethylamine were added to the concentrated residue and reacted at room temperature for 15 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting concentrated residue was dissolved in 5 ml of ethyl acetate, washed twice with 10 ml of 5% aqueous potassium dihydrogen phosphate solution and once with 10 ml of saturated aqueous sodium bicarbonate solution, and then anhydrous. The extract was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 98: 2 (V / V)), and the fraction containing the desired product was reduced in pressure. Concentrated. The obtained concentrated residue was again subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 98: 2 (V / V)), and a fraction containing the target product was obtained. By concentration under reduced pressure and drying under reduced pressure, 139 mg (yield 63%) of the title compound was obtained as a pale yellow foam.
Mass spectrum (CI, m / z): 488 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.20 & 11.71 (br s, total 1H), 9.75-9.43 (m, 1H), 7.42 -7.33 (m, 2H), 7.15-7.06 (m, 2H), 6.28-6.02 (m, 1H), 4.89 (t, J = 5.8 Hz, 1H), 4.81 -4.72 (m, 1H), 4.51 (br s, 2H), 3.66-3.53 (m, 2H), 2.49-2.42 (m, 2H), 2.26- 2.15 (m, 2H), 1.90-1.74 (m, 2H), 1.60 (br s, 3H), 1.53 (br s, 3H), 0.09 (s, 9H).
（実施例２５）
Ｎ－［２－ヒドロキシ－１－（ピリジン－２－イル）エチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－１１５）
Figure JPOXMLDOC01-appb-C000066
 (Example 25)
N- [2-hydroxy-1- (pyridin-2-yl) ethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide (Compound No. IV-115)
Figure JPOXMLDOC01-appb-C000066
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１５２ｍｇ（０．３４４ｍｍｏｌ）、２－アミノ－２－（ピリジン－２－イル）エタノール　２塩酸塩［Ｊ＆Ｗ　ＰＨＡＲＭＬＡＢより購入］２２３ｍｇ（１．０６ｍｍｏｌ）の１，４－ジオキサン４ｍｌ溶液に、アルゴン雰囲気下、ＤＩＰＥＡ０．６０ｍｌ（３．４ｍｍｏｌ）を室温で加えた後、マイクロウエーブ反応装置に供し、１００℃で１時間反応させた。
　反応終了後、反応液を減圧濃縮し、濃縮残渣に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。得られた有機層を無水硫酸ナトリウムで乾燥し、濾過後、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＤＮＨシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～９３：７（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた残渣を再度シリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；酢酸エチル：メタノール＝１００：０～７８：２２（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物７８ｍｇ（収率４８％）を白色泡状物として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：４６９［Ｍ－１］－。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.22 & 11.78 (br s, total 1H), 9.79 - 9.45 (m, 1H), 8.54 -8.49 (m, 1H), 7.74 (dt, J = 1.7, 7.7 Hz, 1H), 7.42 - 7.36 (m, 1H), 7.28 - 7.21 (m, 1H), 6.19 - 6.00 (m, 1H), 4.92 -4.82 (m, 2H), 4.62 - 4.43 (m, 2H), 3.76 - 3.65 (m, 2H), 2.49 - 2.42 (m, 2H),2.27 - 2.15 (m, 2H), 1.92 - 1.72 (m, 2H), 1.68 - 1.50 (m, 6H), 0.10 (s, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 152 mg (0.344 mmol) of 2 (4H) -carboxylate, 2-amino-2- (pyridin-2-yl) ethanol dihydrochloride [purchased from J & W PHARMLAB] 223 mg (1.06 mmol) of 1,4-dioxane 4 ml To the solution, 0.60 ml (3.4 mmol) of DIPEA was added at room temperature under an argon atmosphere, and then the solution was subjected to a microwave reactor and reacted at 100 ° C. for 1 hour.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the concentrated residue, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (DNH silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 93: 7 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained residue was again subjected to silica gel column chromatography (DIOL silica gel, elution solvent; ethyl acetate: methanol = 100: 0 to 78:22 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. By drying, 78 mg (yield 48%) of the title compound was obtained as a white foam.
Mass spectrum (DUIS, m / z): 469 [M−1] − .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.22 & 11.78 (br s, total 1H), 9.79-9.45 (m, 1H), 8.54 -8.49 (m, 1H), 7.74 (dt, J = 1.7, 7.7 Hz, 1H), 7.42-7.36 (m, 1H), 7.28-7.21 (m, 1H), 6.19-6.00 (m, 1H), 4.92 -4.82 (m, 2H), 4.62-4.43 (m, 2H), 3.76-3.65 (m, 2H), 2.49-2.42 (m, 2H), 2.27-2.15 (m, 2H), 1.92-1.72 (m, 2H), 1.68-1.50 (m, 6H), 0.10 ( s, 9H).
（実施例２６）
Ｎ－［２－ヒドロキシ－１－（ピリジン－３－イル）エチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－１１９）
Figure JPOXMLDOC01-appb-C000067
 (Example 26)
N- [2-hydroxy-1- (pyridin-3-yl) ethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide (Compound No. IV-119)
Figure JPOXMLDOC01-appb-C000067
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１５０ｍｇ（０．３４１ｍｍｏｌ）、２－アミノ－２－（ピリジン－３－イル）エタノール　２塩酸塩［Ｊ＆Ｗ　ＰＨＡＲＭＬＡＢより購入］２１８ｍｇ（１．０３ｍｍｏｌ）の１，４－ジオキサン４ｍｌ溶液に、アルゴン雰囲気下、ＤＩＰＥＡ０．６０ｍｌ（３．４ｍｍｏｌ）を室温で加えた後、１００℃で１時間攪拌した。
　反応終了後、反応液を減圧濃縮し、濃縮残渣に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。得られた有機層を無水硫酸マグネシウムで乾燥し、濾過後、濾液を減圧濃縮した。得られた濃縮残渣にメタノール４ｍｌ、トリエチルアミン１ｍｌを加え、マイクロウエーブ反応装置に供し、８０℃で１時間反応させた。
　反応終了後、反応液を減圧濃縮し、得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＮＨシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝９５：５～８８：１２（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた残渣を再度シリカゲルカラムクロマトグラフィー（ＤＮＨシリカゲル，溶出溶媒；酢酸エチル：メタノール＝９６：４～７０：３０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた残渣を再々度シリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；酢酸エチル：メタノール＝９９：１～７３：２７（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物２７ｍｇ（収率１７％）を白色泡状物として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：４７１［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.20 & 11.77 (br s, total 1H), 9.75 - 9.47 (m, 1H), 8.54 (d, J= 2.0 Hz, 1H), 8.41 (dd, J = 2.0, 4.7 Hz, 1H), 7.75 (ddd, J = 2.0, 2.0, 7.6 Hz,1H), 7.32 (dd, J = 4.7, 7.6 Hz, 1H), 6.39 - 6.13 (m, 1H), 4.97 (t, J = 5.8 Hz,1H), 4.84 -4.76 (m, 1H), 4.61 - 4.42 (m, 2H), 3.71 - 3.59 (m, 2H), 2.49 - 2.42 (m, 2H), 2.27 - 2.14(m, 2H), 1.89 - 1.72 (m, 2H), 1.60 (br s, 3H), 1.52 (br s, 3H), 0.09 (s, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 2 (4H) -carboxylate 150 mg (0.341 mmol), 2-amino-2- (pyridin-3-yl) ethanol dihydrochloride [purchased from J & W PHARMLAB] 218 mg (1.03 mmol) 1,4-dioxane 4 ml To the solution, 0.60 ml (3.4 mmol) of DIPEA was added at room temperature under an argon atmosphere, followed by stirring at 100 ° C. for 1 hour.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the concentrated residue, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. To the obtained concentrated residue, 4 ml of methanol and 1 ml of triethylamine were added, and the mixture was subjected to a microwave reaction apparatus and reacted at 80 ° C. for 1 hour.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting concentrated residue was subjected to silica gel column chromatography (DNH silica gel, elution solvent; 1,2-dichloroethane: methanol = 95: 5 to 88:12 (V / V)). The fraction containing the desired product was concentrated under reduced pressure. The obtained residue was again subjected to silica gel column chromatography (DNH silica gel, elution solvent; ethyl acetate: methanol = 96: 4 to 70:30 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The obtained residue was again subjected to silica gel column chromatography (DIOL silica gel, elution solvent; ethyl acetate: methanol = 99: 1 to 73:27 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. By drying under reduced pressure, 27 mg (yield 17%) of the title compound was obtained as a white foam.
Mass spectrum (DUIS, m / z): 471 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.20 & 11.77 (br s, total 1H), 9.75-9.47 (m, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.41 (dd , J = 2.0, 4.7 Hz, 1H), 7.75 (ddd, J = 2.0, 2.0, 7.6 Hz, 1H), 7.32 (dd, J = 4.7, 7.6 Hz, 1H), 6.39-6.13 (m, 1H), 4.97 (t, J = 5.8 Hz, 1H), 4.84 -4.76 (m, 1H), 4.61-4.42 (m, 2H), 3.71-3.59 (m, 2H), 2.49-2.42 (m, 2H), 2.27- 2.14 (m, 2H), 1.89-1.72 (m, 2H), 1.60 (br s, 3H), 1.52 (br s, 3H), 0.09 (s, 9H).
（実施例２７）
（Ｓ）－Ｎ－（１－シクロヘキシル－２－ヒドロキシエチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－１０５）
Figure JPOXMLDOC01-appb-C000068
 (Example 27)
(S) -N- (1-cyclohexyl-2-hydroxyethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide (Compound No. IV-105)
Figure JPOXMLDOC01-appb-C000068
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート３２６ｍｇ（０．７３９ｍｍｏｌ）の脱水ＴＨＦ４ｍｌ溶液に、窒素雰囲気下，ＤＩＰＥＡ０．３３ｍｌ（１．９ｍｍｏｌ）、（Ｓ）－２－アミノ－２－シクロヘキシルエタノール［Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．Ｌｅｔｔ．，２００９，１９，９２６－９２９．に記載の方法に準じて合成］３０４ｍｇ（２．１２ｍｍｏｌ）を室温で加えた後、加熱還流させながら１．５時間撹拌した。次いで、反応液にトリエチルアミン０．９０ｍｌ（６．５ｍｍｏｌ）、メタノール０．９０ｍｌ（２２ｍｍｏｌ）を加えた後、加熱還流させながら１．５時間撹拌した。
　反応終了後、反応液に水を加え、ジクロロメタンで３回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣に酢酸８５μｌを加えた後、シリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ジクロロメタン：メタノール＝１００：０～９７：３（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣に対しジクロロメタン／ｎ－ヘキサンで晶析を行い、析出した固体を濾取し、ｎ－ヘキサンで掛け洗いした後、減圧乾燥することにより標記化合物２９５ｍｇ（収率８４％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４７６［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.20 & 11.71 (br s, total 1H), 9.70 -9.44 (m, 1H), 5.46 - 5.15 (m, 1H), 4.54 (t, J = 5.0 Hz,1H), 4.49 - 4.21 (m, 2H), 3.53 - 3.40 (m, 3H), 2.48 - 2.40 (m, 2H), 2.27 - 2.10(m, 2H), 1.88 - 1.45 (m, 14H), 1.28 - 1.03 (m, 3H), 1.03 - 0.83 (m, 2H), 0.08(s, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 To a solution of 326 mg (0.739 mmol) of 2 (4H) -carboxylate in 4 ml of dehydrated THF, 0.33 ml (1.9 mmol) of DIPEA, (S) -2-amino-2-cyclohexylethanol [Bioorg. Med. Chem. Lett. , 2009, 19, 926-929. Synthesis according to the method described in 1) After adding 304 mg (2.12 mmol) at room temperature, the mixture was stirred for 1.5 hours while being heated to reflux. Next, 0.90 ml (6.5 mmol) of triethylamine and 0.90 ml (22 mmol) of methanol were added to the reaction solution, followed by stirring for 1.5 hours while heating to reflux.
After completion of the reaction, water was added to the reaction solution and extracted three times with dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After adding 85 μl of acetic acid to the obtained concentrated residue, it was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; dichloromethane: methanol = 100: 0 to 97: 3 (V / V)), The minutes were concentrated under reduced pressure. The resulting concentrated residue was crystallized from dichloromethane / n-hexane, and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to obtain 295 mg (yield 84%) of the title compound. Obtained as a white solid.
Mass spectrum (CI, m / z): 476 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.20 & 11.71 (br s, total 1H), 9.70 -9.44 (m, 1H), 5.46-5.15 (m, 1H), 4.54 (t, J = 5.0 Hz, 1H), 4.49-4.21 (m, 2H), 3.53-3.40 (m, 3H), 2.48-2.40 (m, 2H), 2.27-2.10 (m, 2H), 1.88-1.45 (m, 14H) , 1.28-1.03 (m, 3H), 1.03-0.83 (m, 2H), 0.08 (s, 9H).
（実施例２８）
（Ｓ）－Ｎ－（１－ヒドロキシ－３－メチルブタン－２－イル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－１０３）
Figure JPOXMLDOC01-appb-C000069
 (Example 28)
(S) -N- (1-Hydroxy-3-methylbutan-2-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c Pyrazole-5 (1H) -carboxamide (Compound No. IV-103)
Figure JPOXMLDOC01-appb-C000069
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート２０１ｍｇ（０．４５６ｍｍｏｌ）の１，４－ジオキサン４．５ｍｌ溶液に、窒素雰囲気下、（Ｓ）－２－アミノ－３－メチルブタン－１－オール２３５ｍｇ（２．２７ｍｍｏｌ）、ＤＩＰＥＡ０．１６ｍｌ（０．９１ｍｍｏｌ）を室温で加えた後、１００℃で１時間攪拌した。
　反応終了後、反応液を減圧濃縮し、濃縮残渣に酢酸エチル、水及び飽和塩化ナトリウム水溶液を加え、分液した。水層を酢酸エチルで抽出し、得られた全有機層を無水硫酸マグネシウムで乾燥、濾過後、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝９９：１～９６：４（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣にアセトンを加えた後に超音波処理し、析出した固体を濾取、減圧乾燥することにより、標記化合物１２９ｍｇ（収率６５％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４３６［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.20 & 11.67 (br s, total 1H), 9.60 - 9.48 (m, 1H), 5.45 -5.20 (m, 1H), 4.62 - 4.24 (m, 3H), 3.52 - 3.39 (m, 3H), 2.49 - 2.41 (m, 2H),2.24 - 2.13 (m, 2H), 1.91 - 1.73 (m, 3H), 1.60 (br s, 6H), 0.92 - 0.82 (m,6H), 0.08 (s, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 To a solution of 201 mg (0.456 mmol) of 2 (4H) -carboxylate in 4.5 ml of 1,4-dioxane, 235 mg (2.27 mmol) of (S) -2-amino-3-methylbutan-1-ol under a nitrogen atmosphere Then, 0.16 ml (0.91 mmol) of DIPEA was added at room temperature, followed by stirring at 100 ° C. for 1 hour.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate, water and a saturated aqueous sodium chloride solution were added to the concentrated residue, followed by liquid separation. The aqueous layer was extracted with ethyl acetate, and the entire organic layer obtained was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 99: 1 to 96: 4 (V / V)), and the fraction containing the desired product was reduced in pressure. Concentrated. Acetone was added to the resulting concentrated residue, followed by sonication, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 129 mg (yield 65%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 436 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.20 & 11.67 (br s, total 1H), 9.60-9.48 (m, 1H), 5.45 -5.20 (m, 1H), 4.62-4.24 (m, 3H), 3.52-3.39 (m, 3H), 2.49-2.41 (m, 2H), 2.24-2.13 (m, 2H), 1.91-1.73 (m, 3H), 1.60 (br s, 6H), 0.92-0.82 (m, 6H), 0.08 (s, 9H).
（実施例２９）
（Ｓ）－Ｎ－（１－ヒドロキシプロパン－２－イル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－１０１）
Figure JPOXMLDOC01-appb-C000070
 (Example 29)
(S) -N- (1-hydroxypropan-2-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide (Compound No. IV-101)
Figure JPOXMLDOC01-appb-C000070
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート２００ｍｇ（０．４５４ｍｍｏｌ）の１，４－ジオキサン４．５ｍｌ溶液に、（Ｓ）－２－アミノプロパン－１－オール１７０ｍｇ（２．２６ｍｍｏｌ）、ＤＩＰＥＡ０．１６ｍｌ（０．９１ｍｍｏｌ）を室温で加えた後、マイクロウエーブ反応装置に供し、１００℃で１時間反応させた。
　反応終了後、反応液を減圧濃縮し、濃縮残渣に酢酸エチル、水及び飽和塩化ナトリウム水溶液を加え、分液した。水層を酢酸エチルで抽出し、得られた全有機層を無水硫酸マグネシウムで乾燥、濾過後、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝９９：１～９５：５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣に酢酸エチルを加え、超音波処理し、析出した固体を濾取、減圧乾燥することにより、標記化合物１４５ｍｇ（収率７８％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４０８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.18 & 11.64 (br s, total 1H), 9.52 (s, 1H), 5.70 - 5.32 (m, 1H), 4.65 (t, J = 5.6 Hz, 1H), 4.44 - 4.28 (m, 2H), 3.77 - 3.64 (m, 1H), 3.41 - 3.34 (m,1H), 3.30 - 3.23 (m, 1H), 2.49 - 2.40 (m, 2H), 2.24 - 2.13 (m, 2H), 1.88 - 1.72 (m, 2H), 1.60 (s,6H), 1.05 (d, J = 6.7 Hz, 3H), 0.08 (s, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 To a solution of 200 mg (0.454 mmol) of 2 (4H) -carboxylate in 4.5 ml of 1,4-dioxane, 170 mg (2.26 mmol) of (S) -2-aminopropan-1-ol and 0.16 ml of DIPEA (0. 91 mmol) was added at room temperature, and the mixture was then subjected to a microwave reactor and reacted at 100 ° C. for 1 hour.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate, water and a saturated aqueous sodium chloride solution were added to the concentrated residue, followed by liquid separation. The aqueous layer was extracted with ethyl acetate, and the entire organic layer obtained was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 99: 1 to 95: 5 (V / V)), and the fraction containing the desired product was reduced in pressure. Concentrated. Ethyl acetate was added to the obtained concentrated residue and sonicated, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 145 mg (yield 78%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 408 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.18 & 11.64 (br s, total 1H), 9.52 (s, 1H), 5.70-5.32 (m, 1H), 4.65 (t, J = 5.6 Hz , 1H), 4.44-4.28 (m, 2H), 3.77-3.64 (m, 1H), 3.41-3.34 (m, 1H), 3.30-3.23 (m, 1H), 2.49-2.40 (m, 2H), 2.24 -2.13 (m, 2H), 1.88-1.72 (m, 2H), 1.60 (s, 6H), 1.05 (d, J = 6.7 Hz, 3H), 0.08 (s, 9H).
（実施例３０）
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　アセタート（化合物番号Ｖ－８６）
Figure JPOXMLDOC01-appb-C000071
 (Example 30)
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl acetate (Compound No. V-86)
Figure JPOXMLDOC01-appb-C000071
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート３６０ｍｇ（０．８１６ｍｍｏｌ）のＴＨＦ１０ｍｌ溶液に、参考例２７と同様にして合成した（Ｓ）－２－アミノ－２－フェニルエチル　アセタート　塩酸塩８８３ｍｇ（４．０９ｍｍｏｌ）、ＤＩＰＥＡ２．０ｍｌ（１２ｍｍｏｌ）を室温で加え、マイクロウエーブ反応装置に供し、１００℃で２時間反応した。次いで、メタノール１．１ｍｌ（２７ｍｍｏｌ）を加えた後、マイクロウエーブ反応装置に供し、８０℃で１時間反応した。更にメタノール２．０ｍｌ（４９ｍｍｏｌ）及びトリエチルアミン１．０ｍｌ（７．２ｍｍｏｌ）を加えた後、マイクロウエーブ反応装置に供し、８０℃で１時間反応した。
　反応終了後、反応液を減圧濃縮し、得られた濃縮残渣に酢酸エチル１５ｍｌ、飽和塩化ナトリウム水溶液１５ｍｌを加え、分液した。水層をジクロロメタン１５ｍｌで抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～９０：１０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣に酢酸エチル及びジエチルエーテルを少量加えた後に超音波処理し、氷水にて冷却後、濾過した。得られた固体を再度シリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；酢酸エチル：メタノール＝１００：０～９９：１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣に酢酸エチル及びジエチルエーテルを少量加えた後に超音波処理し、氷水冷却後、濾過することにより白色固体Ａを得た。濾液は減圧濃縮し、得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；酢酸エチル：メタノール＝１００：０～９９：１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣に酢酸エチル及びジエチルエーテルを少量加えた後に超音波処理し、氷水冷却後、濾過することにより白色固体Ｂを得た。白色固体Ａ及びＢを酢酸エチルに溶解後にジエチルエーテルを加え，析出した固体を濾過、減圧乾燥することにより、標記化合物１４２ｍｇ（収率３４％）を白色固体として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：５１２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.21 & 11.71 (br. s, total 1H), 9.76 - 9.33 (m, 1H), 7.43 -7.37 (m, 2H), 7.37 - 7.31 (m, 2H), 7.28 - 7.22 (m, 1H), 6.65 - 6.38 (m, 1H),5.12 - 5.03 (m, 1H), 4.49 (br s, 2H), 4.30 - 4.19 (m, 2H), 2.49 - 2.41 (m,2H), 2.25 - 2.14 (m, 2H), 1.98 (s, 3H), 1.89 - 1.74 (m, 2H), 1.61 (br s, 3H), 1.53 (br s, 3H), 0.09 (s, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 (S) -2-Amino-2-phenylethyl acetate hydrochloride 883 mg (4.09 mmol), DIPEA2 synthesized in a similar manner to Reference Example 27 in a solution of 360 mg (0.816 mmol) of 2 (4H) -carboxylate in 10 ml of THF 0.0 ml (12 mmol) was added at room temperature, and it was subjected to a microwave reactor and reacted at 100 ° C. for 2 hours. Next, after adding 1.1 ml (27 mmol) of methanol, it was subjected to a microwave reactor and reacted at 80 ° C. for 1 hour. Further, 2.0 ml (49 mmol) of methanol and 1.0 ml (7.2 mmol) of triethylamine were added, followed by reaction in a microwave reactor at 80 ° C. for 1 hour.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and 15 ml of ethyl acetate and 15 ml of a saturated aqueous sodium chloride solution were added to the resulting concentrated residue to separate the layers. The aqueous layer was extracted with 15 ml of dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 90:10 (V / V)), and the fraction containing the desired product was reduced in pressure. Concentrated. A small amount of ethyl acetate and diethyl ether were added to the resulting concentrated residue, followed by sonication, cooling with ice water, and filtration. The obtained solid was again subjected to silica gel column chromatography (DIOL silica gel, elution solvent; ethyl acetate: methanol = 100: 0 to 99: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. A small amount of ethyl acetate and diethyl ether was added to the resulting concentrated residue, followed by sonication, cooling with ice water, and filtration to obtain a white solid A. The filtrate was concentrated under reduced pressure, and the resulting concentrated residue was subjected to silica gel column chromatography (elution solvent; ethyl acetate: methanol = 100: 0 to 99: 1 (V / V)), and the fraction containing the desired product was reduced under reduced pressure. Concentrated. A small amount of ethyl acetate and diethyl ether was added to the resulting concentrated residue, followed by sonication, cooling with ice water, and filtration to obtain a white solid B. Diethyl ether was added after dissolving the white solids A and B in ethyl acetate, and the precipitated solid was filtered and dried under reduced pressure to obtain 142 mg (yield 34%) of the title compound as a white solid.
Mass spectrum (DUIS, m / z): 512 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.21 & 11.71 (br. S, total 1H), 9.76-9.33 (m, 1H), 7.43 -7.37 (m, 2H), 7.37-7.31 (m , 2H), 7.28-7.22 (m, 1H), 6.65-6.38 (m, 1H), 5.12-5.03 (m, 1H), 4.49 (br s, 2H), 4.30-4.19 (m, 2H), 2.49- 2.41 (m, 2H), 2.25-2.14 (m, 2H), 1.98 (s, 3H), 1.89-1.74 (m, 2H), 1.61 (br s, 3H), 1.53 (br s, 3H), 0.09 ( s, 9H).
（実施例３１）
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　プロピオナート（化合物番号Ｖ－８７）
Figure JPOXMLDOC01-appb-C000072
 (Example 31)
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl propionate (Compound No. V-87)
Figure JPOXMLDOC01-appb-C000072
　参考例３０と同様にして合成した（Ｓ）－エチル　５－［（２－ヒドロキシ－１－フェニルエチル）カルバモイル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート２００ｍｇ（０．３６９ｍｍｏｌ）、トリエチルアミン０．１０ｍｌ（０．７４ｍｍｏｌ）の脱水ジクロロメタン３ｍｌ溶液に、アルゴン雰囲気下、無水プロピオン酸０．０７１ｍｌ（０．５５ｍｍｏｌ）、４－ジメチルアミノピリジン９．７ｍｇ（０．０７９ｍｍｏｌ）を室温で順次加えた後、室温で５時間反応させた。次いで、メタノール１ｍｌ、トリエチルアミン０．５ｍｌを加え、室温で２時間反応させた。
　反応終了後、反応液を減圧濃縮し、得られた濃縮残渣に酢酸エチル１０ｍｌ、水０．５ｍｌ、飽和塩化ナトリウム水溶液１０ｍｌを加えて分液した。水層をジクロロメタン１０ｍｌで２回抽出し、得られた全有機層を無水硫酸マグネシウムで乾燥後、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～９５：５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣にジエチルエーテルを加えて超音波処理後、不溶物を濾過、減圧乾燥することにより、標記化合物１３８ｍｇ（収率７１％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５２６［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.20 & 11.66 (br s, total 1H), 9.70 - 9.39 (m, 1H), 7.45 - 7.30 (m,4H), 7.28 - 7.21 (m, 1H), 6.64 - 6.39 (m, 1H), 5.16 - 5.03 (m, 1H), 4.57 - 4.39 (m,2H), 4.32 - 4.19 (m, 2H), 2.49 - 2.41 (m, 2H), 2.27 (q, J = 7.5 Hz, 2H), 2.24 - 2.14 (m, 2H), 1.91- 1.72 (m,2H), 1.67 - 1.47 (m, 6H), 0.99 (t, J = 7.5 Hz, 3H), 0.09 (s, 9H)。 (S) -ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5, synthesized in the same manner as in Reference Example 30 To a solution of 6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate 200 mg (0.369 mmol) and triethylamine 0.10 ml (0.74 mmol) in dehydrated dichloromethane 3 ml under argon atmosphere 0.071 ml (0.55 mmol) and 4-dimethylaminopyridine 9.7 mg (0.079 mmol) were sequentially added at room temperature, followed by reaction at room temperature for 5 hours. Subsequently, 1 ml of methanol and 0.5 ml of triethylamine were added and reacted at room temperature for 2 hours.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and 10 ml of ethyl acetate, 0.5 ml of water, and 10 ml of a saturated aqueous sodium chloride solution were added to the resulting concentrated residue for liquid separation. The aqueous layer was extracted twice with 10 ml of dichloromethane, and the entire organic layer obtained was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired product was reduced in pressure. Concentrated. Diethyl ether was added to the resulting concentrated residue, followed by sonication, and the insoluble matter was filtered and dried under reduced pressure to obtain 138 mg (yield 71%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 526 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.20 & 11.66 (br s, total 1H), 9.70-9.39 (m, 1H), 7.45-7.30 (m, 4H), 7.28-7.21 (m, 1H), 6.64-6.39 (m, 1H), 5.16-5.03 (m, 1H), 4.57-4.39 (m, 2H), 4.32-4.19 (m, 2H), 2.49-2.41 (m, 2H), 2.27 ( q, J = 7.5 Hz, 2H), 2.24-2.14 (m, 2H), 1.91- 1.72 (m, 2H), 1.67-1.47 (m, 6H), 0.99 (t, J = 7.5 Hz, 3H), 0.09 (s, 9H).
（実施例３２）
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　ブタノアート（化合物番号Ｖ－８８）
Figure JPOXMLDOC01-appb-C000073
 (Example 32)
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl butanoate (Compound No. V-88)
Figure JPOXMLDOC01-appb-C000073
　参考例３０と同様にして合成した（Ｓ）－エチル　５－［（２－ヒドロキシ－１－フェニルエチル）カルバモイル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－１（４Ｈ）－カルボキシラート、及び（Ｓ）－エチル　５－［（２－ヒドロキシ－１－フェニルエチル）カルバモイル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラートの混合物２５０ｍｇ（０．４６１ｍｍｏｌ）、トリエチルアミン０．１０ｍｌ（０．７４ｍｍｏｌ）の１，４－ジオキサン４．５ｍｌ溶液に、アルゴン雰囲気下、酪酸無水物０．０９ｍｌ（０．６ｍｍｏｌ）、４－ジメチルアミノピリジン９．０ｍｇ（０．０７４ｍｍｏｌ）を室温で順次加えた後、１００℃で１．５時間反応させた。次いで、メタノール１．５ｍｌ（３７ｍｍｏｌ）及びトリエチルアミン０．７５ｍｌ（５．４ｍｍｏｌ）を加え、マイクロウエーブ反応装置に供し、８０℃で２時間反応させた。
　反応終了後、反応液を減圧濃縮し、得られた濃縮残渣に酢酸エチル８ｍｌ、水０．４ｍｌ、飽和塩化ナトリウム水溶液８ｍｌを加え分液した。水層をジクロロメタン１０ｍｌで２回抽出し、得られた全有機層を無水硫酸マグネシウムで乾燥後、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～９５：５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した後、得られた濃縮残渣を再度シリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：酢酸エチル＝１００：０～５１：４９（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。濃縮残渣に水を加えて超音波処理後、不溶物を濾過、減圧乾燥することにより、標記化合物８０ｍｇ（収率３２％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５４０［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.20 & 11.65 (br s, total 1H), 9.69 - 9.40 (m, 1H), 7.45 - 7.37 (m,2H), 7.37 - 7.29 (m, 2H), 7.28 - 7.21 (m, 1H), 6.64 - 6.39 (m, 1H), 5.15 - 5.04 (m, 1H), 4.57 -4.38 (m, 2H), 4.31 - 4.20 (m, 2H), 2.49 - 2.41 (m, 2H), 2.28 - 2.14 (m, 4H),1.92 - 1.73 (m, 2H), 1.64 - 1.44 (m, 8H), 0.83 (t, J = 7.4 Hz, 3H), 0.09 (s,9H)。 (S) -ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5, synthesized in the same manner as in Reference Example 30 6-dihydropyrrolo [3,4-c] pyrazole-1 (4H) -carboxylate and (S) -ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3 -[1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate mixture 250 mg (0.461 mmol), triethylamine 0.10 ml (0.74 mmol) ) In 1,4-dioxane (4.5 ml) under an argon atmosphere, 0.09 ml (0 6 mmol), were successively added 4-dimethylaminopyridine 9.0mg of (0.074 mmol) at room temperature and 1.5 hours at 100 ° C.. Subsequently, 1.5 ml (37 mmol) of methanol and 0.75 ml (5.4 mmol) of triethylamine were added, and the mixture was subjected to a microwave reactor and reacted at 80 ° C. for 2 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and 8 ml of ethyl acetate, 0.4 ml of water, and 8 ml of a saturated aqueous sodium chloride solution were added to the resulting concentrated residue for liquid separation. The aqueous layer was extracted twice with 10 ml of dichloromethane, and the entire organic layer obtained was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired product was reduced in pressure. After concentration, the concentrated residue obtained was subjected again to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: ethyl acetate = 100: 0 to 51:49 (V / V)) to obtain the desired product. The fraction containing was concentrated under reduced pressure. Water was added to the concentrated residue, followed by sonication, and the insoluble material was filtered and dried under reduced pressure to obtain 80 mg (yield 32%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 540 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.20 & 11.65 (br s, total 1H), 9.69-9.40 (m, 1H), 7.45-7.37 (m, 2H), 7.37-7.29 (m, 2H), 7.28-7.21 (m, 1H), 6.64-6.39 (m, 1H), 5.15-5.04 (m, 1H), 4.57 -4.38 (m, 2H), 4.31-4.20 (m, 2H), 2.49- 2.41 (m, 2H), 2.28-2.14 (m, 4H), 1.92-1.73 (m, 2H), 1.64-1.44 (m, 8H), 0.83 (t, J = 7.4 Hz, 3H), 0.09 (s, 9H).
（実施例３３）
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　ペンタノアート（化合物番号Ｖ－９０）
Figure JPOXMLDOC01-appb-C000074
 (Example 33)
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl pentanoate (Compound No. V-90)
Figure JPOXMLDOC01-appb-C000074
　参考例３０と同様にして合成した（Ｓ）－エチル　５－［（２－ヒドロキシ－１－フェニルエチル）カルバモイル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート２００ｍｇ（０．３６９ｍｍｏｌ）、トリエチルアミン０．１０ｍｌ（０．７４ｍｍｏｌ）の１，４－ジオキサン３ｍｌ溶液に、アルゴン雰囲気下、吉草酸無水物０．０９ｍｌ（０．５ｍｍｏｌ）、４－ジメチルアミノピリジン９．０ｍｇ（０．０７４ｍｍｏｌ）を室温で加えた後、１００℃で１時間反応させた。次いで、メタノール１ｍｌ、トリエチルアミン０．５ｍｌを加え、マイクロウエーブ反応装置に供し、８０℃で１時間反応させた。
　反応終了後、反応液を減圧濃縮し、得られた濃縮残渣に酢酸エチル１０ｍｌ、１０％リン酸二水素カリウム１０ｍｌを加え分液した。水層をジクロロメタン１０ｍｌで２回抽出し、得られた全有機層を水１０ｍｌ、飽和炭酸水素ナトリウム水溶液１０ｍｌ、飽和塩化ナトリウム水溶液１０ｍｌで順次洗浄した後、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：酢酸エチル＝１００：０～５１：４９（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣に精製水を加え超音波処理後、不溶物を濾過、減圧乾燥することにより、標記化合物３９ｍｇ（収率１９％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５５４［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.20 & 11.63 (br s, total 1H), 9.54 (s, 1H), 7.44 - 7.37 (m,2H), 7.36 - 7.30 (m, 2H), 7.28 - 7.21 (m, 1H), 6.66 - 6.39 (m, 1H), 5.14 - 5.04 (m, 1H), 4.59 - 4.40 (m,  2H),4.25 (d, J = 7.5 Hz, 2H), 2.49 - 2.41 (m, 2H), 2.29 - 2.14 (m, 4H), 1.92 - 1.73(m, 2H), 1.61 (br s, 3H), 1.56 - 1.41 (m, 5H), 1.29 - 1.18 (m, 2H), 0.80 (t, J= 7.3 Hz, 3H), 0.09 (s, 9H)。 (S) -ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5, synthesized in the same manner as in Reference Example 30 To a solution of 6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate 200 mg (0.369 mmol), triethylamine 0.10 ml (0.74 mmol) in 1,4-dioxane 3 ml under an argon atmosphere After adding 0.09 ml (0.5 mmol) of valeric anhydride and 9.0 mg (0.074 mmol) of 4-dimethylaminopyridine at room temperature, the mixture was reacted at 100 ° C. for 1 hour. Next, 1 ml of methanol and 0.5 ml of triethylamine were added, and the mixture was subjected to a microwave reactor and reacted at 80 ° C. for 1 hour.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and 10 ml of ethyl acetate and 10 ml of 10% potassium dihydrogen phosphate were added to the resulting concentrated residue for liquid separation. The aqueous layer was extracted twice with 10 ml of dichloromethane, and the entire organic layer obtained was washed successively with 10 ml of water, 10 ml of saturated aqueous sodium hydrogen carbonate solution and 10 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. went. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: ethyl acetate = 100: 0 to 51:49 (V / V)), and a fraction containing the target product was obtained. Concentrated under reduced pressure. Purified water was added to the resulting concentrated residue, followed by sonication. The insoluble material was filtered and dried under reduced pressure to obtain 39 mg (yield 19%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 554 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.20 & 11.63 (br s, total 1H), 9.54 (s, 1H), 7.44-7.37 (m, 2H), 7.36-7.30 (m, 2H) , 7.28-7.21 (m, 1H), 6.66-6.39 (m, 1H), 5.14-5.04 (m, 1H), 4.59-4.40 (m, 2H), 4.25 (d, J = 7.5 Hz, 2H), 2.49 -2.41 (m, 2H), 2.29-2.14 (m, 4H), 1.92-1.73 (m, 2H), 1.61 (br s, 3H), 1.56-1.41 (m, 5H), 1.29-1.18 (m, 2H ), 0.80 (t, J = 7.3 Hz, 3H), 0.09 (s, 9H).
（実施例３４）
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　オクタノアート（化合物番号Ｖ－９３）
Figure JPOXMLDOC01-appb-C000075
 (Example 34)
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl octanoate (Compound No. V-93)
Figure JPOXMLDOC01-appb-C000075
　参考例３０と同様にして合成した（Ｓ）－エチル　５－［（２－ヒドロキシ－１－フェニルエチル）カルバモイル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－１（４Ｈ）－カルボキシラート、及び（Ｓ）－エチル　５－［（２－ヒドロキシ－１－フェニルエチル）カルバモイル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラートの混合物１８３ｍｇ（０．３２９ｍｍｏｌ）の脱水ジクロロメタン３ｍｌ溶液に、窒素雰囲気下、トリエチルアミン０．１０ｍｌ（０．７２ｍｍｏｌ）、ｎ－オクタン酸無水物０．１５ｍｌ（０．５１ｍｍｏｌ）、４－ジメチルアミノピリジン１０．６ｍｇ（０．０８７ｍｍｏｌ）を室温で順次加えた後、同温度で２時間撹拌した。次いで、反応液にトリエチルアミン１．０ｍｌ（７．２ｍｍｏｌ）、メタノール１．０ｍｌ（２５ｍｍｏｌ）を加えた後、室温で２０．５時間撹拌した。反応液にトリエチルアミン１．０ｍｌ（７．２ｍｍｏｌ）、メタノール１．０ｍｌ（２５ｍｍｏｌ）を追加し、５０℃で２時間撹拌後、６０℃に昇温して４時間撹拌した。
　反応終了後、反応液に水を加え、ジクロロメタンで３回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ジクロロメタン：メタノール＝１００：０～９７：３（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣にｎ－ヘキサンを加え超音波処理後、析出した固体を濾取し、ｎ－ヘキサンで掛け洗いした後、減圧乾燥することにより、標記化合物１１５ｍｇ（収率５８％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５９６［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.16 & 11.77 (br s, total 1H), 9.55 (br s, 1H), 7.47 - 7.37(m, 2H), 7.37 - 7.29 (m, 2H), 7.29 - 7.20 (m, 1H), 6.64 - 6.43 (m, 1H), 5.16 -5.02 (m, 1H), 4.49 (s, 2H), 4.34 - 4.18 (m, 2H), 2.49 - 2.41 (m, 2H), 2.28 -2.14 (m, 4H), 1.89 - 1.73 (m, 2H), 1.60 (s, 3H), 1.53 (s, 3H), 1.50 - 1.43 (m,2H), 1.24 - 1.13 (m, 8H), 0.83 - 0.75 (m, 3H), 0.09 (s, 9H)。 (S) -ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5, synthesized in the same manner as in Reference Example 30 6-dihydropyrrolo [3,4-c] pyrazole-1 (4H) -carboxylate and (S) -ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3 To a solution of 183 mg (0.329 mmol) of [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate in 3 ml of dehydrated dichloromethane under a nitrogen atmosphere Below, 0.10 ml (0.72 mmol) of triethylamine, 0.15 ml of n-octanoic acid anhydride ( .51Mmol), were successively added 4-dimethylaminopyridine 10.6mg of (0.087 mmol) at room temperature and stirred for 2 hours at the same temperature. Next, 1.0 ml (7.2 mmol) of triethylamine and 1.0 ml (25 mmol) of methanol were added to the reaction solution, followed by stirring at room temperature for 20.5 hours. To the reaction solution, triethylamine (1.0 ml, 7.2 mmol) and methanol (1.0 ml, 25 mmol) were added, stirred at 50 ° C. for 2 hours, then heated to 60 ° C. and stirred for 4 hours.
After completion of the reaction, water was added to the reaction solution and extracted three times with dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; dichloromethane: methanol = 100: 0 to 97: 3 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. N-Hexane was added to the obtained concentrated residue and subjected to ultrasonic treatment. The precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 115 mg (yield 58%) of the title compound as white. Obtained as a solid.
Mass spectrum (CI, m / z): 596 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.16 & 11.77 (br s, total 1H), 9.55 (br s, 1H), 7.47-7.37 (m, 2H), 7.37-7.29 (m, 2H ), 7.29-7.20 (m, 1H), 6.64-6.43 (m, 1H), 5.16 -5.02 (m, 1H), 4.49 (s, 2H), 4.34-4.18 (m, 2H), 2.49-2.41 (m , 2H), 2.28 -2.14 (m, 4H), 1.89-1.73 (m, 2H), 1.60 (s, 3H), 1.53 (s, 3H), 1.50-1.43 (m, 2H), 1.24-1.13 (m , 8H), 0.83-0.75 (m, 3H), 0.09 (s, 9H).
（実施例３５）
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　ドデカノアート（化合物番号Ｖ－９４）
Figure JPOXMLDOC01-appb-C000076
 (Example 35)
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl dodecanoate (Compound No. V-94)
Figure JPOXMLDOC01-appb-C000076
　参考例３０と同様にして合成した（Ｓ）－エチル　５－［（２－ヒドロキシ－１－フェニルエチル）カルバモイル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート２０２ｍｇ（０．３７３ｍｍｏｌ）、トリエチルアミン０．１１ｍｌ（０．７９ｍｍｏｌ）、４－ジメチルアミノピリジン１０ｍｇ（０．０８２ｍｍｏｌ）の脱水ジクロロメタン２ｍｌ溶液に、アルゴン雰囲気下、ドデカン酸無水物２２４ｍｇ（０．５８５ｍｍｏｌ）を室温で加え、室温で１時間攪拌した。次いで、反応液へトリエチルアミン１ｍｌ、メタノール１ｍｌを加え、室温で１６時間攪拌した。
　反応終了後、反応液を減圧濃縮した。得られた濃縮残渣をシリカゲルクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９５：５～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１３９ｍｇ（収率５７％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：６５２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.18 & 11.66 (br s, total 1H), 9.83 - 9.28(m, 1H), 7.42 - 7.37 (m, 2H), 7.37 - 7.30 (m, 2H), 7.28 - 7.21 (m, 1H), 6.67 -6.35 (m, 1H), 5.14 - 5.03 (m, 1H), 4.56 - 4.42 (m, 2H), 4.30 - 4.20 (m, 2H), 2.49 - 2.42 (m, 2H), 2.28 - 2.13 (m, 4H), 1.89 - 1.73 (m, 2H), 1.60 (br s,3H), 1.57 - 1.43 (m, 5H), 1.30 - 1.14 (m, 16H), 0.85 (t, J = 6.9 Hz, 3H), 0.09(s, 9H)。 (S) -ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5, synthesized in the same manner as in Reference Example 30 Dehydration of 6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate 202 mg (0.373 mmol), triethylamine 0.11 ml (0.79 mmol), 4-dimethylaminopyridine 10 mg (0.082 mmol) Under an argon atmosphere, 224 mg (0.585 mmol) of dodecanoic anhydride was added to a dichloromethane 2 ml solution at room temperature, and the mixture was stirred at room temperature for 1 hour. Next, 1 ml of triethylamine and 1 ml of methanol were added to the reaction solution, and stirred at room temperature for 16 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 95: 5 to 50:50 (V / V)), and the fraction containing the target compound is concentrated under reduced pressure and dried under reduced pressure. This gave 139 mg (57% yield) of the title compound as a white solid.
Mass spectrum (CI, m / z): 652 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.18 & 11.66 (br s, total 1H), 9.83-9.28 (m, 1H), 7.42-7.37 (m, 2H), 7.37-7.30 (m, 2H), 7.28-7.21 (m, 1H), 6.67 -6.35 (m, 1H), 5.14-5.03 (m, 1H), 4.56-4.42 (m, 2H), 4.30-4.20 (m, 2H), 2.49- 2.42 (m, 2H), 2.28-2.13 (m, 4H), 1.89-1.73 (m, 2H), 1.60 (br s, 3H), 1.57-1.43 (m, 5H), 1.30-1.14 (m, 16H) , 0.85 (t, J = 6.9 Hz, 3H), 0.09 (s, 9H).
（実施例３６）
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　パルミタート（化合物番号Ｖ－９５）
Figure JPOXMLDOC01-appb-C000077
 (Example 36)
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl palmitate (Compound No. V-95)
Figure JPOXMLDOC01-appb-C000077
　参考例３０と同様にして合成した（Ｓ）－エチル　５－［（２－ヒドロキシ－１－フェニルエチル）カルバモイル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート２２０ｍｇ（０．４０６ｍｍｏｌ）、トリエチルアミン０．１１５ｍｌ（０．８２５ｍｍｏｌ）、パルミチン酸無水物３００ｍｇ（０．６０６ｍｍｏｌ）のジクロロメタン３ｍｌ溶液に、アルゴン雰囲気下、４－ジメチルアミノピリジン１０ｍｇ（０．０８２ｍｍｏｌ）を室温で加え、同温度で１．５時間攪拌した。次いで、反応液へメタノール１．０ｍｌ、トリエチルアミン０．５ｍｌを加え、室温で１５時間攪拌した。
　反応終了後、反応液を減圧濃縮した。得られた濃縮残渣をシリカゲルクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９０：１０～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１９５ｍｇ（収率６８％）を白色固体として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：７０８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.18 & 11.64 (br s, total 1H), 9.64 -9.50 (m, 1H), 7.43 - 7.38 (m, 2H), 7.36 - 7.30 (m, 2H), 7.27 - 7.21 (m, 1H), 6.63- 6.39 (m, 1H), 5.13 - 5.04 (m, 1H), 4.55 - 4.42 (m, 2H), 4.30 - 4.20 (m, 2H),2.48 - 2.40 (m, 2H), 2.29 - 2.14 (m, 4H), 1.89 - 1.74 (m, 2H), 1.60 (br s, 3H), 1.57 - 1.43 (m, 5H), 1.29 - 1.14 (m, 24H), 0.89 - 0.81 (m, 3H), 0.09 (s,9H)。 (S) -ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5, synthesized in the same manner as in Reference Example 30 6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate 220 mg (0.406 mmol), triethylamine 0.115 ml (0.825 mmol), palmitic anhydride 300 mg (0.606 mmol) in dichloromethane 3 ml To the solution, 10 mg (0.082 mmol) of 4-dimethylaminopyridine was added at room temperature under an argon atmosphere, and the mixture was stirred at the same temperature for 1.5 hours. Next, 1.0 ml of methanol and 0.5 ml of triethylamine were added to the reaction solution, and the mixture was stirred at room temperature for 15 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 50:50 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure and dried under reduced pressure. This gave 195 mg (68% yield) of the title compound as a white solid.
Mass spectrum (DUIS, m / z): 708 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.18 & 11.64 (br s, total 1H), 9.64 -9.50 (m, 1H), 7.43-7.38 (m, 2H), 7.36-7.30 (m, 2H), 7.27-7.21 (m, 1H), 6.63- 6.39 (m, 1H), 5.13-5.04 (m, 1H), 4.55-4.42 (m, 2H), 4.30-4.20 (m, 2H), 2.48- 2.40 (m, 2H), 2.29-2.14 (m, 4H), 1.89-1.74 (m, 2H), 1.60 (br s, 3H), 1.57-1.43 (m, 5H), 1.29-1.14 (m, 24H) , 0.89-0.81 (m, 3H), 0.09 (s, 9H).
（実施例３７）
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　イソブタノアート（化合物番号Ｖ－８９）
Figure JPOXMLDOC01-appb-C000078
 (Example 37)
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl isobutanoate (Compound No. V-89)
Figure JPOXMLDOC01-appb-C000078
　参考例３０と同様にして合成した（Ｓ）－エチル　５－［（２－ヒドロキシ－１－フェニルエチル）カルバモイル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート２４７ｍｇ（０．４５６ｍｍｏｌ）の脱水ジクロロメタン３ｍｌ溶液に、窒素雰囲気下で、トリエチルアミン０．１５ｍｌ（１．１ｍｍｏｌ）、イソブチリルクロリド０．０６０ｍｌ（０．５７ｍｍｏｌ）を室温で順次加えた後、同温度で１００分間撹拌した。次いで、反応液にトリエチルアミン１．０ｍｌ（７．２ｍｍｏｌ）、メタノール１．０ｍｌ（２５ｍｍｏｌ）を加えた後、室温で４．５時間撹拌した。
　反応終了後、反応液に水を加え、ジクロロメタンで３回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ジクロロメタン：メタノール＝１００：０～９９：１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣に対し酢酸エチル／ｎ－ヘキサンで晶析を行い、得られた固体を濾取し、ｎ－ヘキサンで掛け洗いした後、減圧乾燥することにより標記化合物２０２ｍｇ（収率８２％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５４０［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.20 & 11.61 (br s, total 1H), 9.53 (s, 1H), 7.47 - 7.38 (m,2H), 7.38 - 7.29 (m, 2H), 7.29 - 7.20 (m, 1H), 6.71 - 6.34 (m, 1H), 5.20 - 5.03 (m,1H), 4.57 - 4.38 (m, 2H), 4.33 - 4.15 (m, 2H), 2.48 - 2.42 (m, 3H), 2.27 - 2.13(m, 2H), 1.92 - 1.73 (m, 2H), 1.65 - 1.47 (m, 6H), 1.08 - 0.99 (m, 6H), 0.14 -0.05 (m, 9H)。 (S) -ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5, synthesized in the same manner as in Reference Example 30 To a solution of 247 mg (0.456 mmol) of 6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate in 3 ml of dehydrated dichloromethane was added 0.15 ml (1.1 mmol) of triethylamine, 0.060 ml (0.57 mmol) of ril chloride was sequentially added at room temperature, followed by stirring at the same temperature for 100 minutes. Next, 1.0 ml (7.2 mmol) of triethylamine and 1.0 ml (25 mmol) of methanol were added to the reaction solution, followed by stirring at room temperature for 4.5 hours.
After completion of the reaction, water was added to the reaction solution and extracted three times with dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; dichloromethane: methanol = 100: 0 to 99: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The concentrated residue thus obtained was crystallized from ethyl acetate / n-hexane, and the resulting solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 202 mg of the title compound (yield 82%). ) Was obtained as a white solid.
Mass spectrum (CI, m / z): 540 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.20 & 11.61 (br s, total 1H), 9.53 (s, 1H), 7.47-7.38 (m, 2H), 7.38-7.29 (m, 2H) , 7.29-7.20 (m, 1H), 6.71-6.34 (m, 1H), 5.20-5.03 (m, 1H), 4.57-4.38 (m, 2H), 4.33-4.15 (m, 2H), 2.48-2.42 ( m, 3H), 2.27-2.13 (m, 2H), 1.92-1.73 (m, 2H), 1.65-1.47 (m, 6H), 1.08-0.99 (m, 6H), 0.14 -0.05 (m, 9H).
（実施例３８）
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　ピバラート（化合物番号Ｖ－９１）
Figure JPOXMLDOC01-appb-C000079
 (Example 38)
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl pivalate (Compound No. V-91)
Figure JPOXMLDOC01-appb-C000079
　参考例３０と同様にして合成した（Ｓ）－エチル　５－［（２－ヒドロキシ－１－フェニルエチル）カルバモイル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート２１０ｍｇ（０．３８７ｍｍｏｌ）、トリエチルアミン０．１１ｍｌ（０．７９ｍｍｏｌ）の脱水ジクロロメタン３ｍｌ溶液に、アルゴン雰囲気下、ピバル酸無水物０．１２ｍｌ（０．５９ｍｍｏｌ）、４－ジメチルアミノピリジン１０．５ｍｇ（０．０８６ｍｍｏｌ）を加え、室温で４．５時間攪拌した。次いで、反応液へトリエチルアミン０．５ｍｌ、メタノール１ｍｌを加え、室温で１４時間反応させた。
　反応終了後、反応液を減圧濃縮した。得られた濃縮残渣をシリカゲルクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９０：１０～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥した。得られた濃縮残渣にジイソプロピルエーテルを加え超音波処理後、不溶物を濾取、減圧乾燥することにより、標記化合物１４４ｍｇ（収率６７％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５５４［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.20 & 11.66 (br s, total 1H), 9.55 (s,1H), 7.45 - 7.38 (m, 2H), 7.37 - 7.31 (m, 2H), 7.28 - 7.22 (m, 1H), 6.68 - 6.40(m, 1H), 5.20 - 5.09 (m, 1H), 4.48 (br s, 2H), 4.29 - 4.19 (m, 2H), 2.49 -2.41 (m, 2H), 2.26 - 2.14 (m, 2H), 1.90 - 1.74 (m, 2H), 1.59 (s, 3H), 1.55 (s, 3H), 1.08 (s, 9H), 0.09 (s, 9H)。 (S) -ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5, synthesized in the same manner as in Reference Example 30 To a solution of 210 mg (0.387 mmol) of 6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate and 0.11 ml (0.79 mmol) of triethylamine in 3 ml of dehydrated dichloromethane, an anhydrous pivalic acid was added under an argon atmosphere. 0.12 ml (0.59 mmol) of the product and 10.5 mg (0.086 mmol) of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 4.5 hours. Subsequently, 0.5 ml of triethylamine and 1 ml of methanol were added to the reaction solution, and the mixture was reacted at room temperature for 14 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 50:50 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure. . Diisopropyl ether was added to the obtained concentrated residue, followed by sonication. Insoluble matters were collected by filtration and dried under reduced pressure to obtain 144 mg (yield 67%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 554 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.20 & 11.66 (br s, total 1H), 9.55 (s, 1H), 7.45-7.38 (m, 2H), 7.37-7.31 (m, 2H) , 7.28-7.22 (m, 1H), 6.68-6.40 (m, 1H), 5.20-5.09 (m, 1H), 4.48 (br s, 2H), 4.29-4.19 (m, 2H), 2.49 -2.41 (m , 2H), 2.26-2.14 (m, 2H), 1.90-1.74 (m, 2H), 1.59 (s, 3H), 1.55 (s, 3H), 1.08 (s, 9H), 0.09 (s, 9H).
（実施例３９）
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　３－メチルブタノアート（化合物番号Ｖ－９２）
Figure JPOXMLDOC01-appb-C000080
 (Example 39)
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl 3-methylbutanoate (Compound No. V-92)
Figure JPOXMLDOC01-appb-C000080
　参考例３０と同様にして合成した（Ｓ）－エチル　５－［（２－ヒドロキシ－１－フェニルエチル）カルバモイル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－１（４Ｈ）－カルボキシラート、及び（Ｓ）－エチル　５－［（２－ヒドロキシ－１－フェニルエチル）カルバモイル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラートの混合物２０１ｍｇ（０．３７１ｍｍｏｌ）、トリエチルアミン０．１０ｍｌ（０．７４ｍｍｏｌ）のジクロロメタン３ｍｌ溶液に、アルゴン雰囲気下、イソ吉草酸無水物０．１１ｍｌ（０．５６ｍｍｏｌ）、４－ジメチルアミノピリジン１０．６ｍｇ（０．０８７ｍｍｏｌ）を室温で加えた後、同温度で３時間反応させた。次いで、メタノール１．０ｍｌ及びトリエチルアミン０．５ｍｌを加え、室温で１５．５時間反応させた後、反応液を減圧濃縮し、得られた濃縮残渣に再度メタノール１．０ｍｌ及びトリエチルアミン０．５ｍｌを加え、４０℃で６時間反応させた。
　反応終了後、反応液を減圧濃縮し、得られた濃縮残渣に酢酸エチル８ｍｌ、水０．４ｍｌ、飽和塩化ナトリウム水溶液８ｍｌを加え分液した。水層をジクロロメタン１０ｍｌで２回抽出し、得られた全有機層を無水硫酸マグネシウムで乾燥後、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～９５：５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣にジエチルエーテルを加え超音波処理した後、減圧濃縮した。得られた濃縮残渣に水を加え超音波処理し、一晩静置後に不溶物を濾過、減圧乾燥することにより、標記化合物９７ｍｇ（収率４７％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５５４［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.50 - 11.49 (m, 1H), 9.55 (s, 1H), 7.44 - 7.38 (m, 2H), 7.37 -7.30 (m, 2H), 7.29 - 7.22 (m, 1H), 6.84 - 6.25 (m, 1H), 5.13 - 5.06 (m, 1H),4.55 - 4.41 (m, 2H), 4.31 - 4.21 (m, 2H), 2.49 - 2.42 (m, 2H), 2.26 - 2.11 (m,4H), 2.01 - 1.87 (m, 1H), 1.87 - 1.74 (m, 2H), 1.59 (s, 3H), 1.53 (s, 3H), 0.87- 0.82 (m, 6H), 0.09 (s, 9H)。 (S) -ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5, synthesized in the same manner as in Reference Example 30 6-dihydropyrrolo [3,4-c] pyrazole-1 (4H) -carboxylate and (S) -ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3 -[1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate mixture 201 mg (0.371 mmol), triethylamine 0.10 ml (0.74 mmol) ) In dichloromethane (3 ml) under an argon atmosphere, 0.11 ml (0. 6 mmol), after addition of 4-dimethylaminopyridine 10.6mg of (0.087 mmol) at room temperature and reacted for 3 hours at the same temperature. Next, 1.0 ml of methanol and 0.5 ml of triethylamine were added and reacted at room temperature for 15.5 hours. Then, the reaction solution was concentrated under reduced pressure, and 1.0 ml of methanol and 0.5 ml of triethylamine were again added to the resulting concentrated residue. And reacted at 40 ° C. for 6 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and 8 ml of ethyl acetate, 0.4 ml of water, and 8 ml of a saturated aqueous sodium chloride solution were added to the resulting concentrated residue for liquid separation. The aqueous layer was extracted twice with 10 ml of dichloromethane, and the entire organic layer obtained was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired product was reduced in pressure. Concentrated. Diethyl ether was added to the concentrated residue thus obtained and subjected to ultrasonic treatment, followed by concentration under reduced pressure. Water was added to the resulting concentrated residue, followed by sonication. After standing overnight, the insoluble material was filtered and dried under reduced pressure to obtain 97 mg (yield 47%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 554 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.50-11.49 (m, 1H), 9.55 (s, 1H), 7.44-7.38 (m, 2H), 7.37 -7.30 (m, 2H), 7.29 -7.22 (m, 1H), 6.84-6.25 (m, 1H), 5.13-5.06 (m, 1H), 4.55-4.41 (m, 2H), 4.31-4.21 (m, 2H), 2.49-2.42 (m, 2H), 2.26-2.11 (m, 4H), 2.01-1.87 (m, 1H), 1.87-1.74 (m, 2H), 1.59 (s, 3H), 1.53 (s, 3H), 0.87- 0.82 (m, 6H), 0.09 (s, 9H).
（実施例４０）
（Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　ベンゾアート（化合物番号Ｖ－９６）
Figure JPOXMLDOC01-appb-C000081
 (Example 40)
(S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl benzoate (Compound No. V-96)
Figure JPOXMLDOC01-appb-C000081
　参考例３０と同様にして合成した（Ｓ）－エチル　５－［（２－ヒドロキシ－１－フェニルエチル）カルバモイル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１３２ｍｇ（０．２４４ｍｍｏｌ）、トリエチルアミン０．０６８ｍｌ（０．４９ｍｍｏｌ）の脱水ジクロロメタン２．５ｍｌ溶液に、アルゴン雰囲気下、塩化ベンゾイル０．０４２ｍｌ（０．３６ｍｍｏｌ）を室温で加え、同温度で１時間攪拌した。次いで、反応液へトリエチルアミン０．５ｍｌ、メタノール０．５ｍｌを加え、室温で２０時間攪拌した。
　反応終了後、反応液を減圧濃縮した。得られた濃縮残渣をシリカゲルクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９０：１０～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物９４ｍｇ（収率６７％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５７４［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.19 & 11.71 (br s, total 1H), 9.55 (br.s., 1H), 7.95 - 7.91 (m, 2H), 7.66 - 7.60 (m, 1H), 7.52 - 7.46 (m, 4H), 7.39 -7.33 (m, 2H), 7.30 - 7.24 (m, 1H), 6.73 - 6.59 (m, 1H), 5.35 - 5.26 (m, 1H),4.57 - 4.44 (m, 4H), 2.48 - 2.42 (m, 2H), 2.23 - 2.15 (m, 2H), 1.87 - 1.73 (m,2H), 1.57 (s, 3H), 1.55 (s, 3H), 0.08 (s, 9H)。 (S) -ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5, synthesized in the same manner as in Reference Example 30 To a solution of 132 mg (0.244 mmol) of 6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate and 0.068 ml (0.49 mmol) of triethylamine in 2.5 ml of dehydrated dichloromethane was added chloride under an argon atmosphere. 0.042 ml (0.36 mmol) of benzoyl was added at room temperature and stirred at the same temperature for 1 hour. Next, 0.5 ml of triethylamine and 0.5 ml of methanol were added to the reaction solution, and the mixture was stirred at room temperature for 20 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 50:50 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure and dried under reduced pressure. This gave 94 mg (yield 67%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 574 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.19 & 11.71 (br s, total 1H), 9.55 (br.s., 1H), 7.95-7.91 (m, 2H), 7.66-7.60 (m , 1H), 7.52-7.46 (m, 4H), 7.39 -7.33 (m, 2H), 7.30-7.24 (m, 1H), 6.73-6.59 (m, 1H), 5.35-5.26 (m, 1H), 4.57 -4.44 (m, 4H), 2.48-2.42 (m, 2H), 2.23-2.15 (m, 2H), 1.87-1.73 (m, 2H), 1.57 (s, 3H), 1.55 (s, 3H), 0.08 (s, 9H).
（実施例４１）
（Ｓ）－４－（２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエトキシ）－４－オキソブタン酸ナトリウム（化合物番号Ｖ－９７のナトリウム塩）
Figure JPOXMLDOC01-appb-C000082
 (Example 41)
(S) -4- (2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide } -2-Phenylethoxy) -4-oxobutanoic acid sodium salt (sodium salt of Compound No. V-97)
Figure JPOXMLDOC01-appb-C000082
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート２０１ｍｇ（０．４５６ｍｍｏｌ）の１，４－ジオキサン７．０ｍｌ溶液に、参考例３２と同様にして合成した（Ｓ）－２－アミノ－２－フェニルエチル　ベンジル　スクシナート　トリフルオロ酢酸塩６２８ｍｇ（不純物を含む）、ＤＩＰＥＡ１．０ｍｌ（５．７ｍｍｏｌ）を加え、マイクロウエーブ反応装置に供し、１００℃で１時間反応した。次いで、メタノール１ｍｌ、トリエチルアミン１ｍｌを加え、マイクロウエーブ反応装置に供し、８０℃で３時間反応した。
　反応終了後、反応液を減圧濃縮し、得られた濃縮残渣に酢酸エチルを加え、１０％リン酸二水素カリウム水溶液、水、飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥し、濾過後、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：酢酸エチル＝１００：０～７０：３０（Ｖ／Ｖ））に付し、（Ｓ）－ベンジル　（２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル）スクシナートを含む画分を減圧濃縮し、濃縮残渣を得た。
　得られた濃縮残渣１７１ｍｇのエタノール２０ｍｌ溶液に、窒素雰囲気下、パラジウム／炭素（ＡＳＣＡ２（商品名），Ｎ．Ｅ．ＣＨＥＭＣＡＴ社製，５２％含水）２５．４ｍｇを加えた後、減圧下水素雰囲気へと置換し、室温で２時間撹拌した。
　反応終了後、アルゴン雰囲気へ置換を行い、反応液をセライト濾過した。濾液に１Ｎ水酸化ナトリウム水溶液０．２６ｍｌ（０．２６ｍｍｏｌ）を加え、減圧濃縮した。得られた残渣にジエチルエーテルを加えた後、超音波処理し、析出した固体を濾取、減圧乾燥することにより、標記化合物１４７ｍｇ（収率５４％［２工程］）を白色固体として得た。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：13.32 (br. s, 1H), 10.75 (br. s, 1H), 7.44 - 7.38 (m, 2H), 7.36 -7.29 (m, 2H), 7.28 - 7.19 (m, 1H), 6.47 (d, J = 7.3 Hz, 1H), 5.11 - 5.02 (m,1H), 4.57 - 4.41 (m, 2H), 4.28 (dd, J = 5.6, 10.8 Hz, 1H), 4.17 (dd, J = 8.0,10.8 Hz, 1H), 2.49 - 2.42 (m, 2H), 2.35 (t, J = 7.2 Hz, 2H), 2.25 - 2.16 (m,2H), 2.11 (t, J = 7.2 Hz, 2H), 1.87 - 1.71 (m, 2H), 1.58 (s, 3H), 1.51 (s, 3H),0.08 (s, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 (S) -2-Amino-2-phenylethyl benzyl succinate trifluoro synthesized in the same manner as in Reference Example 32 in a solution of 201 mg (0.456 mmol) of 2 (4H) -carboxylate in 7.0 ml of 1,4-dioxane Acetate 628 mg (containing impurities) and DIPEA 1.0 ml (5.7 mmol) were added, and the mixture was subjected to a microwave reactor and reacted at 100 ° C. for 1 hour. Next, 1 ml of methanol and 1 ml of triethylamine were added, and the mixture was subjected to a microwave reactor and reacted at 80 ° C. for 3 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the resulting concentrated residue, washed successively with 10% aqueous potassium dihydrogen phosphate, water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, and then anhydrous sulfuric acid. After drying over magnesium and filtration, the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: ethyl acetate = 100: 0 to 70:30 (V / V)), and (S) -benzyl (2 -{6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2-phenylethyl) succinate The fraction containing was concentrated under reduced pressure to obtain a concentrated residue.
After adding 25.4 mg of palladium / carbon (ASCA2 (trade name), manufactured by NE CHEMCAT, containing 52% water) to a solution of 171 mg of the concentrated residue in 20 ml of ethanol under a nitrogen atmosphere, a hydrogen atmosphere under reduced pressure. And stirred at room temperature for 2 hours.
After completion of the reaction, the atmosphere was replaced with an argon atmosphere, and the reaction solution was filtered through celite. To the filtrate was added 0.26 ml (0.26 mmol) of 1N aqueous sodium hydroxide solution, and the mixture was concentrated under reduced pressure. Diethyl ether was added to the resulting residue, followed by sonication, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 147 mg (yield 54% [2 steps]) of the title compound as a white solid.
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 13.32 (br. S, 1H), 10.75 (br. S, 1H), 7.44-7.38 (m, 2H), 7.36 -7.29 (m, 2H) , 7.28-7.19 (m, 1H), 6.47 (d, J = 7.3 Hz, 1H), 5.11-5.02 (m, 1H), 4.57-4.41 (m, 2H), 4.28 (dd, J = 5.6, 10.8 Hz , 1H), 4.17 (dd, J = 8.0,10.8 Hz, 1H), 2.49-2.42 (m, 2H), 2.35 (t, J = 7.2 Hz, 2H), 2.25-2.16 (m, 2H), 2.11 ( t, J = 7.2 Hz, 2H), 1.87-1.71 (m, 2H), 1.58 (s, 3H), 1.51 (s, 3H), 0.08 (s, 9H).
（実施例４２）
（Ｓ）－（２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエトキシ）メチル　ピバラート（化合物番号ＶＩ－１２５）
Figure JPOXMLDOC01-appb-C000083
 (Example 42)
(S)-(2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide}- 2-Phenylethoxy) methyl pivalate (Compound No. VI-125)
Figure JPOXMLDOC01-appb-C000083
　参考例３４と同様にして合成した（Ｓ）－(２－アミノ－２－フェニルエトキシ)メチル　ピバラート２７２ｍｇ（１．０８ｍｍｏｌ）の脱水ＴＨＦ２ｍｌ溶液に、窒素雰囲気下、ＤＩＰＥＡ０．１５ｍｌ（０．８６ｍｍｏｌ）、参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１６２ｍｇ（０．３６８ｍｍｏｌ）を室温で順次加えた後、加熱還流させながら１３０分間撹拌した。次いで、反応液にトリエチルアミン１．０ｍｌ、メタノール０．８ｍｌを加えた後、加熱還流させながら７０分間撹拌した。
　反応終了後、反応液に水を加え、ジクロロメタンで３回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＮＨシリカゲル，溶出溶媒；ジクロロメタン：メタノール＝１００：０～９８：２（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣に対し酢酸エチル／ｎ－ヘキサンで晶析を行い、析出した固体を濾取し、ｎ－ヘキサンで掛け洗いした後、減圧乾燥することにより標記化合物１７６ｍｇ（収率８２％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５８４［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.20 & 11.64 (br s, total 1H), 9.59 - 9.49 (m, 1H), 7.41 -7.35 (m, 2H), 7.35 - 7.27 (m, 2H), 7.25 - 7.19 (m, 1H), 6.42 & 6.28 (d, J = 8.0 Hz, total 1H), 5.29 (d, J = 6.2 Hz, 1H), 5.22 (d, J = 6.2 Hz, 1H), 5.02 - 4.94 (m, 1H), 4.57 -4.37 (m, 2H), 3.91 - 3.83 (m, 1H), 3.79 (dd, J = 6.0, 10.0 Hz, 1H), 2.49 - 2.40 (m, 2H), 2.28 - 2.13 (m, 2H), 1.92- 1.73 (m, 2H), 1.67 - 1.45 (m, 6H), 1.13 (s, 9H), 0.14 - 0.06 (m, 9H)。 To a solution of 272 mg (1.08 mmol) of (S)-(2-amino-2-phenylethoxy) methyl pivalate synthesized in the same manner as in Reference Example 2 in 2 ml of dehydrated THF, 0.15 ml (0.86 mmol) of DIPEA in a nitrogen atmosphere, Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 After sequentially adding 162 mg (0.368 mmol) of 2 (4H) -carboxylate at room temperature, the mixture was stirred for 130 minutes while heating to reflux. Next, 1.0 ml of triethylamine and 0.8 ml of methanol were added to the reaction solution, followed by stirring for 70 minutes while heating to reflux.
After completion of the reaction, water was added to the reaction solution and extracted three times with dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DNH silica gel, elution solvent; dichloromethane: methanol = 100: 0 to 98: 2 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The concentrated residue thus obtained was crystallized from ethyl acetate / n-hexane, and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 176 mg of the title compound (yield 82%). Was obtained as a white solid.
Mass spectrum (CI, m / z): 584 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.20 & 11.64 (br s, total 1H), 9.59-9.49 (m, 1H), 7.41 -7.35 (m, 2H), 7.35-7.27 (m, 2H), 7.25-7.19 (m, 1H), 6.42 & 6.28 (d, J = 8.0 Hz, total 1H), 5.29 (d, J = 6.2 Hz, 1H), 5.22 (d, J = 6.2 Hz, 1H) , 5.02-4.94 (m, 1H), 4.57 -4.37 (m, 2H), 3.91-3.83 (m, 1H), 3.79 (dd, J = 6.0, 10.0 Hz, 1H), 2.49-2.40 (m, 2H) , 2.28-2.13 (m, 2H), 1.92-1.73 (m, 2H), 1.67-1.45 (m, 6H), 1.13 (s, 9H), 0.14-0.06 (m, 9H).
（実施例４３）
（Ｓ）－２－アセトキシ－１－フェニルエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキシラート（化合物番号Ｖ－７５）
Figure JPOXMLDOC01-appb-C000084
 (Example 43)
(S) -2-Acetoxy-1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H)- Carboxylate (Compound No. V-75)
Figure JPOXMLDOC01-appb-C000084
　参考例２と同様にして合成した５－ｔｅｒｔ－ブチル　２－エチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］ピロロ［３，４－ｃ］ピラゾール－２，５（４Ｈ，６Ｈ）－ジカルボキシラート５０６ｍｇ（１．０６ｍｍｏｌ）を用いて参考例４７と同様にして合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート４１２ｍｇ（不純物を含む）の脱水ＴＨＦ４ｍｌ溶液に、窒素雰囲気下、ＤＩＰＥＡ０．７０ｍｌ（４．０ｍｍｏｌ）、参考例３５と同様にして合成した（Ｓ）－２－（｛［（２，５－ジオキソピロリジン－１－イル）オキシ］カルボニル｝オキシ）－２－フェニルエチル　アセタート１．３０ｇ（３．８４ｍｍｏｌ）を室温で順次加えた後、加熱還流させながら１．５時間撹拌した。次いで、反応液にトリエチルアミン２．０ｍｌ（１４ｍｍｏｌ）、メタノール１．５ｍｌ（３７ｍｍｏｌ）を加えた後、加熱還流させながら３．５時間撹拌した。
　反応終了後、反応液に水を加え、ジクロロメタンで３回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝８０：２０～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮して、濃縮残渣２２５ｍｇを得た。
　得られた濃縮残渣の内、約５０ｍｇを分取ＨＰＬＣ（カラム；Ｘ－Ｂｒｉｄｇｅ（商品名）ＯＤＳ，溶出溶媒；アセトニトリル：１ｍＭ　リン酸水素ニカリウム水溶液＝５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮してアセトニトリルを留去した。濃縮残渣を酢酸エチルで２回抽出し、得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣に対し酢酸エチル／ジイソプロピルエーテル／ｎ－ヘキサンで晶析を行い、析出した固体を濾取し、ｎ－ヘキサンで掛け洗いした後、減圧乾燥することにより標記化合物１１．６ｍｇ（収率２％［２工程］）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５１３［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.35 - 12.21 & 11.97 - 11.83 (m, total 1H), 9.87 - 9.45 (m, 1H),7.47 - 7.24 (m, 5H), 5.99 - 5.85 (m, 1H), 4.65 - 4.17 (m, 4H), 2.48 - 2.36 (m, 2H), 2.28 - 2.10 (m, 2H), 2.05 - 1.95 (m, 3H), 1.92 - 1.72 (m, 2H), 1.71 - 1.43 (m,6H), 0.16 - 0.02 (m, 9H)。 5-tert-butyl 2-ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] pyrrolo [3,4-c] pyrazole-2,5 (4H, synthesized in the same manner as in Reference Example 2 6H) -Dicarboxylate synthesized in the same manner as in Reference Example 47 using 506 mg (1.06 mmol) of ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [ 3,4-c] pyrazole-2 (4H) -carboxylate 412 mg (containing impurities) in dehydrated THF 4 ml was synthesized in the same manner as in Reference Example 35 under a nitrogen atmosphere with 0.70 ml (4.0 mmol) of DIPEA ( S) -2-({[(2,5-Dioxopyrrolidin-1-yl) oxy] carbonyl} oxy) -2- Were successively added Eniruechiru acetate 1.30g of (3.84 mmol) at room temperature and stirred for 1.5 hours while heating under reflux. Next, 2.0 ml (14 mmol) of triethylamine and 1.5 ml (37 mmol) of methanol were added to the reaction solution, followed by stirring for 3.5 hours while heating to reflux.
After completion of the reaction, water was added to the reaction solution and extracted three times with dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 80: 20 to 50:50 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. As a result, 225 mg of concentrated residue was obtained.
About 50 mg of the obtained concentrated residue was subjected to preparative HPLC (column; X-Bridge (trade name) ODS, elution solvent: acetonitrile: 1 mM aqueous solution of dipotassium hydrogen phosphate = 50: 50 (V / V)). The fraction containing the desired product was concentrated under reduced pressure to distill off acetonitrile. The concentrated residue was extracted twice with ethyl acetate, and the entire organic layer obtained was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue thus obtained was crystallized from ethyl acetate / diisopropyl ether / n-hexane, and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 11.6 mg of the title compound ( Yield 2% [2 steps]) was obtained as a white solid.
Mass spectrum (CI, m / z): 513 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.35-12.21 & 11.97-11.83 (m, total 1H), 9.87-9.45 (m, 1H), 7.47-7.24 (m, 5H), 5.99-5.85 (m, 1H), 4.65-4.17 (m, 4H), 2.48-2.36 (m, 2H), 2.28-2.10 (m, 2H), 2.05-1.95 (m, 3H), 1.92-1.72 (m, 2H) , 1.71-1.43 (m, 6H), 0.16-0.02 (m, 9H).
（実施例４４）
（Ｓ）－ベンジル　２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルアセタート（化合物番号ＩＶ－９７）
Figure JPOXMLDOC01-appb-C000085
 (Example 44)
(S) -Benzyl 2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide}- 2-Phenyl acetate (Compound No. IV-97)
Figure JPOXMLDOC01-appb-C000085
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１９５ｍｇ（０．４４２ｍｍｏｌ）の１，４－ジオキサン７ｍｌ溶液に、アルゴン雰囲気下、参考例３７と同様にして合成した（Ｓ）－ベンジル　２－アミノ－２－フェニルアセタート　トリフルオロ酢酸塩５６５ｍｇ（不純物を含む）、ＤＩＰＥＡ０．５０ｍｌ（２．９ｍｍｏｌ）を室温で加えた後、マイクロウエーブ反応装置に供し、１００℃で１時間攪拌した。反応後、反応液を減圧濃縮し、得られた濃縮残渣にメタノール４ｍｌ、トリエチルアミン１ｍｌを加え、マイクロウエーブ反応装置に供し、８０℃で１時間反応させた。
　反応終了後、反応液を減圧濃縮し、得られた濃縮残渣に酢酸エチルを加え、１０％リン酸二水素カリウム水溶液、飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄後、有機層を無水硫酸マグネシウムで乾燥し、濾過後、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：酢酸エチル＝１００：０～５５：４５（Ｖ／Ｖ））に付し、標記化合物を主成分とする画分及び副生成物［（Ｓ）－メチル　２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルアセタート］を主成分とする画分をそれぞれ減圧濃縮した。標記化合物を主成分とする画分の濃縮残渣を再度シリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：酢酸エチル＝１００：０～５５：４５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物９９ｍｇ（収率３９％）を白色泡状物として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：５７４［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.21 & 11.70 (br s, total 1H), 9.63 - 9.44 (m, 1H), 7.51 -7.41 (m, 2H), 7.38 - 7.23 (m, 8H), 6.81 - 6.47 (m, 1H), 5.42 (d, J = 7.2 Hz,1H), 5.17 (d, J = 12.7 Hz, 1H), 5.11 (d, J = 12.7 Hz, 1H), 4.61 - 4.39 (m, 2H),2.49 - 2.38 (m, 2H), 2.25 - 2.12 (m, 2H), 1.91 - 1.72 (m, 2H), 1.68 - 1.52 (m,6H), 0.07 (s, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 (S) -benzyl 2-amino-2-phenylacetate synthesized in the same manner as in Reference Example 37 in a 7 ml 1,4-dioxane solution containing 195 mg (0.442 mmol) of 2 (4H) -carboxylate in an argon atmosphere After adding 565 mg (containing impurities) of trifluoroacetate salt and 0.50 ml (2.9 mmol) of DIPEA at room temperature, the mixture was supplied to a microwave reactor and stirred at 100 ° C. for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure, 4 ml of methanol and 1 ml of triethylamine were added to the resulting concentrated residue, and the mixture was subjected to a microwave reaction apparatus and reacted at 80 ° C. for 1 hour.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the resulting concentrated residue. After washing sequentially with 10% aqueous potassium dihydrogen phosphate solution, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, the organic layer was dehydrated. After drying over magnesium sulfate and filtration, the filtrate was concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: ethyl acetate = 100: 0 to 55:45 (V / V)), and the title compound is the main component. Fraction and by-products [(S) -methyl 2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] Fractions mainly comprising pyrazole-5-carboxamide} -2-phenylacetate] were each concentrated under reduced pressure. The concentrated residue of the fraction containing the title compound as the main component is again subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: ethyl acetate = 100: 0 to 55:45 (V / V)). The fraction containing the desired product was concentrated under reduced pressure to obtain 99 mg (yield 39%) of the title compound as a white foam.
Mass spectrum (DUIS, m / z): 574 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.21 & 11.70 (br s, total 1H), 9.63-9.44 (m, 1H), 7.51 -7.41 (m, 2H), 7.38-7.23 (m, 8H), 6.81-6.47 (m, 1H), 5.42 (d, J = 7.2 Hz, 1H), 5.17 (d, J = 12.7 Hz, 1H), 5.11 (d, J = 12.7 Hz, 1H), 4.61- 4.39 (m, 2H), 2.49-2.38 (m, 2H), 2.25-2.12 (m, 2H), 1.91-1.72 (m, 2H), 1.68-1.52 (m, 6H), 0.07 (s, 9H).
（実施例４５）
（Ｓ）－メチル　２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルアセタート（化合物番号ＩＶ－９９）
Figure JPOXMLDOC01-appb-C000086
 (Example 45)
(S) -Methyl 2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide}- 2-Phenyl acetate (Compound No. IV-99)
Figure JPOXMLDOC01-appb-C000086
　実施例４４の作業工程における１回目のシリカゲルカラムクロマトグラフィー精製時に回収した標記化合物を主成分とする画分の濃縮残渣を再度シリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：酢酸エチル＝１００：０～５５：４５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物２９ｍｇ（収率１３％）を白色泡状物として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：４９８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.21 & 11.71 (br s, total 1H), 9.63 - 9.46 (m, 1H), 7.48 -7.41 (m, 2H), 7.40 - 7.28 (m, 3H), 6.73 - 6.56 (m, 1H), 5.36 (d, J = 7.2 Hz,1H), 4.61 - 4.38 (m, 2H), 3.62 (s, 3H), 2.49 - 2.38 (m, 2H), 2.27 - 2.10 (m,2H), 1.92 - 1.71 (m, 2H), 1.67 - 1.51 (m, 6H), 0.08 (s, 9H)。 The concentrated residue of the fraction consisting mainly of the title compound recovered during the first silica gel column chromatography purification in the working process of Example 44 was again subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: acetic acid). The fraction containing the target compound was concentrated under reduced pressure to give 29 mg (yield 13%) of the title compound as a white foam.
Mass spectrum (DUIS, m / z): 498 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.21 & 11.71 (br s, total 1H), 9.63-9.46 (m, 1H), 7.48 -7.41 (m, 2H), 7.40-7.28 (m, 3H), 6.73-6.56 (m, 1H), 5.36 (d, J = 7.2 Hz, 1H), 4.61-4.38 (m, 2H), 3.62 (s, 3H), 2.49-2.38 (m, 2H), 2.27 -2.10 (m, 2H), 1.92-1.71 (m, 2H), 1.67-1.51 (m, 6H), 0.08 (s, 9H).
（実施例４６）
Ｎ－（２，２－ジフルオロ－３－ヒドロキシ－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－８９）
Figure JPOXMLDOC01-appb-C000087
 (Example 46)
N- (2,2-difluoro-3-hydroxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide (Compound No. IV-89)
Figure JPOXMLDOC01-appb-C000087
　参考例４０と同様にして合成した３－アミノ－２，２－ジフルオロ－３－フェニルプロパン－１－オール２４９ｍｇ（１．３３ｍｍｏｌ）の脱水１，４－ジオキサン２ｍｌ溶液に、窒素雰囲気下、ＤＩＰＥＡ０．３０ｍｌ（１．７ｍｍｏｌ）、参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１７８ｍｇ（０．４０３ｍｍｏｌ）を室温で順次加えた後、８０℃で７時間撹拌した。次いで、室温まで放冷した反応液に２－アミノエタノール０．１０ｍｌ（１．７ｍｍｏｌ）を加えた後、そのまま室温で１．５時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加えて撹拌し、次いでジクロロメタンで３回抽出した。全有機層を無水硫酸マグネシウムで乾燥後、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝６０：４０～３０：７０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を酢酸エチルに溶解させた後、ｎ－ヘキサンを加えて析出させた固体を濾取し、ｎ－ヘキサンで洗浄してから減圧乾燥することにより、標記化合物１５５ｍｇ（収率７４％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５２０［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.43 - 11.84 (m, 1H), 10.02 - 9.36 (m, 1H), 7.56 - 7.50 (m, 2H), 7.40 - 7.27 (m, 3H), 6.61 (br s, 1H), 5.71 (br s, 1H), 5.49 - 5.34 (m, 1H), 4.70 - 4.56 (m, 1H), 4.47 (br d, J = 12.0 Hz, 1H), 3.73 - 3.45 (m, 2H), 2.57 - 2.42 (m, 2H), 2.26 - 2.15 (m, 2H), 1.90 - 1.74 (m, 2H), 1.61 (s, 3H), 1.51 (s, 3H), 0.09 (s, 9H)。 To a solution of 249 mg (1.33 mmol) of 3-amino-2,2-difluoro-3-phenylpropan-1-ol synthesized in the same manner as in Reference Example 2 in 2 ml of dehydrated 1,4-dioxane, was added DIPEA 0. 30 ml (1.7 mmol) of ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo synthesized in the same manner as in Reference Example 3 , 4-c] pyrazole-2 (4H) -carboxylate (178 mg, 0.403 mmol) was sequentially added at room temperature, followed by stirring at 80 ° C. for 7 hours. Next, 0.10 ml (1.7 mmol) of 2-aminoethanol was added to the reaction solution which was allowed to cool to room temperature, and then stirred at room temperature for 1.5 hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and stirred, and then extracted with dichloromethane three times. All organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 60: 40 to 30:70 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was dissolved in ethyl acetate, then n-hexane was added and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 155 mg (yield 74). %) As a white solid.
Mass spectrum (CI, m / z): 520 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.43-11.84 (m, 1H), 10.02-9.36 (m, 1H), 7.56-7.50 (m, 2H), 7.40-7.27 (m, 3H) , 6.61 (br s, 1H), 5.71 (br s, 1H), 5.49-5.34 (m, 1H), 4.70-4.56 (m, 1H), 4.47 (br d, J = 12.0 Hz, 1H), 3.73- 3.45 (m, 2H), 2.57-2.42 (m, 2H), 2.26-2.15 (m, 2H), 1.90-1.74 (m, 2H), 1.61 (s, 3H), 1.51 (s, 3H), 0.09 ( s, 9H).
（実施例４７）
（Ｓ）－Ｎ－［１－（２－クロロフェニル）－２－ヒドロキシエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－２８６）
Figure JPOXMLDOC01-appb-C000088
 (Example 47)
(S) —N- [1- (2-chlorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide (Compound No. IV-286)
Figure JPOXMLDOC01-appb-C000088
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート ０．１０５ｇ（０．２３８ｍｍｏｌ）、（Ｓ）－２－アミノ－２－（２－クロロフェニル）エタノール［Ａｍａｔｅｋ　Ｃｈｅｍｉｃａｌ　Ｃｏ．，　Ｌｔｄ．より購入］０．１２４ｇ（０．７２３ｍｍｏｌ）の脱水１，４－ジオキサン２．５ｍｌ溶液に、窒素雰囲気下、ＤＩＰＥＡ０．２００ｍｌ（１．１５ｍｍｏｌ）を室温で加えた後、１００℃で１時間攪拌した。放冷後、メタノール０．５０ｍｌ（１２ｍｍｏｌ）及び２－アミノエタノール０．０７０ｍｌ（１．２ｍｍｏｌ）を加え、室温で１時間撹拌した。
　反応終了後、反応溶液を減圧濃縮し、残渣に酢酸エチルを加え、１０％リン酸二水素カリウム水溶液、飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄し、有機層を無水硫酸マグネシウムで乾燥し、ろ過後、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：酢酸エチル＝８４：１６～３３：６７（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮し、残渣を少量のジクロロメタンに溶解し、ｎ－ヘキサンを加え、超音波処理した後、析出した固体をろ取、減圧乾燥することにより、標記化合物０．０９５８ｇ（収率８０％）を白色固体として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：５０４［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.21 & 11.75 (br s, total 1H), 9.71 - 9.52 (m, 1H), 7.51 (dd, J=1.6, 7.7 Hz, 1H), 7.38 (dd, J=1.2, 7.8 Hz, 1H), 7.33 - 7.20 (m, 2H), 6.36 - 6.14 (m, 1H), 5.21 - 5.12 (m, 1H), 5.04 (t, J = 6.0 Hz, 1H), 4.66 - 4.45 (m, 2H), 3.64 - 3.48 (m, 2H), 2.57 - 2.41 (m, 2H), 2.28 - 2.13 (m, 2H), 1.91 - 1.72 (m, 2H), 1.66 - 1.42 (m, 6H), 0.10 (s, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 2 (4H) -carboxylate 0.105 g (0.238 mmol), (S) -2-amino-2- (2-chlorophenyl) ethanol [Amatek Chemical Co. , Ltd., Ltd. Purchased] To a solution of 0.124 g (0.723 mmol) of dehydrated 1,4-dioxane in 2.5 ml was added DIPEA 0.200 ml (1.15 mmol) at room temperature in a nitrogen atmosphere and then stirred at 100 ° C. for 1 hour. . After allowing to cool, 0.50 ml (12 mmol) of methanol and 0.070 ml (1.2 mmol) of 2-aminoethanol were added and stirred at room temperature for 1 hour.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, washed successively with 10% aqueous potassium dihydrogen phosphate solution, saturated aqueous sodium hydrogen carbonate solution, saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: ethyl acetate = 84: 16 to 33:67 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure, The residue was dissolved in a small amount of dichloromethane, and n-hexane was added, followed by sonication. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 0.0958 g (yield 80%) of the title compound as a white solid. It was.
Mass spectrum (DUIS, m / z): 504 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.21 & 11.75 (br s, total 1H), 9.71-9.52 (m, 1H), 7.51 (dd, J = 1.6, 7.7 Hz, 1H), 7.38 (dd, J = 1.2, 7.8 Hz, 1H), 7.33-7.20 (m, 2H), 6.36-6.14 (m, 1H), 5.21-5.12 (m, 1H), 5.04 (t, J = 6.0 Hz, 1H ), 4.66-4.45 (m, 2H), 3.64-3.48 (m, 2H), 2.57-2.41 (m, 2H), 2.28-2.13 (m, 2H), 1.91-1.72 (m, 2H), 1.66-1.42 (m, 6H), 0.10 (s, 9H).
（実施例４８）
（Ｓ）－Ｎ－［２－ヒドロキシ－１－（ｏ－トリル）エチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－３０６）
Figure JPOXMLDOC01-appb-C000089
 (Example 48)
(S) -N- [2-hydroxy-1- (o-tolyl) ethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide (Compound No. IV-306)
Figure JPOXMLDOC01-appb-C000089
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート０．１０４ｇ（０．２３５ｍｍｏｌ）、（Ｓ）－２－アミノ－２－（ｏ－トリル）エタノール塩酸塩［Ａｃｅｓｙｓ　Ｐｈａｒｍａｔｅｃｈ　Ｌｔｄ．より購入］０．１３１ｇ（０．６９６ｍｍｏｌ）の脱水１，４－ジオキサン２．５ｍｌ溶液に、窒素雰囲気下、ＤＩＰＥＡ０．４００ｍｌ（２．３０ｍｍｏｌ）を室温で加えた後、１００℃で１時間加熱攪拌した。放冷後、メタノール０．５０ｍｌ（１２ｍｍｏｌ）及び２－アミノエタノール０．０７０ｍｌ（１．２ｍｍｏｌ）を加え、室温で１時間撹拌した。
　反応終了後、反応溶液を減圧濃縮し、酢酸エチルを加え、１０％リン酸二水素カリウム水溶液、飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄し、有機層を無水硫酸マグネシウムで乾燥し、ろ過後、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：酢酸エチル＝８４：１６～３３：６７（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮し、残渣を少量のジクロロメタンに溶解し、ｎ－ヘキサンを加え、超音波処理した後、析出した固体をろ取、減圧乾燥することにより、標記化合物０．０７３８ｇ（収率６５％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４８４［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.20 & 11.66 (br s, total 1H), 9.63 - 9.50 (m, 1H), 7.40 (d, J = 7.4 Hz, 1H), 7.18 - 7.03 (m, 3H), 6.28 - 6.05 (m, 1H), 5.04 - 4.95 (m, 1H), 4.89 (t, J = 6.0 Hz, 1H), 4.58 - 4.41 (m, 2H), 3.61 - 3.43 (m, 2H), 2.56 - 2.41 (m, 2H), 2.36 (s, 3H), 2.27 - 2.11 (m, 2H), 1.93 - 1.70 (m, 2H), 1.69 - 1.41 (m, 6H), 0.10 (s, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 2 (4H) -carboxylate 0.104 g (0.235 mmol), (S) -2-amino-2- (o-tolyl) ethanol hydrochloride [Acesys Pharmatech Ltd. Purchased] To a solution of 0.131 g (0.696 mmol) of dehydrated 1,4-dioxane in 2.5 ml of nitrogen was added DIPEA (0.400 ml, 2.30 mmol) at room temperature, and then heated and stirred at 100 ° C. for 1 hour. did. After allowing to cool, 0.50 ml (12 mmol) of methanol and 0.070 ml (1.2 mmol) of 2-aminoethanol were added and stirred at room temperature for 1 hour.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, added with ethyl acetate, washed successively with 10% aqueous potassium dihydrogen phosphate, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, and the organic layer was dried over anhydrous magnesium sulfate, After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: ethyl acetate = 84: 16 to 33:67 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure, The residue was dissolved in a small amount of dichloromethane, added with n-hexane and sonicated, and then the precipitated solid was collected by filtration and dried under reduced pressure to obtain 0.0738 g (yield 65%) of the title compound as a white solid. It was.
Mass spectrum (CI, m / z): 484 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.20 & 11.66 (br s, total 1H), 9.63-9.50 (m, 1H), 7.40 (d, J = 7.4 Hz, 1H), 7.18-7.03 (m, 3H), 6.28-6.05 (m, 1H), 5.04-4.95 (m, 1H), 4.89 (t, J = 6.0 Hz, 1H), 4.58-4.41 (m, 2H), 3.61-3.43 (m , 2H), 2.56-2.41 (m, 2H), 2.36 (s, 3H), 2.27-2.11 (m, 2H), 1.93-1.70 (m, 2H), 1.69-1.41 (m, 6H), 0.10 (s , 9H).
（実施例４９）
（Ｓ）－Ｎ－（１－ヒドロキシ－３－フェニルプロパン－２－イル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－２２７）
Figure JPOXMLDOC01-appb-C000090
 (Example 49)
(S) -N- (1-hydroxy-3-phenylpropan-2-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide (Compound No. IV-227)
Figure JPOXMLDOC01-appb-C000090
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１０１ｍｇ（０．２２９ｍｍｏｌ）の１，４－ジオキサン３ｍｌ溶液に、アルゴン雰囲気下、ＤＩＰＥＡ０．１１５ｍｌ（０．６７３ｍｍｏｌ）、（Ｓ）－２－アミノ－３－フェニルプロパン－１－オール１０２ｍｇ（０．６７５ｍｍｏｌ）を順次加えた後、１００℃で１時間撹拌した。次いで、反応液を減圧濃縮し、メタノール２ｍｌ、トリエチルアミン０．５ｍｌを室温で順次加え、マイクロウェーブ反応装置で８０℃で１時間攪拌した。
　反応終了後、反応液を減圧濃縮し、濃縮残渣を酢酸エチル５ｍｌに溶解し、５％リン酸二水素カリウム水溶液で２回洗浄した後、有機層を飽和炭酸水素ナトリウム水溶液５ｍｌで洗浄した。有機層を無水硫酸マグネシウムで乾燥後、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；酢酸エチル：メタノール＝１００：０～８６：１４（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮し、次いで５０℃で減圧乾燥することにより標記化合物８８．５ｍｇ（収率８０％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４８４［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.19 & 11.71 (br s, total 1H), 9.54 (br s, 1H), 7.28 - 7.18 (m, 4H), 7.18 - 7.12 (m, 1H), 5.72 - 5.45 (m, 1H), 4.77 (t, J = 5.5 Hz, 1H), 4.46 - 4.17 (m, 2H), 3.90 - 3.77 (m, 1H), 3.44 - 3.28 (m, 2H), 2.87 - 2.70 (m, 2H), 2.54 - 2.40 (m, 2H), 2.25 - 2.13 (m, 2H), 1.92 - 1.70 (m, 2H), 1.58 (br s, 3H), 1.50 (br s, 3H), 0.09 (s, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 To a solution of 101 mg (0.229 mmol) of 2 (4H) -carboxylate in 3 ml of 1,4-dioxane, 0.115 ml (0.673 mmol) of DIPEA, (S) -2-amino-3-phenylpropane-1 under an argon atmosphere -All 102 mg (0.675 mmol) of all were added in turn and then stirred at 100 ° C for 1 hour. Next, the reaction solution was concentrated under reduced pressure, 2 ml of methanol and 0.5 ml of triethylamine were sequentially added at room temperature, and the mixture was stirred at 80 ° C. for 1 hour in a microwave reactor.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. The concentrated residue was dissolved in 5 ml of ethyl acetate, washed twice with 5% aqueous potassium dihydrogen phosphate solution, and then the organic layer was washed with 5 ml of saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; ethyl acetate: methanol = 100: 0 to 86:14 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure, Subsequently, it was dried under reduced pressure at 50 ° C. to obtain 88.5 mg (yield 80%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 484 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.19 & 11.71 (br s, total 1H), 9.54 (br s, 1H), 7.28-7.18 (m, 4H), 7.18-7.12 (m, 1H ), 5.72-5.45 (m, 1H), 4.77 (t, J = 5.5 Hz, 1H), 4.46-4.17 (m, 2H), 3.90-3.77 (m, 1H), 3.44-3.28 (m, 2H), 2.87-2.70 (m, 2H), 2.54-2.40 (m, 2H), 2.25-2.13 (m, 2H), 1.92-1.70 (m, 2H), 1.58 (br s, 3H), 1.50 (br s, 3H ), 0.09 (s, 9H).
（実施例５０）
Ｎ－［５－（３－ヒドロキシ－２－フェニルプロパノイル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド（化合物番号ＩＶ－１２５）
Figure JPOXMLDOC01-appb-C000091
 (Example 50)
N- [5- (3-Hydroxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- ( Trimethylsilyl) cyclobutanecarboxamide (Compound No. IV-125)
Figure JPOXMLDOC01-appb-C000091
　窒素雰囲気下、３－（ベンジルオキシ）－２－フェニルプロパン酸［Ｔｅｔｒａｈｅｄｒｏｎ　Ｌｅｔｔ．，２００２（４３），９６９１－９６９３．に記載の方法に準じて合成］１３９ｍｇ（０．５４０ｍｍｏｌ）の脱水ＤＭＦ３ｍｌ溶液に、ＤＩＰＥＡ０．１８ｍｌ（１．０ｍｍｏｌ）、（１－シアノ－２－エトキシ－２－オキソエチリデンアミノオキシ）ジメチルアミノモルホリノカルベニウムヘキサフルオロリン酸塩［ＣＯＭＵ（商品名）］２３３ｍｇ（０．５４４ｍｍｏｌ）を０℃で順次加えた後、そのままの温度で１５分間撹拌した。次いで、参考例５と同様にして合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－１（４Ｈ）－カルボキシラート１５８ｍｇ（０．４１８ｍｍｏｌ）を０℃で加えた後、室温で３．５時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加えて撹拌し、次いで酢酸エチルで３回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥後、濾過、減圧濃縮することにより、濃縮残渣を得た。
　窒素雰囲気下、得られた濃縮残渣のＴＨＦ４ｍｌ溶液に、トリエチルアミン０．２５ｍｌ（１．８ｍｍｏｌ）、２－アミノエタノール０．１０ｍｌ（１．７ｍｍｏｌ）を室温で順次加えた後、そのままの温度で１．５時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加えて撹拌し、次いで、ジクロロメタンで３回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥後、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７０：３０～５０：５０（Ｖ／Ｖ））に付し、次いで減圧濃縮、減圧乾燥することにより、濃縮残渣を得た。
　窒素雰囲気下、得られた濃縮残渣のエタノール２ｍｌ溶液に、２０％水酸化パラジウム／炭素［５０ｗｔ％含水］２５．４ｍｇを室温で加えた後、減圧下水素雰囲気へと置換し、室温で１．５時間撹拌した。反応容器内を減圧下窒素雰囲気へと置換し、次いで２０％水酸化パラジウム／炭素［５０ｗｔ％含水］６８．３ｍｇを室温で加えた後、再度減圧下水素雰囲気へと置換し、室温で３．５時間撹拌した。
　反応終了後、反応容器内を減圧下窒素雰囲気へと置換した。反応液をセライトフィルターを用いて濾過し、次いで除去した固体をエタノールで洗浄した後、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７０：３０～３０：７０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を酢酸エチルに溶解させた後、ｎ－ヘキサンを加えて析出させた固体を濾取し、ｎ－ヘキサンで洗浄してから減圧乾燥することにより、標記化合物１０４ｍｇ（収率５５％［２工程］）を白色固体として得た。
マススペクトル（ＥＩ，ｍ／ｚ）：４５４［Ｍ］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.45 - 11.70 (m, 1H), 9.58 (br s, 1H), 7.35 - 7.20 (m, 5H), 4.81 - 4.64 (m, 2H), 4.23 (d, J = 12.0 Hz, 1H), 3.98 - 3.89 (m, 1H), 3.84 (dd, J = 5.4, 8.2 Hz, 1H), 3.52 - 3.44 (m, 1H), 2.58 - 2.37 (m, 2H), 2.24 - 2.12 (m, 2H), 1.87 - 1.73 (m, 2H), 1.69 (s, 3H), 1.58 (s, 3H), 0.05 (s, 9H)。 Under nitrogen atmosphere, 3- (benzyloxy) -2-phenylpropanoic acid [Tetrahedron Lett. , 2002 (43), 9691-9963. In a solution of 139 mg (0.540 mmol) in dehydrated DMF, 0.18 ml (1.0 mmol) of DIPEA, (1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholinocarbe Nitrofluorophosphate [COMU (trade name)] (233 mg, 0.544 mmol) was sequentially added at 0 ° C., and the mixture was stirred at the same temperature for 15 minutes. Next, ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-1 (4H)-synthesized in the same manner as in Reference Example 5 Carboxylate (158 mg, 0.418 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 3.5 hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and stirred, and then extracted with ethyl acetate three times. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a concentrated residue.
Under a nitrogen atmosphere, 0.25 ml (1.8 mmol) of triethylamine and 0.10 ml (1.7 mmol) of 2-aminoethanol were sequentially added to a solution of the obtained concentrated residue in 4 ml of THF at room temperature. Stir for 5 hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and stirred, and then extracted with dichloromethane three times. The entire organic layer obtained was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30 to 50:50 (V / V)), then concentrated under reduced pressure and dried under reduced pressure. A concentrated residue was obtained.
Under a nitrogen atmosphere, 25.4 mg of 20% palladium hydroxide / carbon [containing 50 wt% water] was added to a 2 ml ethanol solution of the obtained concentrated residue at room temperature, and then replaced with a hydrogen atmosphere under reduced pressure. Stir for 5 hours. The inside of the reaction vessel was replaced with a nitrogen atmosphere under reduced pressure, and then 68.3 mg of 20% palladium hydroxide / carbon [containing 50 wt% water] was added at room temperature, and then replaced with a hydrogen atmosphere under reduced pressure again. Stir for 5 hours.
After completion of the reaction, the inside of the reaction vessel was replaced with a nitrogen atmosphere under reduced pressure. The reaction solution was filtered using a Celite filter, and the removed solid was washed with ethanol, and then the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30 to 30:70 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was dissolved in ethyl acetate, then n-hexane was added and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 104 mg of the title compound (yield 55 % [2 steps]) as a white solid.
Mass spectrum (EI, m / z): 454 [M] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.45-11.70 (m, 1H), 9.58 (br s, 1H), 7.35-7.20 (m, 5H), 4.81-4.64 (m, 2H), 4.23 (d, J = 12.0 Hz, 1H), 3.98-3.89 (m, 1H), 3.84 (dd, J = 5.4, 8.2 Hz, 1H), 3.52-3.44 (m, 1H), 2.58-2.37 (m, 2H), 2.24-2.12 (m, 2H), 1.87-1.73 (m, 2H), 1.69 (s, 3H), 1.58 (s, 3H), 0.05 (s, 9H).
（実施例５１）
（Ｓ）－Ｎ－［５－（３－ヒドロキシ－２－フェニルプロパノイル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド（化合物番号ＩＶ－１２６）
Figure JPOXMLDOC01-appb-C000092
 (Example 51)
(S) -N- [5- (3-Hydroxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (Trimethylsilyl) cyclobutanecarboxamide (Compound No. IV-126)
Figure JPOXMLDOC01-appb-C000092
　参考例４８と同様にして合成した（Ｓ）－Ｎ－｛５－［３－（ベンジルオキシ）－２－フェニルプロパノイル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド１３９ｍｇ（０．２５６ｍｍｏｌ）のエタノール２ｍｌ溶液に、窒素雰囲気下、２０％水酸化パラジウム／炭素［５０ｗｔ％含水］５８．４ｍｇを室温で加えた後、減圧下水素雰囲気へと置換し、室温で３時間撹拌した。
　反応終了後、反応容器内を減圧下窒素雰囲気へと置換した。反応液をセライトフィルターを用いて濾過し、次いで除去した固体を酢酸エチルで洗浄した後、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝８５：１５～３５：６５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を酢酸エチルに溶解させた後、ｎ－ヘキサンを加えて析出させた固体を濾取し、ｎ－ヘキサンで洗浄してから減圧乾燥することにより、標記化合物５５ｍｇ（収率４７％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４５５［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.24 & 11.85 (br s, total 1H), 9.73 - 9.44 (m, 1H), 7.35 - 7.20 (m, 5H), 4.81 - 4.63 (m, 2H), 4.33 - 4.11 (m, 1H), 3.98 - 3.89 (m, 1H), 3.88 - 3.80 (m, 1H), 3.52 - 3.44 (m, 1H), 2.60 - 2.36 (m, 2H), 2.26 - 2.10 (m, 2H), 1.89 - 1.64 (m, 5H), 1.58 (br s, 3H), 0.05 (s, 9H)。 (S) -N- {5- [3- (benzyloxy) -2-phenylpropanoyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [6] synthesized in the same manner as in Reference Example 48 3,4-c] pyrazol-3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide in a solution of 139 mg (0.256 mmol) of ethanol in 2 ml of ethanol under a nitrogen atmosphere, 20% palladium hydroxide / carbon [containing 50 wt% water] After adding 4 mg at room temperature, the atmosphere was replaced with a hydrogen atmosphere under reduced pressure, and the mixture was stirred at room temperature for 3 hours.
After completion of the reaction, the inside of the reaction vessel was replaced with a nitrogen atmosphere under reduced pressure. The reaction solution was filtered using a celite filter, and the removed solid was washed with ethyl acetate, and then the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 85: 15 to 35:65 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was dissolved in ethyl acetate, then n-hexane was added and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 55 mg (yield 47) %) As a white solid.
Mass spectrum (CI, m / z): 455 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.24 & 11.85 (br s, total 1H), 9.73-9.44 (m, 1H), 7.35-7.20 (m, 5H), 4.81-4.63 (m, 2H), 4.33-4.11 (m, 1H), 3.98-3.89 (m, 1H), 3.88-3.80 (m, 1H), 3.52-3.44 (m, 1H), 2.60-2.36 (m, 2H), 2.26- 2.10 (m, 2H), 1.89-1.64 (m, 5H), 1.58 (br s, 3H), 0.05 (s, 9H).
（実施例５２）
（Ｒ）－Ｎ－［５－（２－メトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド（化合物番号ＩＶ－３３１）
Figure JPOXMLDOC01-appb-C000093
 (Example 52)
(R) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (Trimethylsilyl) cyclobutanecarboxamide (Compound No. IV-331)
Figure JPOXMLDOC01-appb-C000093
　（Ｒ）－２－メトキシ－２－フェニル酢酸２６３ｍｇ（１．５８ｍｍｏｌ）の脱水ジクロロメタン５ｍｌ溶液に、アルゴン雰囲気下で塩化オキサリル０．２４ｍｌ（２．８ｍｍｏｌ）、ＤＭＦ０．０２５ｍｌ（０．３２ｍｍｏｌ）を０℃で順次加えた後、そのままの温度で３時間攪拌した。
　反応終了後、反応液を室温で減圧濃縮して、濃縮残渣を得た。
　得られた濃縮残渣の脱水ジクロロメタン３ｍｌ溶液を、アルゴン雰囲気下、参考例４７と同様にして合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート３００ｍｇ（０．７９３ｍｍｏｌ）、ＤＩＰＥＡ０．５５ｍｌ（３．２ｍｍｏｌ）の脱水ジクロロメタン５ｍｌ溶液に、０℃で滴下した後、室温で１５時間攪拌した。次いで、Ｎ，Ｎ－ジメチルエタン－１，２－ジアミン０．３７ｍｌ（４．０ｍｍｏｌ）を室温で反応液に加えた後、そのままの温度で３時間攪拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。得られた全有機層を飽和塩化アンモニウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥した後、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝５０：５０～３５：６５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣に酢酸エチルを加えて溶解させた後、ｎ－ヘキサンを加えて析出させた固体を濾取し、減圧乾燥することにより、標記化合物２２４ｍｇ（収率６２％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４５５［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.26 & 11.86 (br s, total 1H), 9.71 - 9.47 (m, 1H), 7.44 - 7.27 (m, 5H), 4.96 (s, 1H), 4.74 - 4.52 (m, 1H), 4.39 - 4.21 (m, 1H), 3.31 (s, 3H), 2.48 - 2.36 (m, 2H), 2.26 - 2.07 (m, 2H), 1.92 - 1.53 (m, 8H), 0.05 (s, 9H)。 To a solution of 263 mg (1.58 mmol) of (R) -2-methoxy-2-phenylacetic acid in 5 ml of dehydrated dichloromethane was added 0.24 ml (2.8 mmol) of oxalyl chloride and 0.025 ml (0.32 mmol) of DMF in an argon atmosphere. After sequentially adding at 0 ° C., the mixture was stirred at the same temperature for 3 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure at room temperature to obtain a concentrated residue.
A solution of the obtained concentrated residue in 3 ml of dehydrated dichloromethane was synthesized in the same manner as in Reference Example 47 under an argon atmosphere, with ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo. [3,4-c] pyrazole-2 (4H) -carboxylate 300 mg (0.793 mmol) and DIPEA 0.55 ml (3.2 mmol) in dehydrated dichloromethane 5 ml were added dropwise at 0 ° C. and then stirred at room temperature for 15 hours. did. Next, 0.37 ml (4.0 mmol) of N, N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature, and then stirred at the same temperature for 3 hours.
After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained all organic layers were washed successively with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 50: 50 to 35:65 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. Ethyl acetate was added to the resulting concentrated residue for dissolution, then n-hexane was added and the precipitated solid was collected by filtration and dried under reduced pressure to give 224 mg (yield 62%) of the title compound as a white solid. Obtained.
Mass spectrum (CI, m / z): 455 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.26 & 11.86 (br s, total 1H), 9.71-9.47 (m, 1H), 7.44-7.27 (m, 5H), 4.96 (s, 1H) , 4.74-4.52 (m, 1H), 4.39-4.21 (m, 1H), 3.31 (s, 3H), 2.48-2.36 (m, 2H), 2.26-2.07 (m, 2H), 1.92-1.53 (m, 8H), 0.05 (s, 9H).
（実施例５３）
（Ｓ）－Ｎ－［５－（２－メトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド（化合物番号ＩＶ－３３２）
Figure JPOXMLDOC01-appb-C000094
 (Example 53)
(S) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (Trimethylsilyl) cyclobutanecarboxamide (Compound No. IV-332)
Figure JPOXMLDOC01-appb-C000094
　（Ｓ）－２－メトキシ－２－フェニル酢酸２６３ｍｇ（１．５８ｍｍｏｌ）の脱水ジクロロメタン５ｍｌ溶液に、アルゴン雰囲気下で塩化オキサリル０．２４ｍｌ（２．８ｍｍｏｌ）、ＤＭＦ０．０２５ｍｌ（０．３２ｍｍｏｌ）を０℃で順次加えた後、そのままの温度で３時間攪拌した。
　反応終了後、反応液を室温で減圧濃縮して、濃縮残渣を得た。
　得られた濃縮残渣の脱水ジクロロメタン３ｍｌ溶液を、アルゴン雰囲気下、参考例４７と同様にして合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート３００ｍｇ（０．７９３ｍｍｏｌ）、ＤＩＰＥＡ０．５５ｍｌ（３．２ｍｍｏｌ）の脱水ジクロロメタン５ｍｌ溶液に、０℃で滴下した後、室温で１５時間攪拌した。次いで、Ｎ，Ｎ－ジメチルエタン－１，２－ジアミン０．３７ｍｌ（４．０ｍｍｏｌ）を室温で反応液に加えた後、そのままの温度で３時間攪拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。得られた全有機層を飽和塩化アンモニウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥した後、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝５０：５０～３５：６５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣に酢酸エチルを加えて溶解させた後、ｎ－ヘキサンを加えて析出させた固体を濾取し、減圧乾燥することにより、標記化合物２０６ｍｇ（収率５７％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４５５［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.26 & 11.86 (br s, total 1H), 9.71 - 9.45 (m, 1H), 7.46 - 7.26 (m, 5H), 4.96 (s, 1H), 4.73 - 4.53 (m, 1H), 4.30 (br d, J = 12.3 Hz, 1H), 3.31 (s, 3H), 2.47 - 2.36 (m, 2H), 2.24 - 2.11 (m, 2H), 1.89 - 1.53 (m, 8H), 0.05 (s, 9H)。 To a solution of 263 mg (1.58 mmol) of (S) -2-methoxy-2-phenylacetic acid in 5 ml of dehydrated dichloromethane was added 0.24 ml (2.8 mmol) of oxalyl chloride and 0.025 ml (0.32 mmol) of DMF in an argon atmosphere. After sequentially adding at 0 ° C., the mixture was stirred at the same temperature for 3 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure at room temperature to obtain a concentrated residue.
A solution of the obtained concentrated residue in 3 ml of dehydrated dichloromethane was synthesized in the same manner as in Reference Example 47 under an argon atmosphere, with ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo. [3,4-c] pyrazole-2 (4H) -carboxylate 300 mg (0.793 mmol) and DIPEA 0.55 ml (3.2 mmol) in dehydrated dichloromethane 5 ml were added dropwise at 0 ° C. and then stirred at room temperature for 15 hours. did. Next, 0.37 ml (4.0 mmol) of N, N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature, and then stirred at the same temperature for 3 hours.
After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained all organic layers were washed successively with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 50: 50 to 35:65 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. Ethyl acetate was added to the resulting concentrated residue for dissolution, and then n-hexane was added and the precipitated solid was collected by filtration and dried under reduced pressure to give 206 mg (yield 57%) of the title compound as a white solid. Obtained.
Mass spectrum (CI, m / z): 455 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.26 & 11.86 (br s, total 1H), 9.71-9.45 (m, 1H), 7.46-7.26 (m, 5H), 4.96 (s, 1H) , 4.73-4.53 (m, 1H), 4.30 (br d, J = 12.3 Hz, 1H), 3.31 (s, 3H), 2.47-2.36 (m, 2H), 2.24-2.11 (m, 2H), 1.89- 1.53 (m, 8H), 0.05 (s, 9H).
（実施例５４）
Ｎ－［５－（３－メトキシ－２－フェニルプロパノイル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド（化合物番号ＩＶ－１２７）
Figure JPOXMLDOC01-appb-C000095
 (Example 54)
N- [5- (3-Methoxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- ( Trimethylsilyl) cyclobutanecarboxamide (Compound No. IV-127)
Figure JPOXMLDOC01-appb-C000095
　窒素雰囲気下、参考例５０と同様に合成した３－メトキシ－２－フェニルプロパン酸２１２ｍｇ（１．１８ｍｍｏｌ）の脱水ジクロロメタン６ｍｌ溶液に、塩化オキサリル０．１４ｍｌ（１．６ｍｍｏｌ）、脱水ＤＭＦ０．００６０ｍｌ（０．０７７ｍｍｏｌ）を０℃で順次加えた後、そのままの温度で２．５時間撹拌した。
反応終了後、反応液を減圧濃縮することにより濃縮残渣を得た。
　窒素雰囲気下、得られた濃縮残渣の脱水ジクロロメタン１ｍｌ溶液を、参考例４７と同様に合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１５６ｍｇ（０．４１３ｍｍｏｌ）、ＤＩＰＥＡ０．３６ｍｌ（２．１ｍｍｏｌ）の脱水ジクロロメタン３ｍｌ溶液に０℃で加えた後、そのままの温度で１．５時間撹拌した。次いで、反応液にＮ，Ｎ－ジメチルエタン－１，２－ジアミン０．２３ｍｌ（２．１ｍｍｏｌ）を０℃で加えた後、室温で２時間撹拌した。
　反応終了後、ジクロロメタンで希釈した反応液を５％硫酸水素カリウム水溶液で洗浄した後、分液した。水層をジクロロメタンで２回抽出した後、得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７０：３０～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を再度シリカゲルカラムクロマトグラフィー（溶出溶媒；ジクロロメタン：メタノール＝１００：０～９５：５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を分取ＨＰＬＣ（カラム；Ｘ－Ｂｒｉｄｇｅ（商品名）ＯＤＳ，溶出溶媒；アセトニトリル：１ｍＭ　リン酸水素２カリウム水溶液＝４０：６０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮してアセトニトリルを留去した。得られた濃縮残渣を酢酸エチルで３回抽出した後、得られた全有機層を飽和塩化ナトリウム水溶液で洗浄し、次いで無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。得られた濃縮残渣を酢酸エチルに溶解させた後、ｎ－ヘキサンを加えて析出させた固体を濾取し、ｎ－ヘキサンで洗浄してから減圧乾燥することにより、標記化合物１０１ｍｇ（収率５２％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４６９［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.50 - 11.61 (m, 1H), 9.57 (br s, 1H), 7.36 - 7.22 (m, 5H), 4.70 (d, J = 12.3 Hz, 1H), 4.22 (d, J = 12.3 Hz, 1H), 3.99 - 3.92 (m, 1H), 3.90 - 3.83 (m, 1H), 3.40 (dd, J = 5.7, 8.8 Hz, 1H), 3.23 (s, 3H), 2.57 - 2.37 (m, 2H), 2.22 - 2.12 (m, 2H), 1.86 - 1.74 (m, 2H), 1.68 (s, 3H), 1.57 (s, 3H), 0.05 (s, 9H)。 Under a nitrogen atmosphere, 0.14 ml (1.6 mmol) of oxalyl chloride and 0.0060 ml of dehydrated DMF were added to a solution of 212 mg (1.18 mmol) of 3-methoxy-2-phenylpropanoic acid synthesized in the same manner as Reference Example 50 in 6 ml of dehydrated dichloromethane. 0.077 mmol) was sequentially added at 0 ° C., and the mixture was stirred at the same temperature for 2.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentrated residue.
Under a nitrogen atmosphere, 1 ml of dehydrated dichloromethane solution of the obtained concentrated residue was synthesized in the same manner as in Reference Example 47. Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [ 3,4-c] pyrazole-2 (4H) -carboxylate 156 mg (0.413 mmol) and DIPEA 0.36 ml (2.1 mmol) in dehydrated dichloromethane 3 ml solution was added at 0 ° C. Stir for hours. Next, 0.23 ml (2.1 mmol) of N, N-dimethylethane-1,2-diamine was added to the reaction solution at 0 ° C., followed by stirring at room temperature for 2 hours.
After completion of the reaction, the reaction solution diluted with dichloromethane was washed with 5% aqueous potassium hydrogen sulfate solution, and then separated. The aqueous layer was extracted twice with dichloromethane, and then the entire organic layer obtained was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30 to 50:50 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was again subjected to silica gel column chromatography (elution solvent; dichloromethane: methanol = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The obtained concentrated residue was subjected to preparative HPLC (column; X-Bridge (trade name) ODS, elution solvent: acetonitrile: 1 mM dipotassium hydrogen phosphate aqueous solution = 40: 60 (V / V)), and the target product was obtained. The containing fraction was concentrated under reduced pressure to distill off acetonitrile. The obtained concentrated residue was extracted three times with ethyl acetate, and the obtained all organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was dissolved in ethyl acetate, then n-hexane was added and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 101 mg of the title compound (yield 52 %) As a white solid.
Mass spectrum (CI, m / z): 469 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.50-11.61 (m, 1H), 9.57 (br s, 1H), 7.36-7.22 (m, 5H), 4.70 (d, J = 12.3 Hz, 1H), 4.22 (d, J = 12.3 Hz, 1H), 3.99-3.92 (m, 1H), 3.90-3.83 (m, 1H), 3.40 (dd, J = 5.7, 8.8 Hz, 1H), 3.23 (s , 3H), 2.57-2.37 (m, 2H), 2.22-2.12 (m, 2H), 1.86-1.74 (m, 2H), 1.68 (s, 3H), 1.57 (s, 3H), 0.05 (s, 9H ).
（実施例５５）
Ｎ－［５－（４－メトキシ－２－フェニルブタノイル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド（化合物番号ＩＶ－３７６）
Figure JPOXMLDOC01-appb-C000096
 (Example 55)
N- [5- (4-Methoxy-2-phenylbutanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- ( Trimethylsilyl) cyclobutanecarboxamide (Compound No. IV-376)
Figure JPOXMLDOC01-appb-C000096
　参考例５２と同様にして合成した４－メトキシ－２－フェニルブタン酸１５４ｍｇ（０．７９３ｍｍｏｌ）の脱水ジクロロメタン３ｍｌ溶液に、アルゴン雰囲気下で塩化オキサリル０．１４ｍｌ（１．６ｍｍｏｌ）、ＤＭＦ０．００９２ｍｌ（０．１２ｍｍｏｌ）を０℃で順次加えた後、そのままの温度で１時間攪拌した。
　反応終了後、反応液を室温で減圧濃縮して、濃縮残渣を得た。
　得られた濃縮残渣の脱水ジクロロメタン３ｍｌ溶液を、アルゴン雰囲気下、参考例４７と同様にして合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１５０ｍｇ（０．３９６ｍｍｏｌ）、ＤＩＰＥＡ０．２８ｍｌ（１．６ｍｍｏｌ）の脱水ジクロロメタン３ｍｌ溶液に、０℃で滴下した後、室温で３時間攪拌した。次いで、Ｎ，Ｎ－ジメチルエタン－１，２－ジアミン０．１８５ｍｌ（１．９８ｍｍｏｌ）を室温で反応液に加えた後、そのままの温度で１４時間攪拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。得られた全有機層を飽和塩化アンモニウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥した後、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝６０：４０～４０：６０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を分取ＨＰＬＣ（カラム；ＸＳｅｌｅｃｔ（商品名）ＨＳＳ　Ｃ１８，溶出溶媒；アセトニトリル：１ｍＭリン酸二水素カリウム水溶液＝５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮してアセトニトリルを留去した。得られた濃縮残渣を酢酸エチルで抽出し、得られた全有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した後、濾過、減圧濃縮した。得られた濃縮残渣に酢酸エチルを加えて溶解させた後、ｎ－ヘキサンを加えて析出させた固体を濾取し、減圧乾燥することにより、標記化合物７８ｍｇ（収率４１％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４８３［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.24 & 11.95 (br s, total 1H), 9.78 - 9.46 (m, 1H), 7.39 - 7.18 (m, 5H), 4.79 - 4.57 (m, 1H), 4.24 (br d, J = 12.2 Hz, 1H), 3.92 - 3.75 (m, 1H), 3.29 - 3.21 (m, 2H), 3.20 (s, 3H), 2.59 - 2.37 (m, 2H), 2.25 - 2.11 (m, 3H), 1.88 - 1.62 (m, 6H), 1.57 (br s, 3H), 0.05 (s, 9H)。 To a solution of 154 mg (0.793 mmol) of 4-methoxy-2-phenylbutanoic acid synthesized in the same manner as in Reference Example 3 in 3 ml of dehydrated dichloromethane, 0.14 ml (1.6 mmol) of oxalyl chloride, 0.0092 ml of DMF ( 0.12 mmol) was sequentially added at 0 ° C., followed by stirring at the same temperature for 1 hour.
After completion of the reaction, the reaction solution was concentrated under reduced pressure at room temperature to obtain a concentrated residue.
A solution of the obtained concentrated residue in 3 ml of dehydrated dichloromethane was synthesized in the same manner as in Reference Example 47 under an argon atmosphere, with ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo. [3,4-c] pyrazole-2 (4H) -carboxylate (150 mg, 0.396 mmol) and DIPEA (0.28 ml, 1.6 mmol) in 3 ml of dehydrated dichloromethane were added dropwise at 0 ° C. and then stirred at room temperature for 3 hours. did. Next, 0.185 ml (1.98 mmol) of N, N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature, followed by stirring at the same temperature for 14 hours.
After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained all organic layers were washed successively with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 60: 40 to 40:60 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue is subjected to preparative HPLC (column; XSelect (trade name) HSS C18, elution solvent; acetonitrile: 1 mM aqueous potassium dihydrogen phosphate solution = 50: 50 (V / V)) and contains the target product. The fraction was concentrated under reduced pressure to distill off acetonitrile. The obtained concentrated residue was extracted with ethyl acetate, and the entire organic layer obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Ethyl acetate was added to the resulting concentrated residue for dissolution, then n-hexane was added and the precipitated solid was collected by filtration and dried under reduced pressure to give 78 mg (yield 41%) of the title compound as a white solid. Obtained.
Mass spectrum (CI, m / z): 483 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.24 & 11.95 (br s, total 1H), 9.78-9.46 (m, 1H), 7.39-7.18 (m, 5H), 4.79-4.57 (m, 1H), 4.24 (br d, J = 12.2 Hz, 1H), 3.92-3.75 (m, 1H), 3.29-3.21 (m, 2H), 3.20 (s, 3H), 2.59-2.37 (m, 2H), 2.25-2.11 (m, 3H), 1.88-1.62 (m, 6H), 1.57 (br s, 3H), 0.05 (s, 9H).
（実施例５６）
（Ｓ）－Ｎ－［５－（３－ヒドロキシ－２－フェニルプロパノイル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロプロパンカルボキサミド（化合物番号ＩＩＩ－３１）
Figure JPOXMLDOC01-appb-C000097
 (Example 56)
(S) -N- [5- (3-Hydroxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (Trimethylsilyl) cyclopropanecarboxamide (Compound No. III-31)
Figure JPOXMLDOC01-appb-C000097
　参考例５３と同様にして合成した（Ｓ）－Ｎ－｛５－［３－（ベンジルオキシ）－２－フェニルプロパノイル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロプロパンカルボキサミド４５．８ｍｇ（０．０８６４ｍｍｏｌ）のエタノール１ｍｌ溶液に、窒素雰囲気下、２０％水酸化パラジウム／炭素［５０ｗｔ％含水］１３．６ｍｇを室温で加えた後、減圧下水素雰囲気へと置換し、室温で２．５時間撹拌した。
　反応終了後、反応容器内を減圧下窒素雰囲気へと置換した。反応液をセライトフィルターを用いて濾過し、次いで除去した固体を酢酸エチルで洗浄した後、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７０：３０～３０：７０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を再度シリカゲルカラムクロマトグラフィー（溶出溶媒；ジクロロメタン：メタノール＝９９：１～９５：５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を酢酸エチルに溶解させた後、ｎ－ヘキサンを加えて析出させた固体を濾取し、ｎ－ヘキサンで洗浄してから減圧乾燥することにより、標記化合物１９ｍｇ（収率５０％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４４１［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.25 & 11.96 (br s, total 1H), 9.98 - 9.65 (m, 1H), 7.37 - 7.19 (m, 5H), 4.80 - 4.58 (m, 2H), 4.33 - 4.10 (m, 1H), 3.98 - 3.88 (m, 1H), 3.88 - 3.80 (m, 1H), 3.52 - 3.43 (m, 1H), 1.68 (br s, 3H), 1.57 (br s, 3H), 1.05 - 0.91 (m, 2H), 0.80 - 0.56 (m, 2H), 0.01 (s, 9H)。 (S) -N- {5- [3- (benzyloxy) -2-phenylpropanoyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [6] synthesized in the same manner as in Reference Example 53 3,4-c] pyrazol-3-yl} -1- (trimethylsilyl) cyclopropanecarboxamide in a solution of 45.8 mg (0.0864 mmol) in ethanol under 20% palladium hydroxide / carbon [50 wt% water content under a nitrogen atmosphere After adding 13.6 mg at room temperature, it was replaced with a hydrogen atmosphere under reduced pressure and stirred at room temperature for 2.5 hours.
After completion of the reaction, the inside of the reaction vessel was replaced with a nitrogen atmosphere under reduced pressure. The reaction solution was filtered using a celite filter, and the removed solid was washed with ethyl acetate, and then the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30 to 30:70 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was again subjected to silica gel column chromatography (elution solvent; dichloromethane: methanol = 99: 1 to 95: 5 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The obtained concentrated residue was dissolved in ethyl acetate, then n-hexane was added, and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 19 mg (yield 50%) of the title compound. %) As a white solid.
Mass spectrum (CI, m / z): 441 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.25 & 11.96 (br s, total 1H), 9.98-9.65 (m, 1H), 7.37-7.19 (m, 5H), 4.80-4.58 (m, 2H), 4.33-4.10 (m, 1H), 3.98-3.88 (m, 1H), 3.88-3.80 (m, 1H), 3.52-3.43 (m, 1H), 1.68 (br s, 3H), 1.57 (br s, 3H), 1.05-0.91 (m, 2H), 0.80-0.56 (m, 2H), 0.01 (s, 9H).
（実施例５７）
（Ｒ）－Ｎ－［５－（２－メトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロプロパンカルボキサミド（化合物番号ＩＩＩ－５６）
Figure JPOXMLDOC01-appb-C000098
 (Example 57)
(R) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (Trimethylsilyl) cyclopropanecarboxamide (Compound No. III-56)
Figure JPOXMLDOC01-appb-C000098
　（Ｒ）－２－メトキシ－２－フェニル酢酸１８２ｍｇ（１．１０ｍｍｏｌ）の脱水ジクロロメタン５ｍｌ溶液に、アルゴン雰囲気下で塩化オキサリル０．１６５ｍｌ（１．９２ｍｍｏｌ）、ＤＭＦ０．０１７ｍｌ（０．２２ｍｍｏｌ）を０℃で順次加えた後、そのままの温度で１時間攪拌した。
　反応終了後、反応液を室温で減圧濃縮して、濃縮残渣を得た。
　得られた濃縮残渣の脱水ジクロロメタン３ｍｌ溶液を、アルゴン雰囲気下、参考例３８と同様にして合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート２００ｍｇ（０．５４９ｍｍｏｌ）、ＤＩＰＥＡ０．３８ｍｌ（２．２ｍｍｏｌ）の脱水ジクロロメタン５ｍｌ溶液に、０℃で滴下した後、室温で１．５時間攪拌した。次いで、Ｎ，Ｎ－ジメチルエタン－１，２－ジアミン０．２６ｍｌ（２．７ｍｍｏｌ）を室温で反応液に加えた後、そのままの温度で１時間攪拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。得られた全有機層を飽和塩化アンモニウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥した後、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７０：３０～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を再度シリカゲルカラムクロマトグラフィー（溶出溶媒；１，２－ジクロロエタン：メタノール＝９７：３～９０：１０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１９１ｍｇ（収率７９％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４４１［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.38 - 11.88 (m, 1H), 9.97 - 9.65 (m, 1H), 7.45 - 7.27 (m, 5H), 4.96 (s, 1H), 4.71 - 4.49 (m, 1H), 4.29 (br d, J = 12.8 Hz, 1H), 3.31 (s, 3H), 1.68 (br s, 3H), 1.59 (s, 3H), 1.05 - 0.91 (m, 2H), 0.78 - 0.58 (m, 2H), 0.01 (s, 9H)。 To a solution of 182 mg (1.10 mmol) of (R) -2-methoxy-2-phenylacetic acid in 5 ml of dehydrated dichloromethane was added 0.165 ml (1.92 mmol) of oxalyl chloride and 0.017 ml (0.22 mmol) of DMF in an argon atmosphere. After sequentially adding at 0 ° C., the mixture was stirred at the same temperature for 1 hour.
After completion of the reaction, the reaction solution was concentrated under reduced pressure at room temperature to obtain a concentrated residue.
An ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -5,6-dihydro compound synthesized in the same manner as in Reference Example 38 under argon atmosphere was added to a 3 ml solution of the obtained concentrated residue in dehydrated dichloromethane. To the solution of pyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate 200 mg (0.549 mmol) and DIPEA 0.38 ml (2.2 mmol) in 5 ml of dehydrated dichloromethane was added dropwise at 0 ° C. Stir for 5 hours. Next, 0.26 ml (2.7 mmol) of N, N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature, and then stirred at that temperature for 1 hour.
After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained all organic layers were washed successively with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30 to 50:50 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was again subjected to silica gel column chromatography (elution solvent; 1,2-dichloroethane: methanol = 97: 3 to 90:10 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. By drying under reduced pressure, 191 mg (yield 79%) of the title compound was obtained as a white solid.
Mass spectrum (CI, m / z): 441 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.38-11.88 (m, 1H), 9.97-9.65 (m, 1H), 7.45-7.27 (m, 5H), 4.96 (s, 1H), 4.71 -4.49 (m, 1H), 4.29 (br d, J = 12.8 Hz, 1H), 3.31 (s, 3H), 1.68 (br s, 3H), 1.59 (s, 3H), 1.05-0.91 (m, 2H ), 0.78-0.58 (m, 2H), 0.01 (s, 9H).
（実施例５８）
（Ｒ）－Ｎ－｛５－［２－（ジフルオロメトキシ）－２－フェニルアセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド（化合物番号ＩＶ－３３６）
Figure JPOXMLDOC01-appb-C000099
 (Example 58)
(R) -N- {5- [2- (Difluoromethoxy) -2-phenylacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3- Yl} -1- (trimethylsilyl) cyclobutanecarboxamide (Compound No. IV-336)
Figure JPOXMLDOC01-appb-C000099
　アルゴン雰囲気下、（Ｒ）－ベンジル　２－ヒドロキシ－２－フェニルアセタート１．０１ｇ（４．１７ｍｍｏｌ）、ヨウ化銅（Ｉ）１５８ｍｇ（０．８３ｍｍｏｌ）のアセトニトリル１５ｍｌ溶液に、６０℃で２，２－ジフルオロ－２－（フルオロスルホニル）酢酸２．２ｍｌ（１７ｍｍｏｌ）のアセトニトリル２０ｍｌ溶液を２ｍｌずつ５分おきに分割添加し、そのままの温度で２時間攪拌した。
　反応終了後、室温まで放冷した反応液を減圧濃縮し、酢酸エチルで希釈した。有機層を飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄した後、無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９０：１０～７０：３０（Ｖ／Ｖ））に付し、次いで目的物を含む画分を減圧濃縮することにより、濃縮残渣０．６７ｇを無色油状物として得た。
　得られた濃縮残渣０．６７ｇのメタノール２０ｍｌ溶液にアルゴン雰囲気下、パラジウム／炭素７０ｍｇ（ＡＳＣＡ２（商品名），Ｎ．Ｅ．ＣＨＥＭＣＡＴ社製，５４％含水）を加えた後、減圧下水素雰囲気へと置換し、室温で２時間攪拌した。
反応終了後、窒素雰囲気へと置換し、反応液をセライト濾過し、固体成分をメタノールで洗浄した後、ろ液を減圧濃縮することにより、濃縮残渣０．４２ｇを薄黄色固体として得た。
　アルゴン雰囲気下、得られた濃縮残渣のうち１１５ｍｇの脱水ジクロロメタン３ｍｌ溶液に、塩化オキサリル０．０７２ｍｌ（０．８２ｍｍｏｌ）、脱水ＤＭＦ０．０１０ｍｌ（０．１３ｍｍｏｌ）を室温で順次加えた後、そのままの温度で１５分間撹拌した。
　反応終了後、反応液を減圧濃縮することにより濃縮残渣を得た。
　アルゴン雰囲気下、得られた濃縮残渣の脱水ジクロロメタン１ｍｌ溶液を、参考例４７と同様に合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１０３ｍｇ（０．２７３ｍｍｏｌ）、ＤＩＰＥＡ０．２４ｍｌ（１．４ｍｍｏｌ）の脱水ジクロロメタン３ｍｌ溶液に室温で加えた後、そのままの温度で３．５時間撹拌した。次いで、反応液にＮ，Ｎ－ジメチルエタン－１，２－ジアミン０．１５ｍｌ（１．４ｍｍｏｌ）を室温で加えた後、室温で１時間撹拌した。
　反応終了後、５％硫酸水素カリウム水溶液を加え、酢酸エチルで抽出した。有機層は飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムを加え乾燥、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝５０：５０～０：１００（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を酢酸エチルに溶解し、ｎ－ヘキサンを加えた。析出した固体を濾取し、減圧乾燥することにより、標記化合物４８．１ｍｇ（収率３６％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４９１［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.30 & 11.86 (br s, total 1H), 9.67 - 9.51 (m, 1H), 7.48 - 7.37 (m, 5H), 6.83 (t, J = 76.0 Hz, 1H), 5.78 (s, 1H), 4.83 - 4.61 (m, 1H), 4.24 - 4.07 (m, 1H), 2.56 - 2.35 (m, 2H), 2.24 - 2.10 (m, 2H), 1.91 - 1.50 (m, 8H), 0.04 (s, 9H)。 Under an argon atmosphere, a solution of 1.01 g (4.17 mmol) of (R) -benzyl 2-hydroxy-2-phenylacetate and 158 mg (0.83 mmol) of copper (I) iodide in 15 ml of acetonitrile at 60 ° C. A solution of 2-difluoro-2- (fluorosulfonyl) acetic acid (2.2 ml, 17 mmol) in acetonitrile (20 ml) was added in portions of 2 ml every 5 minutes and stirred at the same temperature for 2 hours.
After completion of the reaction, the reaction solution was allowed to cool to room temperature, concentrated under reduced pressure, and diluted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 70:30 (V / V)), and then the fraction containing the desired product is concentrated under reduced pressure. Gave 0.67 g of the concentrated residue as a colorless oil.
After adding 70 mg of palladium / carbon (ASCA2 (trade name), manufactured by NE CHEMCAT, 54% water content) to a 20 ml methanol solution of 0.67 g of the obtained concentrated residue under an argon atmosphere, the mixture was added to a hydrogen atmosphere under reduced pressure. And stirred at room temperature for 2 hours.
After completion of the reaction, the atmosphere was replaced with a nitrogen atmosphere, the reaction solution was filtered through Celite, the solid component was washed with methanol, and the filtrate was concentrated under reduced pressure to obtain 0.42 g of a concentrated residue as a pale yellow solid.
Under an argon atmosphere, 0.072 ml (0.82 mmol) of oxalyl chloride and 0.010 ml (0.13 mmol) of dehydrated DMF were sequentially added at room temperature to 115 mg of a dehydrated dichloromethane 3 ml solution of the obtained concentrated residue. For 15 minutes.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentrated residue.
Under an argon atmosphere, a 1 ml solution of the obtained concentrated residue in dehydrated dichloromethane was synthesized in the same manner as in Reference Example 47. Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [ 3,4-c] pyrazole-2 (4H) -carboxylate (103 mg, 0.273 mmol) and DIPEA (0.24 ml, 1.4 mmol) in dehydrated dichloromethane (3 ml) were added at room temperature, and the temperature was maintained for 3.5 hours. Stir. Next, 0.15 ml (1.4 mmol) of N, N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature, followed by stirring at room temperature for 1 hour.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 50: 50 to 0: 100 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was dissolved in ethyl acetate, and n-hexane was added. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 48.1 mg (yield 36%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 491 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.30 & 11.86 (br s, total 1H), 9.67-9.51 (m, 1H), 7.48-7.37 (m, 5H), 6.83 (t, J = 76.0 Hz, 1H), 5.78 (s, 1H), 4.83-4.61 (m, 1H), 4.24-4.07 (m, 1H), 2.56-2.35 (m, 2H), 2.24-2.10 (m, 2H), 1.91 -1.50 (m, 8H), 0.04 (s, 9H).
（実施例５９）
（Ｒ）－Ｎ－［５－（２－エトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド（化合物番号ＩＶ－３４４）
Figure JPOXMLDOC01-appb-C000100
 (Example 59)
(R) -N- [5- (2-Ethoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (Trimethylsilyl) cyclobutanecarboxamide (Compound No. IV-344)
Figure JPOXMLDOC01-appb-C000100
　アルゴン雰囲気下、参考例５５と同様にして得られた（Ｒ）－２－エトキシ－２－フェニル酢酸１２８ｍｇ（０．７１０ｍｍｏｌ）の脱水ジクロロメタン３ｍｌ溶液に、塩化オキサリル０．０９０ｍｌ（１．０ｍｍｏｌ）、脱水ＤＭＦ０．０１０ｍｌ（０．１３ｍｍｏｌ）を０℃で順次加えた後、そのままの温度で１時間撹拌した。
　反応終了後、反応液を減圧濃縮することにより濃縮残渣を得た。
　アルゴン雰囲気下、得られた濃縮残渣の脱水ジクロロメタン１ｍｌ溶液を、参考例４７と同様に合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１１２ｍｇ（０．２９５ｍｍｏｌ）、ＤＩＰＥＡ０．３０ｍｌ（１．７ｍｍｏｌ）の脱水ジクロロメタン３ｍｌ溶液に０℃で加えた後、そのままの温度で３０分間撹拌した。次いで、反応液にＮ，Ｎ－ジメチルエタン－１，２－ジアミン０．１１ｍｌ（１．０１ｍｍｏｌ）を０℃で加えた後、室温で１時間撹拌した。
　反応終了後、水を加え、酢酸エチルで抽出した。有機層は５％硫酸水素カリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムを加え乾燥、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝５０：５０～０：１００（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を酢酸エチルに溶解し、ｎ－ヘキサンを加えて析出した固体を濾取し、減圧乾燥することにより、標記化合物６９．７ｍｇ（収率５０％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４６９［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.26 & 11.85 (br s, total 1H), 9.67 - 9.48 (m, 1H), 7.43 - 7.27 (m, 5H), 5.04 (s, 1H), 4.73 - 4.47 (m, 1H), 4.44 - 4.24 (m, 1H), 3.62 - 3.40 (m, 2H), 2.58 - 2.36 (m, 2H), 2.25 - 2.10 (m, 2H), 1.90 - 1.53 (m, 8H), 1.14 (t, J = 7.0 Hz, 3H), 0.05 (s, 9H)。 Under an argon atmosphere, 0.090 ml (1.0 mmol) of oxalyl chloride was added to 3 ml of a dehydrated dichloromethane solution of 128 mg (0.710 mmol) of (R) -2-ethoxy-2-phenylacetic acid obtained in the same manner as in Reference Example 55. Dehydrated DMF (0.010 ml, 0.13 mmol) was sequentially added at 0 ° C., followed by stirring at the same temperature for 1 hour.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentrated residue.
Under an argon atmosphere, a 1 ml solution of the obtained concentrated residue in dehydrated dichloromethane was synthesized in the same manner as in Reference Example 47. Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [ 3,4-c] pyrazole-2 (4H) -carboxylate (112 mg, 0.295 mmol) and DIPEA (0.30 ml, 1.7 mmol) in dehydrated dichloromethane (3 ml) were added at 0 ° C. and stirred at that temperature for 30 minutes. did. Next, 0.11 ml (1.01 mmol) of N, N-dimethylethane-1,2-diamine was added to the reaction solution at 0 ° C., followed by stirring at room temperature for 1 hour.
After completion of the reaction, water was added and extracted with ethyl acetate. The organic layer was washed successively with 5% aqueous potassium hydrogen sulfate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 50: 50 to 0: 100 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was dissolved in ethyl acetate, n-hexane was added and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 69.7 mg (yield 50%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 469 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.26 & 11.85 (br s, total 1H), 9.67-9.48 (m, 1H), 7.43-7.27 (m, 5H), 5.04 (s, 1H) , 4.73-4.47 (m, 1H), 4.44-4.24 (m, 1H), 3.62-3.40 (m, 2H), 2.58-2.36 (m, 2H), 2.25-2.10 (m, 2H), 1.90-1.53 ( m, 8H), 1.14 (t, J = 7.0 Hz, 3H), 0.05 (s, 9H).
（実施例６０）
（Ｒ）－１－（エチルジメチルシリル）－Ｎ－［５－（２－メトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］シクロブタンカルボキサミド（化合物番号ＩＶ－３３４）
Figure JPOXMLDOC01-appb-C000101
 (Example 60)
(R) -1- (Ethyldimethylsilyl) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c ] Pyrazol-3-yl] cyclobutanecarboxamide (Compound No. IV-334)
Figure JPOXMLDOC01-appb-C000101
　窒素雰囲気下、（Ｒ）－２－メトキシ－２－フェニル酢酸１０７ｍｇ（０．６４６ｍｍｏｌ）の脱水ジクロロメタン２ｍｌ溶液に、塩化オキサリル０．０８０ｍｌ（０．９３ｍｍｏｌ）、脱水ＤＭＦ０．００５０ｍｌ（０．０６５ｍｍｏｌ）を０℃で順次加えた後、そのままの温度で３時間撹拌した。
　反応終了後、反応液を減圧濃縮することにより濃縮残渣を得た。
　窒素雰囲気下、得られた濃縮残渣の脱水ジクロロメタン１ｍｌ溶液を、参考例１２と同様に合成したエチル　３－［１－（エチルジメチルシリル）シクロブタンカルボキサミド］－６，６－ジメチル－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１１７ｍｇ（０．２９９ｍｍｏｌ）、ＤＩＰＥＡ０．２１ｍｌ（１．２ｍｍｏｌ）の脱水ジクロロメタン１ｍｌ溶液に０℃で加えた後、そのままの温度で２．５時間撹拌した。次いで、反応液にＮ，Ｎ－ジメチルエタン－１，２－ジアミン０．１６ｍｌ（１．５ｍｍｏｌ）を０℃で加えた後、室温で１．５時間撹拌した。
　反応終了後、ジクロロメタンで希釈した反応液を５％硫酸水素カリウム水溶液で洗浄した後、分液した。水層をジクロロメタンで２回抽出した後、得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝８０：２０～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を酢酸エチルに溶解させた後、ｎ－ヘキサンを加えて析出させた固体を濾取し、ｎ－ヘキサンで洗浄してから減圧乾燥することにより、標記化合物１１５ｍｇ（収率８２％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４６９［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.26 & 11.84 (s, total 1H), 9.67 - 9.48 (m, 1H), 7.42 - 7.27 (m, 5H), 4.95 (s, 1H), 4.71 - 4.52 (m, 1H), 4.35 - 4.23 (m, 1H), 3.30 (s, 3H), 2.56 - 2.37 (m, 2H), 2.26 - 2.11 (m, 2H), 1.90 - 1.52 (m, 8H), 0.88 (t, J = 7.8 Hz, 3H), 0.53 (q, J = 7.8 Hz, 2H), 0.09 - 0.01 (m, 6H)。 Under a nitrogen atmosphere, 0.080 ml (0.93 mmol) of oxalyl chloride and 0.0050 ml (0.065 mmol) of dehydrated DMF were added to a solution of 107 mg (0.646 mmol) of (R) -2-methoxy-2-phenylacetic acid in 2 ml of dehydrated dichloromethane. After sequentially adding at 0 ° C., the mixture was stirred at the same temperature for 3 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentrated residue.
Under a nitrogen atmosphere, a solution of the obtained concentrated residue in 1 ml of dehydrated dichloromethane was combined with ethyl 3- [1- (ethyldimethylsilyl) cyclobutanecarboxamide] -6,6-dimethyl-5,6-dihydro synthesized in the same manner as in Reference Example 12. After adding pyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate 117 mg (0.299 mmol) and DIPEA 0.21 ml (1.2 mmol) in dehydrated dichloromethane 1 ml at 0 ° C. Stir for 5 hours. Next, 0.16 ml (1.5 mmol) of N, N-dimethylethane-1,2-diamine was added to the reaction solution at 0 ° C., followed by stirring at room temperature for 1.5 hours.
After completion of the reaction, the reaction solution diluted with dichloromethane was washed with 5% aqueous potassium hydrogen sulfate solution, and then separated. The aqueous layer was extracted twice with dichloromethane, and then the entire organic layer obtained was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 80: 20 to 50:50 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was dissolved in ethyl acetate, then n-hexane was added and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 115 mg of the title compound (yield 82 %) As a white solid.
Mass spectrum (CI, m / z): 469 [M + 1] + .
1 H-NMR spectrum (400MHz, DMSO-d 6) δ: 12.26 & 11.84 (s, total 1H), 9.67 - 9.48 (m, 1H), 7.42 - 7.27 (m, 5H), 4.95 (s, 1H), 4.71-4.52 (m, 1H), 4.35-4.23 (m, 1H), 3.30 (s, 3H), 2.56-2.37 (m, 2H), 2.26-2.11 (m, 2H), 1.90-1.52 (m, 8H ), 0.88 (t, J = 7.8 Hz, 3H), 0.53 (q, J = 7.8 Hz, 2H), 0.09-0.01 (m, 6H).
（実施例６１）
（Ｒ）－Ｎ－［５－（２－シクロプロポキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド（化合物番号ＩＶ－３６４）
Figure JPOXMLDOC01-appb-C000102
 (Example 61)
(R) -N- [5- (2-Cyclopropoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (Trimethylsilyl) cyclobutanecarboxamide (Compound No. IV-364)
Figure JPOXMLDOC01-appb-C000102
　参考例５７と同様の方法で合成した（Ｒ）－２－シクロプロポキシ－２－フェニル酢酸１４０ｍｇ（０．７２８ｍｍｏｌ）の脱水ジクロロメタン２ｍｌ溶液に、アルゴン雰囲気下で撹拌しながらＤＭＦ０．００６ｍｌ（０．０８ｍｍｏｌ）、塩化オキサリル０．０８３ｍｌ（０．９５ｍｍｏｌ）を０℃で加え、室温で１．５時間撹拌した。
　反応終了後、反応液を減圧濃縮して、濃縮残渣を得た。
　得られた濃縮残渣の脱水ジクロロメタン３ｍｌ溶液を、参考例４７と同様の方法で合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１５０ｍｇ（０．３９６ｍｍｏｌ）、ＤＩＰＥＡ０．３５０ｍｌ（２．００ｍｍｏｌ）の脱水ジクロロメタン２ｍｌ溶液に、アルゴン雰囲気下、撹拌しながら０℃で滴下し、室温で２時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。得られた有機層を水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～７０：３０（Ｖ／Ｖ））に付し、次いで減圧濃縮、減圧乾燥を行うことにより濃縮残渣を得た。
　アルゴン雰囲気下、得られた濃縮残渣の脱水ジクロロメタン２ｍｌ溶液にＮ，Ｎ－ジメチルエタン－１，２－ジアミン０．１３０ｍｌ（１．１９ｍｍｏｌ）を室温で加えた後、室温で１６時間撹拌した。
　反応終了後、反応液に５％硫酸水素カリウム水溶液を加えて撹拌した後、ジクロロメタンで抽出した。得られた有機層を飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄した後、無水硫酸ナトリウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を酢酸エチルに溶解させた後、ｎ－ヘキサンに加えて析出させた固体を濾取し、減圧乾燥することにより、標記化合物８０ｍｇ（収率４２％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４８１［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.37 - 11.83 (m, 1H), 9.59 (br s, 1H), 7.42 - 7.28 (m, 5H), 5.10 (s, 1H), 4.73 - 4.54 (m, 1H), 4.35 (d, J = 12.4 Hz, 1H), 3.40 (tt, J = 3.0, 6.1 Hz, 1H), 2.59 - 2.37 (m, 2H), 2.24 - 2.12 (m, 2H), 1.90 - 1.74 (m, 2H), 1.70 (s, 3H), 1.61 (s, 3H), 0.69 - 0.53 (m, 2H), 0.51 - 0.39 (m, 2H), 0.05 (s, 9H)。 To a solution of (R) -2-cyclopropoxy-2-phenylacetic acid 140 mg (0.728 mmol) synthesized in the same manner as in Reference Example 57 in 2 ml of dehydrated dichloromethane, 0.006 ml (0.08 mmol) of DMF with stirring in an argon atmosphere. ), 0.083 ml (0.95 mmol) of oxalyl chloride was added at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentrated residue.
A solution of the obtained concentrated residue in 3 ml of dehydrated dichloromethane was synthesized in the same manner as in Reference Example 47 using ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3, 4-c] pyrazole-2 (4H) -carboxylate (150 mg, 0.396 mmol) and DIPEA (0.350 ml, 2.00 mmol) in dehydrated dichloromethane (2 ml) were added dropwise at 0 ° C. with stirring in an argon atmosphere at room temperature. Stir for 2 hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 70:30 (V / V)), and then concentrated under reduced pressure and dried under reduced pressure. Gave a concentrated residue.
Under an argon atmosphere, 0.130 ml (1.19 mmol) of N, N-dimethylethane-1,2-diamine was added at room temperature to a solution of the resulting concentrated residue in 2 ml of dehydrated dichloromethane, followed by stirring at room temperature for 16 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture and stirred, followed by extraction with dichloromethane. The obtained organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 50:50 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was dissolved in ethyl acetate and then added to n-hexane, and the precipitated solid was collected by filtration and dried under reduced pressure to give 80 mg (yield 42%) of the title compound as a white solid. .
Mass spectrum (CI, m / z): 481 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.37-11.83 (m, 1H), 9.59 (br s, 1H), 7.42-7.28 (m, 5H), 5.10 (s, 1H), 4.73- 4.54 (m, 1H), 4.35 (d, J = 12.4 Hz, 1H), 3.40 (tt, J = 3.0, 6.1 Hz, 1H), 2.59-2.37 (m, 2H), 2.24-2.12 (m, 2H) , 1.90-1.74 (m, 2H), 1.70 (s, 3H), 1.61 (s, 3H), 0.69-0.53 (m, 2H), 0.51-0.39 (m, 2H), 0.05 (s, 9H).
（実施例６２）
（Ｒ）－Ｎ－［５－（２－イソプロポキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド（化合物番号ＩＶ－３６０）
Figure JPOXMLDOC01-appb-C000103
 (Example 62)
(R) -N- [5- (2-Isopropoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (Trimethylsilyl) cyclobutanecarboxamide (Compound No. IV-360)
Figure JPOXMLDOC01-appb-C000103
　アルゴン雰囲気下、参考例５８と同様にして合成した（Ｒ）－２－イソプロポキシ－２－フェニル酢酸１６５ｍｇ（０．８４９ｍｍｏｌ）の脱水ジクロロメタン２ｍｌ溶液に、塩化オキサリル０．１０ｍｌ（１．２ｍｍｏｌ）、脱水ＤＭＦ０．００５０ｍｌ（０．０６５ｍｍｏｌ）を０℃で順次加えた後、そのままの温度で２．５時間撹拌した。
　反応終了後、反応液を減圧濃縮、減圧乾燥することにより濃縮残渣を得た。
　アルゴン雰囲気下、得られた濃縮残渣の脱水ジクロロメタン１ｍｌ溶液を、参考例４７と同様にして合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１２８ｍｇ（０．３３８ｍｍｏｌ）、ＤＩＰＥＡ０．３０ｍｌ（１．７ｍｍｏｌ）の脱水ジクロロメタン１ｍｌ溶液に０℃で加えた後、そのままの温度で１．５時間撹拌した。
　反応終了後、反応液に酢酸エチル、飽和炭酸水素ナトリウム水溶液を加えて撹拌した。分液した後、水層を酢酸エチルで２回抽出した。全有機層を無水硫酸マグネシウムで乾燥後、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝８０：２０～６０：４０（Ｖ／Ｖ））に付し、次いで減圧濃縮、減圧乾燥を行うことにより濃縮残渣を得た。
　アルゴン雰囲気下、得られた濃縮残渣のＴＨＦ２ｍｌ溶液にＮ，Ｎ－ジメチルエタン－１，２－ジアミン０．１５ｍｌ（１．４ｍｍｏｌ）を室温で加えた後、室温で２時間撹拌した。
　反応終了後、反応液に５％硫酸水素カリウム水溶液を加えて撹拌した後、酢酸エチルで３回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝８０：２０～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を酢酸エチルに溶解させた後、ｎ－ヘキサンを加えて析出させた固体を濾取し、ｎ－ヘキサンで洗浄してから減圧乾燥することにより、標記化合物１３５ｍｇ（収率８３％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４８３［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.40 - 11.82 (m, 1H), 9.75 - 9.42 (m, 1H), 7.40 - 7.27 (m, 5H), 5.11 (s, 1H), 4.65 - 4.38 (m, 2H), 3.68 (spt, J = 6.0 Hz, 1H), 2.47 - 2.35 (m, 2H), 2.23 - 2.09 (m, 2H), 1.87 - 1.71 (m, 2H), 1.67 (s, 3H), 1.61 (s, 3H), 1.16 (d, J = 6.0 Hz, 3H), 1.13 (d, J = 6.0 Hz, 3H), 0.04 (s, 9H)。 Under an argon atmosphere, a solution of 165 mg (0.849 mmol) of (R) -2-isopropoxy-2-phenylacetic acid synthesized in the same manner as in Reference Example 58 was added to 0.10 ml (1.2 mmol) of oxalyl chloride, After adding 0.0050 ml (0.065 mmol) of dehydrated DMF sequentially at 0 ° C., the mixture was stirred at the same temperature for 2.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure and dried under reduced pressure to obtain a concentrated residue.
Under an argon atmosphere, a 1 ml solution of the obtained concentrated residue in dehydrated dichloromethane was synthesized in the same manner as in Reference Example 47, and ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo was synthesized. A solution of [3,4-c] pyrazole-2 (4H) -carboxylate 128 mg (0.338 mmol) and DIPEA 0.30 ml (1.7 mmol) in dehydrated dichloromethane 1 ml at 0 ° C. Stir for 5 hours.
After completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution and stirred. After liquid separation, the aqueous layer was extracted twice with ethyl acetate. All organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 80: 20 to 60:40 (V / V)), and then concentrated under reduced pressure and dried under reduced pressure. Got.
Under an argon atmosphere, 0.15 ml (1.4 mmol) of N, N-dimethylethane-1,2-diamine was added to a 2 ml THF solution of the obtained concentrated residue, and the mixture was stirred at room temperature for 2 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture and stirred, followed by extraction with ethyl acetate three times. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 80: 20 to 50:50 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was dissolved in ethyl acetate, then n-hexane was added and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 135 mg of the title compound (yield 83 %) As a white solid.
Mass spectrum (CI, m / z): 483 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.40-11.82 (m, 1H), 9.75-9.42 (m, 1H), 7.40-7.27 (m, 5H), 5.11 (s, 1H), 4.65 -4.38 (m, 2H), 3.68 (spt, J = 6.0 Hz, 1H), 2.47-2.35 (m, 2H), 2.23-2.09 (m, 2H), 1.87-1.71 (m, 2H), 1.67 (s , 3H), 1.61 (s, 3H), 1.16 (d, J = 6.0 Hz, 3H), 1.13 (d, J = 6.0 Hz, 3H), 0.04 (s, 9H).
（実施例６３）
（Ｒ）－Ｎ－｛６，６－ジメチル－５－［２－フェニル－２－（トリフルオロメトキシ）アセチル］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド（化合物番号ＩＶ－３４０）
Figure JPOXMLDOC01-appb-C000104
 (Example 63)
(R) -N- {6,6-dimethyl-5- [2-phenyl-2- (trifluoromethoxy) acetyl] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3 -Il} -1- (trimethylsilyl) cyclobutanecarboxamide (Compound No. IV-340)
Figure JPOXMLDOC01-appb-C000104
　参考例６０と同様の方法で合成した（Ｒ）－２－フェニル－２－（トリフルオロメトキシ）酢酸１６０ｍｇ（不純物含む）の脱水ジクロロメタン２ｍｌ溶液に、アルゴン雰囲気下で撹拌しながら塩化オキサリル０．０８３ｍｌ（０．９５ｍｍｏｌ）、ＤＭＦ０．００６ｍｌ（０．０８ｍｍｏｌ）を０℃で加え、室温で１．５時間撹拌した。
　反応終了後、反応液を減圧濃縮して、濃縮残渣を得た。
　得られた濃縮残渣の脱水ジクロロメタン３ｍｌ溶液を、参考例４７と同様の方法で合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１５０ｍｇ（０．３９６ｍｍｏｌ）、ＤＩＰＥＡ０．３５０ｍｌ（２．００ｍｍｏｌ）の脱水ジクロロメタン２ｍｌ溶液に、アルゴン雰囲気下、撹拌しながら０℃で滴下し、室温で２時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。得られた有機層を水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～７０：３０（Ｖ／Ｖ））に付し、次いで減圧濃縮、減圧乾燥を行うことにより濃縮残渣を得た。
　アルゴン雰囲気下、得られた濃縮残渣の脱水ジクロロメタン２ｍｌ溶液にＮ，Ｎ－ジメチルエタン－１，２－ジアミン０．１３０ｍｌ（１．１９ｍｍｏｌ）を室温で加えた後、室温で２時間撹拌した。
　反応終了後、反応液に５％硫酸水素カリウム水溶液を加えて撹拌した後、ジクロロメタンで抽出した。得られた有機層を飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄した後、無水硫酸ナトリウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を酢酸エチルに溶解させた後、ｎ－ヘキサンに加えて析出させた固体を濾取し、減圧乾燥することにより、標記化合物９７．６ｍｇ（収率４８％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５０９［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.39 - 11.84 (m, 1H), 9.58 (br s, 1H), 7.54 - 7.41 (m, 5H), 6.06 (s, 1H), 4.78 (br d, J = 11.9 Hz, 1H), 4.08 (br d, J = 11.9 Hz, 1H), 2.58 - 2.35 (m, 2H), 2.23 - 2.10 (m, 2H), 1.88 - 1.73 (m, 2H), 1.70 (s, 3H), 1.60 (s, 3H), 0.04 (s, 9H)。 To a solution of 160 mg of (R) -2-phenyl-2- (trifluoromethoxy) acetic acid (containing impurities) synthesized in the same manner as in Reference Example 60 in 2 ml of dehydrated dichloromethane, 0.083 ml of oxalyl chloride was stirred under an argon atmosphere. (0.95 mmol) and 0.006 ml (0.08 mmol) of DMF were added at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentrated residue.
A solution of the obtained concentrated residue in 3 ml of dehydrated dichloromethane was synthesized in the same manner as in Reference Example 47 using ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3, 4-c] pyrazole-2 (4H) -carboxylate (150 mg, 0.396 mmol) and DIPEA (0.350 ml, 2.00 mmol) in dehydrated dichloromethane (2 ml) were added dropwise at 0 ° C. with stirring in an argon atmosphere at room temperature. Stir for 2 hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 70:30 (V / V)), and then concentrated under reduced pressure and dried under reduced pressure. Gave a concentrated residue.
Under an argon atmosphere, 0.130 ml (1.19 mmol) of N, N-dimethylethane-1,2-diamine was added at room temperature to 2 ml of a dehydrated dichloromethane solution of the resulting concentrated residue, followed by stirring at room temperature for 2 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture and stirred, followed by extraction with dichloromethane. The obtained organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 50:50 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was dissolved in ethyl acetate, then added to n-hexane and the precipitated solid was collected by filtration and dried under reduced pressure to give 97.6 mg (yield 48%) of the title compound as a white solid. Obtained.
Mass spectrum (CI, m / z): 509 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.39-11.84 (m, 1H), 9.58 (br s, 1H), 7.54-7.41 (m, 5H), 6.06 (s, 1H), 4.78 ( br d, J = 11.9 Hz, 1H), 4.08 (br d, J = 11.9 Hz, 1H), 2.58-2.35 (m, 2H), 2.23-2.10 (m, 2H), 1.88-1.73 (m, 2H) , 1.70 (s, 3H), 1.60 (s, 3H), 0.04 (s, 9H).
（実施例６４）
（Ｒ）－Ｎ－［６，６－ジメチル－５－（２－フェニル－２－プロポキシアセチル）－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド（化合物番号ＩＶ－３５２）
Figure JPOXMLDOC01-appb-C000105
 (Example 64)
(R) -N- [6,6-Dimethyl-5- (2-phenyl-2-propoxyacetyl) -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (Trimethylsilyl) cyclobutanecarboxamide (Compound No. IV-352)
Figure JPOXMLDOC01-appb-C000105
　アルゴン雰囲気下、参考例６２と同様にして合成した（Ｒ）－２－フェニル－２－プロポキシ酢酸１４６ｍｇ（０．７５３ｍｍｏｌ）の脱水ジクロロメタン２ｍｌ溶液に、塩化オキサリル０．１０ｍｌ（１．２ｍｍｏｌ）、脱水ＤＭＦ０．００５０ｍｌ（０．０６５ｍｍｏｌ）を０℃で順次加えた後、そのままの温度で１．５時間撹拌した。
　反応終了後、反応液を減圧濃縮、減圧乾燥することにより濃縮残渣を得た。
　アルゴン雰囲気下、得られた濃縮残渣の脱水ジクロロメタン１ｍｌ溶液を、参考例４７と同様にして合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１４４ｍｇ（０．３８０ｍｍｏｌ）、ＤＩＰＥＡ０．３３ｍｌ（１．９ｍｍｏｌ）の脱水ジクロロメタン１ｍｌ溶液に０℃で加えた後、そのままの温度で１．５時間撹拌した。
　反応終了後、反応液に酢酸エチル、飽和炭酸水素ナトリウム水溶液を加えて撹拌した。分液した後、水層を酢酸エチルで２回抽出した。全有機層を無水硫酸マグネシウムで乾燥後、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝８５：１５～６０：４０（Ｖ／Ｖ））に付し、次いで減圧濃縮、減圧乾燥を行うことにより濃縮残渣を得た。
　アルゴン雰囲気下、得られた濃縮残渣のＴＨＦ２ｍｌ溶液にＮ，Ｎ－ジメチルエタン－１，２－ジアミン０．１７ｍｌ（１．６ｍｍｏｌ）を室温で加えた後、室温で３時間撹拌した。
　反応終了後、反応液に５％硫酸水素カリウム水溶液を加えて撹拌した後、酢酸エチルで３回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝８５：１５～６０：４０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を酢酸エチルに溶解させた後、ｎ－ヘキサンを加えて析出させた固体を濾取し、ｎ－ヘキサンで洗浄してから減圧乾燥することにより、標記化合物１４４ｍｇ（収率８０％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４８３［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.43 - 11.75 (m, 1H), 9.56 (br s, 1H), 7.43 - 7.27 (m, 5H), 5.03 (s, 1H), 4.71 - 4.47 (m, 1H), 4.39 (br d, J = 12.5 Hz, 1H), 3.51 - 3.43 (m, 1H), 3.41 - 3.24 (m, 1H), 2.60 - 2.36 (m, 2H), 2.25 - 2.10 (m, 2H), 1.88 - 1.72 (m, 2H), 1.68 (s, 3H), 1.65 - 1.48 (m, 5H), 0.87 (t, J = 7.4 Hz, 3H), 0.04 (s, 9H)。 Under an argon atmosphere, 146 mg (0.753 mmol) of (R) -2-phenyl-2-propoxyacetic acid synthesized in the same manner as in Reference Example 62 was added to 0.10 ml (1.2 mmol) of oxalyl chloride and dehydrated. After adding 0.0050 ml (0.065 mmol) of DMF sequentially at 0 ° C., the mixture was stirred at the same temperature for 1.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure and dried under reduced pressure to obtain a concentrated residue.
Under an argon atmosphere, a 1 ml solution of the obtained concentrated residue in dehydrated dichloromethane was synthesized in the same manner as in Reference Example 47, and ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo was synthesized. After adding [3,4-c] pyrazole-2 (4H) -carboxylate 144 mg (0.380 mmol) and DIPEA 0.33 ml (1.9 mmol) in dehydrated dichloromethane 1 ml at 0 ° C. Stir for 5 hours.
After completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution and stirred. After liquid separation, the aqueous layer was extracted twice with ethyl acetate. All organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 85: 15 to 60:40 (V / V)), and then concentrated under reduced pressure and dried under reduced pressure. Got.
Under an argon atmosphere, 0.17 ml (1.6 mmol) of N, N-dimethylethane-1,2-diamine was added to a 2 ml THF solution of the obtained concentrated residue, and the mixture was stirred at room temperature for 3 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture and stirred, followed by extraction with ethyl acetate three times. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 85: 15 to 60:40 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was dissolved in ethyl acetate, and n-hexane was added, and the precipitated solid was collected by filtration, washed with n-hexane and then dried under reduced pressure to give 144 mg of the title compound (yield 80%). %) As a white solid.
Mass spectrum (CI, m / z): 483 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.43-11.75 (m, 1H), 9.56 (br s, 1H), 7.43-7.27 (m, 5H), 5.03 (s, 1H), 4.71- 4.47 (m, 1H), 4.39 (br d, J = 12.5 Hz, 1H), 3.51-3.43 (m, 1H), 3.41-3.24 (m, 1H), 2.60-2.36 (m, 2H), 2.25-2.10 (m, 2H), 1.88-1.72 (m, 2H), 1.68 (s, 3H), 1.65-1.48 (m, 5H), 0.87 (t, J = 7.4 Hz, 3H), 0.04 (s, 9H).
（実施例６５）
Ｎ－｛５－［２－（４－フルオロフェニル）－２－メトキシアセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド（化合物番号ＩＶ－３９４）
Figure JPOXMLDOC01-appb-C000106
 (Example 65)
N- {5- [2- (4-Fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl} -1- (Trimethylsilyl) cyclobutanecarboxamide (Compound No. IV-394)
Figure JPOXMLDOC01-appb-C000106
　参考例６４と同様の方法で合成した２－（４－フルオロフェニル）－２－メトキシ酢酸２２９ｍｇ（不純物含む）の脱水ジクロロメタン２ｍｌ懸濁液に、アルゴン雰囲気下で撹拌しながら塩化オキサリル０．１５０ｍｌ（１．７１ｍｍｏｌ）、ＤＭＦ０．０１１ｍｌ（０．１４ｍｍｏｌ）を０℃で加え、室温で１．５時間撹拌した。
　反応終了後、反応液を減圧濃縮して、濃縮残渣を得た。
　得られた濃縮残渣の脱水ジクロロメタン３ｍｌ溶液を、参考例４７と同様の方法で合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート２６５ｍｇ（０．７００ｍｍｏｌ）、ＤＩＰＥＡ０．６２０ｍｌ（３．５５ｍｍｏｌ）の脱水ジクロロメタン２ｍｌ溶液に、アルゴン雰囲気下、撹拌しながら０℃で滴下し、室温で１時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。得られた有機層を水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～７０：３０（Ｖ／Ｖ））に付し、次いで減圧濃縮、減圧乾燥を行うことにより濃縮残渣を得た。
　アルゴン雰囲気下、得られた濃縮残渣の脱水ジクロロメタン２ｍｌ溶液にＮ，Ｎ－ジメチルエタン－１，２－ジアミン０．２３０ｍｌ（２．１１ｍｍｏｌ）を室温で加えた後、室温で１時間撹拌した。
　反応終了後、反応液に５％硫酸水素カリウム水溶液を加えて撹拌した後、ジクロロメタンで抽出した。得られた有機層を飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄した後、無水硫酸ナトリウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣をジクロロメタンに溶解させた後、５％硫酸水素カリウム水溶液を加えて撹拌し分液した。得られた有機層を飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄した後、無水硫酸ナトリウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣を酢酸エチルに溶解させた後、ｎ－ヘキサンに加えて析出させた固体を濾取し、減圧乾燥することにより、標記化合物１７４ｍｇ（収率５３％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４７３［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.27 & 11.91 (br s, total 1H), 9.58 (br s, 1H), 7.47 - 7.36 (m, 2H), 7.26 - 7.14 (m, 2H), 4.99 (s, 1H), 4.76 - 4.53 (m, 1H), 4.32 (br d, J = 12.4 Hz, 1H), 3.29 (s, 3H), 2.58 - 2.36 (m, 2H), 2.25 - 2.10 (m, 2H), 1.88 - 1.72 (m, 2H), 1.69 (br s, 3H), 1.60 (s, 3H), 0.05 (s, 9H)。 To a suspension of 229 mg of 2- (4-fluorophenyl) -2-methoxyacetic acid (containing impurities) synthesized in the same manner as in Reference Example 64 in 2 ml of dehydrated dichloromethane was added 0.150 ml of oxalyl chloride with stirring under an argon atmosphere ( 1.71 mmol) and 0.011 ml (0.14 mmol) of DMF were added at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentrated residue.
A solution of the obtained concentrated residue in 3 ml of dehydrated dichloromethane was synthesized in the same manner as in Reference Example 47 using ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3, 4-c] pyrazole-2 (4H) -carboxylate 265 mg (0.700 mmol) and DIPEA 0.620 ml (3.55 mmol) in dehydrated dichloromethane 2 ml was added dropwise at 0 ° C. with stirring in an argon atmosphere at room temperature. Stir for 1 hour.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 70:30 (V / V)), and then concentrated under reduced pressure and dried under reduced pressure. Gave a concentrated residue.
Under an argon atmosphere, 0.230 ml (2.11 mmol) of N, N-dimethylethane-1,2-diamine was added to a 2 ml solution of dehydrated dichloromethane of the obtained concentrated residue at room temperature, followed by stirring at room temperature for 1 hour.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture and stirred, followed by extraction with dichloromethane. The obtained organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 50:50 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was dissolved in dichloromethane, 5% aqueous potassium hydrogen sulfate solution was added, and the mixture was stirred and separated. The obtained organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was dissolved in ethyl acetate and then added to n-hexane, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 174 mg (yield 53%) of the title compound as a white solid. .
Mass spectrum (CI, m / z): 473 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.27 & 11.91 (br s, total 1H), 9.58 (br s, 1H), 7.47-7.36 (m, 2H), 7.26-7.14 (m, 2H ), 4.99 (s, 1H), 4.76-4.53 (m, 1H), 4.32 (br d, J = 12.4 Hz, 1H), 3.29 (s, 3H), 2.58-2.36 (m, 2H), 2.25-2.10 (m, 2H), 1.88-1.72 (m, 2H), 1.69 (br s, 3H), 1.60 (s, 3H), 0.05 (s, 9H).
（実施例６６）
Ｎ－｛５－［２－（３－フルオロフェニル）－２－メトキシアセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド（化合物番号ＩＶ－３８９）
Figure JPOXMLDOC01-appb-C000107
 Example 66
N- {5- [2- (3-Fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl} -1- (Trimethylsilyl) cyclobutanecarboxamide (Compound No. IV-389)
Figure JPOXMLDOC01-appb-C000107
　参考例６７と同様の方法で合成した２－（３－フルオロフェニル）－２－メトキシ酢酸１４６ｍｇ（不純物含む）の脱水ジクロロメタン２ｍｌ懸濁液に、アルゴン雰囲気下で撹拌しながら塩化オキサリル０．０８０ｍｌ（０．９１ｍｍｏｌ）、ＤＭＦ０．０１０ｍｌ（０．１３ｍｍｏｌ）を０℃で加え、室温で１．５時間撹拌した。
　反応終了後、反応液を減圧濃縮して、濃縮残渣を得た。
　得られた濃縮残渣の脱水ジクロロメタン３ｍｌ溶液を、参考例４７と同様の方法で合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート２００ｍｇ（０．５２８ｍｍｏｌ）、ＤＩＰＥＡ０．４６２ｍｌ（２．６５ｍｍｏｌ）の脱水ジクロロメタン２ｍｌ溶液に、アルゴン雰囲気下、撹拌しながら室温で滴下し、室温で１時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。得られた有機層を水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～７０：３０（Ｖ／Ｖ））に付し、次いで減圧濃縮、減圧乾燥を行うことにより濃縮残渣を得た。
　アルゴン雰囲気下、得られた濃縮残渣の脱水ジクロロメタン２ｍｌ溶液にＮ，Ｎ－ジメチルエタン－１，２－ジアミン０．１７３ｍｌ（１．５９ｍｍｏｌ）を室温で加えた後、室温で１６時間撹拌した。
　反応終了後、反応液に５％硫酸水素カリウム水溶液を加えて撹拌した後、ジクロロメタンで抽出した。得られた有機層を飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄した後、無水硫酸ナトリウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣をメタノールに溶解させた後、水に加えて析出させた固体を濾取し、減圧乾燥することにより、標記化合物１８７ｍｇ（収率７５％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４７３［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.40 - 11.81 (m, 1H), 9.60 (br s, 1H), 7.48 - 7.38 (m, 1H), 7.24 - 7.13 (m, 3H), 5.03 (s, 1H), 4.75 - 4.54 (m, 1H), 4.39 (br d, J = 12.7 Hz, 1H), 3.32 (s, 3H), 2.59 - 2.36 (m, 2H), 2.24 - 2.10 (m, 2H), 1.88 - 1.72 (m, 2H), 1.69 (s, 3H), 1.60 (s, 3H), 0.05 (s, 9H)。 To a suspension of 146 mg of 2- (3-fluorophenyl) -2-methoxyacetic acid (including impurities) synthesized in the same manner as in Reference Example 67 in 2 ml of dehydrated dichloromethane, 0.080 ml of oxalyl chloride was added while stirring under an argon atmosphere ( 0.91 mmol) and 0.010 ml (0.13 mmol) of DMF were added at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentrated residue.
A solution of the obtained concentrated residue in 3 ml of dehydrated dichloromethane was synthesized in the same manner as in Reference Example 47 using ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3, 4-c] pyrazole-2 (4H) -carboxylate 200 mg (0.528 mmol) and DIPEA 0.462 ml (2.65 mmol) in 2 ml of dehydrated dichloromethane was added dropwise at room temperature under stirring in an argon atmosphere at room temperature. Stir for hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 70:30 (V / V)), and then concentrated under reduced pressure and dried under reduced pressure. Gave a concentrated residue.
Under an argon atmosphere, 0.173 ml (1.59 mmol) of N, N-dimethylethane-1,2-diamine was added at room temperature to a 2 ml solution of the obtained concentrated residue in dehydrated dichloromethane, followed by stirring at room temperature for 16 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture and stirred, followed by extraction with dichloromethane. The obtained organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 50:50 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was dissolved in methanol, and the solid precipitated by adding to water was collected by filtration and dried under reduced pressure to obtain 187 mg (yield 75%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 473 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.40-11.81 (m, 1H), 9.60 (br s, 1H), 7.48-7.38 (m, 1H), 7.24-7.13 (m, 3H), 5.03 (s, 1H), 4.75-4.54 (m, 1H), 4.39 (br d, J = 12.7 Hz, 1H), 3.32 (s, 3H), 2.59-2.36 (m, 2H), 2.24-2.10 (m , 2H), 1.88-1.72 (m, 2H), 1.69 (s, 3H), 1.60 (s, 3H), 0.05 (s, 9H).
（実施例６７）
（Ｒ）－Ｎ－｛５－［２－（２－フルオロフェニル）－２－メトキシアセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド（化合物番号ＩＶ－３８５）
Figure JPOXMLDOC01-appb-C000108
 (Example 67)
(R) -N- {5- [2- (2-Fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole- 3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide (Compound No. IV-385)
Figure JPOXMLDOC01-appb-C000108
　参考例６９と同様の方法で合成した（Ｒ）－２－（２－フルオロフェニル）－２－メトキシ酢酸２００ｍｇ（１．０９ｍｍｏｌ）の脱水ジクロロメタン２ｍｌ懸濁液に、アルゴン雰囲気下で撹拌しながら塩化オキサリル０．１１１ｍｌ（１．２７ｍｍｏｌ）、ＤＭＦ０．０１０ｍｌ（０．１３ｍｍｏｌ）を０℃で加え、室温で１．５時間撹拌した。
　反応終了後、反応液を減圧濃縮して、濃縮残渣を得た。
　得られた濃縮残渣の脱水ジクロロメタン３ｍｌ溶液を、参考例４７と同様の方法で合成したエチル ６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート２００ｍｇ（０．５２８ｍｍｏｌ）、ＤＩＰＥＡ０．５００ｍｌ（２．８６ｍｍｏｌ）の脱水ジクロロメタン２ｍｌ溶液に、アルゴン雰囲気下、撹拌しながら室温で滴下し、室温で２時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。得られた有機層を水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～７０：３０（Ｖ／Ｖ））に付し、次いで減圧濃縮、減圧乾燥を行うことにより濃縮残渣を得た。
　アルゴン雰囲気下、得られた濃縮残渣の脱水ジクロロメタン２ｍｌ溶液にＮ，Ｎ－ジメチルエタン－１，２－ジアミン０．１７３ｍｌ（１．５９ｍｍｏｌ）を室温で加えた後、室温で３時間撹拌した。
　反応終了後、反応液に５％硫酸水素カリウム水溶液を加えて撹拌した後、ジクロロメタンで抽出した。得られた有機層を飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄した後、無水硫酸ナトリウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣をメタノールに溶解させた後、水に加えて析出させた固体を濾取し、減圧乾燥することにより、標記化合物１６４ｍｇ（収率６６％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４７３［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.42 - 11.83 (m, 1H), 9.60 (br s, 1H), 7.46 - 7.34 (m, 2H), 7.27 - 7.18 (m, 2H), 5.22 (s, 1H), 4.75 (d, J = 12.3 Hz, 1H), 4.20 (d, J = 12.3 Hz, 1H), 3.32 (s, 3H), 2.58 - 2.37 (m, 2H), 2.25 - 2.11 (m, 2H), 1.88 - 1.73 (m, 2H), 1.70 (s, 3H), 1.60 (s, 3H), 0.05 (s, 9H)。 To a suspension of 200 mg (1.09 mmol) of (R) -2- (2-fluorophenyl) -2-methoxyacetic acid synthesized in the same manner as in Reference Example 69 in 2 ml of dehydrated dichloromethane, chlorinated while stirring under an argon atmosphere. Oxalyl 0.111 ml (1.27 mmol) and DMF 0.010 ml (0.13 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentrated residue.
A solution of the obtained concentrated residue in 3 ml of dehydrated dichloromethane was synthesized in the same manner as in Reference Example 47 using ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3, 4-c] pyrazole-2 (4H) -carboxylate (200 mg, 0.528 mmol) and DIPEA (0.500 ml, 2.86 mmol) in dehydrated dichloromethane (2 ml) were added dropwise at room temperature under stirring in an argon atmosphere at room temperature. Stir for hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 70:30 (V / V)), and then concentrated under reduced pressure and dried under reduced pressure. Gave a concentrated residue.
Under an argon atmosphere, 0.173 ml (1.59 mmol) of N, N-dimethylethane-1,2-diamine was added to a solution of the resulting concentrated residue in 2 ml of dehydrated dichloromethane, and the mixture was stirred at room temperature for 3 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture and stirred, followed by extraction with dichloromethane. The obtained organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 50:50 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was dissolved in methanol, and then the resulting solid added to water was collected by filtration and dried under reduced pressure to obtain 164 mg (yield 66%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 473 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.42-11.83 (m, 1H), 9.60 (br s, 1H), 7.46-7.34 (m, 2H), 7.27-7.18 (m, 2H), 5.22 (s, 1H), 4.75 (d, J = 12.3 Hz, 1H), 4.20 (d, J = 12.3 Hz, 1H), 3.32 (s, 3H), 2.58-2.37 (m, 2H), 2.25-2.11 (m, 2H), 1.88-1.73 (m, 2H), 1.70 (s, 3H), 1.60 (s, 3H), 0.05 (s, 9H).
（実施例６８）
Ｎ－｛５－［２－メトキシ－２－（チオフェン－２－イル）アセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド（化合物番号ＩＶ－３９９）
Figure JPOXMLDOC01-appb-C000109
 Example 68
N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl } -1- (Trimethylsilyl) cyclobutanecarboxamide (Compound No. IV-399)
Figure JPOXMLDOC01-appb-C000109
　参考例７２と同様の方法で合成した２－メトキシ－２－（チオフェン－２－イル）酢酸６０ｍｇ（不純物を含む）の脱水ジクロロメタン２ｍｌ懸濁液に、アルゴン雰囲気下で撹拌しながら塩化オキサリル０．０３６ｍｌ（０．４１ｍｍｏｌ）、ＤＭＦ０．００５ｍｌ（０．０７ｍｍｏｌ）を０℃で加え、室温で１．５時間撹拌した。
　反応終了後、反応液を減圧濃縮して、濃縮残渣を得た。
　得られた濃縮残渣の脱水ジクロロメタン３ｍｌ溶液を、参考例４７と同様の方法で合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１２０ｍｇ（０．３１７ｍｍｏｌ）、ＤＩＰＥＡ０．１６６ｍｌ（０．９５０ｍｍｏｌ）の脱水ジクロロメタン２ｍｌ溶液に、アルゴン雰囲気下、撹拌しながら０℃で滴下し、室温で２時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。得られた有機層を水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～７０：３０（Ｖ／Ｖ））に付し、次いで減圧濃縮、減圧乾燥を行うことにより濃縮残渣を得た。
　アルゴン雰囲気下、得られた濃縮残渣の脱水ジクロロメタン２ｍｌ溶液にＮ，Ｎ－ジメチルエタン－１，２－ジアミン０．１０４ｍｌ（０．９５４ｍｍｏｌ）を室温で加えた後、室温で１６時間撹拌した。
　反応終了後、反応液に５％硫酸水素カリウム水溶液を加えて撹拌した後、ジクロロメタンで抽出した。得られた有機層を飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄した後、無水硫酸ナトリウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣をメタノールに溶解させた後、水に加えて析出させた固体を濾取し、減圧乾燥することにより、標記化合物６２ｍｇ（収率４２％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４６１［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.41 - 11.86 (m, 1H), 9.82 - 9.47 (m, 1H), 7.57 (dd, J = 1.3, 5.0 Hz, 1H), 7.13 - 7.06 (m, 1H), 7.01 (dd, J = 3.5, 5.0 Hz, 1H), 5.26 (s, 1H), 4.84 - 4.64 (m, 1H), 4.41 (br d, J = 12.4 Hz, 1H), 3.28 (s, 3H), 2.58 - 2.37 (m, 2H), 2.26 - 2.10 (m, 2H), 1.89 - 1.73 (m, 2H), 1.70 (s, 3H), 1.62 (s, 3H), 0.06 (s, 9H)。 To a suspension of 60 mg of 2-methoxy-2- (thiophen-2-yl) acetic acid (containing impurities) synthesized in the same manner as in Reference Example 72 in 2 ml of dehydrated dichloromethane, 0. 036 ml (0.41 mmol) and DMF 0.005 ml (0.07 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentrated residue.
A solution of the obtained concentrated residue in 3 ml of dehydrated dichloromethane was synthesized in the same manner as in Reference Example 47 using ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3, 4-c] pyrazole-2 (4H) -carboxylate (120 mg, 0.317 mmol) and DIPEA (0.166 ml, 0.950 mmol) in dehydrated dichloromethane (2 ml) were added dropwise at 0 ° C. with stirring in an argon atmosphere at room temperature. Stir for 2 hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 70:30 (V / V)), and then concentrated under reduced pressure and dried under reduced pressure. Gave a concentrated residue.
Under an argon atmosphere, 0.104 ml (0.954 mmol) of N, N-dimethylethane-1,2-diamine was added to a solution of the resulting concentrated residue in 2 ml of dehydrated dichloromethane, and the mixture was stirred at room temperature for 16 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture and stirred, followed by extraction with dichloromethane. The obtained organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 50:50 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was dissolved in methanol, and the solid precipitated by adding to water was collected by filtration and dried under reduced pressure to obtain 62 mg (yield 42%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 461 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.41-11.86 (m, 1H), 9.82-9.47 (m, 1H), 7.57 (dd, J = 1.3, 5.0 Hz, 1H), 7.13-7.06 (m, 1H), 7.01 (dd, J = 3.5, 5.0 Hz, 1H), 5.26 (s, 1H), 4.84-4.64 (m, 1H), 4.41 (br d, J = 12.4 Hz, 1H), 3.28 (s, 3H), 2.58-2.37 (m, 2H), 2.26-2.10 (m, 2H), 1.89-1.73 (m, 2H), 1.70 (s, 3H), 1.62 (s, 3H), 0.06 (s , 9H).
（実施例６９）
（－）－Ｎ－｛５－［２－メトキシ－２－（チオフェン－２－イル）アセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド（化合物番号ＩＶ－４０１） (Example 69)
(-)-N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole -3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide (Compound No. IV-401)
　実施例６８と同様にして合成したＮ－｛５－［２－メトキシ－２－（チオフェン－２－イル）アセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド０．０４１ｇ（０．０８９ｍｍｏｌ）を光学分割分取クロマトグラフィー（カラム；ＣＨＩＲＡＬＰＡＫ（商品名）ＩＤ，溶出溶媒；ｎ－ヘキサン：エタノール＝８５：１５（Ｖ／Ｖ））に付し、先に溶出する光学活性体を含む画分を減圧濃縮することにより、標記化合物１７ｍｇ（収率４１％）を白色固体として得た。
比旋光度：［α］Ｄ ２０＝－５１°　（ｃ＝０．２０，メタノール）。
マススペクトル（ＣＩ，ｍ／ｚ）：４６１［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.23 (br s, 1H), 9.67 (br s, 1H), 7.57 (dd, J = 1.2, 5.0 Hz, 1H), 7.13 - 7.06 (m, 1H), 7.01 (dd, J = 3.5, 5.0 Hz, 1H), 5.26 (s, 1H), 4.74 (br d, J = 12.5 Hz, 1H), 4.41 (d, J = 12.5 Hz, 1H), 3.28 (s, 3H), 2.58 - 2.37 (m, 2H), 2.24 - 2.11 (m, 2H), 1.89 - 1.74 (m, 2H), 1.70 (s, 3H), 1.62 (s, 3H), 0.06 (s, 9H)。
ＨＰＬＣ分析：
カラム；ＣＨＩＲＡＬＰＡＫ（商品名）ＩＤ　４．６×２５０ｍｍ
溶離液；ｎ－ヘキサン／エタノール＝８５／１５（Ｖ／Ｖ）
流速；１．０ｍｌ／ｍｉｎ
温度；４０℃
検出波長；２５４ｎｍ
保持時間；７．６分
光学純度：＞９９％ｅｅ N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3, synthesized in the same manner as in Example 68 4-c] pyrazol-3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide 0.041 g (0.089 mmol) was subjected to optical resolution preparative chromatography (column; CHIRALPAK (trade name) ID, elution solvent; n-hexane: (Ethanol = 85: 15 (V / V)), and the fraction containing the optically active substance eluted earlier was concentrated under reduced pressure to obtain 17 mg (yield 41%) of the title compound as a white solid.
Specific rotation: [α] D 20 = −51 ° (c = 0.20, methanol).
Mass spectrum (CI, m / z): 461 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.23 (br s, 1H), 9.67 (br s, 1H), 7.57 (dd, J = 1.2, 5.0 Hz, 1H), 7.13-7.06 (m , 1H), 7.01 (dd, J = 3.5, 5.0 Hz, 1H), 5.26 (s, 1H), 4.74 (br d, J = 12.5 Hz, 1H), 4.41 (d, J = 12.5 Hz, 1H), 3.28 (s, 3H), 2.58-2.37 (m, 2H), 2.24-2.11 (m, 2H), 1.89-1.74 (m, 2H), 1.70 (s, 3H), 1.62 (s, 3H), 0.06 ( s, 9H).
HPLC analysis:
Column; CHIRALPAK (trade name) ID 4.6 × 250 mm
Eluent: n-hexane / ethanol = 85/15 (V / V)
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection wavelength: 254 nm
Retention time; 7.6 minutes Optical purity:> 99% ee
（実施例７０）
（＋）－Ｎ－｛５－［２－メトキシ－２－（チオフェン－２－イル）アセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド（化合物番号ＩＶ－４００） (Example 70)
(+)-N- {5- [2-Methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole -3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide (Compound No. IV-400)
　実施例６９の光学分割分取クロマトグラフィー操作において、後から溶出する光学活性体を含む画分を減圧濃縮することにより、標記化合物１４ｍｇ（収率３４％）を白色固体として得た。
比旋光度：［α］Ｄ ２０＝＋６６°　（ｃ＝０．２０，メタノール）。
マススペクトル（ＣＩ，ｍ／ｚ）：４６１［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.23 (br s, 1H), 9.66 (br s, 1H), 7.57 (dd, J = 1.2, 5.0 Hz, 1H), 7.14 - 7.06 (m, 1H), 7.01 (dd, J = 3.5, 5.0 Hz, 1H), 5.26 (s, 1H), 4.74 (br d, J = 12.4 Hz, 1H), 4.41 (d, J = 12.4 Hz, 1H), 3.28 (s, 3H), 2.58 - 2.37 (m, 2H), 2.26 - 2.10 (m, 2H), 1.89 - 1.74 (m, 2H), 1.70 (s, 3H), 1.62 (s, 3H), 0.06 (s, 9H)。
ＨＰＬＣ分析：
カラム；ＣＨＩＲＡＬＰＡＫ（商品名）ＩＤ　４．６×２５０ｍｍ
溶離液；ｎ－ヘキサン／エタノール＝８５／１５（Ｖ／Ｖ）
流速；１．０ｍｌ／ｍｉｎ
温度；４０℃
検出波長；２５４ｎｍ
保持時間；９．７分
光学純度：＞９９％ｅｅ In the optical resolution preparative chromatography operation of Example 69, the fraction containing the optically active compound eluted later was concentrated under reduced pressure to obtain 14 mg (yield 34%) of the title compound as a white solid.
Specific rotation: [α] D 20 = + 66 ° (c = 0.20, methanol).
Mass spectrum (CI, m / z): 461 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.23 (br s, 1H), 9.66 (br s, 1H), 7.57 (dd, J = 1.2, 5.0 Hz, 1H), 7.14-7.06 (m , 1H), 7.01 (dd, J = 3.5, 5.0 Hz, 1H), 5.26 (s, 1H), 4.74 (br d, J = 12.4 Hz, 1H), 4.41 (d, J = 12.4 Hz, 1H), 3.28 (s, 3H), 2.58-2.37 (m, 2H), 2.26-2.10 (m, 2H), 1.89-1.74 (m, 2H), 1.70 (s, 3H), 1.62 (s, 3H), 0.06 ( s, 9H).
HPLC analysis:
Column; CHIRALPAK (trade name) ID 4.6 × 250 mm
Eluent: n-hexane / ethanol = 85/15 (V / V)
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection wavelength: 254 nm
Retention time: 9.7 minutes Optical purity:> 99% ee
（実施例７１）
Ｎ－｛［１－（ヒドロキシメチル）シクロブチル］（フェニル）メチル｝－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－１７９）
Figure JPOXMLDOC01-appb-C000110
 (Example 71)
N-{[1- (hydroxymethyl) cyclobutyl] (phenyl) methyl} -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide (Compound No. IV-179)
Figure JPOXMLDOC01-appb-C000110
　アルゴン雰囲気下、参考例７３と同様にして合成した２－エチル　５－（トリクロロメチル）　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］ピロロ［３，４－ｃ］ピラゾール－２，５（４Ｈ，６Ｈ）－ジカルボキラート１３１ｍｇ（０．２４３ｍｍｏｌ）とエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート７９ｍｇ（０．１８ｍｍｏｌ）の混合物の脱水１，４－ジオキサン３ｍｌ溶液に、ＤＩＰＥＡ０．３４ｍｌ（２．０ｍｍｏｌ）、参考例７４と同様にして合成した｛１－［アミノ（フェニル）メチル］シクロブチル｝メタノール２３５ｍｇ（１．２３ｍｍｏｌ）を室温で順次加えた後、９０℃で１．５時間撹拌した。反応液が室温になるまで放冷した後、Ｎ，Ｎ－ジメチルエタン－１，２－ジアミン０．２１ｍｌ（１．９ｍｍｏｌ）を室温で加え、そのままの温度で２時間撹拌した。
　反応終了後、反応液に５％硫酸水素カリウム水溶液を加えて撹拌した後、酢酸エチルで３回抽出した。全有機層を無水硫酸マグネシウムで乾燥後、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝６０：４０～３０：７０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を酢酸エチルに溶解させた後、ｎ－ヘキサンを加えて析出させた固体を濾取し、ｎ－ヘキサンで洗浄してから減圧乾燥することにより、白色固体１８７ｍｇを得た。得られた固体を分取ＨＰＬＣ（カラム；Ｘ－Ｂｒｉｄｇｅ（商品名）ＯＤＳ，溶出溶媒；アセトニトリル：１ｍＭリン酸二水素カリウム水溶液＝５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮してアセトニトリルを留去した。濃縮過程で析出した固体を濾取し、水で洗浄した後、減圧乾燥することにより、標記化合物１５６ｍｇ（収率７０％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５２４［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.34 - 11.78 (m, 1H), 9.87 - 9.34 (m, 1H), 7.35 - 7.27 (m, 4H), 7.24 - 7.16 (m, 1H), 6.75 (d, J = 7.9 Hz, 1H), 5.49 (br s, 1H), 4.95 (d, J = 7.9 Hz, 1H), 4.47 - 4.20 (m, 2H), 3.49 - 3.41 (m, 1H), 3.26 - 3.18 (m, 1H), 2.57 - 2.39 (m, 2H), 2.26 - 2.14 (m, 2H), 2.11 - 1.99 (m, 2H), 1.98 - 1.74 (m, 5H), 1.61 (s, 3H), 1.53 (s, 3H), 1.26 - 1.13 (m, 1H), 0.08 (s, 9H)。 2-ethyl 5- (trichloromethyl) 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] pyrrolo [3,4-c] pyrazole-2 synthesized in the same manner as in Reference Example 73 under an argon atmosphere , 5 (4H, 6H) -dicarboxylate 131 mg (0.243 mmol) and ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo To a solution of 79 mg (0.18 mmol) of [3,4-c] pyrazole-2 (4H) -carboxylate in 3 ml of dehydrated 1,4-dioxane, 0.34 ml (2.0 mmol) of DIPEA was used in the same manner as in Reference Example 74. 235 mg of {1- [amino (phenyl) methyl] cyclobutyl} methanol synthesized Were successively added .23Mmol) was stirred at room temperature for 1.5 hours at 90 ° C.. The reaction mixture was allowed to cool to room temperature, 0.21 ml (1.9 mmol) of N, N-dimethylethane-1,2-diamine was added at room temperature, and the mixture was stirred at that temperature for 2 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture and stirred, followed by extraction with ethyl acetate three times. All organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 60: 40 to 30:70 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was dissolved in ethyl acetate, n-hexane was added and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to obtain 187 mg of a white solid. The obtained solid is subjected to preparative HPLC (column; X-Bridge (trade name) ODS, elution solvent: acetonitrile: 1 mM aqueous potassium dihydrogen phosphate solution = 50: 50 (V / V)), and contains the desired product. The fraction was concentrated under reduced pressure to distill off acetonitrile. The solid precipitated in the concentration process was collected by filtration, washed with water, and dried under reduced pressure to obtain 156 mg (yield 70%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 524 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.34-11.78 (m, 1H), 9.87-9.34 (m, 1H), 7.35-7.27 (m, 4H), 7.24-7.16 (m, 1H) , 6.75 (d, J = 7.9 Hz, 1H), 5.49 (br s, 1H), 4.95 (d, J = 7.9 Hz, 1H), 4.47-4.20 (m, 2H), 3.49-3.41 (m, 1H) , 3.26-3.18 (m, 1H), 2.57-2.39 (m, 2H), 2.26-2.14 (m, 2H), 2.11-1.99 (m, 2H), 1.98-1.74 (m, 5H), 1.61 (s, 3H), 1.53 (s, 3H), 1.26-1.13 (m, 1H), 0.08 (s, 9H).
（実施例７２）
（Ｒ）－Ｎ－［２－（１－ヒドロキシシクロプロピル）－１－フェニルエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－２００）
Figure JPOXMLDOC01-appb-C000111
 (Example 72)
(R) -N- [2- (1-hydroxycyclopropyl) -1-phenylethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 4-c] pyrazole-5 (1H) -carboxamide (Compound No. IV-200)
Figure JPOXMLDOC01-appb-C000111
　アルゴン雰囲気下、参考例７６と同様にして合成した（Ｒ）－１－（２－アミノ－２－フェニルエチル）シクロプロパノール１２８ｍｇ（不純物を含む）の脱水１，４－ジオキサン２ｍｌ溶液に、ＤＩＰＥＡ０．２６ｍｌ（１．５ｍｍｏｌ）、参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１５４ｍｇ（０．３４９ｍｍｏｌ）を室温で順次加えた後、９０℃で２時間撹拌した。反応液が室温になるまで放冷した後、Ｎ，Ｎ－ジメチルエタン－１，２－ジアミン０．１６ｍｌ（１．５ｍｍｏｌ）を室温で加え、そのままの温度で２時間撹拌した。
　反応終了後、反応液に５％硫酸水素カリウム水溶液を加えて撹拌した後、酢酸エチルで２回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７０：３０～４０：６０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を酢酸エチル／ｎ－ヘキサン混合溶媒に懸濁させて撹拌した後で不溶物を濾取し、ｎ－ヘキサンで洗浄してから減圧乾燥することにより、標記化合物１３９ｍｇ（収率７９％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５１０［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.23 & 11.80 (br s, total 1H), 9.75 - 9.47 (m, 1H), 7.43 - 7.37 (m, 2H), 7.34 - 7.27 (m, 2H), 7.23 - 7.17 (m, 1H), 6.51 - 6.33 (m, 1H), 5.54 - 5.37 (m, 1H), 5.14 - 5.05 (m, 1H), 4.66 - 4.29 (m, 2H), 2.61 - 2.39 (m, 2H), 2.26 - 2.06 (m, 3H), 1.90 - 1.50 (m, 9H), 0.55 - 0.37 (m, 3H), 0.18 - 0.04 (m, 10H)。 In a 2 ml solution of dehydrated 1,4-dioxane of 128 mg (containing impurities) of (R) -1- (2-amino-2-phenylethyl) cyclopropanol synthesized in the same manner as in Reference Example 76 under an argon atmosphere, DIPEA 0. 26 ml (1.5 mmol), ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3 synthesized in the same manner as in Reference Example 3 , 4-c] pyrazole-2 (4H) -carboxylate (154 mg, 0.349 mmol) was sequentially added at room temperature, followed by stirring at 90 ° C. for 2 hours. After the reaction solution was allowed to cool to room temperature, 0.16 ml (1.5 mmol) of N, N-dimethylethane-1,2-diamine was added at room temperature and stirred at that temperature for 2 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture and stirred, followed by extraction twice with ethyl acetate. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30 to 40:60 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was suspended in a mixed solvent of ethyl acetate / n-hexane and stirred, and then insoluble matter was collected by filtration, washed with n-hexane and dried under reduced pressure to give 139 mg of the title compound (yield) 79%) was obtained as a white solid.
Mass spectrum (CI, m / z): 510 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.23 & 11.80 (br s, total 1H), 9.75-9.47 (m, 1H), 7.43-7.37 (m, 2H), 7.34-7.27 (m, 2H), 7.23-7.17 (m, 1H), 6.51-6.33 (m, 1H), 5.54-5.37 (m, 1H), 5.14-5.05 (m, 1H), 4.66-4.29 (m, 2H), 2.61- 2.39 (m, 2H), 2.26-2.06 (m, 3H), 1.90-1.50 (m, 9H), 0.55-0.37 (m, 3H), 0.18-0.04 (m, 10H).
（実施例７３）
（Ｒ）－Ｎ－（３－エチル－３－ヒドロキシ－１－フェニルペンチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－２１５）
Figure JPOXMLDOC01-appb-C000112
 (Example 73)
(R) -N- (3-Ethyl-3-hydroxy-1-phenylpentyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide (Compound No. IV-215)
Figure JPOXMLDOC01-appb-C000112
　アルゴン雰囲気下、参考例７８と同様にして合成した（Ｒ）－１－アミノ－３－エチル－１－フェニルペンタン－３－オール１１８ｍｇ（０．５６８ｍｍｏｌ）の脱水１，４－ジオキサン２ｍｌ溶液に、ＤＩＰＥＡ０．２０ｍｌ（１．１ｍｍｏｌ）、参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１２８ｍｇ（０．２９０ｍｍｏｌ）を室温で順次加えた後、９０℃で２時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加えて撹拌した後、酢酸エチルで３回抽出した。全有機層を無水硫酸マグネシウムで乾燥後、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７５：２５～４０：６０（Ｖ／Ｖ））に付し、次いで減圧濃縮、減圧乾燥を行うことにより濃縮残渣を得た。
　アルゴン雰囲気下、得られた濃縮残渣のＴＨＦ２ｍｌ溶液にＮ，Ｎ－ジメチルエタン－１，２－ジアミン０．１３ｍｌ（１．２ｍｍｏｌ）を室温で加えた後、室温で２時間撹拌した。
　反応終了後、反応液に５％硫酸水素カリウム水溶液を加えて撹拌した後、酢酸エチルで３回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７０：３０～３０：７０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を酢酸エチル／ｎ－ヘキサン混合溶媒に懸濁させ、室温で撹拌した後に不溶物を濾取し、ｎ－ヘキサンで洗浄してから減圧乾燥することにより、標記化合物１２３ｍｇ（収率７９％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５４０［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.35 - 11.68 (m, 1H), 9.56 (br s, 1H), 7.37 - 7.24 (m, 4H), 7.19 - 7.13 (m, 1H), 6.56 (d, J = 5.8 Hz, 1H), 4.91 - 4.81 (m, 1H), 4.54 - 4.31 (m, 3H), 2.58 - 2.41 (m, 2H), 2.26 - 2.13 (m, 2H), 1.95 - 1.73 (m, 3H), 1.63 - 1.55 (m, 4H), 1.53 (s, 3H), 1.49 - 1.33 (m, 4H), 0.82 (t, J = 7.4 Hz, 3H), 0.77 (t, J = 7.4 Hz, 3H), 0.09 (s, 9H)。 Under an argon atmosphere, a solution of 118 mg (0.568 mmol) of (R) -1-amino-3-ethyl-1-phenylpentan-3-ol synthesized in the same manner as in Reference Example 78 was added to a 2 ml solution of dehydrated 1,4-dioxane. DIPEA 0.20 ml (1.1 mmol), ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo synthesized as in Reference Example 3 128 mg (0.290 mmol) of [3,4-c] pyrazole-2 (4H) -carboxylate was sequentially added at room temperature, followed by stirring at 90 ° C. for 2 hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and stirred, followed by extraction three times with ethyl acetate. All organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 75: 25 to 40:60 (V / V)), and then concentrated under reduced pressure and dried under reduced pressure. Got.
Under an argon atmosphere, 0.13 ml (1.2 mmol) of N, N-dimethylethane-1,2-diamine was added to a 2 ml THF solution of the obtained concentrated residue, and the mixture was stirred at room temperature for 2 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture and stirred, followed by extraction with ethyl acetate three times. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30 to 30:70 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was suspended in a mixed solvent of ethyl acetate / n-hexane, stirred at room temperature, insoluble matter was collected by filtration, washed with n-hexane, and dried under reduced pressure to give 123 mg (yield) of the title compound. 79%) was obtained as a white solid.
Mass spectrum (CI, m / z): 540 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.35-11.68 (m, 1H), 9.56 (br s, 1H), 7.37-7.24 (m, 4H), 7.19-7.13 (m, 1H), 6.56 (d, J = 5.8 Hz, 1H), 4.91-4.81 (m, 1H), 4.54-4.31 (m, 3H), 2.58-2.41 (m, 2H), 2.26-2.13 (m, 2H), 1.95- 1.73 (m, 3H), 1.63-1.55 (m, 4H), 1.53 (s, 3H), 1.49-1.33 (m, 4H), 0.82 (t, J = 7.4 Hz, 3H), 0.77 (t, J = 7.4 Hz, 3H), 0.09 (s, 9H).
（実施例７４）
（Ｒ）－Ｎ－［１－（４－フルオロフェニル）－３－ヒドロキシ－３－メチルブチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－２７２）
Figure JPOXMLDOC01-appb-C000113
 (Example 74)
(R) -N- [1- (4-Fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [ 3,4-c] pyrazole-5 (1H) -carboxamide (Compound No. IV-272)
Figure JPOXMLDOC01-appb-C000113
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート５９９ｍｇ（１．３６ｍｍｏｌ）の１，４－ジオキサン３ｍｌ溶液に、アルゴン気流下で参考例８２と同様にして合成した（Ｒ）－４－アミノ－４－（４－フルオロフェニル）－２－メチルブタン－２－オール１３４ｍｇ（不純物を含む）、ＤＩＰＥＡ０．６０２ｍｌ（３．４０ｍｍｏｌ）を室温で順次加えた後、１００℃で１時間攪拌した。次いで、Ｎ，Ｎ－ジメチルエタン－１，２－ジアミン０．３１８ｍｌ（３．４０ｍｍｏｌ）を室温で加え、そのままの温度で２時間攪拌した。
　反応終了後、反応液に５％硫酸水素カリウム水溶液を加え、酢酸エチルで抽出した。得られた有機層を飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥した後、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；酢酸エチル：メタノール＝１００：０～９０：１０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を分取ＨＰＬＣ（カラム；Ｘ－Ｂｒｉｄｇｅ（商品名）ＯＤＳ，溶出溶媒；アセトニトリル：１ｍＭリン酸二水素カリウム水溶液＝３０：７０～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮してアセトニトリルを留去し、酢酸エチルで抽出した。得られた有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した後、濾過、減圧濃縮、減圧乾燥することにより、標記化合物４８ｍｇ（収率８％［２工程］）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５３０［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.20 & 11.77 (br s, total 1H), 9.74 - 9.41 (m, 1H), 7.40 - 7.32 (m, 2H), 7.14 - 7.05 (m, 2H), 6.66 - 6.44 (m, 1H), 4.94 - 4.84 (m, 1H), 4.75 - 4.60 (m, 1H), 4.52 - 4.31 (m, 2H), 2.59 - 2.39 (m, 2H), 2.27 - 2.11 (m, 2H), 2.04 - 1.73 (m, 3H), 1.70 - 1.45 (m, 7H), 1.15 (s, 3H),  1.13 (s, 3H), 0.09 (s, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 (R) -4-amino-4- (4-fluoro) synthesized in the same manner as in Reference Example 82 under a stream of argon in a solution of 599 mg (1.36 mmol) of 2 (4H) -carboxylate in 3 ml of 1,4-dioxane. Phenyl) -2-methylbutan-2-ol (134 mg, including impurities) and DIPEA (0.602 ml, 3.40 mmol) were sequentially added at room temperature, followed by stirring at 100 ° C. for 1 hour. Next, 0.318 ml (3.40 mmol) of N, N-dimethylethane-1,2-diamine was added at room temperature, and the mixture was stirred at that temperature for 2 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; ethyl acetate: methanol = 100: 0 to 90:10 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The obtained concentrated residue was subjected to preparative HPLC (column; X-Bridge (trade name) ODS, elution solvent: acetonitrile: 1 mM potassium dihydrogen phosphate aqueous solution = 30: 70 to 50:50 (V / V)). The fraction containing the desired product was concentrated under reduced pressure to distill off acetonitrile, and extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and dried under reduced pressure to give 48 mg of the title compound (yield 8% [2 steps]) as a white solid. Obtained.
Mass spectrum (CI, m / z): 530 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.20 & 11.77 (br s, total 1H), 9.74-9.41 (m, 1H), 7.40-7.32 (m, 2H), 7.14-7.05 (m, 2H), 6.66-6.44 (m, 1H), 4.94-4.84 (m, 1H), 4.75-4.60 (m, 1H), 4.52-4.31 (m, 2H), 2.59-2.39 (m, 2H), 2.27- 2.11 (m, 2H), 2.04-1.73 (m, 3H), 1.70-1.45 (m, 7H), 1.15 (s, 3H), 1.13 (s, 3H), 0.09 (s, 9H).
（実施例７５）
（Ｒ）－Ｎ－［１－（３－フルオロフェニル）－３－ヒドロキシ－３－メチルブチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－２５４）
Figure JPOXMLDOC01-appb-C000114
 (Example 75)
(R) -N- [1- (3-Fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [ 3,4-c] pyrazole-5 (1H) -carboxamide (Compound No. IV-254)
Figure JPOXMLDOC01-appb-C000114
　参考例８７と同様にして合成した（Ｒ）－エチル　５－｛［１－（３－フルオロフェニル）－３－ヒドロキシ－３－メチルブチル］カルバモイル｝－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１４９ｍｇ（０．２４８ｍｍｏｌ）のジクロロメタン３ｍｌ溶液に、アルゴン気流下撹拌しながらＮ，Ｎ－ジメチルエタン－１，２－ジアミン０．１０８ｍｌ（０．９９２ｍｍｏｌ）を室温で一度に加え、室温で１時間撹拌した。
　反応終了後、反応溶液に５％硫酸水素カリウム水溶液を加え、その混合液から酢酸エチルで２回抽出した。有機層は５％硫酸水素カリウム水溶液で洗浄、無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７０：３０～１７：８３（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を少量の酢酸エチルに溶解させ、ｎ－ヘキサンを加えることで固体を析出させた。固体を濾取、ｎ－ヘキサンで洗浄、５０℃で減圧乾燥することで、標記化合物１０１ｍｇ（収率７７％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５３０［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.21 & 11.77 (br s, total 1H), 9.71 - 9.47 (m, 1H), 7.37 - 7.26 (m, 1H), 7.22 - 7.11 (m, 2H), 7.02 - 6.92 (m, 1H), 6.65 - 6.51 (m, 1H), 4.95 - 4.87 (m, 1H), 4.76 - 4.60 (m, 1H), 4.55 - 4.35 (m, 2H), 2.57 - 2.40 (m, 2H), 2.27 - 2.12 (m, 2H), 2.03 - 1.74 (m, 3H), 1.66 (dd, J = 3.1, 14.2 Hz, 1H), 1.59 (br s, 3H), 1.54 (br s, 3H), 1.16 (s, 3H), 1.13 (s, 3H), 0.09 (s, 9H)。 (R) -Ethyl 5-{[1- (3-fluorophenyl) -3-hydroxy-3-methylbutyl] carbamoyl} -6,6-dimethyl-3- [1- () synthesized in the same manner as in Reference Example 87 Trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate in a solution of 149 mg (0.248 mmol) in dichloromethane with stirring under N, N- Dimethylethane-1,2-diamine (0.108 ml, 0.992 mmol) was added at once at room temperature, and the mixture was stirred at room temperature for 1 hour.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with 5% aqueous potassium hydrogen sulfate solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30 to 17:83 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was dissolved in a small amount of ethyl acetate, and n-hexane was added to precipitate a solid. The solid was collected by filtration, washed with n-hexane, and dried under reduced pressure at 50 ° C. to give 101 mg (yield 77%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 530 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.21 & 11.77 (br s, total 1H), 9.71-9.47 (m, 1H), 7.37-7.26 (m, 1H), 7.22-7.11 (m, 2H), 7.02-6.92 (m, 1H), 6.65-6.51 (m, 1H), 4.95-4.87 (m, 1H), 4.76-4.60 (m, 1H), 4.55-4.35 (m, 2H), 2.57- 2.40 (m, 2H), 2.27-2.12 (m, 2H), 2.03-1.74 (m, 3H), 1.66 (dd, J = 3.1, 14.2 Hz, 1H), 1.59 (br s, 3H), 1.54 (br s, 3H), 1.16 (s, 3H), 1.13 (s, 3H), 0.09 (s, 9H).
（実施例７６）
（Ｒ）－Ｎ－［１－（２－フルオロフェニル）－３－ヒドロキシ－３－メチルブチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－２３６）
Figure JPOXMLDOC01-appb-C000115
 (Example 76)
(R) -N- [1- (2-Fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [ 3,4-c] pyrazole-5 (1H) -carboxamide (Compound No. IV-236)
Figure JPOXMLDOC01-appb-C000115
　参考例９２と同様にして合成した（Ｒ）－エチル　５－｛［１－（２－フルオロフェニル）－３－ヒドロキシ－３－メチルブチル］カルバモイル｝－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１５０ｍｇ（０．２４９ｍｍｏｌ）のジクロロメタン３ｍｌ溶液に、アルゴン気流下撹拌しながらＮ，Ｎ－ジメチルエタン－１，２－ジアミン０．１０９ｍｌ（１．００ｍｍｏｌ）を室温で一度に加え、室温で１時間撹拌した。
　反応終了後、反応溶液に５％硫酸水素カリウム水溶液を加え、その混合液から酢酸エチルで２回抽出した。有機層は５％硫酸水素カリウム水溶液で洗浄、無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７０：３０～１７：８３（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を少量の酢酸エチルに溶解させ、ｎ－ヘキサンを加えることで固体を析出させた。固体を濾取、ｎ－ヘキサンで洗浄、５０℃で減圧乾燥することで、標記化合物１１２ｍｇ（収率８５％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５３０［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.20 & 11.76 (br s, total 1H), 9.72 - 9.46 (m, 1H), 7.54 - 7.43 (m, 1H), 7.26 - 7.17 (m, 1H), 7.17 - 7.04 (m, 2H), 6.62 - 6.47 (m, 1H), 5.23 - 5.14 (m, 1H), 4.78 - 4.62 (m, 1H), 4.55 - 4.35 (m, 2H), 2.58 - 2.40 (m, 2H), 2.27 - 2.12 (m, 2H), 2.02 - 1.73 (m, 3H), 1.67 - 1.45 (m, 7H), 1.18 (s, 3H), 1.15 (s, 3H), 0.09 (s, 9H)。 (R) -Ethyl 5-{[1- (2-fluorophenyl) -3-hydroxy-3-methylbutyl] carbamoyl} -6,6-dimethyl-3- [1- () synthesized in the same manner as in Reference Example 92 Trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate 150 mg (0.249 mmol) in 3 ml dichloromethane with stirring under N, N- Dimethylethane-1,2-diamine (0.109 ml, 1.00 mmol) was added at once at room temperature, and the mixture was stirred at room temperature for 1 hour.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with 5% aqueous potassium hydrogen sulfate solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30 to 17:83 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was dissolved in a small amount of ethyl acetate, and n-hexane was added to precipitate a solid. The solid was collected by filtration, washed with n-hexane, and dried under reduced pressure at 50 ° C. to give 112 mg (yield 85%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 530 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.20 & 11.76 (br s, total 1H), 9.72-9.46 (m, 1H), 7.54-7.43 (m, 1H), 7.26-7.17 (m, 1H), 7.17-7.04 (m, 2H), 6.62-6.47 (m, 1H), 5.23-5.14 (m, 1H), 4.78-4.62 (m, 1H), 4.55-4.35 (m, 2H), 2.58- 2.40 (m, 2H), 2.27-2.12 (m, 2H), 2.02-1.73 (m, 3H), 1.67-1.45 (m, 7H), 1.18 (s, 3H), 1.15 (s, 3H), 0.09 ( s, 9H).
（実施例７７）
（Ｒ）－Ｎ－（５－ヒドロキシ－２，５－ジメチルヘキサン－３－イル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－２２１）
Figure JPOXMLDOC01-appb-C000116
 (Example 77)
(R) -N- (5-hydroxy-2,5-dimethylhexane-3-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 4-c] pyrazole-5 (1H) -carboxamide (Compound No. IV-221)
Figure JPOXMLDOC01-appb-C000116
　参考例９６と同様にして合成した（Ｒ）－エチル　５－［（５－ヒドロキシ－２，５－ジメチルヘキサン－３－イル）カルバモイル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート９９ｍｇ（０．１８ｍｍｏｌ）のジクロロメタン３ｍｌ溶液に、アルゴン気流下撹拌しながらＮ，Ｎ－ジメチルエタン－１，２－ジアミン０．０７８ｍｌ（０．７２ｍｍｏｌ）を室温で一度に加え、室温で１時間撹拌した。
　反応終了後、反応溶液に５％硫酸水素カリウム水溶液を加え、その混合液から酢酸エチルで２回抽出した。有機層は５％硫酸水素カリウム水溶液で洗浄、無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝５０：５０～１６：８４（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を少量の酢酸エチルに溶解させ、ｎ－ヘキサンを加えることで固体を析出させた。固体を濾取、ｎ－ヘキサンで洗浄、５０℃で減圧乾燥することで、標記化合物７２ｍｇ（収率８４％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４７８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.19 & 11.81 (br s, total 1H), 9.71 - 9.44 (m, 1H), 5.63 (br s, 1H), 4.47 - 4.25 (m, 3H), 3.71 - 3.60 (m, 1H),  2.57 - 2.39 (m, 2H), 2.27 - 2.11 (m, 2H), 1.90 - 1.66 (m, 3H), 1.65 - 1.52 (m, 7H), 1.49 - 1.42 (m, 1H), 1.10 (s, 3H), 1.09 (s, 3H), 0.82 (d, J = 6.8 Hz, 6H), 0.08 (s, 9H)。 (R) -Ethyl 5-[(5-hydroxy-2,5-dimethylhexane-3-yl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) synthesized in the same manner as in Reference Example 96 Cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate 99 mg (0.18 mmol) in dichloromethane 3 ml with stirring under N 2 N-dimethylethane 0.078 ml (0.72 mmol) of -1,2-diamine was added at a time at room temperature and stirred at room temperature for 1 hour.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with 5% aqueous potassium hydrogen sulfate solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 50: 50 to 16:84 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was dissolved in a small amount of ethyl acetate, and n-hexane was added to precipitate a solid. The solid was collected by filtration, washed with n-hexane, and dried under reduced pressure at 50 ° C. to obtain 72 mg (yield 84%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 478 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.19 & 11.81 (br s, total 1H), 9.71-9.44 (m, 1H), 5.63 (br s, 1H), 4.47-4.25 (m, 3H ), 3.71-3.60 (m, 1H), 2.57-2.39 (m, 2H), 2.27-2.11 (m, 2H), 1.90-1.66 (m, 3H), 1.65-1.52 (m, 7H), 1.49-1.42 (m, 1H), 1.10 (s, 3H), 1.09 (s, 3H), 0.82 (d, J = 6.8 Hz, 6H), 0.08 (s, 9H).
（実施例７８）
Ｎ－［１－（４－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－２７６）
Figure JPOXMLDOC01-appb-C000117
 (Example 78)
N- [1- (4-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxamide (Compound No. IV-276)
Figure JPOXMLDOC01-appb-C000117
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート０．７４５ｇ（１．６９ｍｍｏｌ）の１，４－ジオキサン８ｍｌ溶液に、アルゴン気流下撹拌しながらＤＩＰＥＡ１．４７ｍｌ（８．４４ｍｍｏｌ）、参考例９８と同様にして合成した３－アミノ－３－（４－フルオロフェニル）－２，２－ジメチルプロパン－１－オール１．００ｇ（５．０７ｍｍｏｌ）を室温で順次加え、９０℃で１．５時間撹拌した。次いで、反応溶液を室温まで放冷した後、Ｎ，Ｎ－ジメチルエタン－１，２－ジアミン０．７３８ｍｌ（６．７８ｍｍｏｌ）を室温で滴下し、室温で４時間撹拌した。
　反応終了後、反応溶液に５％硫酸水素カリウム水溶液を加え、その混合液から酢酸エチルで２回抽出した。有機層は飽和塩化ナトリウム水溶液で洗浄、無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７０：３０～１９：８１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。濃縮残渣を６０ｍｌの酢酸エチルに溶かし、５％硫酸水素カリウム水溶液１０ｍｌで３回洗浄した。有機層は飽和塩化ナトリウム水溶液で洗浄、無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮した。得られた濃縮残渣を少量の酢酸エチルに溶解させ、ｎ－ヘキサンを加えることで固体を析出させた。固体を濾取、ｎ－ヘキサンで洗浄、５０℃で減圧乾燥することで、標記化合物５０９ｍｇ（収率５７％）を白色固体として得た。
マススペクトル（ＥＳＩ，ｍ／ｚ）：５３０［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.21 & 11.80 (br s, total 1H), 9.68 - 9.44 (m, 1H), 7.39 - 7.32 (m, 2H), 7.17 - 7.09 (m, 2H), 6.91 - 6.78 (m, 1H), 5.46 (br s, 1H), 4.65 (d, J = 7.9 Hz, 1H), 4.45 - 4.28 (m, 2H), 3.23 (dd, J = 4.2, 10.6 Hz, 1H), 3.08 - 2.99 (m, 1H), 2.60 - 2.39 (m, 2H), 2.27 - 2.14 (m, 2H), 1.91 - 1.73 (m, 2H), 1.65 - 1.49 (m, 6H), 1.05 (s, 3H), 0.64 (s, 3H), 0.09 (s, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 Synthesized in the same manner as in Reference Example 98, 1.47 ml (8.44 mmol) of DIPEA in a solution of 0.745 g (1.69 mmol) of 2 (4H) -carboxylate in 8 ml of 1,4-dioxane while stirring under an argon stream 3 -Amino-3- (4-fluorophenyl) -2,2-dimethylpropan-1-ol (1.00 g, 5.07 mmol) was sequentially added at room temperature, followed by stirring at 90 ° C. for 1.5 hours. Next, the reaction solution was allowed to cool to room temperature, and 0.738 ml (6.78 mmol) of N, N-dimethylethane-1,2-diamine was added dropwise at room temperature, followed by stirring at room temperature for 4 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30 to 19:81 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The concentrated residue was dissolved in 60 ml of ethyl acetate and washed 3 times with 10 ml of 5% aqueous potassium hydrogen sulfate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was dissolved in a small amount of ethyl acetate, and n-hexane was added to precipitate a solid. The solid was collected by filtration, washed with n-hexane, and dried under reduced pressure at 50 ° C. to give 509 mg (yield 57%) of the title compound as a white solid.
Mass spectrum (ESI, m / z): 530 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.21 & 11.80 (br s, total 1H), 9.68-9.44 (m, 1H), 7.39-7.32 (m, 2H), 7.17-7.09 (m, 2H), 6.91-6.78 (m, 1H), 5.46 (br s, 1H), 4.65 (d, J = 7.9 Hz, 1H), 4.45-4.28 (m, 2H), 3.23 (dd, J = 4.2, 10.6 Hz, 1H), 3.08-2.99 (m, 1H), 2.60-2.39 (m, 2H), 2.27-2.14 (m, 2H), 1.91-1.73 (m, 2H), 1.65-1.49 (m, 6H), 1.05 (s, 3H), 0.64 (s, 3H), 0.09 (s, 9H).
（実施例７９）
Ｎ－［１－（３－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－２５８）
Figure JPOXMLDOC01-appb-C000118
 (Example 79)
N- [1- (3-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxamide (Compound No. IV-258)
Figure JPOXMLDOC01-appb-C000118
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１６２ｍｇ（０．３６７ｍｍｏｌ）の１，４－ジオキサン４ｍｌ溶液に、アルゴン雰囲気下、ＤＩＰＥＡ０．３２ｍｌ（１．９ｍｍｏｌ）、参考例１００と同様にして合成した３－アミノ－３－（３－フルオロフェニル）－２，２－ジメチルプロパン－１－オール２２７ｍｇ（１．１５ｍｍｏｌ）を室温で加えた後、１００℃で２．５時間反応した。放冷後、Ｎ，Ｎ－ジメチル－１，２－ジアミン０．１２ｍｌ（１．１ｍｍｏｌ）を加え、室温で１時間撹拌した。
　反応終了後、反応液を減圧濃縮し、残渣に酢酸エチル２０ｍｌを加え、５％硫酸水素カリウム水溶液１０ｍｌ、飽和炭酸水素ナトリウム水溶液１０ｍｌ、飽和塩化ナトリウム水溶液１０ｍｌで順次洗浄し、有機層を無水硫酸マグネシウムで乾燥し、ろ過後、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：酢酸エチル＝８１：１９～３０：７０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を少量のジクロロメタンに溶解させた後、ｎ－ヘキサンを加えて析出させた固体をろ取、減圧乾燥することにより、標記化合物１５９ｍｇ（収率８２％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５３０［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.22 & 11.89 (br s, total 1H), 9.79 - 9.40 (m, 1H), 7.39 - 7.29 (m, 1H), 7.22 - 7.13 (m, 2H), 7.08 - 7.01 (m, 1H), 6.86 (d, J = 8.0 Hz, 1H), 5.56 - 5.41 (m, 1H), 4.67 (d, J = 8.0 Hz, 1H), 4.49 - 4.27 (m, 2H), 3.25 (dd, J = 4.0, 10.6 Hz, 1H), 3.05 (dd, J = 4.0, 10.6 Hz, 1H), 2.56 - 2.40 (m, 2H), 2.29 - 2.13 (m, 2H), 1.92 - 1.72 (m, 2H), 1.60 (br s, 3H), 1.52 (br s, 3H), 1.05 (s, 3H), 0.67 (s, 3H), 0.09 (s, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 3-Amino-3 synthesized in the same manner as Reference Example 100 in DIPEA 0.32 ml (1.9 mmol) in 4 ml of 1,4-dioxane in 162 ml (0.367 mmol) of 2 (4H) -carboxylate under argon atmosphere After adding 227 mg (1.15 mmol) of-(3-fluorophenyl) -2,2-dimethylpropan-1-ol at room temperature, the mixture was reacted at 100 ° C. for 2.5 hours. After allowing to cool, 0.12 ml (1.1 mmol) of N, N-dimethyl-1,2-diamine was added, and the mixture was stirred at room temperature for 1 hour.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure, 20 ml of ethyl acetate was added to the residue, and the mixture was washed successively with 10 ml of 5% aqueous potassium hydrogensulfate solution, 10 ml of saturated aqueous sodium bicarbonate solution and 10 ml of saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. After filtration and filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: ethyl acetate = 81: 19 to 30:70 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The obtained concentrated residue was dissolved in a small amount of dichloromethane, and then n-hexane was added and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 159 mg (yield 82%) of the title compound as a white solid. .
Mass spectrum (CI, m / z): 530 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.22 & 11.89 (br s, total 1H), 9.79-9.40 (m, 1H), 7.39-7.29 (m, 1H), 7.22-7.13 (m, 2H), 7.08-7.01 (m, 1H), 6.86 (d, J = 8.0 Hz, 1H), 5.56-5.41 (m, 1H), 4.67 (d, J = 8.0 Hz, 1H), 4.49-4.27 (m , 2H), 3.25 (dd, J = 4.0, 10.6 Hz, 1H), 3.05 (dd, J = 4.0, 10.6 Hz, 1H), 2.56-2.40 (m, 2H), 2.29-2.13 (m, 2H), 1.92-1.72 (m, 2H), 1.60 (br s, 3H), 1.52 (br s, 3H), 1.05 (s, 3H), 0.67 (s, 3H), 0.09 (s, 9H).
（実施例８０）
（－）－Ｎ－［１－（３－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－２６０） (Example 80)
(−) — N- [1- (3-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- Dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide (Compound No. IV-260)
　実施例７９と同様にして合成したＮ－［１－（３－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド０．１２９ｇ（０．２４４ｍｍｏｌ）を光学分割分取クロマトグラフィー（カラム；ＣＨＩＲＡＬＰＡＫ（商品名）ＩＤ，溶出溶媒；ｎ－ヘキサン：エタノール：メタノール＝９５：５：１（Ｖ／Ｖ））に付し、先に溶出する光学活性体を含む画分を減圧濃縮することにより、標記化合物４７ｍｇ（収率３６％）を白色固体として得た。
比旋光度：［α］Ｄ ２０＝－５３°　（ｃ＝０．２３，メタノール）。
マススペクトル（ＣＩ，ｍ／ｚ）：５３０［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.21 & 11.88 (br s, total 1H), 9.78 - 9.41 (m, 1H), 7.38 - 7.30 (m, 1H), 7.21 - 7.13 (m, 2H), 7.08 - 7.01 (m, 1H), 6.86 (br d, J = 8.3 Hz, 1H), 5.56 - 5.40 (m, 1H), 4.67 (d, J = 8.3 Hz, 1H), 4.47 - 4.30 (m, 2H), 3.25 (br dd, J = 3.9, 10.5 Hz, 1H), 3.05 (br dd, J = 3.9, 10.5 Hz, 1H), 2.60 - 2.40 (m, 2H), 2.26 - 2.13 (m, 2H), 1.90 - 1.73 (m, 2H), 1.60 (br s, 3H), 1.52 (s, 3H), 1.05 (s, 3H), 0.67 (s, 3H), 0.09 (s, 9H)。
ＨＰＬＣ分析：
カラム；ＣＨＩＲＡＬＰＡＫ（商品名）ＩＤ　４．６×２５０ｍｍ
溶離液；ｎ－ヘキサン／エタノール／メタノール＝９５／５／１（Ｖ／Ｖ）
流速；１．０ｍｌ／ｍｉｎ
温度；４０℃
検出波長；２５４ｎｍ
保持時間；８．８分
光学純度：＞９９％ｅｅ N- [1- (3-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] synthesized in the same manner as in Example 79 -4,6-Dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide 0.129 g (0.244 mmol) was subjected to optical resolution preparative chromatography (column; CHIRALPAK (trade name) ID, elution solvent; n-hexane: ethanol: methanol = 95: 5: 1 (V / V)), and the fraction containing the optically active substance eluting first is concentrated under reduced pressure to give 47 mg (yield 36%) of the title compound. Was obtained as a white solid.
Specific rotation: [α] D 20 = −53 ° (c = 0.23, methanol).
Mass spectrum (CI, m / z): 530 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.21 & 11.88 (br s, total 1H), 9.78-9.41 (m, 1H), 7.38-7.30 (m, 1H), 7.21-7.13 (m, 2H), 7.08-7.01 (m, 1H), 6.86 (br d, J = 8.3 Hz, 1H), 5.56-5.40 (m, 1H), 4.67 (d, J = 8.3 Hz, 1H), 4.47-4.30 ( m, 2H), 3.25 (br dd, J = 3.9, 10.5 Hz, 1H), 3.05 (br dd, J = 3.9, 10.5 Hz, 1H), 2.60-2.40 (m, 2H), 2.26-2.13 (m, 2H), 1.90-1.73 (m, 2H), 1.60 (br s, 3H), 1.52 (s, 3H), 1.05 (s, 3H), 0.67 (s, 3H), 0.09 (s, 9H).
HPLC analysis:
Column; CHIRALPAK (trade name) ID 4.6 × 250 mm
Eluent: n-hexane / ethanol / methanol = 95/5/1 (V / V)
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection wavelength: 254 nm
Retention time: 8.8 minutes Optical purity:> 99% ee
（実施例８１）
（＋）－Ｎ－［１－（３－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－２５９） (Example 81)
(+)-N- [1- (3-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- Dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide (Compound No. IV-259)
実施例８０の光学分割分取クロマトグラフィー操作において、後から溶出する光学活性体を含む画分を減圧濃縮することにより、標記化合物４５ｍｇ（収率３５％）を白色固体として得た。
比旋光度：［α］Ｄ ２０＝＋５９°　（ｃ＝０．２２，メタノール）。
マススペクトル（ＣＩ，ｍ／ｚ）：５３０［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.21 & 11.94 (br s, total 1H), 9.78 - 9.41 (m, 1H), 7.38 - 7.30 (m, 1H), 7.21 - 7.13 (m, 2H), 7.08 - 7.01 (m, 1H), 6.86 (br d, J = 8.1 Hz, 1H), 5.56 - 5.39 (m, 1H), 4.67 (d, J = 8.1 Hz, 1H), 4.47 - 4.30 (m, 2H), 3.25 (br dd, J = 3.8, 10.5 Hz, 1H), 3.05 (br dd, J = 3.8, 10.5 Hz, 1H), 2.59 - 2.40 (m, 2H), 2.27 - 2.13 (m, 2H), 1.90 - 1.73 (m, 2H), 1.60 (br s, 3H), 1.52 (s, 3H), 1.05 (s, 3H), 0.67 (s, 3H), 0.09 (s, 9H)。
ＨＰＬＣ分析：
カラム；ＣＨＩＲＡＬＰＡＫ（商品名）ＩＤ　４．６×２５０ｍｍ
溶出溶媒；ｎ－ヘキサン／エタノール／メタノール＝９５／５／１（Ｖ／Ｖ）
流速；１．０ｍｌ／ｍｉｎ
温度；４０℃
検出波長；２５４ｎｍ
保持時間；１１．６分
光学純度：＞９８％ｅｅ In the optical resolution preparative chromatography operation of Example 80, the fraction containing the optically active compound eluted later was concentrated under reduced pressure to obtain 45 mg (yield 35%) of the title compound as a white solid.
Specific rotation: [α] D 20 = + 59 ° (c = 0.22, methanol).
Mass spectrum (CI, m / z): 530 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.21 & 11.94 (br s, total 1H), 9.78-9.41 (m, 1H), 7.38-7.30 (m, 1H), 7.21-7.13 (m, 2H), 7.08-7.01 (m, 1H), 6.86 (br d, J = 8.1 Hz, 1H), 5.56-5.39 (m, 1H), 4.67 (d, J = 8.1 Hz, 1H), 4.47-4.30 ( m, 2H), 3.25 (br dd, J = 3.8, 10.5 Hz, 1H), 3.05 (br dd, J = 3.8, 10.5 Hz, 1H), 2.59-2.40 (m, 2H), 2.27-2.13 (m, 2H), 1.90-1.73 (m, 2H), 1.60 (br s, 3H), 1.52 (s, 3H), 1.05 (s, 3H), 0.67 (s, 3H), 0.09 (s, 9H).
HPLC analysis:
Column; CHIRALPAK (trade name) ID 4.6 × 250 mm
Elution solvent: n-hexane / ethanol / methanol = 95/5/1 (V / V)
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detection wavelength: 254 nm
Retention time; 11.6 minutes Optical purity:> 98% ee
（実施例８２）
Ｎ－［１－（２－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－２４０）
Figure JPOXMLDOC01-appb-C000119
 (Example 82)
N- [1- (2-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxamide (Compound No. IV-240)
Figure JPOXMLDOC01-appb-C000119
　参考例１０１と同様にして合成した３－アミノ－３－（２－フルオロフェニル）－２，２－ジメチルプロパン－１－オール２２５ｍｇ（１．１４ｍｍｏｌ）の１，４－ジオキサン４ｍｌ溶液に、アルゴン雰囲気下、ＤＩＰＥＡ０．３２ｍｌ（１．９ｍｍｏｌ）、参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１６６ｍｇ（０．３７６ｍｍｏｌ）を室温で加えた後、１００℃で２．５時間反応した。放冷後、Ｎ，Ｎ－ジメチルエタン－１，２－ジアミン０．１２ｍｌ（１．１ｍｍｏｌ）を加え、室温で１時間撹拌した。
　反応終了後、反応液を減圧濃縮し、残渣に酢酸エチル２０ｍｌを加え、５％硫酸水素カリウム水溶液１０ｍｌ、飽和炭酸水素ナトリウム水溶液１０ｍｌ、飽和塩化ナトリウム水溶液１０ｍｌで順次洗浄し、有機層を無水硫酸マグネシウムで乾燥し、ろ過後、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：酢酸エチル＝８１：１９～３０：７０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を少量のジクロロメタンに溶解させた後、ｎ－ヘキサンを加えて析出させた固体をろ取、減圧乾燥することにより、標記化合物１５４ｍｇ（収率７７％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５３０［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.22 & 11.87 (br s, total 1H), 9.75 - 9.42 (m, 1H), 7.53 - 7.44 (m, 1H), 7.32 - 7.24 (m, 1H), 7.23 - 7.17 (m, 1H), 7.17 - 7.08 (m, 1H), 6.96 - 6.85 (m, 1H), 5.53 (br s, 1H), 5.03 (d, J = 7.9 Hz, 1H), 4.46 - 4.26 (m, 2H), 3.40 - 3.28 (m, 1H), 3.08 (dd, J = 4.0, 10.5 Hz, 1H), 2.56 - 2.39 (m, 2H), 2.27 - 2.12 (m, 2H), 1.92 - 1.72 (m, 2H), 1.65 - 1.47 (m, 6H), 1.10 (s, 3H), 0.69 - 0.60 (m, 3H), 0.09 (s, 9H)。 To a solution of 225 mg (1.14 mmol) of 3-amino-3- (2-fluorophenyl) -2,2-dimethylpropan-1-ol synthesized in the same manner as in Reference Example 101 in 4 ml of 1,4-dioxane, an argon atmosphere Below, DIPEA 0.32 ml (1.9 mmol), ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6- After adding 166 mg (0.376 mmol) of dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate at room temperature, the mixture was reacted at 100 ° C. for 2.5 hours. After allowing to cool, 0.12 ml (1.1 mmol) of N, N-dimethylethane-1,2-diamine was added, and the mixture was stirred at room temperature for 1 hour.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure, 20 ml of ethyl acetate was added to the residue, and the mixture was washed successively with 10 ml of 5% aqueous potassium hydrogensulfate solution, 10 ml of saturated aqueous sodium bicarbonate solution and 10 ml of saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. After filtration and filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: ethyl acetate = 81: 19 to 30:70 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The obtained concentrated residue was dissolved in a small amount of dichloromethane, and then n-hexane was added and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 154 mg (yield 77%) of the title compound as a white solid. .
Mass spectrum (CI, m / z): 530 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.22 & 11.87 (br s, total 1H), 9.75-9.42 (m, 1H), 7.53-7.44 (m, 1H), 7.32-7.24 (m, 1H), 7.23-7.17 (m, 1H), 7.17-7.08 (m, 1H), 6.96-6.85 (m, 1H), 5.53 (br s, 1H), 5.03 (d, J = 7.9 Hz, 1H), 4.46-4.26 (m, 2H), 3.40-3.28 (m, 1H), 3.08 (dd, J = 4.0, 10.5 Hz, 1H), 2.56-2.39 (m, 2H), 2.27-2.12 (m, 2H), 1.92-1.72 (m, 2H), 1.65-1.47 (m, 6H), 1.10 (s, 3H), 0.69-0.60 (m, 3H), 0.09 (s, 9H).
（実施例８３）
Ｎ－（１－ヒドロキシ－２，２，４－トリメチルペンタン－３－イル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－２２５）
Figure JPOXMLDOC01-appb-C000120
 (Example 83)
N- (1-hydroxy-2,2,4-trimethylpentan-3-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide (Compound No. IV-225)
Figure JPOXMLDOC01-appb-C000120
　アルゴン雰囲気下、参考例７３と同様にして合成した２－エチル　５－（トリクロロメチル）　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］ピロロ［３，４－ｃ］ピラゾール－２，５（４Ｈ，６Ｈ）－ジカルボキラート１３３ｍｇ（０．２４６ｍｍｏｌ）とエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート８０ｍｇ（０．１８ｍｍｏｌ）の混合物の脱水１，４－ジオキサン３ｍｌ溶液に、ＤＩＰＥＡ０．３７ｍｌ（２．１ｍｍｏｌ）、参考例１０３と同様にして合成した３－アミノ－２，２，４－トリメチルペンタン－１－オ－ル１８９ｍｇ（１．３０ｍｍｏｌ）を室温で順次加えた後、９０℃で２．５時間撹拌した。反応液が室温になるまで放冷した後、Ｎ，Ｎ－ジメチルエタン－１，２－ジアミン０．２３ｍｌ（２．１ｍｍｏｌ）を室温で加え、そのままの温度で１４時間撹拌した。
　反応終了後、反応液に５％硫酸水素カリウム水溶液を加えて撹拌した後、酢酸エチルで３回抽出した。全有機層を無水硫酸マグネシウムで乾燥後、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝６０：４０～３０：７０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を酢酸エチルに溶解させた後、ｎ－ヘキサンを加えて析出させた固体を濾取し、ｎ－ヘキサンで洗浄してから減圧乾燥することにより、標記化合物１０７ｍｇ（収率５２％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４７８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.42 - 11.70 (m, 1H), 9.86 - 9.33 (m, 1H), 5.48 (br d, J = 9.2 Hz, 1H), 5.13 - 4.93 (m, 1H), 4.48 - 4.22 (m, 2H), 3.55 - 3.48 (m, 1H), 3.45 (dd, J = 3.9, 10.7 Hz, 1H), 3.04 (dd, J = 5.4, 10.7 Hz, 1H), 2.58 - 2.38 (m, 2H), 2.26 - 2.12 (m, 2H), 2.05 - 1.92 (m, 1H), 1.88 - 1.73 (m, 2H), 1.61 (br s, 3H), 1.59 (br s, 3H), 0.93 (s, 3H), 0.89 (d, J = 6.7 Hz, 6H), 0.79 (s, 3H), 0.07 (s, 9H)。 2-ethyl 5- (trichloromethyl) 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] pyrrolo [3,4-c] pyrazole-2 synthesized in the same manner as in Reference Example 73 under an argon atmosphere , 5 (4H, 6H) -dicarboxylate 133 mg (0.246 mmol) and ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo To a solution of 80 mg (0.18 mmol) of [3,4-c] pyrazole-2 (4H) -carboxylate in a 3 ml solution of dehydrated 1,4-dioxane, 0.37 ml (2.1 mmol) of DIPEA was used in the same manner as in Reference Example 103. 3-amino-2,2,4-trimethylpentane-1-ol synthesized in 189 mg (1 Were successively added 30 mmol) was stirred at room temperature for 2.5 hours at 90 ° C.. After allowing the reaction solution to cool to room temperature, 0.23 ml (2.1 mmol) of N, N-dimethylethane-1,2-diamine was added at room temperature and stirred at that temperature for 14 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture and stirred, followed by extraction with ethyl acetate three times. All organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 60: 40 to 30:70 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was dissolved in ethyl acetate, then n-hexane was added and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 107 mg of the title compound (yield: 52 %) As a white solid.
Mass spectrum (CI, m / z): 478 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.42-11.70 (m, 1H), 9.86-9.33 (m, 1H), 5.48 (br d, J = 9.2 Hz, 1H), 5.13-4.93 ( m, 1H), 4.48-4.22 (m, 2H), 3.55-3.48 (m, 1H), 3.45 (dd, J = 3.9, 10.7 Hz, 1H), 3.04 (dd, J = 5.4, 10.7 Hz, 1H) , 2.58-2.38 (m, 2H), 2.26-2.12 (m, 2H), 2.05-1.92 (m, 1H), 1.88-1.73 (m, 2H), 1.61 (br s, 3H), 1.59 (br s, 3H), 0.93 (s, 3H), 0.89 (d, J = 6.7 Hz, 6H), 0.79 (s, 3H), 0.07 (s, 9H).
（実施例８４）
（Ｒ）－Ｎ－（３－ヒドロキシ－３－メチル－１－フェニルブチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＩＩ－２２）
Figure JPOXMLDOC01-appb-C000121
 (Example 84)
(R) -N- (3-hydroxy-3-methyl-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide (Compound No. III-22)
Figure JPOXMLDOC01-appb-C000121
　アルゴン雰囲気下、参考例３８と同様にして合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１．５３ｇ（４．１９ｍｍｏｌ）の脱水ジクロロメタン２０ｍｌ溶液に、ＤＩＰＥＡ２．６０ｍｌ（１４．９ｍｍｏｌ）を室温で加えた。次いで、ビス（トリクロロメチル）カルボナート７００ｍｇ（２．３６ｍｍｏｌ）の脱水ジクロロメタン５ｍｌ溶液を－７８℃で滴下しながら加えた後、そのままの温度で０．５時間、更に室温に昇温して２時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液とジクロロメタンを－７８℃で加えた後、成り行きで室温まで昇温させながら１．５時間撹拌した。反応液を分液後、水層を酢酸エチルで２回抽出した。全有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝８５：１５～７５：２５（Ｖ／Ｖ））に付し、次いで減圧濃縮、減圧乾燥することにより、白色固体１．７５ｇを得た。
　アルゴン雰囲気下、参考例２１と同様にして合成した（Ｒ）－４－アミノ－２－メチル－４－フェニルブタン－２－オール９７．１ｍｇ（０．５４２ｍｍｏｌ）の脱水１，４－ジオキサン２ｍｌ溶液に、ＤＩＰＥＡ０．１８ｍｌ（１．０ｍｍｏｌ）、上記操作で得られた固体の一部１３０ｍｇを室温で順次加えた後、９０℃で１．５時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加えて撹拌した後、酢酸エチルで３回抽出した。全有機層を無水硫酸マグネシウムで乾燥後、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７０：３０～３０：７０（Ｖ／Ｖ））に付し、次いで減圧濃縮、減圧乾燥を行うことにより濃縮残渣を得た。
　アルゴン雰囲気下、得られた濃縮残渣のＴＨＦ２ｍｌ溶液にＮ，Ｎ－ジメチルエタン－１，２－ジアミン０．１２ｍｌ（１．１ｍｍｏｌ）を室温で加えた後、そのままの温度で２時間撹拌した。
　反応終了後、反応液に５％硫酸水素カリウム水溶液を加えて撹拌した後、酢酸エチルで３回抽出した。全有機層を無水硫酸マグネシウムで乾燥後、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝５０：５０～２５：７５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を酢酸エチルに溶解させた後、ｎ－ヘキサンを加えて析出させた固体を濾取し、ｎ－ヘキサンで洗浄してから減圧乾燥することにより、標記化合物９６ｍｇ（収率６２％［２工程］）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４９８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.35 - 11.77 (m, 1H), 9.95 - 9.67 (m, 1H), 7.36 - 7.23 (m, 4H), 7.19 - 7.11 (m, 1H), 6.58 - 6.44 (m, 1H), 4.94 - 4.84 (m, 1H), 4.64 (br s, 1H), 4.40 (br s, 2H), 2.00 - 1.88 (m, 1H), 1.65 (dd, J = 3.2, 14.2 Hz, 1H), 1.57 (br s, 3H), 1.52 (br s, 3H), 1.16 (s, 3H), 1.13 (s, 3H), 0.97 (br s, 2H), 0.98 (br s, 2H), 0.03 (s, 9H)。 Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (synthesized in the same manner as in Reference Example 38 under an argon atmosphere To a solution of 4H) -carboxylate 1.53 g (4.19 mmol) in dehydrated dichloromethane 20 ml, DIPEA 2.60 ml (14.9 mmol) was added at room temperature. Next, a solution of 700 mg (2.36 mmol) of bis (trichloromethyl) carbonate in 5 ml of dehydrated dichloromethane was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 0.5 hour, further warmed to room temperature and stirred for 2 hours. did.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added to the reaction solution at −78 ° C., and the mixture was stirred for 1.5 hours while raising the temperature to room temperature. After separating the reaction solution, the aqueous layer was extracted twice with ethyl acetate. All organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 85: 15 to 75:25 (V / V)), then concentrated under reduced pressure and dried under reduced pressure to obtain a white solid. 1.75 g was obtained.
A solution of 97.1 mg (0.542 mmol) of (R) -4-amino-2-methyl-4-phenylbutan-2-ol synthesized in the same manner as in Reference Example 21 under an argon atmosphere in 2 ml of dehydrated 1,4-dioxane. To this, 0.18 ml (1.0 mmol) of DIPEA and 130 mg of a part of the solid obtained by the above operation were sequentially added at room temperature, followed by stirring at 90 ° C. for 1.5 hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and stirred, followed by extraction three times with ethyl acetate. All organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 70: 30 to 30:70 (V / V)), and then concentrated under reduced pressure and dried under reduced pressure. Got.
Under an argon atmosphere, 0.12 ml (1.1 mmol) of N, N-dimethylethane-1,2-diamine was added to a 2 ml THF solution of the obtained concentrated residue, followed by stirring at the same temperature for 2 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture and stirred, followed by extraction with ethyl acetate three times. All organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 50: 50 to 25:75 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was dissolved in ethyl acetate, then n-hexane was added and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 96 mg of the title compound (yield 62 % [2 steps]) as a white solid.
Mass spectrum (CI, m / z): 498 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.35-11.77 (m, 1H), 9.95-9.67 (m, 1H), 7.36-7.23 (m, 4H), 7.19-7.11 (m, 1H) , 6.58-6.44 (m, 1H), 4.94-4.84 (m, 1H), 4.64 (br s, 1H), 4.40 (br s, 2H), 2.00-1.88 (m, 1H), 1.65 (dd, J = 3.2, 14.2 Hz, 1H), 1.57 (br s, 3H), 1.52 (br s, 3H), 1.16 (s, 3H), 1.13 (s, 3H), 0.97 (br s, 2H), 0.98 (br s , 2H), 0.03 (s, 9H).
（実施例８５）
Ｎ－（３－ヒドロキシ－２，２－ジメチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＩＩ－２５）
Figure JPOXMLDOC01-appb-C000122
 (Example 85)
N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c Pyrazole-5 (1H) -carboxamide (Compound No. III-25)
Figure JPOXMLDOC01-appb-C000122
　アルゴン雰囲気下、参考例３８と同様にして合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１．５３ｇ（４．１９ｍｍｏｌ）の脱水ジクロロメタン２０ｍｌ溶液に、ＤＩＰＥＡ２．６０ｍｌ（１４．９ｍｍｏｌ）を室温で加えた。次いで、ビス（トリクロロメチル）カルボナート７００ｍｇ（２．３６ｍｍｏｌ）の脱水ジクロロメタン５ｍｌ溶液を－７８℃で滴下しながら加えた後、そのままの温度で０．５時間、更に室温に昇温して２時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液とジクロロメタンを－７８℃で加えた後、成り行きで室温まで昇温させながら１．５時間撹拌した。反応液を分液後、水層を酢酸エチルで２回抽出した。全有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝８５：１５～７５：２５（Ｖ／Ｖ））に付し、次いで減圧濃縮、減圧乾燥することにより、白色固体１．７５ｇを得た。
　アルゴン雰囲気下、３－アミノ－２，２－ジメチル－３－フェニルプロパン－１－オール［Ｓｙｎｔｈｅｔｉｃ　Ｃｏｍｍｕｎｉｃａｔｉｏｎｓ　１９９４，２４（７），８９９－９０６．に記載の方法に準じて合成］１０９ｍｇ（０．６０８ｍｍｏｌ）の脱水１，４－ジオキサン２ｍｌ溶液に、ＤＩＰＥＡ０．２０ｍｌ（１．１ｍｍｏｌ）、上記操作で得られた固体の一部１４２ｍｇを室温で順次加えた後、９０℃で２．５時間撹拌した。反応液が室温になるまで放冷した後、Ｎ，Ｎ－ジメチルエタン－１，２－ジアミン０．１３ｍｌ（１．２ｍｍｏｌ）を室温で加え、そのままの温度で２時間撹拌した。
　反応終了後、反応液に５％硫酸水素カリウム水溶液を加えて撹拌した後、酢酸エチルで３回抽出した。全有機層を無水硫酸マグネシウムで乾燥後、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝６０：４０～４０：６０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を酢酸エチルに溶解させた後、ｎ－ヘキサンを加えて析出させた固体を濾取し、ｎ－ヘキサンで洗浄してから減圧乾燥することにより、標記化合物１１２ｍｇ（収率６６％［２工程］）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４９８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.40 - 11.84 (m, 1H), 10.11 - 9.58 (m, 1H), 7.37 - 7.26 (m, 4H), 7.25 - 7.18 (m, 1H), 6.85 (br d, J = 8.2 Hz, 1H), 5.53 - 5.39 (m, 1H), 4.63 (d, J = 8.2 Hz, 1H), 4.45 - 4.25 (m, 2H), 3.29 - 3.22 (m, 1H), 3.07 - 2.98 (m, 1H), 1.58 (s, 3H), 1.51 (s, 3H), 1.06 (s, 3H), 1.03 - 0.94 (m, 2H), 0.76 - 0.58 (m, 5H), 0.03 (s, 9H)。 Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (synthesized in the same manner as in Reference Example 38 under an argon atmosphere To a solution of 4H) -carboxylate 1.53 g (4.19 mmol) in dehydrated dichloromethane 20 ml, DIPEA 2.60 ml (14.9 mmol) was added at room temperature. Next, a solution of 700 mg (2.36 mmol) of bis (trichloromethyl) carbonate in 5 ml of dehydrated dichloromethane was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 0.5 hour, further warmed to room temperature and stirred for 2 hours. did.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added to the reaction solution at −78 ° C., and the mixture was stirred for 1.5 hours while raising the temperature to room temperature. After separating the reaction solution, the aqueous layer was extracted twice with ethyl acetate. All organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 85: 15 to 75:25 (V / V)), then concentrated under reduced pressure and dried under reduced pressure to obtain a white solid. 1.75 g was obtained.
Under an argon atmosphere, 3-amino-2,2-dimethyl-3-phenylpropan-1-ol [Synthetic Communications 1994, 24 (7), 899-906. Synthesis in accordance with the method described in the above] In a 2 ml solution of 109 mg (0.608 mmol) of dehydrated 1,4-dioxane, 0.20 ml (1.1 mmol) of DIPEA and 142 mg of a part of the solid obtained by the above operation were sequentially added at room temperature. After the addition, the mixture was stirred at 90 ° C. for 2.5 hours. After the reaction solution was allowed to cool to room temperature, 0.13 ml (1.2 mmol) of N, N-dimethylethane-1,2-diamine was added at room temperature and stirred at that temperature for 2 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture and stirred, followed by extraction with ethyl acetate three times. All organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 60: 40 to 40:60 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was dissolved in ethyl acetate, then n-hexane was added and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 112 mg (yield 66) % [2 steps]) as a white solid.
Mass spectrum (CI, m / z): 498 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.40-11.84 (m, 1H), 10.11-9.58 (m, 1H), 7.37-7.26 (m, 4H), 7.25-7.18 (m, 1H) , 6.85 (br d, J = 8.2 Hz, 1H), 5.53-5.39 (m, 1H), 4.63 (d, J = 8.2 Hz, 1H), 4.45-4.25 (m, 2H), 3.29-3.22 (m, 1H), 3.07-2.98 (m, 1H), 1.58 (s, 3H), 1.51 (s, 3H), 1.06 (s, 3H), 1.03-0.94 (m, 2H), 0.76-0.58 (m, 5H) , 0.03 (s, 9H).
（実施例８６）
（－）－Ｎ－（３－ヒドロキシ－２，２－ジメチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－１４２） (Example 86)
(−) — N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3, 4-c] pyrazole-5 (1H) -carboxamide (Compound No. IV-142)
　アルゴン雰囲気下、参考例７３と同様にして合成した２－エチル　５－（トリクロロメチル）　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］ピロロ［３，４－ｃ］ピラゾール－２，５（４Ｈ，６Ｈ）－ジカルボキラート５４５ｍｇ（１．１６ｍｍｏｌ）とエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート３２９ｍｇ（０．８５３ｍｍｏｌ）の混合物の脱水１，４－ジオキサン７ｍｌ溶液に、ＤＩＰＥＡ１．８０ｍｌ（１０．３ｍｍｏｌ）、３－アミノ－２，２－ジメチル－３－フェニルプロパン－１－オール［Ｓｙｎｔｈｅｔｉｃ　Ｃｏｍｍｕｎｉｃａｔｉｏｎｓ　１９９４，２４（７），８９９－９０６．に記載の方法に準じて合成］１．１６ｇ（６．４７ｍｍｏｌ）を室温で順次加えた後、９０℃で２時間撹拌した。反応液が室温になるまで放冷した後、Ｎ，Ｎ－ジメチルエタン－１，２－ジアミン０．９０ｍｌ（８．３ｍｍｏｌ）を室温で加え、そのままの温度で２．５時間撹拌した。
　反応終了後、反応液に５％硫酸水素カリウム水溶液を加えて撹拌した後、酢酸エチルで３回抽出した。全有機層を無水硫酸マグネシウムで乾燥後、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝６０：４０～４０：６０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を再度シリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；１，２－ジクロロエタン：酢酸エチル＝１００：０～８５：１５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を酢酸エチル／エタノール混合溶媒に溶解させた後、ｎ－ヘキサンを加えて析出させた固体を濾取し、ｎ－ヘキサンで洗浄してから減圧乾燥することにより、白色固体８０２ｍｇを得た。
　得られた固体の一部０．５０ｇを光学分割分取クロマトグラフィー（カラム；ＣＨＩＲＡＬＰＡＫ（商品名）ＩＤ，溶出溶媒；ｎ－ヘキサン：エタノール＝９０：１０（Ｖ／Ｖ））に付し、先に溶出する光学活性体を含む画分を減圧濃縮した。得られた濃縮残渣をアセトニトリル／水混合溶媒に溶解させた後、凍結乾燥することにより、標記化合物２２５ｍｇ（収率３５％）を白色固体として得た。
比旋光度：［α］Ｄ ２０＝－６６°（ｃ＝０．５０，メタノール）。
マススペクトル（ＣＩ，ｍ／ｚ）：５１２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.35 - 11.77 (m, 1H), 9.86 - 9.35 (m, 1H), 7.36 - 7.27 (m, 4H), 7.25 - 7.17 (m, 1H), 6.86 (br d, J = 8.2 Hz, 1H), 5.45 (br s, 1H), 4.64 (d, J = 8.2 Hz, 1H), 4.46 - 4.30 (m, 2H), 3.45 - 3.23 (m, 1H), 3.06 - 2.99 (m, 1H), 2.58 - 2.40 (m, 2H), 2.26 - 2.14 (m, 2H), 1.90 - 1.73 (m, 2H), 1.60 (s, 3H), 1.52 (s, 3H), 1.06 (s, 3H), 0.64 (s, 3H), 0.09 (s, 9H)。
ＳＦＣ（超臨界流体クロマトグラフィー）分析：
カラム；ＣＨＩＲＡＬＰＡＫ（商品名）ＩＤ　２．１×１５０ｍｍ（粒子径３ｕｍ）
溶離液；ＣＯ２／メタノール＝９０／１０（Ｖ／Ｖ）
流速；０．８５ｍｌ／ｍｉｎ
温度；４０℃
検出波長；２４０ｎｍ
保持時間；５．３分
光学純度：＞９９％ｅｅ 2-ethyl 5- (trichloromethyl) 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] pyrrolo [3,4-c] pyrazole-2 synthesized in the same manner as in Reference Example 73 under an argon atmosphere , 5 (4H, 6H) -dicarboxate 545 mg (1.16 mmol) and ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo To a solution of 329 mg (0.853 mmol) of [3,4-c] pyrazole-2 (4H) -carboxylate in 7 ml of dehydrated 1,4-dioxane, 1.80 ml (10.3 mmol) of DIPEA, 3-amino-2, 2-Dimethyl-3-phenylpropan-1-ol [Synthetic Communi cations 1994, 24 (7), 899-906. 1.16 g (6.47 mmol) was sequentially added at room temperature, followed by stirring at 90 ° C. for 2 hours. After the reaction solution was allowed to cool to room temperature, 0.90 ml (8.3 mmol) of N, N-dimethylethane-1,2-diamine was added at room temperature and stirred at that temperature for 2.5 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture and stirred, followed by extraction with ethyl acetate three times. All organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 60: 40 to 40:60 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was again subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: ethyl acetate = 100: 0 to 85:15 (V / V)) to obtain a fraction containing the desired product. Was concentrated under reduced pressure. The obtained concentrated residue was dissolved in a mixed solvent of ethyl acetate / ethanol, then added with n-hexane, and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 802 mg of a white solid. Got.
A 0.50 g portion of the obtained solid was subjected to optical resolution preparative chromatography (column; CHIRALPAK (trade name) ID, elution solvent; n-hexane: ethanol = 90: 10 (V / V)). The fraction containing the optically active substance eluted in was concentrated under reduced pressure. The obtained concentrated residue was dissolved in a mixed solvent of acetonitrile / water and lyophilized to obtain 225 mg (yield 35%) of the title compound as a white solid.
Specific rotation: [α] D 20 = −66 ° (c = 0.50, methanol).
Mass spectrum (CI, m / z): 512 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.35-11.77 (m, 1H), 9.86-9.35 (m, 1H), 7.36-7.27 (m, 4H), 7.25-7.17 (m, 1H) , 6.86 (br d, J = 8.2 Hz, 1H), 5.45 (br s, 1H), 4.64 (d, J = 8.2 Hz, 1H), 4.46-4.30 (m, 2H), 3.45-3.23 (m, 1H ), 3.06-2.99 (m, 1H), 2.58-2.40 (m, 2H), 2.26-2.14 (m, 2H), 1.90-1.73 (m, 2H), 1.60 (s, 3H), 1.52 (s, 3H ), 1.06 (s, 3H), 0.64 (s, 3H), 0.09 (s, 9H).
SFC (Supercritical Fluid Chromatography) analysis:
Column; CHIRALPAK (trade name) ID 2.1 × 150 mm (particle size 3 μm)
Eluent: CO 2 / methanol = 90/10 (V / V)
Flow rate: 0.85 ml / min
Temperature: 40 ° C
Detection wavelength: 240 nm
Retention time: 5.3 minutes Optical purity:> 99% ee
（実施例８７）
（＋）－Ｎ－（３－ヒドロキシ－２，２－ジメチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－１４１） (Example 87)
(+)-N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 4-c] pyrazole-5 (1H) -carboxamide (Compound No. IV-141)
　実施例８６の光学分割分取クロマトグラフィー操作において、後から溶出する光学活性体を含む画分を減圧濃縮した。得られた濃縮残渣をアセトニトリル／水混合溶媒に溶解させた後、凍結乾燥することにより、標記化合物２２３ｍｇ（収率３５％）を白色固体として得た。
比旋光度：［α］Ｄ ２０＝＋６０°（ｃ＝０．５０，メタノール）。
マススペクトル（ＣＩ，ｍ／ｚ）：５１２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.42 - 11.76 (m, 1H), 9.57 (br s, 1H), 7.35 - 7.27 (m, 4H), 7.25 - 7.18 (m, 1H), 6.86 (br d, J = 8.2 Hz, 1H), 5.45 (br s, 1H), 4.64 (d, J = 8.2 Hz, 1H), 4.44 - 4.30 (m, 2H), 3.44 - 3.23 (m, 1H), 3.06 - 2.98 (m, 1H), 2.59 - 2.40 (m, 2H), 2.26 - 2.14 (m, 2H), 1.89 - 1.74 (m, 2H), 1.60 (s, 3H), 1.52 (s, 3H), 1.06 (s, 3H), 0.64 (s, 3H), 0.09 (s, 9H)。
ＳＦＣ（超臨界流体クロマトグラフィー）分析：
カラム；ＣＨＩＲＡＬＰＡＫ（商品名）ＩＤ　２．１×１５０ｍｍ（粒子径３ｕｍ）
溶離液；ＣＯ２／メタノール＝９０／１０（Ｖ／Ｖ）
流速；０．８５ｍｌ／ｍｉｎ
温度；４０℃
検出波長；２４０ｎｍ
保持時間；６．５分
光学純度：＞９９％ｅｅ In the optical resolution preparative chromatography operation of Example 86, the fraction containing the optically active substance eluted later was concentrated under reduced pressure. The obtained concentrated residue was dissolved in a mixed solvent of acetonitrile / water and lyophilized to obtain 223 mg (yield 35%) of the title compound as a white solid.
Specific rotation: [α] D 20 = + 60 ° (c = 0.50, methanol).
Mass spectrum (CI, m / z): 512 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.42-11.76 (m, 1H), 9.57 (br s, 1H), 7.35-7.27 (m, 4H), 7.25-7.18 (m, 1H), 6.86 (br d, J = 8.2 Hz, 1H), 5.45 (br s, 1H), 4.64 (d, J = 8.2 Hz, 1H), 4.44-4.30 (m, 2H), 3.44-3.23 (m, 1H) , 3.06-2.98 (m, 1H), 2.59-2.40 (m, 2H), 2.26-2.14 (m, 2H), 1.89-1.74 (m, 2H), 1.60 (s, 3H), 1.52 (s, 3H) , 1.06 (s, 3H), 0.64 (s, 3H), 0.09 (s, 9H).
SFC (Supercritical Fluid Chromatography) analysis:
Column; CHIRALPAK (trade name) ID 2.1 × 150 mm (particle size 3 μm)
Eluent: CO 2 / methanol = 90/10 (V / V)
Flow rate: 0.85 ml / min
Temperature: 40 ° C
Detection wavelength: 240 nm
Retention time: 6.5 minutes Optical purity:> 99% ee
（実施例８８）
（Ｒ）－Ｎ－［５－（２－ブトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド（化合物番号ＩＶ－３５６）
Figure JPOXMLDOC01-appb-C000123
 (Example 88)
(R) -N- [5- (2-Butoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (Trimethylsilyl) cyclobutanecarboxamide (Compound No. IV-356)
Figure JPOXMLDOC01-appb-C000123
　参考例１０４と同様の方法で合成した（Ｒ）－ベンジル　２－ブトキシ－２－フェニルアセタート１．６５ｇ（５．５３ｍｍｏｌ）のメタノール８ｍｌ／水８ｍｌ溶液に、水酸化リチウム１水和物３００ｍｇ（７．１５ｍｍｏｌ）を室温で加えた後、撹拌しながら室温で３時間反応させた。
　反応終了後、反応液にジエチルエーテルを加えて分液した。水層に２Ｎ塩酸を加えてｐＨ２に調整した後、酢酸エチルで３回抽出した。得られた全有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮することにより、濃縮残渣１．３４ｇを得た。
　得られた濃縮残渣のうちの一部１５０ｍｇの脱水ジクロロメタン２ｍｌ溶液に、アルゴン雰囲気下で撹拌しながらＤＭＦ０．００６ｍｌ（０．０８ｍｍｏｌ）、塩化オキサリル０．０８３ｍｌ（０．９５ｍｍｏｌ）を０℃で加え、室温で１．５時間撹拌した。
　反応終了後、反応液を減圧濃縮して、濃縮残渣を得た。
　得られた濃縮残渣の脱水ジクロロメタン３ｍｌ溶液を、参考例４７と同様の方法で合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１５０ｍｇ（０．３９６ｍｍｏｌ）、ＤＩＰＥＡ０．３５０ｍｌ（２．００ｍｍｏｌ）の脱水ジクロロメタン溶液２ｍｌに、アルゴン雰囲気下、撹拌しながら０℃で滴下し、室温で３時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。得られた有機層を水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～７０：３０（Ｖ／Ｖ））に付し、次いで減圧濃縮を行うことにより濃縮残渣を得た。
　アルゴン雰囲気下、得られた濃縮残渣の脱水ジクロロメタン２ｍｌ溶液にＮ，Ｎ－ジメチルエタン－１，２－ジアミン０．１３０ｍｌ（１．１９ｍｍｏｌ）を室温で加えた後、室温で１６時間撹拌した。
　反応終了後、反応液に５％硫酸水素カリウム水溶液を加えて撹拌した後、ジクロロメタンで抽出した。得られた有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を分取ＨＰＬＣ（カラム；Ｘ－Ｂｒｉｄｇｅ（商品名）ＯＤＳ，溶出溶媒；アセトニトリル：１ｍＭリン酸２水素カリウム水溶液＝５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分に酢酸エチル及び水を加え、有機層と水層を分液した。得られた有機層を減圧濃縮した。得られた濃縮残渣を酢酸エチルに溶解させた後、ｎ－ヘキサンに加えて析出させた固体を濾取し、減圧乾燥することにより、標記化合物７７ｍｇ（収率３９％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４９７［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.34 - 11.89 (m, 1H), 9.56 (br s, 1H), 7.45 - 7.25 (m, 5H), 5.02 (s, 1H), 4.68 - 4.49 (m, 1H), 4.40 (br d, J = 12.7 Hz, 1H), 3.57 - 3.39 (m, 2H), 2.59 - 2.35 (m, 2H), 2.24 - 2.09 (m, 2H), 1.87 - 1.73 (m, 2H), 1.68 (s, 3H), 1.61 (s, 3H), 1.56 - 1.45 (m, 2H), 1.40 - 1.28 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H), 0.05 (s, 9H)。 To a solution of (R) -benzyl 2-butoxy-2-phenylacetate 1.65 g (5.53 mmol) synthesized in the same manner as in Reference Example 104 in methanol 8 ml / water 8 ml, lithium hydroxide monohydrate 300 mg ( 7.15 mmol) was added at room temperature, and the mixture was reacted at room temperature for 3 hours with stirring.
After completion of the reaction, diethyl ether was added to the reaction solution for liquid separation. The aqueous layer was adjusted to pH 2 by adding 2N hydrochloric acid, and extracted three times with ethyl acetate. The obtained all organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 1.34 g of a concentrated residue.
DMF 0.006 ml (0.08 mmol) and oxalyl chloride 0.083 ml (0.95 mmol) were added at 0 ° C. while stirring under an argon atmosphere to a 150 ml portion of a dehydrated dichloromethane solution of 150 mg of the resulting concentrated residue. Stir at room temperature for 1.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentrated residue.
A solution of the obtained concentrated residue in 3 ml of dehydrated dichloromethane was synthesized in the same manner as in Reference Example 47 using ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3, 4-c] pyrazole-2 (4H) -carboxylate (150 mg, 0.396 mmol) and DIPEA (0.350 ml, 2.00 mmol) in 2 ml of dehydrated dichloromethane was added dropwise at 0 ° C. with stirring in an argon atmosphere at room temperature. Stir for 3 hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 70:30 (V / V)), and then concentrated under reduced pressure to give a concentrated residue. Got.
Under an argon atmosphere, 0.130 ml (1.19 mmol) of N, N-dimethylethane-1,2-diamine was added at room temperature to a solution of the resulting concentrated residue in 2 ml of dehydrated dichloromethane, followed by stirring at room temperature for 16 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture and stirred, followed by extraction with dichloromethane. The obtained organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 50:50 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was subjected to preparative HPLC (column; X-Bridge (trade name) ODS, elution solvent: acetonitrile: 1 mM aqueous potassium dihydrogen phosphate solution = 50: 50 (V / V)), and the target product was obtained. Ethyl acetate and water were added to the contained fraction, and the organic layer and the aqueous layer were separated. The obtained organic layer was concentrated under reduced pressure. The obtained concentrated residue was dissolved in ethyl acetate, and then the resulting solid added to n-hexane was collected by filtration and dried under reduced pressure to obtain 77 mg (yield 39%) of the title compound as a white solid. .
Mass spectrum (CI, m / z): 497 [M + 1] + .
1 H-NMR spectrum (400MHz, DMSO-d 6) δ: 12.34 - 11.89 (m, 1H), 9.56 (br s, 1H), 7.45 - 7.25 (m, 5H), 5.02 (s, 1H), 4.68 - 4.49 (m, 1H), 4.40 (br d, J = 12.7 Hz, 1H), 3.57-3.39 (m, 2H), 2.59-2.35 (m, 2H), 2.24-2.09 (m, 2H), 1.87-1.73 (m, 2H), 1.68 (s, 3H), 1.61 (s, 3H), 1.56-1.45 (m, 2H), 1.40-1.28 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H), 0.05 (s, 9H).
（実施例８９）
Ｎ－（３－メトキシ－２，２－ジメチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド（化合物番号ＩＶ－１４５）
Figure JPOXMLDOC01-appb-C000124
 Example 89
N- (3-methoxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide (Compound No. IV-145)
Figure JPOXMLDOC01-appb-C000124
　参考例１０８と同様にして合成したエチル　５－［（３－メトキシ－２，２－ジメチル－１－フェニルプロピル）カルバモイル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１３１ｍｇ（０．２１９ｍｍｏｌ）のジクロロメタン３ｍｌ溶液に、アルゴン気流下撹拌しながらＮ，Ｎ－ジメチルエタン－１，２－ジアミン０．０９５ｍｌ（０．８７ｍｏｌ）を室温で一度に加え、室温で１時間撹拌した。
　反応終了後、反応液に５％硫酸水素カリウム水溶液を加え、その混合液から酢酸エチルで２回抽出した。有機層は５％硫酸水素カリウム水溶液で洗浄、無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７０：３０～１３：８７（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を少量の酢酸エチルに溶解させ、ｎ－ヘキサンを加えることで固体を析出させた。固体を濾取、ｎ－ヘキサンで洗浄、５０℃で減圧乾燥することで、標記化合物６２ｍｇ（収率５４％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５２６［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.21 & 11.76 (br s, total 1H), 9.58 (br s, 1H), 7.38 - 7.18 (m, 5H), 6.75 - 6.52 (m, 1H), 4.59 (d, J = 7.7 Hz, 1H), 4.52 - 4.30 (m, 2H), 3.38 (s, 3H), 3.13 (d, J = 9.3 Hz, 1H), 2.92 (d, J = 9.3 Hz, 1H), 2.58 - 2.40 (m, 2H), 2.29 - 2.12 (m, 2H), 1.91 - 1.74 (m, 2H), 1.59 (br s, 3H), 1.50 (s, 3H), 1.12 (s, 3H), 0.68 (s, 3H), 0.09 (s, 9H)。 Ethyl 5-[(3-methoxy-2,2-dimethyl-1-phenylpropyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide]-synthesized in the same manner as in Reference Example 108 To a solution of 131 mg (0.219 mmol) of 5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate in 3 ml of dichloromethane, N, N-dimethylethane-1,2, while stirring under a stream of argon. -0.095 ml (0.87 mol) of diamine was added at once at room temperature and stirred for 1 hour at room temperature.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with 5% aqueous potassium hydrogen sulfate solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30 to 13:87 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. did. The obtained concentrated residue was dissolved in a small amount of ethyl acetate, and n-hexane was added to precipitate a solid. The solid was collected by filtration, washed with n-hexane, and dried under reduced pressure at 50 ° C. to obtain 62 mg (yield 54%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 526 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.21 & 11.76 (br s, total 1H), 9.58 (br s, 1H), 7.38-7.18 (m, 5H), 6.75-6.52 (m, 1H ), 4.59 (d, J = 7.7 Hz, 1H), 4.52-4.30 (m, 2H), 3.38 (s, 3H), 3.13 (d, J = 9.3 Hz, 1H), 2.92 (d, J = 9.3 Hz , 1H), 2.58-2.40 (m, 2H), 2.29-2.12 (m, 2H), 1.91-1.74 (m, 2H), 1.59 (br s, 3H), 1.50 (s, 3H), 1.12 (s, 3H), 0.68 (s, 3H), 0.09 (s, 9H).
（参考例１）
１－（トリメチルシリル）シクロブタンカルボン酸
Figure JPOXMLDOC01-appb-C000125
 (Reference Example 1)
1- (Trimethylsilyl) cyclobutanecarboxylic acid
Figure JPOXMLDOC01-appb-C000125
　アルゴン雰囲気下、脱水ＴＨＦ２００ｍｌに２Ｍリチウムジイソプロピルアミド／ＴＨＦ溶液２１４ｍｌ（４２８ｍｍｏｌ）を加えた後、氷水冷却下で撹拌しながら、シクロブタンカルボン酸１０．１ｍｌ（１０７ｍｍｏｌ）を滴下し、成り行きで室温まで昇温させながら４時間撹拌した。次いで、ヘキサメチルリン酸トリアミド２０ｍｌ（１１６ｍｍｏｌ）を加え、ドライアイス／アセトン冷媒冷却下、内温－６０℃以下を保ちながらクロロトリメチルシラン５１ｍｌ（４９０ｍｍｏｌ）を撹拌下に滴下した後、－７８℃で１６．５時間撹拌した。
　反応終了後、反応液にメタノール６７ｍｌを加え、０℃まで昇温した後、冷水１３４ｍｌを加えた。２Ｎ塩酸を加えｐＨ２．１に調整し、ジエチルエーテル２６８ｍｌを加えて分液し、有機層を飽和塩化ナトリウム水溶液２６８ｍｌで洗浄した。有機層を無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮した。得られた濃縮残渣に２Ｎ水酸化ナトリウム水溶液５０ｍｌ、ｎ－ヘキサン２６７ｍｌを加えて分液した。次いで水層に１Ｎ塩酸を加えｐＨ２．７に調整し、この溶液に酢酸エチル２６７ｍｌを加えて分液した。得られた有機層を無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮した。得られた濃縮残渣にｎ－ヘキサンを加え、氷水浴中で冷却した。生じた固体を濾過し、冷却したｎ－ヘキサンで掛け洗い後、減圧乾燥することにより標記化合物６．２４ｇ（収率３４％）を白色固体として得た。さらに、濾液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～９５：５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物４．３３ｇ（収率２３％）を白色固体として取得した。
マススペクトル（ＣＩ，ｍ／ｚ）：１７３［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：11.64 (br s, 1H), 2.45 - 2.34 (m, 2H), 2.17 - 2.06 (m, 2H), 1.91 -1.70 (m, 2H), 0.06 (s, 9H)。 Under an argon atmosphere, 214 ml (428 mmol) of a 2M lithium diisopropylamide / THF solution was added to 200 ml of dehydrated THF, and then 10.1 ml (107 mmol) of cyclobutanecarboxylic acid was added dropwise while stirring under ice-water cooling. The mixture was stirred for 4 hours. Next, 20 ml (116 mmol) of hexamethylphosphoric triamide was added, and 51 ml (490 mmol) of chlorotrimethylsilane was added dropwise with stirring under cooling with a dry ice / acetone refrigerant while maintaining the internal temperature at −60 ° C. or lower. Stir for 16.5 hours.
After completion of the reaction, 67 ml of methanol was added to the reaction solution, the temperature was raised to 0 ° C., and 134 ml of cold water was added. 2N hydrochloric acid was added to adjust to pH 2.1, 268 ml of diethyl ether was added for liquid separation, and the organic layer was washed with 268 ml of a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. To the obtained concentrated residue, 50 ml of 2N aqueous sodium hydroxide solution and 267 ml of n-hexane were added for liquid separation. Next, 1N hydrochloric acid was added to the aqueous layer to adjust to pH 2.7, and 267 ml of ethyl acetate was added to the solution to separate the layers. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. N-Hexane was added to the resulting concentrated residue and cooled in an ice-water bath. The resulting solid was filtered, washed with cooled n-hexane and dried under reduced pressure to obtain 6.24 g (yield 34%) of the title compound as a white solid. Further, the filtrate is concentrated under reduced pressure, and the obtained residue is subjected to silica gel column chromatography (elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 95: 5 (V / V)) to contain the desired product. The fraction was concentrated under reduced pressure and dried under reduced pressure to obtain 4.33 g (yield 23%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 173 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 11.64 (br s, 1H), 2.45-2.34 (m, 2H), 2.17-2.06 (m, 2H), 1.91 -1.70 (m, 2H), 0.06 (s, 9H).
（参考例２）
５－ｔｅｒｔ－ブチル　２－エチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］ピロロ［３，４－ｃ］ピラゾール－２，５（４Ｈ，６Ｈ）－ジカルボキシラート
Figure JPOXMLDOC01-appb-C000126
 (Reference Example 2)
5-tert-butyl 2-ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] pyrrolo [3,4-c] pyrazole-2,5 (4H, 6H) -dicarboxylate
Figure JPOXMLDOC01-appb-C000126
　参考例１と同様にして合成した１－（トリメチルシリル）シクロブタンカルボン酸１３．９ｇ（８０．４ｍｍｏｌ）の脱水ジクロロメタン１０５ｍｌ溶液に、アルゴン雰囲気下で塩化オキサリル６．９６ｍｌ（８１．２ｍｍｏｌ）、ＤＭＦ０．３２ｍｌ（４．１４ｍｍｏｌ）を－２５℃～－１０℃の間で順次滴下し、その後０℃に昇温して２時間撹拌した。本反応液を、５－ｔｅｒｔ－ブチル　２－エチル　３－アミノ－６，６－ジメチルピロロ［３，４－ｃ］ピラゾール－２，５（４Ｈ，６Ｈ）－ジカルボキシラート［Ｊｏｕｒｎａｌ　ｏｆ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ　２０１２，５５（１０），４７２８－４７３９．に記載の方法に準じて合成］８．７４ｇ（２６．９ｍｍｏｌ）、及びＤＩＰＥＡ２３．５ｍｌ（１３５ｍｍｏｌ）の脱水ジクロロメタン１２２ｍｌ溶液中に、アルゴン雰囲気下、０℃で滴下し、同温度で１６時間撹拌した。
　反応終了後、反応液に５％硫酸水素カリウム水溶液４８６ｍｌを加えて分液した後、水層をジクロロメタン２００ｍｌで２回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝８６：１４～５３：４７（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物８．３０ｇ（収率６４％）を白色泡状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４７９［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：9.98 & 9.72 & 9.71 (s, total 1H), 4.50 - 4.37 (m, 4H), 2.53- 2.43 (m, 2H), 2.32 - 2.07 (m, 2H), 2.02 - 1.72 (m, 2H), 1.65 - 1.55 (m, 6H), 1.51 - 1.42 (m, 9H), 1.38 - 1.31 (m, 3H), 0.10 & 0.06 & 0.01 (s, total 9H)。 To a solution of 13.9 g (80.4 mmol) of 1- (trimethylsilyl) cyclobutanecarboxylic acid synthesized in the same manner as in Reference Example 1 in 105 ml of dehydrated dichloromethane, 6.96 ml (81.2 mmol) of oxalyl chloride and 0.32 ml of DMF in an argon atmosphere. (4.14 mmol) was sequentially added dropwise between −25 ° C. and −10 ° C., then the temperature was raised to 0 ° C. and stirred for 2 hours. This reaction solution was mixed with 5-tert-butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo [3,4-c] pyrazole-2,5 (4H, 6H) -dicarboxylate [Journal of Medicinal Chemistry 2012. , 55 (10), 4728-4739. According to the method described in the above, it was added dropwise to a solution of 8.74 g (26.9 mmol) and 23.5 ml (135 mmol) of DIPEA in 122 ml of dehydrated dichloromethane at 0 ° C. in an argon atmosphere and stirred at the same temperature for 16 hours. .
After completion of the reaction, 486 ml of 5% aqueous potassium hydrogen sulfate solution was added to the reaction solution for liquid separation, and the aqueous layer was extracted twice with 200 ml of dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 86: 14 to 53:47 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure. As a result, 8.30 g (yield 64%) of the title compound was obtained as a white foam.
Mass spectrum (CI, m / z): 479 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 9.98 & 9.72 & 9.71 (s, total 1H), 4.50-4.37 (m, 4H), 2.53- 2.43 (m, 2H), 2.32-2.07 (m , 2H), 2.02-1.72 (m, 2H), 1.65-1.55 (m, 6H), 1.51-1.42 (m, 9H), 1.38-1.31 (m, 3H), 0.10 & 0.06 & 0.01 (s, total 9H ).
（参考例３）
エチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート
Figure JPOXMLDOC01-appb-C000127
 (Reference Example 3)
Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate
Figure JPOXMLDOC01-appb-C000127
　参考例２と同様にして合成した５－ｔｅｒｔ－ブチル　２－エチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］ピロロ［３，４－ｃ］ピラゾール－２，５（４Ｈ，６Ｈ）－ジカルボキシラート８．３０ｇ（１７．３ｍｍｏｌ）の脱水ジクロロメタン８１ｍｌ溶液に、アルゴン雰囲気下、２，６－ルチジン６．０ｍｌ（５２ｍｍｏｌ）、トリメチルシリル　トリフルオロメタンスルホナート９．２ｍｌ（５１ｍｍｏｌ）を０℃で順次滴下し、同温度で２時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液６４ｍｌ、ジクロロメタン６４ｍｌを加えた後、分液した。水層をジクロロメタン７２ｍｌで２回抽出した後、得られた全有機層を飽和炭酸水素ナトリウム水溶液７２ｍｌ、飽和塩化ナトリウム水溶液７２ｍｌで順次洗浄し、次いで無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣に、トルエン５ｍｌを加え減圧濃縮する操作を５回繰り返し、粗エチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラートを得た。
　得られた粗エチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート６．７０ｇの脱水ジクロロメタン２３５ｍｌ溶液に、アルゴン雰囲気下、ＤＩＰＥＡ８．８ｍｌ（５１ｍｍｏｌ）を室温で加えた後、ビス（トリクロロメチル）カルボナート３．７９ｇ（１２．８ｍｍｏｌ）の脱水ジクロロメタン３８ｍｌ溶液を－７８℃で滴下し、同温度で３時間撹拌した。この際、反応開始後１時間、２時間、２．６時間の各時点でＤＩＰＥＡ１．０ｍｌ（５．７ｍｍｏｌ）を追加した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液１５０ｍｌを加え、成り行きで室温まで昇温させながら撹拌した。分液後、水層をジクロロメタン１３０ｍｌで２回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７８：２２～５７：４３（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣にｎ－ヘキサンを加え、超音波処理した。冷蔵庫で冷却した後、析出した固体を濾過、減圧乾燥することにより、標記化合物３．５１ｇ（収率４６％［２工程］）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４４１［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：9.83 - 9.65 (m, 1H), 4.84 (s, 2H), 4.49 -4.37 (m, 2H), 2.54 - 2.43 (m, 2H), 2.31 - 2.21 (m, 2H), 1.95 - 1.83 (m, 2H), 1.71 - 1.58 (m, 6H), 1.35 (t, J= 7.1 Hz, 3H), 0.13 - 0.08 (m, 9H)。 5-tert-butyl 2-ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] pyrrolo [3,4-c] pyrazole-2,5 (4H, synthesized in the same manner as in Reference Example 2 6H) -Dicarboxylate 8.30 g (17.3 mmol) in 81 ml of dehydrated dichloromethane was charged with 6.0 ml (52 mmol) of 2,6-lutidine and 9.2 ml (51 mmol) of trimethylsilyl trifluoromethanesulfonate in an argon atmosphere. The solution was successively added dropwise at 0 ° C. and stirred at the same temperature for 2 hours.
After completion of the reaction, 64 ml of a saturated aqueous sodium hydrogen carbonate solution and 64 ml of dichloromethane were added to the reaction solution, followed by liquid separation. After the aqueous layer was extracted twice with 72 ml of dichloromethane, the obtained all organic layer was washed successively with 72 ml of saturated aqueous sodium hydrogen carbonate solution and 72 ml of saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. . The operation of adding 5 ml of toluene to the obtained concentrated residue and concentrating under reduced pressure was repeated five times to obtain crude ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4]. -C] Pyrazole-2 (4H) -carboxylate was obtained.
Dehydration of the resulting crude ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate 6.70 g To a 235 ml dichloromethane solution, 8.8 ml (51 mmol) of DIPEA was added at room temperature under an argon atmosphere, and then a 38 ml dehydrated dichloromethane solution of 3.79 g (12.8 mmol) of bis (trichloromethyl) carbonate was added dropwise at −78 ° C. Stir at temperature for 3 hours. At this time, 1.0 ml (5.7 mmol) of DIPEA was added at each time point of 1 hour, 2 hours, and 2.6 hours after the start of the reaction.
After completion of the reaction, 150 ml of saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the resulting mixture was stirred while warming to room temperature. After separation, the aqueous layer was extracted twice with 130 ml of dichloromethane. The obtained all organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 78: 22 to 57:43 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. N-Hexane was added to the resulting concentrated residue and sonicated. After cooling in the refrigerator, the precipitated solid was filtered and dried under reduced pressure to obtain 3.51 g (yield 46% [2 steps]) of the title compound as a white solid.
Mass spectrum (CI, m / z): 441 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 9.83-9.65 (m, 1H), 4.84 (s, 2H), 4.49 -4.37 (m, 2H), 2.54-2.43 (m, 2H), 2.31 -2.21 (m, 2H), 1.95-1.83 (m, 2H), 1.71-1.58 (m, 6H), 1.35 (t, J = 7.1 Hz, 3H), 0.13-0.08 (m, 9H).
（参考例４）
５－ｔｅｒｔ－ブチル　１－エチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］ピロロ［３，４－ｃ］ピラゾール－１，５（４Ｈ，６Ｈ）－ジカルボキシラート
Figure JPOXMLDOC01-appb-C000128
 (Reference Example 4)
5-tert-butyl 1-ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] pyrrolo [3,4-c] pyrazole-1,5 (4H, 6H) -dicarboxylate
Figure JPOXMLDOC01-appb-C000128
　参考例１と同様にして合成した１－（トリメチルシリル）シクロブタンカルボン酸２４．５２ｇ（１４２ｍｍｏｌ）の脱水ジクロロメタン１８０ｍｌ溶液に、アルゴン雰囲気下、ＤＭＦ０．５５ｍｌ（７．１ｍｍｏｌ）、塩化オキサリル１２．２ｍｌ（１４２ｍｍｏｌ）を０℃で滴下し、同温度で２時間撹拌した。
　反応終了後、反応液を減圧濃縮（湯浴温度：３０℃）して、濃縮残渣を得た。
　得られた濃縮残渣の脱水ジクロロメタン１２０ｍｌ溶液を、アルゴン雰囲気下、５－ｔｅｒｔ－ブチル　１－エチル　３－アミノ－６，６－ジメチルピロロ［３，４－ｃ］ピラゾール－１，５（４Ｈ，６Ｈ）－ジカルボキシラート［Ｊｏｕｒｎａｌ　ｏｆ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ　２０１２，５５（１０），４７２８－４７３９．に記載の方法に準じて合成］１５．３９ｇ（４７．４ｍｍｏｌ）、ＤＩＰＥＡ４０．６ｍｌ（２３８ｍｍｏｌ）の脱水ジクロロメタン１８０ｍｌ溶液中に０℃で滴下し、同温度で２０時間撹拌した。
　反応終了後、反応溶を５％硫酸水素カリウム水溶液８００ｍｌに注加し、撹拌した後、分液した。水層をジクロロメタン２５０ｍｌで２回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９１：９～７０：３０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１４．６ｇ（収率６４％）を白色泡状物として得た。
マススペクトル（ＥＩ，ｍ／ｚ）：４７８［Ｍ］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：10.32 - 10.20 (m, 1H), 4.46 - 4.32 (m, 4H), 2.48- 2.39 (m, 2H), 2.24 - 2.14 (m, 2H), 1.84 - 1.68 (m, 8H), 1.52 - 1.40 (m, 9H),1.32 (t, J = 7.1 Hz, 3H), 0.07 (s, 9H)。 To a 180 ml solution of dehydrated dichloromethane of 24.52 g (142 mmol) of 1- (trimethylsilyl) cyclobutanecarboxylic acid synthesized in the same manner as in Reference Example 1, 0.55 ml (7.1 mmol) of DMF and 12.2 ml (142 mmol) of oxalyl chloride under an argon atmosphere. ) Was added dropwise at 0 ° C. and stirred at the same temperature for 2 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure (hot water bath temperature: 30 ° C.) to obtain a concentrated residue.
A solution of the obtained concentrated residue in 120 ml of dehydrated dichloromethane was added to 5-tert-butyl 1-ethyl 3-amino-6,6-dimethylpyrrolo [3,4-c] pyrazole-1,5 (4H, 6H) under an argon atmosphere. ) -Dicarboxylate [Journal of Medicinal Chemistry 2012, 55 (10), 4728-4739. According to the method described in the above], it was added dropwise to a solution of 15.39 g (47.4 mmol) and 40.6 ml (238 mmol) of DIPEA in 180 ml of dehydrated dichloromethane at 0 ° C. and stirred at the same temperature for 20 hours.
After completion of the reaction, the reaction solution was poured into 800 ml of 5% aqueous potassium hydrogen sulfate solution, stirred and then separated. The aqueous layer was extracted twice with 250 ml of dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 91: 9 to 70:30 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure. As a result, 14.6 g (yield 64%) of the title compound was obtained as a white foam.
Mass spectrum (EI, m / z): 478 [M] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 10.32-10.20 (m, 1H), 4.46-4.32 (m, 4H), 2.48-2.39 (m, 2H), 2.24-2.14 (m, 2H) , 1.84-1.68 (m, 8H), 1.52-1.40 (m, 9H), 1.32 (t, J = 7.1 Hz, 3H), 0.07 (s, 9H).
（参考例５）
エチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－１（４Ｈ）－カルボキシラート
Figure JPOXMLDOC01-appb-C000129
 (Reference Example 5)
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-1 (4H) -carboxylate
Figure JPOXMLDOC01-appb-C000129
　参考例４と同様にして合成した５－ｔｅｒｔ－ブチル　１－エチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］ピロロ［３，４－ｃ］ピラゾール－１，５（４Ｈ，６Ｈ）－ジカルボキシラート１０．０２ｇ（２０．９ｍｍｏｌ）の脱水ジクロロメタン１００ｍｌ溶液に、アルゴン雰囲気下、２，６－ルチジン７．２６ｍｌ（６２．７ｍｍｏｌ）、トリメチルシリル　トリフルオロメタンスルホナート１１．３ｍｌ（６２．７ｍｍｏｌ）を０℃で滴下し、同温度で１．５時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液６０ｍｌ、ジクロロメタン６０ｍｌを加えた。分液した後、水層をジクロロメタン６０ｍｌで２回抽出した。得られた全有機層を飽和炭酸水素ナトリウム水溶液６０ｍｌ、飽和塩化ナトリウム水溶液６０ｍｌで順次洗浄した後、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣にトルエンを加え、それを減圧濃縮する操作を３回繰り返すことにより、標記化合物７．４３ｇ（収率９４％）を淡黄色固体として得た。
マススペクトル（ＥＩ，ｍ／ｚ）：３７８［Ｍ］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：10.03 (s, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.85 (s, 2H), 2.48 - 2.38(m, 2H), 2.23 - 2.12 (m, 2H), 1.85 - 1.72 (m, 2H), 1.41 (s, 6H), 1.31 (t, J = 7.1Hz, 3H), 0.06 (s, 9H)。 5-tert-butyl 1-ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] pyrrolo [3,4-c] pyrazole-1,5 (4H, synthesized in the same manner as in Reference Example 4 6H) -dicarboxylate in a solution of 10.02 g (20.9 mmol) in 100 ml of dehydrated dichloromethane under an argon atmosphere, 7.26 ml (62.7 mmol) of 2,6-lutidine, 11.3 ml of trimethylsilyl trifluoromethanesulfonate (62. 7 mmol) was added dropwise at 0 ° C., and the mixture was stirred at the same temperature for 1.5 hours.
After completion of the reaction, 60 ml of saturated aqueous sodium hydrogen carbonate solution and 60 ml of dichloromethane were added to the reaction solution. After liquid separation, the aqueous layer was extracted twice with 60 ml of dichloromethane. The obtained all organic layer was washed successively with 60 ml of saturated aqueous sodium hydrogen carbonate solution and 60 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Toluene was added to the obtained concentrated residue and the operation of concentrating it under reduced pressure was repeated three times to obtain 7.43 g (yield 94%) of the title compound as a pale yellow solid.
Mass spectrum (EI, m / z): 378 [M] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 10.03 (s, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.85 (s, 2H), 2.48-2.38 (m, 2H), 2.23-2.12 (m, 2H), 1.85-1.72 (m, 2H), 1.41 (s, 6H), 1.31 (t, J = 7.1Hz, 3H), 0.06 (s, 9H).
（参考例６）
５－ｔｅｒｔ－ブチル　２－エチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］ピロロ［３，４－ｃ］ピラゾール－２，５（４Ｈ，６Ｈ）－ジカルボキシラート
Figure JPOXMLDOC01-appb-C000130
 (Reference Example 6)
5-tert-butyl 2-ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] pyrrolo [3,4-c] pyrazole-2,5 (4H, 6H) -dicarboxylate
Figure JPOXMLDOC01-appb-C000130
　１－（トリメチルシリル）シクロプロパンカルボン酸［Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９８２，４７（５），８９３－８９５．に記載の方法に準じて合成］１．０５ｇ（６．６３ｍｍｏｌ）の脱水ジクロロメタン２０ｍｌ溶液に、窒素雰囲気下で、塩化オキサリル０．７０ｍｌ（８．２ｍｍｏｌ）、ＤＭＦ０．０２０ｍｌ（０．２６ｍｍｏｌ）を０℃で加え、同温度で３時間撹拌した。
　反応終了後、反応液を減圧濃縮（湯浴温度：２５℃）して、濃縮残渣を得た。
　得られた濃縮残渣の脱水ジクロロメタン１５ｍｌ溶液に、窒素雰囲気下で、ＤＩＰＥＡ１．８０ｍｌ（１０．３ｍｍｏｌ）、５－ｔｅｒｔ－ブチル　２－エチル　３－アミノ－６，６－ジメチルピロロ［３，４－ｃ］ピラゾール－２，５（４Ｈ，６Ｈ）－ジカルボキシラート［Ｊｏｕｒｎａｌ　ｏｆ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ　２０１２，５５（１０），４７２８－４７３９．に記載の方法に準じて合成］８３９ｍｇ（２．５９ｍｍｏｌ）を０℃で加え、同温度で２０．５時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで２回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９０：１０～７５：２５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１．１９ｇ（不純物を含む）を微黄色泡状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４６５［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：10.09 & 9.92 (s, total 1H), 4.70 - 4.46 (m, 4H), 1.72 (s,3H), 1.65 (s, 3H), 1.54 - 1.44 (m, 12H), 1.15 - 1.07 (m, 2H), 0.84 - 0.78 (m,2H), 0.17 - 0.07 (m, 9H)。 1- (Trimethylsilyl) cyclopropanecarboxylic acid [J. Org. Chem. 1982, 47 (5), 893-895. In a nitrogen atmosphere, 0.70 ml (8.2 mmol) of oxalyl chloride and 0.020 ml (0.26 mmol) of DMF were added to a solution of 1.05 g (6.63 mmol) in 20 ml of dehydrated dichloromethane. The mixture was added at ° C and stirred at the same temperature for 3 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure (hot water bath temperature: 25 ° C.) to obtain a concentrated residue.
To a 15 ml solution of the obtained concentrated residue in dehydrated dichloromethane, under a nitrogen atmosphere, 1.80 ml (10.3 mmol) of DIPEA, 5-tert-butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo [3,4-c Pyrazole-2,5 (4H, 6H) -dicarboxylate [Journal of Medicinal Chemistry 2012, 55 (10), 4728-4739. Synthesis according to the method described in 1) 839 mg (2.59 mmol) was added at 0 ° C. and the mixture was stirred at the same temperature for 20.5 hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 75:25 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure. As a result, 1.19 g (including impurities) of the title compound was obtained as a slightly yellow foam.
Mass spectrum (CI, m / z): 465 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 10.09 & 9.92 (s, total 1H), 4.70-4.46 (m, 4H), 1.72 (s, 3H), 1.65 (s, 3H), 1.54-1.44 ( m, 12H), 1.15-1.07 (m, 2H), 0.84-0.78 (m, 2H), 0.17-0.07 (m, 9H).
（参考例７）
エチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート　塩酸塩
Figure JPOXMLDOC01-appb-C000131
 (Reference Example 7)
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate hydrochloride
Figure JPOXMLDOC01-appb-C000131
　参考例６と同様にして合成した５－ｔｅｒｔ－ブチル　２－エチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］ピロロ［３，４－ｃ］ピラゾール－２，５（４Ｈ，６Ｈ）－ジカルボキシラート１．１９ｇ（不純物を含む）の酢酸エチル２０ｍｌ溶液に、窒素雰囲気下で、４Ｎ塩化水素／酢酸エチル４．０ｍｌ（１６ｍｍｏｌ）を室温で加え、同温度で６．５時間撹拌した。その後、４Ｎ塩化水素／酢酸エチル２．０ｍｌ（８．０ｍｍｏｌ）を追加し、室温で更に１４．５時間撹拌した。
　反応終了後、反応液を減圧濃縮し、得られた濃縮残渣をジイソプロピルエーテルに懸濁させ、室温で撹拌した。不溶物を濾取し、取得した固体をジイソプロピルエーテルで掛け洗いした後、減圧乾燥することにより、標記化合物０．９１ｇ（収率８８％［２工程］）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：３６５［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：9.99 (br s, 2H), 9.91 (s, 1H), 4.51 - 4.39 (m, 4H), 1.63 (s, 6H), 1.35 (t, J = 7.2Hz, 3H), 1.08 (dd, J = 4.2, 6.0 Hz, 2H), 0.87 (dd, J = 4.2,6.0 Hz, 2H), 0.08 (s, 9H)。 5-tert-butyl 2-ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] pyrrolo [3,4-c] pyrazole-2,5 (4H) synthesized in the same manner as in Reference Example 6. , 6H) -dicarboxylate in a solution of 1.19 g (including impurities) in 20 ml of ethyl acetate under a nitrogen atmosphere was added 4.0 N (16 mmol) of 4N hydrogen chloride / ethyl acetate at room temperature, and 6.5 ml at the same temperature. Stir for hours. Thereafter, 4 ml of 4N hydrogen chloride / ethyl acetate (8.0 mmol) was added, and the mixture was further stirred at room temperature for 14.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting concentrated residue was suspended in diisopropyl ether and stirred at room temperature. Insoluble matter was collected by filtration, and the obtained solid was washed with diisopropyl ether and dried under reduced pressure to obtain 0.91 g (yield 88% [2 steps]) of the title compound as a white solid.
Mass spectrum (CI, m / z): 365 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 9.99 (br s, 2H), 9.91 (s, 1H), 4.51-4.39 (m, 4H), 1.63 (s, 6H), 1.35 (t, J = 7.2 Hz, 3H), 1.08 (dd, J = 4.2, 6.0 Hz, 2H), 0.87 (dd, J = 4.2, 6.0 Hz, 2H), 0.08 (s, 9H).
（参考例８）
２－メチル－２－（トリメチルシリル）プロパン酸
Figure JPOXMLDOC01-appb-C000132
 (Reference Example 8)
2-Methyl-2- (trimethylsilyl) propanoic acid
Figure JPOXMLDOC01-appb-C000132
　アルゴン雰囲気下で脱水ＴＨＦ１００ｍｌに２Ｍリチウムジイソプロピルアミド／ＴＨＦ溶液２００ｍｌ（４００ｍｍｏｌ）を加え、次いでイソブタン酸４．７ｍｌ（５１ｍｍｏｌ）を０℃で滴下した後、室温で４時間撹拌した。ヘキサメチルリン酸トリアミド１０ｍｌ（５８ｍｍｏｌ）を加えた後、クロロトリメチルシラン２９ｍｌ（２３０ｍｍｏｌ）を－７８℃で滴下し、室温まで徐々に昇温させながら２４時間撹拌した。
　反応終了後、反応液にメタノール２５ｍｌ、水５０ｍｌを加えた。次いで、２Ｎ塩酸を加えて溶液を酸性にした後、ジエチルエーテルで抽出した。得られた全有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣を２Ｎ水酸化ナトリウム水溶液に溶解させ、酢酸エチルで洗浄した。分液した後、水層に１Ｎ塩酸を加えて酸性とし、酢酸エチルで抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。得られた濃縮残渣をｎ－ヘキサンに懸濁させ、超音波処理した後、不溶物を濾取した。濾液は減圧濃縮し、得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～９９：１（Ｖ／Ｖ））に付し、目的物を含む画分及び前述の濾取した固体を合わせて減圧濃縮、減圧乾燥することにより、標記化合物２．６６ｇ（収率３２％）を白色固体として取得した。
 マススペクトル（ＣＩ，ｍ／ｚ）：１６１［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：1.22 (s, 6H), 0.08 (s, 9H)。 Under an argon atmosphere, 200 ml (400 mmol) of a 2M lithium diisopropylamide / THF solution was added to 100 ml of dehydrated THF, and then 4.7 ml (51 mmol) of isobutanoic acid was added dropwise at 0 ° C., followed by stirring at room temperature for 4 hours. After adding 10 ml (58 mmol) of hexamethylphosphoric triamide, 29 ml (230 mmol) of chlorotrimethylsilane was added dropwise at −78 ° C., and the mixture was stirred for 24 hours while gradually warming to room temperature.
After completion of the reaction, 25 ml of methanol and 50 ml of water were added to the reaction solution. Next, 2N hydrochloric acid was added to acidify the solution, and the mixture was extracted with diethyl ether. The obtained all organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was dissolved in 2N aqueous sodium hydroxide solution and washed with ethyl acetate. After liquid separation, the aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was suspended in n-hexane and subjected to ultrasonic treatment, and then insoluble matters were collected by filtration. The filtrate was concentrated under reduced pressure, and the resulting concentrated residue was subjected to silica gel column chromatography (elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 99: 1 (V / V)) to obtain a fraction containing the desired product. Minutes and the solid collected by filtration were combined, concentrated under reduced pressure, and dried under reduced pressure to obtain 2.66 g (yield 32%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 161 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 1.22 (s, 6H), 0.08 (s, 9H).
（参考例９）
５－ｔｅｒｔ－ブチル　１－エチル　６，６－ジメチル－３－［２－メチル－２－（トリメチルシリル）プロパンアミド］ピロロ［３，４－ｃ］ピラゾール－１，５（４Ｈ，６Ｈ）－ジカルボキシラート
Figure JPOXMLDOC01-appb-C000133
 (Reference Example 9)
5-tert-butyl 1-ethyl 6,6-dimethyl-3- [2-methyl-2- (trimethylsilyl) propanamide] pyrrolo [3,4-c] pyrazole-1,5 (4H, 6H) -dicarboxyl Rat
Figure JPOXMLDOC01-appb-C000133
　参考例８と同様にして合成した２－メチル－２－（トリメチルシリル）プロパン酸１．３０ｇ（８．１１ｍｍｏｌ）の脱水ジクロロメタン２５ｍｌ溶液に、窒素雰囲気下で、塩化オキサリル０．８５ｍｌ（９．９ｍｍｏｌ）、ＤＭＦ０．０４０ｍｌ（０．５２ｍｍｏｌ）を０℃で順次加え、同温度で３．５時間撹拌した。
　反応終了後、反応液を減圧濃縮（湯浴温度：２５℃）して、濃縮残渣を得た。
　得られた濃縮残渣の脱水ジクロロメタン１５ｍｌ溶液に、窒素雰囲気下で、ＤＩＰＥＡ２．３０ｍｌ（１３．２ｍｍｏｌ）、５－ｔｅｒｔ－ブチル　１－エチル　３－アミノ－６，６－ジメチルピロロ［３，４－ｃ］ピラゾール－１，５（４Ｈ，６Ｈ）－ジカルボキシラート［Ｊｏｕｒｎａｌ　ｏｆ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ　２０１２，５５（１０），４７２８－４７３９．に記載の方法に準じて合成］１．０８ｇ（３．３３ｍｍｏｌ）を０℃で順次加え、同温度で１７．５時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加え撹拌した後、ジクロロメタンで３回抽出した。全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９３：７～８０：２０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１．２８ｇ（収率８２％）を微黄色泡状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４６７［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.87 - 7.74 (m, 1H), 4.60 - 4.47 (m, 4H), 1.84 & 1.78 (s, total 6H), 1.55 - 1.48(m, 9H), 1.47 (t, J = 7.2 Hz, 3H), 1.31 - 1.25 (m, 6H), 0.10 - 0.04(m, 9H)。 To a solution of 1.30 g (8.11 mmol) of 2-methyl-2- (trimethylsilyl) propanoic acid synthesized in the same manner as in Reference Example 8 in 25 ml of dehydrated dichloromethane, 0.85 ml (9.9 mmol) of oxalyl chloride in a nitrogen atmosphere. , 0.040 ml (0.52 mmol) of DMF was sequentially added at 0 ° C., and the mixture was stirred at the same temperature for 3.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure (hot water bath temperature: 25 ° C.) to obtain a concentrated residue.
To a 15 ml solution of the obtained concentrated residue in dehydrated dichloromethane, under a nitrogen atmosphere, 2.30 ml (13.2 mmol) of DIPEA, 5-tert-butyl 1-ethyl 3-amino-6,6-dimethylpyrrolo [3,4-c Pyrazole-1,5 (4H, 6H) -dicarboxylate [Journal of Medicinal Chemistry 2012, 55 (10), 4728-4739. Synthesis according to the method described in 1] 1.08 g (3.33 mmol) was sequentially added at 0 ° C. and stirred at the same temperature for 17.5 hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and stirred, followed by extraction with dichloromethane three times. All organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 93: 7 to 80:20 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure. As a result, 1.28 g (yield 82%) of the title compound was obtained as a slightly yellow foam.
Mass spectrum (CI, m / z): 467 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.87-7.74 (m, 1H), 4.60-4.47 (m, 4H), 1.84 & 1.78 (s, total 6H), 1.55-1.48 (m, 9H), 1.47 (t, J = 7.2 Hz, 3H), 1.31-1.25 (m, 6H), 0.10-0.04 (m, 9H).
（参考例１０）
１－（エチルジメチルシリル）シクロブタンカルボン酸
Figure JPOXMLDOC01-appb-C000134
 (Reference Example 10)
1- (Ethyldimethylsilyl) cyclobutanecarboxylic acid
Figure JPOXMLDOC01-appb-C000134
　アルゴン雰囲気下で、脱水ＴＨＦ２００ｍｌに２Ｍリチウムジイソプロピルアミド／ＴＨＦ溶液２１４ｍｌ（４２８ｍｍｏｌ）を加えた後、シクロブタンカルボン酸１０．７ｍｌ（１１２ｍｍｏｌ）を氷水冷却下で滴下し、成り行きで室温まで昇温させながら撹拌した。次いで、ヘキサメチルリン酸トリアミド２０ｍｌ（１２０ｍｍｏｌ）を加えた。ドライアイス／エタノール冷媒で冷却後、クロロ（エチル）ジメチルシラン６７．６ｍｌ（４８５ｍｍｏｌ）を－７５℃～－６９℃で滴下し、－６０℃以下の温度で一晩撹拌した。
　反応終了後、反応液にメタノール６７ｍｌ、次いで冷水１３４ｍｌを滴下後、室温にした。２Ｎ塩酸２４０ｍｌを加えて酸性（ｐＨ２．０）にし、ジエチルエーテル２００ｍｌを加えた後、分液した。得られた有機層を飽和塩化ナトリウム水溶液２５０ｍｌで洗浄後、無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮を行った。得られた濃縮残渣に２Ｎ水酸化ナトリウム水溶液４１ｍｌを加え、ｎ－ヘキサン２５０ｍｌで洗浄した。水層に１Ｎ塩酸８２ｍｌを加え、再び酸性(ｐＨ２．０)にした。この溶液を酢酸エチル２５０ｍｌで抽出し、有機層を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～９５：５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１１．７ｇ（収率５９％）を白色固体して得た。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：11.71 (br s, 1H), 2.44 - 2.33 (m, 2H), 2.19 -2.08 (m, 2H), 1.91 - 1.73 (m, 2H), 0.92 (t, J = 7.9 Hz, 3H), 0.55 (q, J = 7.9Hz, 2H), 0.05 (s, 6H)。 Under an argon atmosphere, 214 ml (428 mmol) of a 2M lithium diisopropylamide / THF solution was added to 200 ml of dehydrated THF, and then 10.7 ml (112 mmol) of cyclobutanecarboxylic acid was added dropwise with cooling with ice water, followed by stirring while gradually raising the temperature to room temperature. did. Then, 20 ml (120 mmol) of hexamethylphosphoric triamide was added. After cooling with a dry ice / ethanol refrigerant, 67.6 ml (485 mmol) of chloro (ethyl) dimethylsilane was added dropwise at −75 ° C. to −69 ° C. and stirred overnight at a temperature of −60 ° C. or lower.
After completion of the reaction, 67 ml of methanol and then 134 ml of cold water were added dropwise to the reaction solution, and the mixture was brought to room temperature. The mixture was acidified (pH 2.0) by adding 240 ml of 2N hydrochloric acid, and 200 ml of diethyl ether was added, followed by liquid separation. The obtained organic layer was washed with 250 ml of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. To the obtained concentrated residue, 2N aqueous sodium hydroxide solution (41 ml) was added and washed with n-hexane (250 ml). To the aqueous layer, 82 ml of 1N hydrochloric acid was added to make it acidic (pH 2.0) again. This solution was extracted with 250 ml of ethyl acetate, and the organic layer was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure. As a result, 11.7 g (yield 59%) of the title compound was obtained as a white solid.
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 11.71 (br s, 1H), 2.44-2.33 (m, 2H), 2.19 -2.08 (m, 2H), 1.91-1.73 (m, 2H), 0.92 (t, J = 7.9 Hz, 3H), 0.55 (q, J = 7.9 Hz, 2H), 0.05 (s, 6H).
（参考例１１）
５－ｔｅｒｔ－ブチル　２－エチル　３－［１－（エチルジメチルシリル）シクロブタンカルボキサミド］－６，６－ジメチルピロロ［３，４－ｃ］ピラゾール－２，５（４Ｈ，６Ｈ）－ジカルボキシラート
Figure JPOXMLDOC01-appb-C000135
 (Reference Example 11)
5-tert-butyl 2-ethyl 3- [1- (ethyldimethylsilyl) cyclobutanecarboxamide] -6,6-dimethylpyrrolo [3,4-c] pyrazole-2,5 (4H, 6H) -dicarboxylate
Figure JPOXMLDOC01-appb-C000135
　参考例１０と同様にして合成した１－（エチルジメチルシリル）シクロブタンカルボン酸１１．７ｇ（６２．８ｍｍｏｌ）の脱水ジクロロメタン８１ｍｌ溶液に、アルゴン雰囲気下で塩化オキサリル５．３ｍｌ（６２ｍｍｏｌ）、ＤＭＦ０．２４ｍｌ（３．１ｍｍｏｌ）を氷水冷却下で順次加え、同温度で２時間撹拌した。
　反応終了後、反応液を室温で減圧濃縮して、濃縮残渣を得た。
　得られた濃縮残渣の脱水ジクロロメタン５ｍｌ溶液を、窒素雰囲気下、５－ｔｅｒｔ－ブチル　２－エチル　３－アミノ－６，６－ジメチルピロロ［３，４－ｃ］ピラゾール－２，５（４Ｈ，６Ｈ）－ジカルボキシラート［Ｊｏｕｒｎａｌ　ｏｆ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ　２０１２，５５（１０），４７２８－４７３９．に記載の方法に準じて合成］６．７３ｇ（２０．７ｍｍｏｌ）、ＤＩＰＥＡ１８ｍｌ（１００ｍｍｏｌ）の脱水ジクロロメタン９４ｍｌ溶液に、氷水冷下で滴下し、同温度で１６時間撹拌した。
　反応終了後、反応液に５％硫酸水素カリウム水溶液３５０ｍｌを加えて分液後、水層をジクロロメタン１５０ｍｌで２回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥後、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝８６：１４～５３：４７（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮し、標記化合物７．５１ｇ（収率７４％）を淡黄色油状物として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：４９３［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：9.82 - 9.69 (m, 1H), 4.51 - 4.36 (m, 4H), 2.49 -2.42 (m, 2H), 2.32 - 2.23 (m, 2H), 1.95 - 1.84 (m, 2H), 1.62 - 1.55 (m, 6H), 1.49- 1.42 (m, 9H), 1.38 - 1.31 (m, 3H), 0.91 (t, J = 7.9 Hz,3H), 0.57 (q, J = 7.9 Hz, 2H), 0.09 (s, 6H)。 To a solution of 11.7 g (62.8 mmol) of 1- (ethyldimethylsilyl) cyclobutanecarboxylic acid synthesized in the same manner as in Reference Example 81 in 81 ml of dehydrated dichloromethane, 5.3 ml (62 mmol) of oxalyl chloride and 0.24 ml of DMF in an argon atmosphere. (3.1 mmol) was sequentially added under ice water cooling, and the mixture was stirred at the same temperature for 2 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure at room temperature to obtain a concentrated residue.
A solution of the obtained concentrated residue in 5 ml of dehydrated dichloromethane was charged with 5-tert-butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo [3,4-c] pyrazole-2,5 (4H, 6H) under a nitrogen atmosphere. ) -Dicarboxylate [Journal of Medicinal Chemistry 2012, 55 (10), 4728-4739. Synthesis according to the method described in 1) To a solution of 6.73 g (20.7 mmol) and DIPEA 18 ml (100 mmol) in 94 ml of dehydrated dichloromethane was added dropwise under ice-water cooling and stirred at the same temperature for 16 hours.
After completion of the reaction, 350 ml of 5% aqueous potassium hydrogensulfate solution was added to the reaction solution for liquid separation, and the aqueous layer was extracted twice with 150 ml of dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 86: 14 to 53:47 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound 7.51 g (74% yield) was obtained as a pale yellow oil.
Mass spectrum (DUIS, m / z): 493 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 9.82-9.69 (m, 1H), 4.51-4.36 (m, 4H), 2.49 -2.42 (m, 2H), 2.32-2.23 (m, 2H) , 1.95-1.84 (m, 2H), 1.62-1.55 (m, 6H), 1.49-1.42 (m, 9H), 1.38-1.31 (m, 3H), 0.91 (t, J = 7.9 Hz, 3H), 0.57 (q, J = 7.9 Hz, 2H), 0.09 (s, 6H).
（参考例１２）
エチル　３－［１－（エチルジメチルシリル）シクロブタンカルボキサミド］－６，６－ジメチル－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート
Figure JPOXMLDOC01-appb-C000136
 (Reference Example 12)
Ethyl 3- [1- (ethyldimethylsilyl) cyclobutanecarboxamide] -6,6-dimethyl-5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate
Figure JPOXMLDOC01-appb-C000136
　参考例１１と同様にして合成した５－ｔｅｒｔ－ブチル　２－エチル　３－［１－（エチルジメチルシリル）シクロブタンカルボキサミド］－６，６－ジメチルピロロ［３，４－ｃ］ピラゾール－２，５（４Ｈ，６Ｈ）－ジカルボキシラート７．２７ｇ（１４．８ｍｍｏｌ）の脱水ジクロロメタン７０ｍｌ溶液に、アルゴン雰囲気下、２，６－ルチジン５．１ｍｌ（４４ｍｍｏｌ）、トリメチルシリル　トリフルオロメタンスルホナート７．８ｍｌ（４３ｍｍｏｌ）を氷冷下で順次滴下し、同温度で２時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液５７ｍｌ及びジクロロメタン５７ｍｌを加えた後、分液した。水層をジクロロメタン６０ｍｌで２回抽出し、得られた全有機層を飽和炭酸水素ナトリウム水溶液６０ｍｌ、飽和塩化ナトリウム水溶液６０ｍｌで順次洗浄後、無水硫酸マグネシウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣に、トルエンを加えて減圧濃縮する操作を５回行い、標記化合物５．９２ｇ（不純物を含む）を黄色油状物として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：３９３［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：9.68 (s, 1H), 4.39 (q, J = 7.0 Hz,2H), 3.92 (s, 2H), 2.48 - 2.40 (m, 2H), 2.29 - 2.22 (m, 2H), 1.93 - 1.82 (m,2H), 1.33 (t, J = 7.0 Hz, 3H), 1.29 (s, 6H), 0.91 (t, J = 8.1Hz, 3H), 0.56 (q, J = 8.1 Hz, 2H), 0.08 (s, 6H)。 5-tert-butyl 2-ethyl 3- [1- (ethyldimethylsilyl) cyclobutanecarboxamide] -6,6-dimethylpyrrolo [3,4-c] pyrazole-2,5 (synthesized in the same manner as in Reference Example 11 4H, 6H) -dicarboxylate 7.27 g (14.8 mmol) in 70 ml of dehydrated dichloromethane, under argon atmosphere, 5.1 ml (44 mmol) of 2,6-lutidine, 7.8 ml (43 mmol) of trimethylsilyl trifluoromethanesulfonate Were successively added dropwise under ice-cooling and stirred at the same temperature for 2 hours.
After completion of the reaction, 57 ml of a saturated aqueous sodium hydrogen carbonate solution and 57 ml of dichloromethane were added to the reaction solution, followed by liquid separation. The aqueous layer was extracted twice with 60 ml of dichloromethane, and the entire organic layer obtained was washed successively with 60 ml of saturated aqueous sodium hydrogen carbonate solution and 60 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The operation of adding toluene to the obtained concentrated residue and concentrating under reduced pressure was performed 5 times to obtain 5.92 g (including impurities) of the title compound as a yellow oil.
Mass spectrum (DUIS, m / z): 393 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 9.68 (s, 1H), 4.39 (q, J = 7.0 Hz, 2H), 3.92 (s, 2H), 2.48-2.40 (m, 2H), 2.29-2.22 (m, 2H), 1.93-1.82 (m, 2H), 1.33 (t, J = 7.0 Hz, 3H), 1.29 (s, 6H), 0.91 (t, J = 8.1Hz, 3H), 0.56 (q, J = 8.1 Hz, 2H), 0.08 (s, 6H).
（参考例１３）
エチル　５－（クロロカルボニル）－３－［１－（エチルジメチルシリル）シクロブタンカルボキサミド］－６，６－ジメチル－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート
Figure JPOXMLDOC01-appb-C000137
 (Reference Example 13)
Ethyl 5- (chlorocarbonyl) -3- [1- (ethyldimethylsilyl) cyclobutanecarboxamide] -6,6-dimethyl-5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate
Figure JPOXMLDOC01-appb-C000137
　参考例１１と同様にして合成した５－ｔｅｒｔ－ブチル　２－エチル　３－［１－（エチルジメチルシリル）シクロブタンカルボキサミド］－６，６－ジメチルピロロ［３，４－ｃ］ピラゾール－２，５（４Ｈ，６Ｈ）－ジカルボキシラート７．２７ｇ（１４．８ｍｍｏｌ）を用いて参考例１２と同様にして合成したエチル　３－［１－（エチルジメチルシリル）シクロブタンカルボキサミド］－６，６－ジメチル－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート５．９２ｇ（不純物を含む）の脱水ジクロロメタン２００ｍｌ溶液に、アルゴン雰囲気下、ＤＩＰＥＡ７．３ｍｌ（４３ｍｍｏｌ）を室温で加えた後、ビス（トリクロロメチル）カルボナート３．２４ｇ（１０．９ｍｍｏｌ）の脱水ジクロロメタン３３ｍｌ溶液を－６０℃以下で滴下し、同温度で２時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液１３０ｍｌを加え、攪拌しながら成り行きで室温まで昇温した。分液後、水層をジクロロメタン１００ｍｌで２回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７８：２２～５７：４３（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。濃縮残渣にｎ－ヘキサンを加え、再度減圧濃縮することにより標記化合物５．１３ｇ（収率７６％［２工程］）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４５５［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：9.85 - 9.76 (m, 1H), 4.88- 4.81 & 4.53 - 4.48 (m, total 2H), 4.44 (q, J = 7.1 Hz, 2H), 2.55 - 2.44 (m, 2H), 2.35 - 2.24(m, 2H), 1.96 - 1.85 (m, 2H), 1.69 - 1.61 (m, 6H), 1.34 (t, J = 7.1 Hz, 3H),0.92 (t, J = 7.9 Hz, 3H), 0.58 (q, J = 7.9 Hz, 2H), 0.13 - 0.07 (m, 6H)。 5-tert-butyl 2-ethyl 3- [1- (ethyldimethylsilyl) cyclobutanecarboxamide] -6,6-dimethylpyrrolo [3,4-c] pyrazole-2,5 (synthesized in the same manner as in Reference Example 11 Ethyl 3- [1- (ethyldimethylsilyl) cyclobutanecarboxamide] -6,6-dimethyl-5 synthesized in the same manner as in Reference Example 12 using 7.27 g (14.8 mmol) of 4H, 6H) -dicarboxylate , 6-Dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate 5.92 g (containing impurities) in 200 ml of dehydrated dichloromethane was added 7.3 ml (43 mmol) of DIPEA at room temperature under an argon atmosphere. After that, 3.24 g (10.9 mmol) of bis (trichloromethyl) carbonate 33ml solution was added dropwise at -60 ° C. or less, and stirred for 2 hours at the same temperature.
After completion of the reaction, 130 ml of a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the temperature was gradually raised to room temperature while stirring. After separation, the aqueous layer was extracted twice with 100 ml of dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 78: 22 to 57:43 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. N-Hexane was added to the concentrated residue, followed by concentration under reduced pressure again to obtain 5.13 g (yield 76% [2 steps]) of the title compound as a white solid.
Mass spectrum (CI, m / z): 455 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 9.85-9.76 (m, 1H), 4.88- 4.81 & 4.53-4.48 (m, total 2H), 4.44 (q, J = 7.1 Hz, 2H), 2.55-2.44 (m, 2H), 2.35-2.24 (m, 2H), 1.96-1.85 (m, 2H), 1.69-1.61 (m, 6H), 1.34 (t, J = 7.1 Hz, 3H), 0.92 ( t, J = 7.9 Hz, 3H), 0.58 (q, J = 7.9 Hz, 2H), 0.13-0.07 (m, 6H).
（参考例１４）
２－（エチルジメチルシリル）－２－メチルプロパン酸
Figure JPOXMLDOC01-appb-C000138
 (Reference Example 14)
2- (Ethyldimethylsilyl) -2-methylpropanoic acid
Figure JPOXMLDOC01-appb-C000138
　アルゴン雰囲気下、脱水ＴＨＦ１００ｍｌに２Ｍリチウムジイソプロピルアミド／ＴＨＦ溶液１００ｍｌ（２００ｍｍｏｌ)を加えた後、イソブタン酸４．７ｍｌ（５１ｍｍｏｌ）を０℃で滴下し、室温に昇温後４時間攪拌した。次いで、ヘキサメチルリン酸トリアミド１０ｍｌ（５８ｍｍｏｌ）を加えた後、クロロ（エチル）ジメチルシラン３２ｍｌ（２３０ｍｍｏｌ）を－７８℃で滴下した。滴下終了後、成り行きで室温に昇温しながら１日撹拌した。
　反応終了後、氷水冷却下でメタノール２５ｍｌ、次いで水５０ｍｌを加えた。その後、２Ｎ塩酸を加え酸性にし、ジエチルエーテルで抽出した。得られた有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥、濾過、濾液を減圧濃縮した。濃縮残渣に２Ｎ水酸化ナトリウム水溶液を加え、それを酢酸エチルで洗浄した。次いで、水層に１Ｎ塩酸水溶液を加え酸性にし、酢酸エチルで抽出した。得られた有機層を無水硫酸マグネシウムで乾燥、濾過、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～９９：１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物２．２４ｇ（収率２５％）を白色固体して得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１７５［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：11.57 (br s, 1H), 1.23 (s, 6H), 0.95 (t, J = 8.0 Hz, 3H), 0.62 (q, J = 8.0 Hz, 2H), 0.06 (s, 6H)。 Under an argon atmosphere, 100 ml (200 mmol) of 2M lithium diisopropylamide / THF solution was added to 100 ml of dehydrated THF, and then 4.7 ml (51 mmol) of isobutanoic acid was added dropwise at 0 ° C., and the mixture was warmed to room temperature and stirred for 4 hours. Next, 10 ml (58 mmol) of hexamethylphosphoric triamide was added, and then 32 ml (230 mmol) of chloro (ethyl) dimethylsilane was added dropwise at −78 ° C. After completion of dropping, the mixture was stirred for one day while raising the temperature to room temperature.
After completion of the reaction, 25 ml of methanol and then 50 ml of water were added under cooling with ice water. Thereafter, 2N hydrochloric acid was added to acidify, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. To the concentrated residue was added 2N aqueous sodium hydroxide solution, which was washed with ethyl acetate. The aqueous layer was acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 99: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure. As a result, 2.24 g (yield 25%) of the title compound was obtained as a white solid.
Mass spectrum (CI, m / z): 175 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 11.57 (br s, 1H), 1.23 (s, 6H), 0.95 (t, J = 8.0 Hz, 3H), 0.62 (q, J = 8.0 Hz, 2H ), 0.06 (s, 6H).
（参考例１５）
５－ｔｅｒｔ－ブチル　１－エチル　３－［２－（エチルジメチルシリル）－２－メチルプロパンアミド］－６，６－ジメチルピロロ［３，４－ｃ］ピラゾール－１，５（４Ｈ，６Ｈ）－ジカルボキシラート
Figure JPOXMLDOC01-appb-C000139
 (Reference Example 15)
5-tert-butyl 1-ethyl 3- [2- (ethyldimethylsilyl) -2-methylpropanamide] -6,6-dimethylpyrrolo [3,4-c] pyrazole-1,5 (4H, 6H)- Dicarboxylate
Figure JPOXMLDOC01-appb-C000139
　参考例１４と同様にして合成した２－（エチルジメチルシリル）－２－メチルプロパン酸４．７ｇ（２７ｍｍｏｌ）の脱水ジクロロメタン４０ｍｌ溶液に、アルゴン雰囲気下で、塩化オキサリル２．３ｍｌ（２７ｍｍｏｌ）を０℃で滴下し、同温度で１０分間撹拌した。次いで、ＤＭＦ０．１０ｍｌ（１．３ｍｍｏｌ）を０℃で加え、同温度で４時間撹拌した。
　反応終了後、反応液を室温で減圧濃縮して、濃縮残渣を得た。
　得られた濃縮残渣の脱水ジクロロメタン２０ｍｌ溶液を、アルゴン雰囲気下で、５－ｔｅｒｔ－ブチル　１－エチル　３－アミノ－６，６－ジメチルピロロ［３，４－ｃ］ピラゾール－１，５（４Ｈ，６Ｈ）－ジカルボキシラート［Ｊｏｕｒｎａｌ　ｏｆ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ　２０１２，５５（１０），４７２８－４７３９．に記載の方法に準じて合成］２．９ｇ（８．９ｍｍｏｌ）の脱水ジクロロメタン１０ｍｌ溶液に０℃で滴下し、次いでＤＩＰＥＡ７．９ｍｌ（４５ｍｍｏｌ）を加え、０℃で２４時間撹拌した。
　反応終了後、反応液に水を加え、ジクロロメタンで抽出した。得られた有機層を飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸ナトリウムで乾燥、濾過、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９８：２～８０：２０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物３．１８ｇ（収率７４％）を淡黄色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４８１［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.88 - 7.73 (m, 1H), 4.62 - 4.46(m, 4H), 1.87 - 1.75 (m, 6H), 1.55- 1.41 (m, 12H), 1.31 - 1.26 (m, 6H), 0.99 - 0.88 (m,3H), 0.66 - 0.53 (m, 2H), 0.09 - 0.02 (m, 6H)。 To a solution of 4.7 g (27 mmol) of 2- (ethyldimethylsilyl) -2-methylpropanoic acid synthesized in the same manner as in Reference Example 14 in 40 ml of dehydrated dichloromethane, 2.3 ml (27 mmol) of oxalyl chloride was added to 0 ml in an argon atmosphere. The solution was added dropwise at 0 ° C. and stirred at the same temperature for 10 minutes. Next, 0.10 ml (1.3 mmol) of DMF was added at 0 ° C., and the mixture was stirred at the same temperature for 4 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure at room temperature to obtain a concentrated residue.
A solution of the resulting concentrated residue in 20 ml of dehydrated dichloromethane was added to 5-tert-butyl 1-ethyl 3-amino-6,6-dimethylpyrrolo [3,4-c] pyrazole-1,5 (4H, 6H) -dicarboxylate [Journal of Medicinal Chemistry 2012, 55 (10), 4728-4739. According to the method described in 1), 2.9 g (8.9 mmol) of dehydrated dichloromethane in 10 ml was added dropwise at 0 ° C., then DIPEA (7.9 ml, 45 mmol) was added, and the mixture was stirred at 0 ° C. for 24 hours.
After completion of the reaction, water was added to the reaction solution and extracted with dichloromethane. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 98: 2 to 80:20 (V / V)), and the fraction containing the target product was concentrated under reduced pressure. The title compound (3.18 g, yield 74%) was obtained as a pale yellow oil.
Mass spectrum (CI, m / z): 481 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.88-7.73 (m, 1H), 4.62-4.46 (m, 4H), 1.87-1.75 (m, 6H), 1.55- 1.41 (m, 12H), 1.31 -1.26 (m, 6H), 0.99-0.88 (m, 3H), 0.66-0.53 (m, 2H), 0.09-0.02 (m, 6H).
（参考例１６）
エチル　３－［２－（エチルジメチルシリル）－２－メチルプロパンアミド］－６，６－ジメチル－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－１（４Ｈ）－カルボキシラート
Figure JPOXMLDOC01-appb-C000140
 (Reference Example 16)
Ethyl 3- [2- (ethyldimethylsilyl) -2-methylpropanamide] -6,6-dimethyl-5,6-dihydropyrrolo [3,4-c] pyrazole-1 (4H) -carboxylate
Figure JPOXMLDOC01-appb-C000140
　参考例１５と同様にして合成した５－ｔｅｒｔ－ブチル　１－エチル　３－［２－（エチルジメチルシリル）－２－メチルプロパンアミド］－６，６－ジメチルピロロ［３，４－ｃ］ピラゾール－１，５（４Ｈ，６Ｈ）－ジカルボキシラート３．１８ｇ（６．６２ｍｍｏｌ）の脱水ジクロロメタン３０ｍｌ溶液に、アルゴン雰囲気下、２，６－ルチジン２．３ｍｌ（２０ｍｍｏｌ）、トリメチルシリル　トリフルオロメタンスルホナート３．６ｍｌ（２０ｍｍｏｌ）を０℃で順次滴下し、同温度で１時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。得られた有機層を飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥、濾過、濾液を減圧濃縮した。残渣にトルエンを加えた後、減圧濃縮を行うことにより、標記化合物２．４４ｇ（収率９７％）を淡黄色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：３８１［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.77 (s, 1H),4.50 (q, J = 7.2 Hz, 2H), 4.15 (s, 2H), 1.55 (s,6H), 1.46 (t, J = 7.2 Hz, 3H),1.32 - 1.25 (m, 6H), 0.93 (t, J = 8.0 Hz, 3H), 0.60 (q, J = 8.0 Hz, 2H), 0.05 (s, 6H)。 5-tert-butyl 1-ethyl 3- [2- (ethyldimethylsilyl) -2-methylpropanamide] -6,6-dimethylpyrrolo [3,4-c] pyrazole- synthesized in the same manner as in Reference Example 15 To a solution of 3.18 g (6.62 mmol) of 1,5 (4H, 6H) -dicarboxylate in 30 ml of dehydrated dichloromethane, 2.3 ml (20 mmol) of 2,6-lutidine, trimethylsilyl trifluoromethanesulfonate under an argon atmosphere. 6 ml (20 mmol) was sequentially added dropwise at 0 ° C. and stirred at the same temperature for 1 hour.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Toluene was added to the residue, followed by concentration under reduced pressure to obtain 2.44 g (yield 97%) of the title compound as a pale yellow solid.
Mass spectrum (CI, m / z): 381 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.77 (s, 1H), 4.50 (q, J = 7.2 Hz, 2H), 4.15 (s, 2H), 1.55 (s, 6H), 1.46 (t, J = 7.2 Hz, 3H), 1.32-1.25 (m, 6H), 0.93 (t, J = 8.0 Hz, 3H), 0.60 (q, J = 8.0 Hz, 2H), 0.05 (s, 6H).
（参考例１７）
（Ｓ）－２－［（２－メトキシプロパン－２－イル）オキシ］－１－フェニルエタノール
Figure JPOXMLDOC01-appb-C000141
 (Reference Example 17)
(S) -2-[(2-Methoxypropan-2-yl) oxy] -1-phenylethanol
Figure JPOXMLDOC01-appb-C000141
　（Ｓ）－２－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］－２－フェニルエタノール［Ａｎｇｅｗ．Ｃｈｅｍ．Ｉｎｔ．Ｅｄ．，２０１２，５１（３１），７８２５－７８２９．に記載の方法に準じて合成］６６４ｍｇ（２．６３ｍｍｏｌ）のジクロロメタン１５ｍｌ溶液に、窒素雰囲気下で、２－メトキシ－１－プロペン０．３３ｍｌ（３．５ｍｍｏｌ）、ピリジニウム　ｐ－トルエンスルホナート６８．３ｍｇ（０．２７２ｍｍｏｌ）を０℃で加え、同温度で２時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加え撹拌した後、ジクロロメタンで２回抽出した。全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９８：２～９７：３（Ｖ／Ｖ））に付し、（Ｓ）－３，３，８，８，９，９－ヘキサメチル－６－フェニル－２，４，７－トリオキサ－８－シラデカンを含む画分を減圧濃縮、減圧乾燥することにより、濃縮残渣を得た。
　得られた濃縮残渣３４７ｍｇのＴＨＦ１０ｍｌ溶液に、窒素雰囲気下で、テトラブチルアンモニウム　フルオリド４２８ｍｇ（１．６４ｍｍｏｌ）を０℃で加え、同温度で３．５時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加え撹拌した後、酢酸エチル／ｎ－ヘキサン混合溶媒で２回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９０：１０～８５：１５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより標記化合物１６０ｍｇ（収率２９％［２工程］）を無色油状物として得た。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.43 - 7.27 (m,5H), 4.89 - 4.83 (m, 1H), 3.59 (dd, J = 3.2, 9.8 Hz, 1H), 3.45 (dd, J = 9.0, 9.8 Hz, 1H), 3.19 (s, 3H), 2.82 (d, J= 2.4 Hz, 1H), 1.38 (s, 3H), 1.37 (s, 3H)。 (S) -2-[(tert-Butyldimethylsilyl) oxy] -2-phenylethanol [Angew. Chem. Int. Ed. , 2012, 51 (31), 7825-7829. In a nitrogen atmosphere, 0.33 ml (3.5 mmol) of 2-methoxy-1-propene and pyridinium p-toluenesulfonate 68. were prepared in a solution of 664 mg (2.63 mmol) in dichloromethane 15 ml. 3 mg (0.272 mmol) was added at 0 ° C., and the mixture was stirred at the same temperature for 2 hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and stirred, followed by extraction twice with dichloromethane. All organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 98: 2 to 97: 3 (V / V)), and (S) -3, 3, 8, 8, A fraction containing 9,9-hexamethyl-6-phenyl-2,4,7-trioxa-8-siladecane was concentrated under reduced pressure and dried under reduced pressure to obtain a concentrated residue.
Under a nitrogen atmosphere, 428 mg (1.64 mmol) of tetrabutylammonium fluoride was added at 0 ° C. to a solution of the obtained concentrated residue 347 mg in THF 10 ml, and the mixture was stirred at the same temperature for 3.5 hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and stirred, followed by extraction twice with a mixed solvent of ethyl acetate / n-hexane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 85:15 (V / V)), and the fraction containing the target product was concentrated under reduced pressure and dried under reduced pressure. This gave 160 mg (yield 29% [2 steps]) of the title compound as a colorless oil.
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.43-7.27 (m, 5H), 4.89-4.83 (m, 1H), 3.59 (dd, J = 3.2, 9.8 Hz, 1H), 3.45 (dd, J = 9.0, 9.8 Hz, 1H), 3.19 (s, 3H), 2.82 (d, J = 2.4 Hz, 1H), 1.38 (s, 3H), 1.37 (s, 3H).
（参考例１８）
（Ｓ）－２，５－ジオキソピロリジン－１－イル　｛２－［（２－メトキシプロパン－２－イル）オキシ］－１－フェニルエチル｝カルボナート
Figure JPOXMLDOC01-appb-C000142
 (Reference Example 18)
(S) -2,5-dioxopyrrolidin-1-yl {2-[(2-methoxypropan-2-yl) oxy] -1-phenylethyl} carbonate
Figure JPOXMLDOC01-appb-C000142
　参考例１７と同様にして合成した（Ｓ）－２－［（２－メトキシプロパン－２－イル）オキシ］－１－フェニルエタノール１５７ｍｇ（０．７４７ｍｍｏｌ）の脱水アセトニトリル４ｍｌ溶液に、窒素雰囲気下で、トリエチルアミン０．１６ｍｌ（１．２ｍｍｏｌ）、Ｎ，Ｎ’－ジスクシンイミジル　カルボナート２３３ｍｇ（０．９０８ｍｍｏｌ）を室温で加え、同温度で６時間撹拌した。
　反応終了後、反応液を減圧濃縮した。得られた濃縮残渣を酢酸エチルに溶解させ、それを水で洗浄した。分液した後、水層を酢酸エチルで２回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９０：１０～６５：３５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１９０ｍｇ（収率７２％）を無色油状物として得た。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.42 - 7.33 (m,5H), 5.86 (dd, J = 3.4, 8.8 Hz, 1H), 3.83 (dd, J = 8.8,11.0 Hz, 1H), 3.64 (dd, J = 3.4, 11.0 Hz, 1H), 3.20 (s, 3H), 2.81 (s, 4H),1.38 (s, 3H), 1.34 (s, 3H)。 To a solution of 157 mg (0.747 mmol) of (S) -2-[(2-methoxypropan-2-yl) oxy] -1-phenylethanol synthesized as in Reference Example 17 in 4 ml of dehydrated acetonitrile under a nitrogen atmosphere. , 0.16 ml (1.2 mmol) of triethylamine and 233 mg (0.908 mmol) of N, N′-disuccinimidyl carbonate were added at room temperature, followed by stirring at the same temperature for 6 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. The resulting concentrated residue was dissolved in ethyl acetate and washed with water. After liquid separation, the aqueous layer was extracted twice with ethyl acetate. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 65:35 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure. As a result, 190 mg (yield 72%) of the title compound was obtained as a colorless oil.
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.42-7.33 (m, 5H), 5.86 (dd, J = 3.4, 8.8 Hz, 1H), 3.83 (dd, J = 8.8, 11.0 Hz, 1H), 3.64 (dd, J = 3.4, 11.0 Hz, 1H), 3.20 (s, 3H), 2.81 (s, 4H), 1.38 (s, 3H), 1.34 (s, 3H).
（参考例１９）
（Ｒ）－メチル　３－アミノ－３－フェニルプロパノアート　塩酸塩
Figure JPOXMLDOC01-appb-C000143
 (Reference Example 19)
(R) -Methyl 3-amino-3-phenylpropanoate hydrochloride
Figure JPOXMLDOC01-appb-C000143
　（Ｒ）－３－アミノ－３－フェニルプロパン酸［Ｓｈａｎｈａｉ　ＨＣ　Ｂｉｏｔｅｃｈ　ＣＯ．，ＬＴＤ．より購入］２．０１ｇ（１２．２ｍｍｏｌ）の脱水メタノール１００ｍｌ溶液に、窒素雰囲気下、撹拌しながら塩化チオニル１．３２ｍｌ（１８．２ｍｍｏｌ）を室温で滴下した後、同温度で２４時間撹拌した。その後６５℃に昇温して９．５時間攪拌した。
　放冷後、反応液を減圧濃縮し、得られた濃縮残渣にジエチルエーテルを加え、超音波処理し、析出した固体を濾取、減圧乾燥することにより、標記化合物２．５５ｇ（収率９７％）を白色固体として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：１８０［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：8.67 (br s, 3H), 7.57 - 7.50 (m, 2H), 7.45 -7.36 (m, 3H), 4.58 (dd, J = 6.0, 8.6 Hz, 1H), 3.35 (br s, 3H), 3.20 (dd, J = 6.0, 16.3 Hz, 1H), 3.00 (dd, J = 8.6, 16.3 Hz, 1H)。 (R) -3-Amino-3-phenylpropanoic acid [Shanhai HC Biotech CO. , LTD. Purchased] To a solution of 2.01 g (12.2 mmol) in 100 ml of dehydrated methanol was added dropwise thionyl chloride 1.32 ml (18.2 mmol) at room temperature under stirring in a nitrogen atmosphere, and the mixture was stirred at the same temperature for 24 hours. Thereafter, the temperature was raised to 65 ° C. and the mixture was stirred for 9.5 hours.
After allowing to cool, the reaction mixture was concentrated under reduced pressure, diethyl ether was added to the resulting concentrated residue, sonicated, and the precipitated solid was collected by filtration and dried under reduced pressure to give 2.55 g of the title compound (yield 97%). ) Was obtained as a white solid.
Mass spectrum (DUIS, m / z): 180 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 8.67 (br s, 3H), 7.57-7.50 (m, 2H), 7.45-7.36 (m, 3H), 4.58 (dd, J = 6.0, 8.6 Hz, 1H), 3.35 (br s, 3H), 3.20 (dd, J = 6.0, 16.3 Hz, 1H), 3.00 (dd, J = 8.6, 16.3 Hz, 1H).
（参考例２０）
（Ｒ）－メチル　３－フェニル－３－（２，２，２－トリフルオロアセタミド）プロパノアート
Figure JPOXMLDOC01-appb-C000144
 (Reference Example 20)
(R) -Methyl 3-phenyl-3- (2,2,2-trifluoroacetamide) propanoate
Figure JPOXMLDOC01-appb-C000144
　参考例１９と同様にして合成した（Ｒ）－メチル　３－アミノ－３－フェニルプロパノアート　塩酸塩２．５５ｇ（１１．８ｍｍｏｌ）のジクロロメタン５０ｍｌ溶液に、アルゴン雰囲気下、０℃で撹拌しながら、ＤＩＰＥＡ１０．５ｍｌ（６０．３ｍｍｏｌ）、トリフルオロ酢酸無水物１．７５ｍｌ（１２．４ｍｍｏｌ）を順次滴下し、同温度で２時間撹拌し、さらに室温で一晩攪拌した。
　反応終了後、反応液を減圧濃縮した。濃縮残渣に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥、濾過、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９１：９～７０：３０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物２．７５ｇ（収率８５％）を白色固体として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：２７６［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.80 - 7.64 (m, 1H), 7.39 - 7.25 (m, 5H), 5.46 - 5.39 (m,1H), 3.65 (s, 3H), 3.00 (dd, J = 5.5, 16.2 Hz, 1H), 2.93 (dd, J = 5.5, 16.2 Hz,1H)。 (R) -Methyl 3-amino-3-phenylpropanoate synthesized in the same manner as in Reference Example 19 in a solution of 2.55 g (11.8 mmol) of hydrochloride in 50 ml of dichloromethane with stirring at 0 ° C. under an argon atmosphere. , 10.5 ml (60.3 mmol) of DIPEA and 1.75 ml (12.4 mmol) of trifluoroacetic anhydride were sequentially added dropwise, stirred at the same temperature for 2 hours, and further stirred at room temperature overnight.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the concentrated residue, washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 91: 9 to 70:30 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. 2.75 g (yield 85%) of the title compound was obtained as a white solid.
Mass spectrum (DUIS, m / z): 276 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.80-7.64 (m, 1H), 7.39-7.25 (m, 5H), 5.46-5.39 (m, 1H), 3.65 (s, 3H), 3.00 (dd , J = 5.5, 16.2 Hz, 1H), 2.93 (dd, J = 5.5, 16.2 Hz, 1H).
（参考例２１）
（Ｒ）－４－アミノ－２－メチル－４－フェニルブタン－２－オール
Figure JPOXMLDOC01-appb-C000145
 (Reference Example 21)
(R) -4-Amino-2-methyl-4-phenylbutan-2-ol
Figure JPOXMLDOC01-appb-C000145
　参考例２０と同様にして合成した（Ｒ）－メチル　３－フェニル－３－（２，２，２－トリフルオロアセタミド）プロパノアート５０６ｍｇ（１．８４ｍｍｏｌ）の脱水ＴＨＦ５ｍｌ溶液に、アルゴン雰囲気下で、撹拌しながら１．４Ｍメチルマグネシウムブロミド／ＴＨＦ溶液６．６０ｍｌ（９．２４ｍｍｏｌ）を室温で滴下し、室温で３．５時間撹拌した。
　反応終了後、反応液を氷冷下で飽和塩化アンモニウム水溶液１０ｍｌを滴下し、室温に戻してしばらく攪拌した。反応液にジクロロメタン及び水、さらに希水酸化ナトリウム水溶液を加えて水層のｐＨを１０に調整した後、分液した。水層をジクロロメタンで抽出し、得られた全有機層を無水硫酸ナトリウムで乾燥、濾過、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＤＮＨシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～９５：５（Ｖ／Ｖ））に付し、（Ｒ）－２，２，２－トリフルオロ－Ｎ－（３－ヒドロキシ－３－メチル－１－フェニルブチル）アセトアミドを含む画分を減圧濃縮し、濃縮残渣を得た。
　得られた濃縮残渣４２７ｍｇのエタノール５ｍｌ溶液に、室温で水素化ホウ素ナトリウム６４．６ｍｇ（１．７１ｍｍｏｌ）を数回に分割して加えた後、室温で１４時間攪拌した。さらに水素化ホウ素ナトリウム７７．０ｍｇ（２．０４ｍｍｏｌ）を数回に分割して加え、室温で２時間攪拌した後、７５℃で２時間攪拌した。
　反応終了後、反応液を氷冷し、飽和塩化アンモニウム水溶液１０ｍｌを滴下した後、室温で攪拌した。ジクロロメタンと水を加え、希水酸化ナトリウム水溶液を加えて水層のｐＨを１０にした後、分液した。水層をジクロロメタンで抽出し、得られた全有機層を無水硫酸ナトリウムで乾燥、濾過、濾液を減圧濃縮した。濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＮＨシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～９５：５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物１６０ｍｇ（収率４９％）を無色油状物として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：１８０［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：7.37 - 7.26 (m, 4H), 7.21 - 7.15 (m, 1H), 4.05(dd, J = 2.8, 10.7 Hz, 1H), 1.66 (dd, J = 10.7, 14.0 Hz, 1H), 1.52 (dd, J = 2.8,14.0 Hz, 1H), 1.22 (s, 3H), 1.10 (s, 3H)。 To a solution of 506 mg (1.84 mmol) of (R) -methyl 3-phenyl-3- (2,2,2-trifluoroacetamide) propanoate synthesized in the same manner as in Reference Example 5 in 5 ml of dehydrated THF, under an argon atmosphere, While stirring, 6.60 ml (9.24 mmol) of 1.4M methylmagnesium bromide / THF solution was added dropwise at room temperature, and the mixture was stirred at room temperature for 3.5 hours.
After completion of the reaction, 10 ml of a saturated aqueous ammonium chloride solution was added dropwise to the reaction solution under ice cooling, and the resulting mixture was returned to room temperature and stirred for a while. Dichloromethane and water and a dilute aqueous sodium hydroxide solution were added to the reaction solution to adjust the pH of the aqueous layer to 10, followed by liquid separation. The aqueous layer was extracted with dichloromethane, and the entire organic layer obtained was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (DNH silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 95: 5 (V / V)), and (R) -2,2,2 The fraction containing -trifluoro-N- (3-hydroxy-3-methyl-1-phenylbutyl) acetamide was concentrated under reduced pressure to obtain a concentrated residue.
To a solution of the obtained concentrated residue 427 mg in ethanol 5 ml, sodium borohydride 64.6 mg (1.71 mmol) was added in several portions at room temperature, and the mixture was stirred at room temperature for 14 hours. Further, 77.0 mg (2.04 mmol) of sodium borohydride was added in several portions, and the mixture was stirred at room temperature for 2 hours and then stirred at 75 ° C. for 2 hours.
After completion of the reaction, the reaction solution was ice-cooled, 10 ml of a saturated aqueous ammonium chloride solution was added dropwise, and the mixture was stirred at room temperature. Dichloromethane and water were added, dilute aqueous sodium hydroxide was added to adjust the pH of the aqueous layer to 10, and the layers were separated. The aqueous layer was extracted with dichloromethane, and the entire organic layer obtained was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue is subjected to silica gel column chromatography (DNH silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure. Gave 160 mg (49% yield) of the title compound as a colorless oil.
Mass spectrum (DUIS, m / z): 180 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 7.37-7.26 (m, 4H), 7.21-7.15 (m, 1H), 4.05 (dd, J = 2.8, 10.7 Hz, 1H), 1.66 (dd , J = 10.7, 14.0 Hz, 1H), 1.52 (dd, J = 2.8, 14.0 Hz, 1H), 1.22 (s, 3H), 1.10 (s, 3H).
（参考例２２）
（Ｓ）－ｔｅｒｔ－ブチル　［２－（ジフルオロメトキシ）－１－フェニルエチル］カルバマート
Figure JPOXMLDOC01-appb-C000146
 (Reference Example 22)
(S) -tert-butyl [2- (difluoromethoxy) -1-phenylethyl] carbamate
Figure JPOXMLDOC01-appb-C000146
　（Ｓ）－ｔｅｒｔ－ブチル　（２－ヒドロキシ－１－フェニルエチル）カルバマート［Ｎｏｖｏ　Ｃｈｅｍｙ　Ｌｔｄ．より購入］１．００ｇ（４．２１ｍｍｏｌ）の脱水アセトニトリル３０ｍｌ溶液に、アルゴン雰囲気下で、ヨウ化銅（Ｉ）１６５ｍｇ（０．８６６ｍｍｏｌ）を室温で加え、同温度で３０分間攪拌した。次いで、２－（フルオロスルホニル）ジフルオロ酢酸０．８７ｍｌ（８．４ｍｍｏｌ）の脱水アセトニトリル１０ｍｌ溶液を４５℃で４０分かけて１ｍｌずつ分割添加し、同温度で１時間攪拌した。
　反応終了後、室温まで放冷した反応液を減圧濃縮した。得られた濃縮残渣に水、酢酸エチルを加え、その混合液から酢酸エチルで抽出した。得られた有機層を水洗後、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９５：５～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣を再度シリカゲルクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル９５：５～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥し、標記化合物２１３ｍｇ（収率１８％）を黄色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：２８８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：7.55 (d, J = 8.7 Hz, 1H), 7.37 - 7.24 (m, 5H), 6.67 (t, J = 75.9Hz, 1H), 4.83 - 4.73 (m, 1H), 3.95 - 3.86 (m, 2H), 1.42 - 1.23 (m, 9H)。 (S) -tert-butyl (2-hydroxy-1-phenylethyl) carbamate [Novo Chem Ltd. Purchased] To a solution of 1.00 g (4.21 mmol) in 30 ml of dehydrated acetonitrile was added 165 mg (0.866 mmol) of copper (I) iodide at room temperature under an argon atmosphere, and the mixture was stirred at the same temperature for 30 minutes. Then, a solution of 0.87 ml (8.4 mmol) of 2- (fluorosulfonyl) difluoroacetic acid in 10 ml of dehydrated acetonitrile was added in 1 ml portions at 45 ° C. over 40 minutes and stirred at the same temperature for 1 hour.
After completion of the reaction, the reaction solution was allowed to cool to room temperature and concentrated under reduced pressure. Water and ethyl acetate were added to the resulting concentrated residue, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 95: 5 to 50:50 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The obtained concentrated residue is again subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate 95: 5 to 50:50 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure and dried under reduced pressure. 213 mg (18% yield) of the title compound were obtained as a yellow solid.
Mass spectrum (CI, m / z): 288 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 7.55 (d, J = 8.7 Hz, 1H), 7.37-7.24 (m, 5H), 6.67 (t, J = 75.9 Hz, 1H), 4.83- 4.73 (m, 1H), 3.95-3.86 (m, 2H), 1.42-1.23 (m, 9H).
（参考例２３）
（Ｓ）－２－（ジフルオロメトキシ）－１－フェニルエタンアミン　トリフルオロ酢酸塩
Figure JPOXMLDOC01-appb-C000147
 (Reference Example 23)
(S) -2- (Difluoromethoxy) -1-phenylethanamine trifluoroacetate
Figure JPOXMLDOC01-appb-C000147
　参考例２２と同様にして合成した（Ｓ）－ｔｅｒｔ－ブチル　［２－（ジフルオロメトキシ）－１－フェニルエチル］カルバマート２１０ｍｇ（０．７３１ｍｍｏｌ）の脱水ジクロロメタン４ｍｌ溶液に、アルゴン雰囲気下、トリフルオロ酢酸１ｍｌを室温で加え、同温度で２時間攪拌した。
　反応終了後、反応液を減圧濃縮、減圧乾燥することで標記化合物２１０ｍｇ（収率９５％）を黄色油状物として得た。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：8.59 (br s, 3H), 7.54 - 7.40 (m, 5H), 6.76 (t, J = 74.8 Hz, 1H), 4.70 - 4.59 (m, 1H), 4.19 - 4.11 (m, 2H)。 To a solution of 210 mg (0.731 mmol) of (S) -tert-butyl [2- (difluoromethoxy) -1-phenylethyl] carbamate synthesized in the same manner as in Reference Example 22 in 4 ml of dehydrated dichloromethane was added trifluoroacetic acid under an argon atmosphere. 1 ml was added at room temperature and stirred at the same temperature for 2 hours.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure and dried under reduced pressure to obtain 210 mg (yield 95%) of the title compound as a yellow oil.
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 8.59 (br s, 3H), 7.54-7.40 (m, 5H), 6.76 (t, J = 74.8 Hz, 1H), 4.70-4.59 (m, 1H), 4.19-4.11 (m, 2H).
（参考例２４）
（Ｓ）－２－エトキシ－１－フェニルエタンアミン
Figure JPOXMLDOC01-appb-C000148
 (Reference Example 24)
(S) -2-Ethoxy-1-phenylethanamine
Figure JPOXMLDOC01-appb-C000148
　（Ｓ）－２－アミノ－２－フェニルエタノール１．４０ｇ（１０．２ｍｍｏｌ）、１，４，７，１０，１３－ペンタオキサシクロペンタデカン３．０ｍｌ（１５ｍｍｏｌ）の脱水ＴＨＦ１０ｍｌ溶液に、アルゴン雰囲気下で、撹拌しながら、５５％水素化ナトリウム４８１ｍｇ（１１．０ｍｍｏｌ）を室温で分割添加し、同温度で発泡が収まるまで攪拌した。次いで、ヨウ化エチル０．８２ｍｌ（１０ｍｍｏｌ）を室温で滴下し、同温度で２４時間撹拌した。
　反応終了後、反応液に水、ジエチルエーテル加え、分液した。水層をジエチルエーテルで抽出した後、全有機層を飽和塩化ナトリウム水溶液で洗浄、無水硫酸ナトリウムで乾燥、濾過、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＤＮＨシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～９５：５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物１．１７ｇ（収率６９％）を淡黄色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１６６［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：7.39 - 7.33 (m, 2H), 7.33 - 7.25 (m, 2H), 7.25- 7.19 (m, 1H), 4.01 (dd, J = 4.9, 8.0 Hz, 1H), 3.53 - 3.35 (m, 3H), 3.28 (dd, J= 8.0, 9.3 Hz, 1H), 1.82 (br s, 2H), 1.09 (t, J = 7.0 Hz, 3H)。 (S) -2-Amino-2-phenylethanol 1.40 g (10.2 mmol), 1,4,7,10,13-pentaoxacyclopentadecane 3.0 ml (15 mmol) in dehydrated THF 10 ml solution under argon atmosphere While stirring, 481 mg (11.0 mmol) of 55% sodium hydride was added in portions at room temperature and stirred at the same temperature until foaming stopped. Next, 0.82 ml (10 mmol) of ethyl iodide was added dropwise at room temperature, and the mixture was stirred at the same temperature for 24 hours.
After completion of the reaction, water and diethyl ether were added to the reaction solution and the layers were separated. After the aqueous layer was extracted with diethyl ether, the entire organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (DNH silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. This gave 1.17 g (69% yield) of the title compound as a pale yellow oil.
Mass spectrum (CI, m / z): 166 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 7.39-7.33 (m, 2H), 7.33-7.25 (m, 2H), 7.25- 7.19 (m, 1H), 4.01 (dd, J = 4.9, 8.0 Hz, 1H), 3.53-3.35 (m, 3H), 3.28 (dd, J = 8.0, 9.3 Hz, 1H), 1.82 (br s, 2H), 1.09 (t, J = 7.0 Hz, 3H).
（参考例２５）
（Ｒ）－３－メトキシ－１－フェニルプロパン－１－アミン
Figure JPOXMLDOC01-appb-C000149
 (Reference Example 25)
(R) -3-Methoxy-1-phenylpropan-1-amine
Figure JPOXMLDOC01-appb-C000149
　（Ｒ）－３－アミノ－３－フェニルプロパン－１－オール［Ａｒｋ　Ｐｈａｒｍ，Ｉｎｃ．より購入］１．５３ｇ（１０．１ｍｍｏｌ）、１，４，７，１０，１３－ペンタオキサシクロペンタデカン３．０ｍｌ（１５ｍｍｏｌ）の脱水ＴＨＦ１０ｍｌ溶液に、アルゴン雰囲気下で、撹拌しながら、５５％水素化ナトリウム４７３ｍｇ（１０．９ｍｍｏｌ）を室温で分割添加し、同温度で発泡が収まるまで攪拌した。次いで、ヨウ化メチル０．６２ｍｌ（１０ｍｍｏｌ）を０℃で滴下した後、室温で１７時間撹拌した。
　反応終了後、反応液に水、ジエチルエーテル加え、分液した。水層をジエチルエーテルで抽出した後、全有機層を飽和塩化ナトリウム水溶液で洗浄、無水硫酸ナトリウムで乾燥、濾過、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＤＮＨシリカゲル，溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～９５：５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物１．４９ｇ（収率８９％）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１６６［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：7.35 - 7.26 (m, 4H), 7.24 - 7.15 (m, 1H), 3.85(dd, J = 6.4, 7.4 Hz, 1H), 3.38 - 3.20 (m, 2H), 3.19 (s, 3H), 1.93 - 1.63 (m,4H)。 (R) -3-Amino-3-phenylpropan-1-ol [Ark Pharm, Inc. Purchased] 1.53 g (10.1 mmol), 1,4,7,10,13-pentaoxacyclopentadecane 3.0 ml (15 mmol) in dehydrated THF 10 ml solution under argon atmosphere with stirring, 55% hydrogen Sodium 473 mg (10.9 mmol) was added in portions at room temperature and stirred at the same temperature until foaming stopped. Next, 0.62 ml (10 mmol) of methyl iodide was added dropwise at 0 ° C., followed by stirring at room temperature for 17 hours.
After completion of the reaction, water and diethyl ether were added to the reaction solution and the layers were separated. After the aqueous layer was extracted with diethyl ether, the entire organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (DNH silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. As a result, 1.49 g (yield 89%) of the title compound was obtained as a colorless oil.
Mass spectrum (CI, m / z): 166 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 7.35-7.26 (m, 4H), 7.24-7.15 (m, 1H), 3.85 (dd, J = 6.4, 7.4 Hz, 1H), 3.38-3.20 (m, 2H), 3.19 (s, 3H), 1.93-1.63 (m, 4H).
（参考例２６）
（Ｓ）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－２－フェニルエチル　アセタート
Figure JPOXMLDOC01-appb-C000150
 (Reference Example 26)
(S) -2-[(tert-Butoxycarbonyl) amino] -2-phenylethyl acetate
Figure JPOXMLDOC01-appb-C000150
　（Ｓ）－ｔｅｒｔ－ブチル（２－ヒドロキシ－１－フェニルエチル）カルバマート［Ｎｏｖｏ　Ｃｈｅｍｙ　Ｌｔｄ．より購入］１０ｇ（４２ｍｍｏｌ）、トリエチルアミン７．１ｍｌ（５１ｍｍｏｌ）の脱水ジクロロメタン１００ｍｌに、アルゴン雰囲気下、無水酢酸４．８０ｍｌ（５０．８ｍｍｏｌ）を０℃で滴下し、室温まで昇温後２０時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液１００ｍｌを加えた後、分液した。水層をジクロロメタン（１００ｍｌ）で２回抽出し、得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９３：７～７２：２８（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１０．５ｇ（収率８９％）を白色固体として得た。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：7.53 (d, J = 8.9 Hz, 1H), 7.38 - 7.31 (m, 4H),7.30 - 7.22 (m, 1H), 4.87 - 4.74 (m, 1H), 4.15 (dd, J = 4.8, 11.0 Hz, 1H), 4.02(dd, J = 8.8, 11.0 Hz, 1H), 1.98 (s, 3H), 1.43 - 1.20 (m, 9H)。 (S) -tert-butyl (2-hydroxy-1-phenylethyl) carbamate [Novo Chemy Ltd. Purchased] To 80 g of dehydrated dichloromethane of 10 g (42 mmol) and 7.1 ml (51 mmol) of triethylamine, 4.80 ml (50.8 mmol) of acetic anhydride was added dropwise at 0 ° C. in an argon atmosphere, and the mixture was warmed to room temperature and stirred for 20 hours. did.
After completion of the reaction, 100 ml of a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by liquid separation. The aqueous layer was extracted twice with dichloromethane (100 ml), and the entire organic layer obtained was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 93: 7 to 72:28 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure and dried under reduced pressure. This afforded 10.5 g (89% yield) of the title compound as a white solid.
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 7.53 (d, J = 8.9 Hz, 1H), 7.38-7.31 (m, 4H), 7.30-7.22 (m, 1H), 4.87-4.74 (m , 1H), 4.15 (dd, J = 4.8, 11.0 Hz, 1H), 4.02 (dd, J = 8.8, 11.0 Hz, 1H), 1.98 (s, 3H), 1.43-1.20 (m, 9H).
（参考例２７）
（Ｓ）－２－アミノ－２－フェニルエチル　アセタート　塩酸塩
Figure JPOXMLDOC01-appb-C000151
 (Reference Example 27)
(S) -2-Amino-2-phenylethyl acetate hydrochloride
Figure JPOXMLDOC01-appb-C000151
　参考例２６と同様にして合成した（Ｓ）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－２－フェニルエチル　アセタート１０．５ｇ（３７．６ｍｍｏｌ）の脱水ジクロロメタン１１０ｍｌ溶液に、アルゴン雰囲気下、４Ｎ塩化水素／１，４－ジオキサン溶液４７ｍｌ（１８８ｍｍｏｌ）を室温で加え、そのまま１４時間撹拌した。
　反応終了後、反応液を減圧濃縮した。得られた濃縮残渣にジエチルエーテルを加え、超音波処理後、濾過、減圧乾燥することにより、標記化合物６．７８ｇ（収率８４％）を白色固体として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：１８０［Ｍ（Ｆｒｅｅ体）＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：8.80 (br s, 3H), 7.59 - 7.52 (m, 2H), 7.49 -7.38 (m, 3H), 4.58 (dd, J = 6.1, 6.1 Hz, 1H), 4.39 - 4.29 (m, 2H), 2.06 (s, 3H)。 To a solution of (S) -2-[(tert-butoxycarbonyl) amino] -2-phenylethyl acetate 10.5 g (37.6 mmol) synthesized in the same manner as in Reference Example 26 in 110 ml of dehydrated dichloromethane, 4N 47 ml (188 mmol) of a hydrogen chloride / 1,4-dioxane solution was added at room temperature, and the mixture was stirred as it was for 14 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. Diethyl ether was added to the resulting concentrated residue, followed by sonication, filtration and drying under reduced pressure to obtain 6.78 g (yield 84%) of the title compound as a white solid.
Mass spectrum (DUIS, m / z): 180 [M (Free body) +1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 8.80 (br s, 3H), 7.59-7.52 (m, 2H), 7.49 -7.38 (m, 3H), 4.58 (dd, J = 6.1, 6.1 Hz, 1H), 4.39-4.29 (m, 2H), 2.06 (s, 3H).
（参考例２８）
（Ｓ）－ｔｅｒｔ－ブチル　［２－（ベンジルオキシ）－１－フェニルエチル］カルバマート
Figure JPOXMLDOC01-appb-C000152
 (Reference Example 28)
(S) -tert-butyl [2- (benzyloxy) -1-phenylethyl] carbamate
Figure JPOXMLDOC01-appb-C000152
　（Ｓ）－ｔｅｒｔ－ブチル　（２－ヒドロキシ－１－フェニルエチル）カルバマート［Ｎｏｖｏ　Ｃｈｅｍｙ　Ｌｔｄ．より購入］１０．０１ｇ（４２．２ｍｍｏｌ）の脱水ＤＭＦ２００ｍｌ溶液に、アルゴン雰囲気下、６０％水素化ナトリウム２．５８ｇ（６４．５ｍｍｏｌ）を０℃で加え、同温度で２０分間攪拌した。次いで、臭化ベンジル５．５０ｍｌ（４６．３ｍｍｏｌ）を０℃で加え、同温度で１時間攪拌した。
　反応終了後、反応液に飽和塩化アンモニウム水溶液を加え、その混合液から酢酸エチルで抽出した。得られた有機層を水で３回、飽和塩化ナトリウム水溶液で１回洗浄した後、無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９５：５～８０：２０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物９．９４ｇ（収率７２％）を白色固体として得た。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：7.44(d, J = 8.7 Hz, 1H), 7.37 - 7.21 (m, 10H), 4.84 - 4.73 (m, 1H), 4.49 (s, 2H),3.61 - 3.46 (m, 2H), 1.46 - 1.15 (m, 9H)。 (S) -tert-butyl (2-hydroxy-1-phenylethyl) carbamate [Novo Chem Ltd. Purchased] To a 200 ml solution of 10.01 g (42.2 mmol) of dehydrated DMF was added 2.58 g (64.5 mmol) of 60% sodium hydride at 0 ° C. in an argon atmosphere, and the mixture was stirred at the same temperature for 20 minutes. Next, 5.50 ml (46.3 mmol) of benzyl bromide was added at 0 ° C., and the mixture was stirred at the same temperature for 1 hour.
After completion of the reaction, saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed three times with water and once with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 95: 5 to 80:20 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure and dried under reduced pressure. This afforded 9.94 g (yield 72%) of the title compound as a white solid.
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 7.44 (d, J = 8.7 Hz, 1H), 7.37-7.21 (m, 10H), 4.84-4.73 (m, 1H), 4.49 (s, 2H ), 3.61-3.46 (m, 2H), 1.46-1.15 (m, 9H).
（参考例２９）
（Ｓ）－エチル　５－｛［２－（ベンジルオキシ）－１－フェニルエチル］カルバモイル｝－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート
Figure JPOXMLDOC01-appb-C000153
 (Reference Example 29)
(S) -Ethyl 5-{[2- (benzyloxy) -1-phenylethyl] carbamoyl} -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3 , 4-c] pyrazole-2 (4H) -carboxylate
Figure JPOXMLDOC01-appb-C000153
　参考例２８と同様にして合成した（Ｓ）－ｔｅｒｔ－ブチル　［２－（ベンジルオキシ）－１－フェニルエチル］カルバマート９．９４ｇ（３０．４ｍｍｏｌ）のジクロロメタン１２０ｍｌ溶液に、アルゴン雰囲気下で、トリフルオロ酢酸３０ｍｌを室温で加え、同温度で１時間攪拌した。
　反応終了後、反応液を減圧濃縮、減圧乾燥して、濃縮残渣１０．２５ｇを得た。
　得られた濃縮残渣のうちの一部３．０２ｇ、ＤＩＰＥＡ３．１０ｍｌ（１７．８ｍｍｏｌ）の脱水１，４－ジオキサン５０ｍｌ溶液に、アルゴン雰囲気下、参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１．９５ｇ（４．４２ｍｍｏｌ）を室温で加え、６０℃で８時間攪拌した。
　反応終了後、反応液に水を加え、その混合液から酢酸エチルで抽出した。得られた有機層を水、飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９０：１０～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１．８６ｇ（収率６７％）を白色泡状物として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：６３２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：9.80 (s, 1H), 7.43 - 7.18 (m, 10H), 6.56 (d, J = 8.2 Hz, 1H), 5.11 - 5.03 (m, 1H), 4.66 (d, J = 13.8 Hz, 1H), 4.60 (d, J = 13.8 Hz, 1H), 4.52 (s, 2H), 4.42 (q, J = 7.1Hz, 2H), 3.74 (dd, J = 8.0, 10.0 Hz, 1H), 3.63 (dd, J = 6.0, 10.0 Hz, 1H), 2.58- 2.52 (m, 2H), 2.31 - 2.22 (m, 2H), 1.95 - 1.84 (m, 2H), 1.62 (s, 3H), 1.55(s, 3H), 1.34 (t, J = 7.1 Hz, 3H), 0.12 (s, 9H)。 To a solution of 9.94 g (30.4 mmol) of (S) -tert-butyl [2- (benzyloxy) -1-phenylethyl] carbamate synthesized in the same manner as in Reference Example 28 in 120 ml of dichloromethane, was added trimethylamine under an argon atmosphere. 30 ml of fluoroacetic acid was added at room temperature and stirred at the same temperature for 1 hour.
After completion of the reaction, the reaction solution was concentrated under reduced pressure and dried under reduced pressure to obtain 10.25 g of a concentrated residue.
A portion of the resulting concentrated residue (3.02 g), DIPEA (3.10 ml, 17.8 mmol) in dehydrated 1,4-dioxane (50 ml) was synthesized in the same manner as in Reference Example 3 under an argon atmosphere. (Chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate 1.95 g (4. 42 mmol) was added at room temperature, and the mixture was stirred at 60 ° C. for 8 hours.
After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 50:50 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure and dried under reduced pressure. This gave 1.86 g (67% yield) of the title compound as a white foam.
Mass spectrum (DUIS, m / z): 632 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 9.80 (s, 1H), 7.43-7.18 (m, 10H), 6.56 (d, J = 8.2 Hz, 1H), 5.11-5.03 (m, 1H ), 4.66 (d, J = 13.8 Hz, 1H), 4.60 (d, J = 13.8 Hz, 1H), 4.52 (s, 2H), 4.42 (q, J = 7.1Hz, 2H), 3.74 (dd, J = 8.0, 10.0 Hz, 1H), 3.63 (dd, J = 6.0, 10.0 Hz, 1H), 2.58- 2.52 (m, 2H), 2.31-2.22 (m, 2H), 1.95-1.84 (m, 2H), 1.62 (s, 3H), 1.55 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H), 0.12 (s, 9H).
（参考例３０）
（Ｓ）－エチル　５－［（２－ヒドロキシ－１－フェニルエチル）カルバモイル］－６，６－ジメチルー３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート
Figure JPOXMLDOC01-appb-C000154
 (Reference Example 30)
(S) -ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c Pyrazole-2 (4H) -carboxylate
Figure JPOXMLDOC01-appb-C000154
　参考例２９と同様にして合成した（Ｓ）－エチル　５－｛［２－（ベンジルオキシ）－１－フェニルエチル］カルバモイル｝－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１．８６ｇ（２．９４ｍｍｏｌ）の２－プロパノール３０ｍｌ溶液に、アルゴン雰囲気下、２０％水酸化パラジウム／炭素０．１９ｇ（５０ｗｔ％含水）を室温で加えた後、減圧下水素雰囲気へと置換し、室温で１．５時間攪拌した。アルゴン雰囲気へ置換後、反応液をセライト濾過した。セライト上の固体を酢酸エチルで洗浄後、濾液を減圧濃縮した。得られた濃縮残渣の２－プロパノール３０ｍｌ溶液に、アルゴン雰囲気下、２０％水酸化パラジウム／炭素０．１９ｇ（５０ｗｔ％含水）を室温で加え、減圧下水素雰囲気へと置換し、室温で３．５時間攪拌した。
　反応終了後、アルゴン雰囲気へ置換後、反応液をセライト濾過した。セライト上の固体を酢酸エチルで洗浄し、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝８０：２０～６０：４０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１．３４ｇ（収率８４％）を白色泡状物として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：５４２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：9.81(s, 1H), 7.38 - 7.26 (m, 4H), 7.23 - 7.17 (m, 1H), 6.36 (d, J = 7.5 Hz, 1H),4.87 (t, J = 6.0 Hz, 1H), 4.82 - 4.75 (m, 1H), 4.66 (s, 2H), 4.42 (q, J = 7.2Hz, 2H), 3.67 - 3.55 (m, 2H), 2.60 - 2.52 (m, 2H), 2.31 - 2.21 (m, 2H), 1.96 -1.85 (m, 2H), 1.62 (s, 3H), 1.54 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H), 0.13 (s, 9H)。 (S) -Ethyl 5-{[2- (benzyloxy) -1-phenylethyl] carbamoyl} -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] synthesized in the same manner as in Reference Example 29 To a solution of -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate (1.86 g, 2.94 mmol) in 2-propanol (30 ml) under an argon atmosphere, 20% palladium hydroxide / carbon After adding 0.19 g (containing 50 wt% water) at room temperature, the atmosphere was replaced with a hydrogen atmosphere under reduced pressure, and the mixture was stirred at room temperature for 1.5 hours. After replacing with an argon atmosphere, the reaction solution was filtered through Celite. The solid on celite was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. To a 30 ml solution of the obtained concentrated residue in 2-propanol, 0.19 g of 20% palladium hydroxide / carbon (containing 50 wt% water) was added at room temperature under an argon atmosphere, and the atmosphere was replaced with a hydrogen atmosphere under reduced pressure. Stir for 5 hours.
After completion of the reaction, the reaction solution was filtered through Celite after replacing with an argon atmosphere. The solid on celite was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 80: 20 to 60:40 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure and dried under reduced pressure. This gave 1.34 g (84% yield) of the title compound as a white foam.
Mass spectrum (DUIS, m / z): 542 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 9.81 (s, 1H), 7.38-7.26 (m, 4H), 7.23-7.17 (m, 1H), 6.36 (d, J = 7.5 Hz, 1H ), 4.87 (t, J = 6.0 Hz, 1H), 4.82-4.75 (m, 1H), 4.66 (s, 2H), 4.42 (q, J = 7.2Hz, 2H), 3.67-3.55 (m, 2H) , 2.60-2.52 (m, 2H), 2.31-2.21 (m, 2H), 1.96 -1.85 (m, 2H), 1.62 (s, 3H), 1.54 (s, 3H), 1.34 (t, J = 7.2 Hz , 3H), 0.13 (s, 9H).
（参考例３１）
（Ｓ）－ベンジル　｛２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－２－フェニルエチル｝　スクシナート
Figure JPOXMLDOC01-appb-C000155
 (Reference Example 31)
(S) -benzyl {2-[(tert-butoxycarbonyl) amino] -2-phenylethyl} succinate
Figure JPOXMLDOC01-appb-C000155
　（Ｓ）－ｔｅｒｔ－ブチル　（２－ヒドロキシ－１－フェニルエチル）カルバマート［Ｎｏｖｏ　Ｃｈｅｍｙ　Ｌｔｄ．より購入］４９６ｍｇ（２．０９ｍｍｏｌ）及び無水コハク酸２２７ｍｇ（２．２６ｍｍｍｏｌ）の脱水ＤＭＦ３ｍｌ溶液に、窒素雰囲気下、４－ジメチルアミノピリジン２６．２ｍｇ（０．２１４ｍｍｏｌ）を室温で加え、室温で３時間撹拌した。次いで、臭化ベンジル０．２７０ｍｌ（２．２７ｍｍｏｌ）を室温で加え、室温で１５時間撹拌した。
　反応終了後、反応液にトルエンを加え、水で２回、飽和塩化ナトリウム水溶液で１回洗浄した後、得られた有機層を無水硫酸マグネシウムで乾燥し、濾過後、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝８６：１４～６５：３５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物８７２ｍｇ（収率９８％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：４２８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.39 - 7.25 (m, 10H), 5.21 - 5.08 (m, 3H), 5.04- 4.90 (m, 1H), 4.39 - 4.21 (m, 2H), 2.70 - 2.59 (m, 4H), 1.42 (br s, 9H)。 (S) -tert-butyl (2-hydroxy-1-phenylethyl) carbamate [Novo Chem Ltd. Purchased] To a solution of 496 mg (2.09 mmol) and 227 mg (2.26 mmol) of succinic anhydride in 3 ml of dehydrated DMF was added 26.2 mg (0.214 mmol) of 4-dimethylaminopyridine at room temperature under a nitrogen atmosphere. Stir for hours. Next, 0.270 ml (2.27 mmol) of benzyl bromide was added at room temperature and stirred at room temperature for 15 hours.
After completion of the reaction, toluene was added to the reaction solution, which was washed twice with water and once with a saturated aqueous sodium chloride solution. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 86: 14 to 65:35 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The title compound (872 mg, yield 98%) was obtained as a white solid.
Mass spectrum (CI, m / z): 428 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.39-7.25 (m, 10H), 5.21-5.08 (m, 3H), 5.04- 4.90 (m, 1H), 4.39-4.21 (m, 2H), 2.70 -2.59 (m, 4H), 1.42 (br s, 9H).
（参考例３２）
（Ｓ）－２－アミノ－２－フェニルエチル　ベンジル　スクシナート　トリフルオロ酢酸塩
Figure JPOXMLDOC01-appb-C000156
 (Reference Example 32)
(S) -2-Amino-2-phenylethyl benzyl succinate trifluoroacetate
Figure JPOXMLDOC01-appb-C000156
　参考例３１と同様にして合成した（Ｓ）－ベンジル　｛２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－２－フェニルエチル｝　スクシナート６０８ｍｇ（１．４２ｍｍｏｌ）のジクロロメタン１０ｍｌ溶液に、窒素雰囲気下、トリフルオロ酢酸２．０ｍｌ（２６ｍｍｏｌ）を室温で加え、室温で１時間撹拌した。
　反応終了後、反応液を減圧濃縮し、得られた濃縮残渣にトルエンを加え、減圧濃縮する操作を数回繰り返し、標記化合物８１３ｍｇ（不純物を含む）を得た。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：8.57 (br s, 3H), 7.53 - 7.30 (m, 10H), 5.09(s, 2H), 4.67 - 4.55 (m, 1H), 4.38 - 4.27 (m, 2H), 2.66 (s, 4H)。 (S) -benzyl {2-[(tert-butoxycarbonyl) amino] -2-phenylethyl} synthesized in the same manner as in Reference Example 31 was added to a solution of 608 mg (1.42 mmol) of succinate in 10 ml of dichloromethane under nitrogen atmosphere. 2.0 ml (26 mmol) of fluoroacetic acid was added at room temperature, and the mixture was stirred at room temperature for 1 hour.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, toluene was added to the resulting concentrated residue, and the operation of concentration under reduced pressure was repeated several times to obtain 813 mg (including impurities) of the title compound.
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 8.57 (br s, 3H), 7.53-7.30 (m, 10H), 5.09 (s, 2H), 4.67-4.55 (m, 1H), 4.38- 4.27 (m, 2H), 2.66 (s, 4H).
（参考例３３）
（Ｓ）－｛２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－２－フェニルエトキシ｝メチル　ピバラート
Figure JPOXMLDOC01-appb-C000157
 (Reference Example 33)
(S)-{2-[(tert-butoxycarbonyl) amino] -2-phenylethoxy} methyl pivalate
Figure JPOXMLDOC01-appb-C000157
　（Ｓ）－ｔｅｒｔ－ブチル　（２－ヒドロキシ－１－フェニルエチル）カルバマート［Ｎｏｖｏ　Ｃｈｅｍｙ　Ｌｔｄ．より購入］４．０９ｇ（１７．２ｍｍｏｌ）の脱水ＴＨＦ８０ｍｌ溶液に、窒素雰囲気下、６０ｗｔ％水素化ナトリウム０．７６２ｇ（１９．１ｍｍｏｌ）を０℃で加え、同温度で１時間撹拌した。次いで、クロロメチル　ピバラート２．６５ｍｌ（１８．３ｍｍｏｌ）を０℃で加え、同温度で２５分間、更に室温に昇温して２．５時間撹拌した。
　反応終了後、反応液に飽和塩化アンモニウム水を加え撹拌した後、酢酸エチルとｎ－ヘキサンの混合溶媒で２回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９５：５～７５：２５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物３．３２ｇ（収率５５％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：３５２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.36 - 7.23 (m,5H), 5.27 (d, J = 6.3 Hz, 1H), 5.33 - 5.21 (m, 1H), 5.19 (d, J = 6.3Hz, 1H), 4.80 (br s, 1H), 3.91 (dd, J= 4.4, 9.6 Hz, 1H), 3.87 - 3.77 (m,1H), 1.41 (br s, 9H), 1.18 (s, 9H)。 (S) -tert-butyl (2-hydroxy-1-phenylethyl) carbamate [Novo Chem Ltd. Purchased] To a solution of 4.09 g (17.2 mmol) in 80 ml of dehydrated THF was added 0.762 g (19.1 mmol) of 60 wt% sodium hydride at 0 ° C. in a nitrogen atmosphere, and the mixture was stirred at the same temperature for 1 hour. Subsequently, 2.65 ml (18.3 mmol) of chloromethyl pivalate was added at 0 ° C., and the mixture was stirred at the same temperature for 25 minutes and further at room temperature for 2.5 hours.
After completion of the reaction, saturated aqueous ammonium chloride was added to the reaction mixture and stirred, followed by extraction twice with a mixed solvent of ethyl acetate and n-hexane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 95: 5 to 75:25 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure. As a result, 3.32 g (yield 55%) of the title compound was obtained as a white solid.
Mass spectrum (CI, m / z): 352 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.36-7.23 (m, 5H), 5.27 (d, J = 6.3 Hz, 1H), 5.33-5.21 (m, 1H), 5.19 (d, J = 6.3 Hz, 1H), 4.80 (br s, 1H), 3.91 (dd, J = 4.4, 9.6 Hz, 1H), 3.87-3.77 (m, 1H), 1.41 (br s, 9H), 1.18 (s, 9H) .
（参考例３４）
（Ｓ）－（２－アミノ－２－フェニルエトキシ）メチル　ピバラート
Figure JPOXMLDOC01-appb-C000158
 (Reference Example 34)
(S)-(2-Amino-2-phenylethoxy) methyl pivalate
Figure JPOXMLDOC01-appb-C000158
　参考例３３と同様にして合成した（Ｓ）－｛２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－２－フェニルエトキシ｝メチル　ピバラート３．３２ｇ（９．４５ｍｍｏｌ）の脱水ジクロロメタン５０ｍｌ溶液に、窒素雰囲気下、トリフルオロ酢酸６．０ｍｌ（７８ｍｍｏｌ）を０℃で加え、同温度で２時間撹拌後、室温に昇温して７０分間撹拌した。
　反応終了後、反応液を飽和炭酸水素ナトリウム水溶液に注ぎ入れて中和し、ジクロロメタンで３回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＮＨシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９５：５～８０：２０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１．８３ｇ（収率７７％）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：２５２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.40 - 7.24 (m,5H), 5.36 (d, J = 6.1 Hz, 1H),5.26 (d, J = 6.1 Hz, 1H), 4.21(dd, J = 3.8, 8.8 Hz, 1H), 3.78(dd, J = 3.8, 9.6 Hz, 1H), 3.59 (dd, J = 8.8, 9.6Hz, 1H), 1.21 (s, 9H)。 A solution of (S)-{2-[(tert-butoxycarbonyl) amino] -2-phenylethoxy} methyl pivalate (3.32 g, 9.45 mmol) synthesized in the same manner as in Reference Example 33 was added to a 50 ml of dehydrated dichloromethane in a nitrogen atmosphere. Then, 6.0 ml (78 mmol) of trifluoroacetic acid was added at 0 ° C., stirred at the same temperature for 2 hours, then warmed to room temperature and stirred for 70 minutes.
After completion of the reaction, the reaction mixture was neutralized by pouring into a saturated aqueous sodium hydrogen carbonate solution and extracted three times with dichloromethane. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DNH silica gel, elution solvent; n-hexane: ethyl acetate = 95: 5 to 80:20 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. By drying under reduced pressure, 1.83 g (yield 77%) of the title compound was obtained as a colorless oil.
Mass spectrum (CI, m / z): 252 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.40-7.24 (m, 5H), 5.36 (d, J = 6.1 Hz, 1H), 5.26 (d, J = 6.1 Hz, 1H), 4.21 (dd, J = 3.8, 8.8 Hz, 1H), 3.78 (dd, J = 3.8, 9.6 Hz, 1H), 3.59 (dd, J = 8.8, 9.6Hz, 1H), 1.21 (s, 9H).
（参考例３５）
（Ｓ）－２－（｛［（２，５－ジオキソピロリジン－１－イル）オキシ］カルボニル｝オキシ）－２－フェニルエチル　アセタート
Figure JPOXMLDOC01-appb-C000159
 (Reference Example 35)
(S) -2-({[(2,5-dioxopyrrolidin-1-yl) oxy] carbonyl} oxy) -2-phenylethyl acetate
Figure JPOXMLDOC01-appb-C000159
　（Ｓ）－２－ヒドロキシ－２－フェニルエチル　アセタート［Ｊ．Ｏｒｇ．Ｃｈｅｍ．，２０１３，７８（２２），１１６１８－１１６２２．に記載の方法に準じて合成］０．８４ｇ（４．７ｍｍｏｌ）の脱水アセトニトリル３０ｍｌ溶液に、窒素雰囲気下、トリエチルアミン０．９０ｍｌ（６．４ｍｍｏｌ）、Ｎ，Ｎ’－ジスクシンイミジル　カルボナート１．３３ｇ（５．１９ｍｍｏｌ）を室温で順次加え、同温度で１５時間撹拌した。
　反応終了後、反応液を減圧濃縮した。得られた濃縮残渣を酢酸エチルに溶解させ、それを水で洗浄した。有機層と水層を分けた後、水層を酢酸エチルで１回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝８５：１５～６０：４０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１．２８ｇ（収率８５％）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：３２２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.45 - 7.34 (m,5H), 5.95 (dd, J = 5.2, 7.2 Hz,1H), 4.39 (d, J = 5.2 Hz, 1H),4.38 (d, J = 7.2 Hz, 1H), 2.83(s, 4H), 2.12 (s, 3H)。 (S) -2-Hydroxy-2-phenylethyl acetate [J. Org. Chem. , 2013, 78 (22), 11618-11622. Synthesis in accordance with the method described in 1] 0.94 ml (6.4 mmol) of triethylamine, N, N′-disuccinimidyl carbonate in a 30 ml solution of 0.84 g (4.7 mmol) of dehydrated acetonitrile under a nitrogen atmosphere. 33 g (5.19 mmol) was sequentially added at room temperature, and the mixture was stirred at the same temperature for 15 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. The resulting concentrated residue was dissolved in ethyl acetate and washed with water. After separating the organic layer and the aqueous layer, the aqueous layer was extracted once with ethyl acetate. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 85: 15 to 60:40 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure. As a result, 1.28 g (yield 85%) of the title compound was obtained as a colorless oil.
Mass spectrum (CI, m / z): 322 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.45-7.34 (m, 5H), 5.95 (dd, J = 5.2, 7.2 Hz, 1H), 4.39 (d, J = 5.2 Hz, 1H), 4.38 ( d, J = 7.2 Hz, 1H), 2.83 (s, 4H), 2.12 (s, 3H).
（参考例３６）
（Ｓ）－ベンジル　２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－２－フェニルアセタ－ト
Figure JPOXMLDOC01-appb-C000160
 (Reference Example 36)
(S) -Benzyl 2-[(tert-butoxycarbonyl) amino] -2-phenylacetate
Figure JPOXMLDOC01-appb-C000160
　（Ｓ）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－２－フェニル酢酸２．５０ｇ（９．９５ｍｍｏｌ）のＤＭＦ３０ｍｌ溶液に、窒素雰囲気下、撹拌しながら炭酸カリウム１．４７ｇ（１０．６ｍｍｏｌ）を室温で分割添加し、次いで、臭化ベンジル１．２０ｍｌ（１０．１ｍｍｏｌ）を室温で滴下し、同温度で７時間攪拌後、室温で３日放置した。
　反応終了後、反応液にトルエンを加え、水で２回洗浄した。得られた全有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥し、濾過後、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～７９：２１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物３．２４ｇ（収率９５％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：３４２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.37 - 7.27 (m, 8H), 7.23 - 7.15 (m, 2H), 5.61 -5.50 (m, 1H), 5.40 - 5.33 (m, 1H), 5.23 - 5.08 (m, 2H), 1.49 - 1.29 (m, 9H)。 (S) -2-[(tert-Butoxycarbonyl) amino] -2-phenylacetic acid 2.50 g (9.95 mmol) in a DMF 30 ml solution with stirring under nitrogen atmosphere 1.47 g (10.6 mmol) of potassium carbonate Then, 1.20 ml (10.1 mmol) of benzyl bromide was added dropwise at room temperature, stirred at the same temperature for 7 hours, and left at room temperature for 3 days.
After completion of the reaction, toluene was added to the reaction solution and washed twice with water. The obtained all organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 79:21 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The title compound (3.24 g, yield 95%) was obtained as a white solid.
Mass spectrum (CI, m / z): 342 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.37-7.27 (m, 8H), 7.23-7.15 (m, 2H), 5.61 -5.50 (m, 1H), 5.40-5.33 (m, 1H), 5.23 -5.08 (m, 2H), 1.49-1.29 (m, 9H).
（参考例３７）
（Ｓ）－ベンジル　２－アミノ－２－フェニルアセタート　トリフルオロ酢酸塩
Figure JPOXMLDOC01-appb-C000161
 (Reference Example 37)
(S) -Benzyl 2-amino-2-phenyl acetate trifluoroacetate
Figure JPOXMLDOC01-appb-C000161
　参考例３６と同様にして合成した（Ｓ）－ベンジル　２－［（ｔｅｒｔ-ブトキシカルボニル）アミノ］－２－フェニルアセタ－ト４６２ｍｇ（１．３５ｍｍｏｌ）のジクロロメタン１０ｍｌ溶液に、トリフルオロ酢酸２．０ｍｌ（２６ｍｍｏｌ）を室温で加え、室温で２４時間撹拌した。
　反応終了後、反応液を減圧濃縮した。得られた濃縮残渣にジクロロメタンを加え、減圧濃縮する操作を数回繰り返すことにより、標記化合物５７２ｍｇ（不純物を含む）を得た。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：8.93 (br s, 3H), 7.54 - 7.44 (m, 5H), 7.38 -7.31 (m, 3H), 7.27 - 7.21 (m, 2H), 5.40 (br s, 1H), 5.27 (d, J = 12.5 Hz,1H), 5.21 (d, J = 12.5 Hz, 1H)。 To a solution of (S) -benzyl 2-[(tert-butoxycarbonyl) amino] -2-phenylacetate (462 mg, 1.35 mmol) synthesized in the same manner as in Reference Example 36 in 10 ml of dichloromethane, 2.0 ml of trifluoroacetic acid ( 26 mmol) was added at room temperature and stirred at room temperature for 24 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. Dichloromethane was added to the obtained concentrated residue and the operation of concentration under reduced pressure was repeated several times to obtain 572 mg (including impurities) of the title compound.
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 8.93 (br s, 3H), 7.54-7.44 (m, 5H), 7.38 -7.31 (m, 3H), 7.27-7.21 (m, 2H), 5.40 (br s, 1H), 5.27 (d, J = 12.5 Hz, 1H), 5.21 (d, J = 12.5 Hz, 1H).
（参考例３８）
エチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート
Figure JPOXMLDOC01-appb-C000162
 (Reference Example 38)
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate
Figure JPOXMLDOC01-appb-C000162
　１－（トリメチルシリル）シクロプロパンカルボン酸［Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９８２（４７）５，８９３－８９５．に記載の方法に準じて合成］９．７０ｇ（６１．３ｍｍｏｌ）の脱水ジクロロメタン１２０ｍｌ溶液に、窒素雰囲気下、塩化オキサリル６．６０ｍｌ（７６．９ｍｍｏｌ）、脱水ＤＭＦ０．２５ｍｌ（３．２ｍｍｏｌ）を０℃で順次加えた後、そのままの温度で２．５時間撹拌した。
　反応終了後、反応液を減圧濃縮、減圧乾燥することにより濃縮残渣を得た。
　窒素雰囲気下、得られた濃縮残渣の脱水ジクロロメタン３０ｍｌ溶液をＤＩＰＥＡ１９．０ｍｌ（１０９ｍｍｏｌ）、５－ｔｅｒｔ－ブチル　２－エチル　３－アミノ－６，６－ジメチルピロロ［３，４－ｃ］ピラゾール－２，５（４Ｈ，６Ｈ）－ジカルボキシラート［Ｊｏｕｒｎａｌ　ｏｆ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ　２０１２，５５（１０），４７２８－４７３９．に記載の方法に準じて合成］９．９４ｇ（３０．６ｍｍｏｌ）の脱水ジクロロメタン１７０ｍｌ溶液に０℃で加えた後、そのままの温度で２４時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加えて撹拌し、次いでジクロロメタンで１回、酢酸エチルで２回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥後、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９０：１０～７０：３０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。不純物を含む画分の濃縮残渣については再度シリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９０：１０～７５：２５（Ｖ／Ｖ））に付し、先に得られた精製体と合わせて減圧濃縮、減圧乾燥することにより、濃縮残渣１０．６３ｇを得た。
　得られた濃縮残渣の酢酸エチル１００ｍｌ溶液に、窒素雰囲気下、４Ｎ塩化水素／酢酸エチル６０．０ｍｌ（２４０ｍｍｏｌ）を室温で加えた後、そのままの温度で５時間撹拌した。
　反応終了後、反応液を減圧濃縮した。得られた濃縮残渣をジイソプロピルエーテルに懸濁させ、その懸濁液を室温で撹拌した。不溶物を濾取し、取得した固体をジイソプロピルエーテルで洗浄した。得られた固体を水に溶解させた後、飽和炭酸水素ナトリウム水溶液とジクロロメタンを加え、室温で５分間撹拌した。分液した後、水層をジクロロメタンで２回抽出した。全有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮、減圧乾燥することにより、標記化合物８．２７ｇ（収率７３％［２工程］）を微橙色固体として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：３６５［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：10.02 (s, 1H), 4.53 (q, J = 7.2 Hz, 2H), 4.16 (s, 2H), 1.50 - 1.43 (m, 9H), 1.14 - 1.08 (m, 2H), 0.84 - 0.77 (m, 2H), 0.12 (s, 9H)。 1- (Trimethylsilyl) cyclopropanecarboxylic acid [J. Org. Chem. 1982 (47) 5,893-895. Synthesis of 9.70 g (61.3 mmol) of dehydrated dichloromethane in 120 ml solution under a nitrogen atmosphere was added 6.60 ml (76.9 mmol) of oxalyl chloride and 0.25 ml (3.2 mmol) of dehydrated DMF to 0. After sequentially adding at 0 ° C., the mixture was stirred at the same temperature for 2.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure and dried under reduced pressure to obtain a concentrated residue.
Under nitrogen atmosphere, 30 ml of a dehydrated dichloromethane solution of the obtained concentrated residue was mixed with 19.0 ml (109 mmol) of DIPEA, 5-tert-butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo [3,4-c] pyrazole-2. , 5 (4H, 6H) -dicarboxylate [Journal of Medicinal Chemistry 2012, 55 (10), 4728-4739. Was added to a solution of 9.94 g (30.6 mmol) of dehydrated dichloromethane in 170 ml at 0 ° C. and then stirred at the same temperature for 24 hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and stirred, followed by extraction once with dichloromethane and twice with ethyl acetate. The entire organic layer obtained was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 70:30 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The concentrated residue of the fraction containing impurities is again subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 75:25 (V / V)), and the purified product obtained earlier. And concentrated under reduced pressure and dried under reduced pressure to obtain 10.63 g of a concentrated residue.
To a solution of the concentrated residue obtained in 100 ml of ethyl acetate was added 60.0 ml (240 mmol) of 4N hydrogen chloride / ethyl acetate at room temperature in a nitrogen atmosphere, followed by stirring at the same temperature for 5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained concentrated residue was suspended in diisopropyl ether, and the suspension was stirred at room temperature. The insoluble material was collected by filtration, and the obtained solid was washed with diisopropyl ether. The obtained solid was dissolved in water, saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added, and the mixture was stirred at room temperature for 5 min. After liquid separation, the aqueous layer was extracted twice with dichloromethane. The whole organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and dried under reduced pressure to obtain 8.27 g (yield 73% [2 steps]) of the title compound as a slightly orange solid. It was.
Mass spectrum (DUIS, m / z): 365 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 10.02 (s, 1H), 4.53 (q, J = 7.2 Hz, 2H), 4.16 (s, 2H), 1.50-1.43 (m, 9H), 1.14- 1.08 (m, 2H), 0.84-0.77 (m, 2H), 0.12 (s, 9H).
（参考例３９）
Ｎ－（２，２－ジフルオロ－３－ヒドロキシ－１－フェニルプロピル）－２－メチルプロパン－２－スルフィンアミド
Figure JPOXMLDOC01-appb-C000163
 (Reference Example 39)
N- (2,2-difluoro-3-hydroxy-1-phenylpropyl) -2-methylpropane-2-sulfinamide
Figure JPOXMLDOC01-appb-C000163
　アルゴン雰囲気下、脱気した脱水ＴＨＦ３２ｍｌに、活性亜鉛粉末３．２９ｇ（５０．３ｍｍｏｌ）を室温で加えた後、４０℃に加熱した。次いで、反応液にエチル　ブロモジフルオロアセタート８．６０ｍｌ（６６．１ｍｍｏｌ）を４０℃で分割添加した後、４０℃で１時間撹拌した。室温まで放冷した反応液にＮ－ベンジリデン－２－メチルプロパン－２－スルフィンアミド［Ｏｒｇ．　Ｌｅｔｔ．，２００５，７，５４９３－５４９６．に記載の方法に準じて合成］３．４７ｇ（１６．６ｍｍｏｌ）の脱水ＴＨＦ１８ｍｌ溶液を室温で加えた後、室温で２３時間撹拌した。
　反応終了後、反応液に酢酸エチルと飽和炭酸水素ナトリウム水溶液を加えた後、室温で１０分間撹拌した。得られた懸濁液をセライトフィルターを用いて濾過し、次いで除去した固体を酢酸エチルで洗浄した後、ろ液を分液した。水層を酢酸エチルで２回抽出後、得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝８５：１５～６５：３５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、濃縮残渣４．０８ｇを得た。
　得られた濃縮残渣の一部１．０１ｇの脱水ＴＨＦ２０ｍｌ溶液に、窒素雰囲気下で水素化ホウ素リチウム１３６ｍｇ（６．２３ｍｍｏｌ）を室温で加えた後、そのままの温度で１．５時間撹拌した。
　反応終了後、反応液に飽和塩化アンモニウム水溶液を発泡が治まるまで滴下しながら加えた後、更に過剰量の飽和塩化アンモニウム水溶液を加え、室温で１０分間撹拌した。次いで、酢酸エチルで３回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥後、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝８０：２０～５０：５０（Ｖ／Ｖ））に付し、次いで減圧濃縮、減圧乾燥することにより、標記化合物５７３ｍｇ（収率４８％［２工程］）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：２９２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.42 - 7.33 (m, 5H), 4.97 - 4.85 (m, 1H), 4.37 (d, J = 6.8 Hz, 1H), 4.03 - 3.74 (m, 3H), 1.25 (s, 9H)。 Under an argon atmosphere, 3.29 g (50.3 mmol) of active zinc powder was added to 32 ml of degassed dehydrated THF at room temperature, and then heated to 40 ° C. Next, 8.60 ml (66.1 mmol) of ethyl bromodifluoroacetate was added to the reaction solution in portions at 40 ° C., followed by stirring at 40 ° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, and N-benzylidene-2-methylpropane-2-sulfinamide [Org. Lett. 2005, 7, 5493-5396. Synthesis according to the method described in 1.] A solution of 3.47 g (16.6 mmol) in 18 ml of dehydrated THF was added at room temperature, followed by stirring at room temperature for 23 hours.
After completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the mixture was stirred at room temperature for 10 minutes. The obtained suspension was filtered using a celite filter, and then the removed solid was washed with ethyl acetate, and then the filtrate was separated. The aqueous layer was extracted twice with ethyl acetate, and the entire organic layer obtained was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 85: 15 to 65:35 (V / V)), and the fraction containing the target product was concentrated under reduced pressure and dried under reduced pressure. As a result, 4.08 g of concentrated residue was obtained.
136 mg (6.23 mmol) of lithium borohydride was added to a 1.01 g portion of the obtained concentrated residue in 20 ml of dehydrated THF at room temperature under a nitrogen atmosphere, and then stirred at the same temperature for 1.5 hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added dropwise to the reaction solution until effervescence ceased, and then an excess amount of a saturated aqueous ammonium chloride solution was added and stirred at room temperature for 10 minutes. It was then extracted 3 times with ethyl acetate. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 80: 20 to 50:50 (V / V)), then concentrated under reduced pressure and dried under reduced pressure to give the title compound. 573 mg (yield 48% [2 steps]) was obtained as a colorless oil.
Mass spectrum (CI, m / z): 292 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.42-7.33 (m, 5H), 4.97-4.85 (m, 1H), 4.37 (d, J = 6.8 Hz, 1H), 4.03-3.74 (m, 3H ), 1.25 (s, 9H).
（参考例４０）
３－アミノ－２，２－ジフルオロ－３－フェニルプロパン－１－オール
Figure JPOXMLDOC01-appb-C000164
 (Reference Example 40)
3-Amino-2,2-difluoro-3-phenylpropan-1-ol
Figure JPOXMLDOC01-appb-C000164
　窒素雰囲気下、参考例３９と同様にして合成したＮ－（２，２－ジフルオロ－３－ヒドロキシ－１－フェニルプロピル）－２－メチルプロパン－２－スルフィンアミド５６８ｍｇ（１．９５ｍｍｏｌ）のエタノール５ｍｌ溶液に、４Ｎ塩化水素／１，４－ジオキサン２．０ｍｌ（８．０ｍｍｏｌ）を室温で加えた後、そのままの温度で１．５時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加えて中和した後、ジクロロメタンで３回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥後、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７０：３０～３０：７０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物２５４ｍｇ（収率７０％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１８８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.46 - 7.32 (m, 5H), 4.44 (dd, J = 9.8, 13.1 Hz, 1H), 3.88 (ddd, J = 8.6, 12.4, 17.8 Hz, 1H), 3.79 - 3.67 (m, 1H)。 N- (2,2-difluoro-3-hydroxy-1-phenylpropyl) -2-methylpropane-2-sulfinamide 568 mg (1.95 mmol) ethanol 5 ml synthesized in the same manner as in Reference Example 39 under nitrogen atmosphere To the solution was added 4N hydrogen chloride / 1,4-dioxane (2.0 ml, 8.0 mmol) at room temperature, and the mixture was stirred at the same temperature for 1.5 hours.
After completion of the reaction, the reaction mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with dichloromethane three times. The obtained all organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 70: 30 to 30:70 (V / V)), and the fraction containing the target product was concentrated under reduced pressure and dried under reduced pressure. As a result, 254 mg (yield 70%) of the title compound was obtained as a white solid.
Mass spectrum (CI, m / z): 188 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.46-7.32 (m, 5H), 4.44 (dd, J = 9.8, 13.1 Hz, 1H), 3.88 (ddd, J = 8.6, 12.4, 17.8 Hz, 1H ), 3.79-3.67 (m, 1H).
（参考例４１）
メチル　２－｛［（ベンジルオキシ）カルボニル］（２－シアノエチル）アミノ｝－２－メチルプロパノアート
Figure JPOXMLDOC01-appb-C000165
 (Reference Example 41)
Methyl 2-{[(benzyloxy) carbonyl] (2-cyanoethyl) amino} -2-methylpropanoate
Figure JPOXMLDOC01-appb-C000165
　メチル　２－［（２－シアノエチル）アミノ］－２－メチルプロパノアート［Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９６８，１１（３），６１６－６１８．に記載の方法に準じて合成］５．００ｇ（２９．４ｍｍｏｌ）のトルエン２３ｍｌ溶液に、アルゴン雰囲気下、攪拌しながらＤＩＰＥＡ１５．５ｍｌ（９０．７ｍｏｌ）、３０－３５％クロロギ酸ベンジル　トルエン溶液［東京化成工業(株)より購入］３２．０ｍｌを室温で順次加え、そのままの温度で１．５時間攪拌した。次いで５０℃で１．５時間攪拌した後、室温まで放冷しＮ，Ｎ－ジメチルエタン－１，２－ジアミン４．８０ｍｌ（４４．１ｍｍｏｌ）を室温で加え、そのままの温度で２．５時間攪拌した。
　反応終了後、反応液を２Ｎ塩酸に注ぎ、攪拌した。水層と有機層とを分液し、有機層を飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥、濾過後、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝８４：１６～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮し、標記化合物８．３２ｇ（収率９３％）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：３０５［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：7.43 - 7.28 (m, 5H), 5.07 (s, 2H), 3.64 (t, J = 6.7 Hz, 2H), 3.50 (br s, 3H), 2.76 (t, J = 6.7 Hz, 2H), 1.45 (s, 6H)。 Methyl 2-[(2-cyanoethyl) amino] -2-methylpropanoate [J. Med. Chem. 1968, 11 (3), 616-618. Synthesis of 5.00 g (29.4 mmol) of toluene in a 23 ml toluene solution with stirring in an argon atmosphere, 15.5 ml (90.7 mol) of DIPEA, 30-35% benzyl chloroformate in toluene [Tokyo Purchased from Kasei Kogyo Co., Ltd.] 32.0 ml was sequentially added at room temperature and stirred at the same temperature for 1.5 hours. Next, the mixture was stirred at 50 ° C. for 1.5 hours, and then allowed to cool to room temperature. Stir.
After completion of the reaction, the reaction solution was poured into 2N hydrochloric acid and stirred. The aqueous layer and the organic layer were separated, and the organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and then the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 84: 16 to 50:50 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give the title 8.32 g (yield 93%) of the compound was obtained as a colorless oil.
Mass spectrum (CI, m / z): 305 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 7.43-7.28 (m, 5H), 5.07 (s, 2H), 3.64 (t, J = 6.7 Hz, 2H), 3.50 (br s, 3H) , 2.76 (t, J = 6.7 Hz, 2H), 1.45 (s, 6H).
（参考例４２）
ベンジル　４－シアノ－３－ヒドロキシ－２，２－ジメチル－２，５－ジヒドロ－１Ｈ－ピロール－１－カルボキシラート
Figure JPOXMLDOC01-appb-C000166
 (Reference Example 42)
Benzyl 4-cyano-3-hydroxy-2,2-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxylate
Figure JPOXMLDOC01-appb-C000166
　１ｍｏｌ／Ｌ　カリウム　ｔｅｒｔ－ブトキシド　ＴＨＦ溶液５２ｍｌ（５２ｍｍｏｌ）を６０℃に加熱し、アルゴン気流下、攪拌しながら参考例４１と同様にして合成したメチル　２－｛［（ベンジルオキシ）カルボニル］（２－シアノエチル）アミノ｝－２－メチルプロパノアート１２．１ｇ（３９．７ｍｍｏｌ）の脱水ＴＨＦ３０ｍｌ溶液を滴下し、加熱還流させながら１時間攪拌した。
　反応終了後、室温まで放冷した反応液に水９０ｍｌを加え、さらに２Ｎ塩酸を加え、ｐＨ＜２に調整した。その混合液から酢酸エチル１００ｍｌで２回抽出を行い、全有機層を合わせて水１００ｍｌ、飽和塩化ナトリウム水溶液１００ｍｌで順次洗浄した。硫酸マグネシウムで乾燥した後、濾過、減圧濃縮を行い溶媒の半量を留去した。得られた溶液に活性炭１２ｇを加え室温で３０分間攪拌し、濾過、減圧濃縮を行った。得られた濃縮残渣をジイソプロピルエーテル１０ｍｌで希釈し、そこへｎ－ヘキサン５０ｍｌを加え、析出した固体を破砕した後、室温で３０分間攪拌した。固体成分をろ取し、５０℃で減圧乾燥することで標記化合物８．２７ｇ（収率７６％）を薄黄色固体として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：２７３［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.32 (br s, 1H), 7.46 - 7.25 (m, 5H), 5.18 - 5.02 (m, 2H), 4.24 - 4.02 (m, 2H), 1.51 - 1.35 (m, 6H)。 Methyl 2-{[(benzyloxy) carbonyl] (2-) synthesized in the same manner as in Reference Example 41 while heating 52 ml (52 mmol) of 1 mol / L potassium tert-butoxide in THF at 60 ° C. and stirring in an argon stream. A solution of 12.1 g (39.7 mmol) of cyanoethyl) amino} -2-methylpropanoate in 30 ml of dehydrated THF was added dropwise and stirred for 1 hour while heating to reflux.
After completion of the reaction, 90 ml of water was added to the reaction solution which had been allowed to cool to room temperature, and 2N hydrochloric acid was further added to adjust pH <2. The mixture was extracted twice with 100 ml of ethyl acetate, and all the organic layers were combined and washed successively with 100 ml of water and 100 ml of a saturated aqueous sodium chloride solution. After drying with magnesium sulfate, filtration and concentration under reduced pressure were performed to distill off half of the solvent. 12 g of activated carbon was added to the resulting solution, and the mixture was stirred at room temperature for 30 minutes, filtered and concentrated under reduced pressure. The resulting concentrated residue was diluted with 10 ml of diisopropyl ether, 50 ml of n-hexane was added thereto, the precipitated solid was crushed, and stirred at room temperature for 30 minutes. The solid component was collected by filtration and dried under reduced pressure at 50 ° C. to obtain 8.27 g (yield 76%) of the title compound as a pale yellow solid.
Mass spectrum (DUIS, m / z): 273 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.32 (br s, 1H), 7.46-7.25 (m, 5H), 5.18-5.02 (m, 2H), 4.24-4.02 (m, 2H), 1.51-1.35 (m, 6H).
（参考例４３）
ベンジル　３－アミノ－６，６－ジメチル－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキシラート
Figure JPOXMLDOC01-appb-C000167
 (Reference Example 43)
Benzyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxylate
Figure JPOXMLDOC01-appb-C000167
　参考例４２と同様にして合成したベンジル　４－シアノ－３－ヒドロキシ－２，２－ジメチル－２，５－ジヒドロ－１Ｈ－ピロール－１－カルボキシラート２００ｍｇ（０．７３４ｍｍｏｌ）のエタノール５ｍｌ溶液に、アルゴン気流下、攪拌しながら酢酸０．３３６ｍｌ（５.８７ｍｍｏｌ）を室温で加え、室温で５分間攪拌した。次いで、ヒドラジン一水和物０．１７８ｍｌ（３．６６ｍｍｏｌ）を攪拌下に室温で滴下し、加熱還流下で１２時間攪拌した。
　反応終了後、室温まで放冷した反応液に水１５ｍｌを加えた後、炭酸水素ナトリウム水溶液を加え、ｐＨ８とした。その混合溶液から酢酸エチルで３回抽出し、全有機層を飽和塩化ナトリウム水溶液で洗浄、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝５０：５０～０：１００（Ｖ／Ｖ）→１，２－ジクロロエタン：メタノール＝８０：２０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮し、標記化合物１４１ｍｇ（収率６７％）を微黄色泡状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：２８７［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：11.20 (br s, 1H), 7.45 - 7.28 (m, 5H), 5.18 - 5.05 (m, 2H), 5.05 - 4.77 (m, 2H), 4.28 - 4.14 (m, 2H), 1.58- 1.46 (m, 6H)。 To a 5 ml ethanol solution of 200 mg (0.734 mmol) of benzyl 4-cyano-3-hydroxy-2,2-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxylate synthesized in the same manner as in Reference Example 42, Acetic acid 0.336 ml (5.87 mmol) was added at room temperature with stirring under an argon stream, and the mixture was stirred at room temperature for 5 minutes. Subsequently, 0.178 ml (3.66 mmol) of hydrazine monohydrate was added dropwise at room temperature with stirring, and the mixture was stirred for 12 hours while heating under reflux.
After completion of the reaction, 15 ml of water was added to the reaction solution allowed to cool to room temperature, and then an aqueous sodium hydrogen carbonate solution was added to adjust the pH to 8. The mixed solution was extracted three times with ethyl acetate, and the entire organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 50: 50 to 0: 100 (V / V) → 1,2-dichloroethane: methanol = 80: 20 (V / V)) The fraction containing the desired product was concentrated under reduced pressure to obtain 141 mg (yield 67%) of the title compound as a pale yellow foam.
Mass spectrum (CI, m / z): 287 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 11.20 (br s, 1H), 7.45-7.28 (m, 5H), 5.18-5.05 (m, 2H), 5.05-4.77 (m, 2H), 4.28-4.14 (m, 2H), 1.58-1.46 (m, 6H).
（参考例４４）
５－ベンジル　２－エチル　３－アミノ－６，６－ジメチルピロロ［３，４－ｃ］ピラゾール－２，５（４Ｈ，６Ｈ）－ジカルボキシラート
Figure JPOXMLDOC01-appb-C000168
 (Reference Example 44)
5-Benzyl 2-ethyl 3-amino-6,6-dimethylpyrrolo [3,4-c] pyrazole-2,5 (4H, 6H) -dicarboxylate
Figure JPOXMLDOC01-appb-C000168
　参考例４３と同様にして合成したベンジル　３－アミノ－６，６－ジメチル－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキシラート４００ｍｇ（１．４０ｍｍｏｌ）の脱水ＴＨＦ４ｍｌ溶液に、アルゴン気流下、攪拌しながらＤＩＰＥＡ０．５９４ｍｌ（３．４９ｍｍｏｌ）を室温で加え、室温で３分間攪拌した。次いで、クロロギ酸エチル０．１３３ｍｌ（１．４０ｍｍｏｌ）を攪拌下に０℃で滴下し、０℃で３０分間攪拌した。
　反応終了後、反応溶液に水を加え、その混合溶液から酢酸エチルで２回抽出した。全有機層は飽和塩化ナトリウム水溶液で洗浄、無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７１：２９～３０：７０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮し、標記化合物２００ｍｇ（収率４０％）を白色泡状物として、標記化合物の異性体（５－ベンジル　１－エチル　３－アミノ－６，６－ジメチルピロロ［３，４－ｃ］ピラゾール－１，５（４Ｈ，６Ｈ）－ジカルボキシラート）１９０ｍｇ（収率３８％）を白色泡状物としてそれぞれ得た。
標記化合物（５－ベンジル　２－エチル　３－アミノ－６，６－ジメチルピロロ［３，４－ｃ］ピラゾール－２，５（４Ｈ，６Ｈ）－ジカルボキシラート）
マススペクトル（ＣＩ，ｍ／ｚ）：３５９［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：7.45 - 7.29 (m, 5H), 6.63 - 6.49 (m, 2H), 5.19 - 5.04 (m, 2H), 4.41 - 4.30 (m, 2H), 4.28 - 4.15 (m, 2H), 1.62 - 1.49 (m, 6H), 1.36 - 1.28 (m, 3H)。
標記化合物の異性体（５－ベンジル　１－エチル　３－アミノ－６，６－ジメチルピロロ［３，４－ｃ］ピラゾール－１，５（４Ｈ，６Ｈ）－ジカルボキシラート）
マススペクトル（ＣＩ，ｍ／ｚ）：３５９［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：7.45 - 7.29 (m, 5H), 5.78 - 5.65 (m, 2H), 5.19 - 5.05 (m, 2H), 4.36 - 4.17 (m, 4H), 1.79 - 1.66 (m, 6H), 1.33 - 1.25 (m, 3H)。 Dehydration of 400 mg (1.40 mmol) of benzyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxylate synthesized as in Reference Example 43 To a 4 ml THF solution, 0.594 ml (3.49 mmol) of DIPEA was added at room temperature while stirring under an argon stream, and the mixture was stirred at room temperature for 3 minutes. Next, 0.133 ml (1.40 mmol) of ethyl chloroformate was added dropwise at 0 ° C. with stirring, and the mixture was stirred at 0 ° C. for 30 minutes.
After completion of the reaction, water was added to the reaction solution, and the mixture solution was extracted twice with ethyl acetate. All organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent: n-hexane: ethyl acetate = 71: 29-30: 70 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound The isomer of the title compound (5-benzyl 1-ethyl 3-amino-6,6-dimethylpyrrolo [3,4-c] pyrazole-1,5 (4H , 6H) -dicarboxylate) 190 mg (38% yield) were obtained as white foams, respectively.
Title compound (5-benzyl 2-ethyl 3-amino-6,6-dimethylpyrrolo [3,4-c] pyrazole-2,5 (4H, 6H) -dicarboxylate)
Mass spectrum (CI, m / z): 359 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 7.45-7.29 (m, 5H), 6.63-6.49 (m, 2H), 5.19-5.04 (m, 2H), 4.41-4.30 (m, 2H) , 4.28-4.15 (m, 2H), 1.62-1.49 (m, 6H), 1.36-1.28 (m, 3H).
Isomer of the title compound (5-benzyl 1-ethyl 3-amino-6,6-dimethylpyrrolo [3,4-c] pyrazole-1,5 (4H, 6H) -dicarboxylate)
Mass spectrum (CI, m / z): 359 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 7.45-7.29 (m, 5H), 5.78-5.65 (m, 2H), 5.19-5.05 (m, 2H), 4.36-4.17 (m, 4H) , 1.79-1.66 (m, 6H), 1.33-1.25 (m, 3H).
（参考例４５）
５－ベンジル　２－エチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］ピロロ［３，４－ｃ］ピラゾール－２，５（４Ｈ，６Ｈ）－ジカルボキシラート
Figure JPOXMLDOC01-appb-C000169
 (Reference Example 45)
5-Benzyl 2-ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] pyrrolo [3,4-c] pyrazole-2,5 (4H, 6H) -dicarboxylate
Figure JPOXMLDOC01-appb-C000169
　アルゴン雰囲気下、参考例１と同様にして合成した１－（トリメチルシリル）シクロブタンカルボン酸８８５ｍｇ（５．１４ｍｍｏｌ）の脱水ジクロロメタン２０ｍｌ溶液に、塩化オキサリル０．５３０ｍｌ（６．１７ｍｍｏｌ）、ＤＭＦ０．０２０ｍＬ（０．２６ｍｍｏｌ）を０℃で順次加え、そのままの温度で１時攪拌した。
　反応終了後、反応液を減圧濃縮した。
　アルゴン雰囲気下、得られた濃縮残渣の脱水ジクロロメタン１０ｍｌ溶液を、ＤＩＰＥＡ２．２５ｍｌ（１２．９ｍｍｏｌ）、参考例４４と同様にして合成した５－ベンジル　２－エチル　３－アミノ－６，６－ジメチルピロロ［３，４－ｃ］ピラゾール－２，５（４Ｈ，６Ｈ）－ジカルボキシラート９２０ｍｇ（２．５７ｍｍｏｌ）の脱水ジクロロメタン１０ｍｌ溶液に０℃で滴下した後、室温で２４時間攪拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加え、その溶液からジクロロメタンで２回抽出した。全有機層を合わせ、５％硫酸水素カリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～７０：３０（Ｖ／Ｖ））に付し目的物を含む画分を減圧濃縮し、標記化合物９９１ｍｇ（収率７５％）を微黄色泡状物として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：５１３［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：9.78 - 9.70 (m, 1H), 7.45 - 7.29 (m, 5H), 5.20 - 5.08 (m, 2H), 4.63 - 4.50 (m, 2H), 4.47 - 4.37 (m, 2H), 2.58 - 2.41 (m, 2H), 2.31 - 2.18 (m, 2H), 1.95 - 1.80 (m, 2H), 1.67 - 1.51 (m, 6H), 1.39 - 1.29 (m, 3H), 0.12 - 0.06 (m, 9H)。 Under an argon atmosphere, a solution of 885 mg (5.14 mmol) of 1- (trimethylsilyl) cyclobutanecarboxylic acid synthesized in the same manner as in Reference Example 1 in 20 ml of dehydrated dichloromethane was mixed with 0.530 ml (6.17 mmol) of oxalyl chloride and 0.020 mL (0 .26 mmol) was added sequentially at 0 ° C., and the mixture was stirred at that temperature for 1 hour.
After completion of the reaction, the reaction solution was concentrated under reduced pressure.
Under an argon atmosphere, a solution of the concentrated residue obtained in 10 ml of dehydrated dichloromethane was synthesized in the same manner as Reference Example 44 using 2.25 ml (12.9 mmol) of DIPEA and 5-benzyl 2-ethyl 3-amino-6,6-dimethylpyrrolo. To the solution of [3,4-c] pyrazole-2,5 (4H, 6H) -dicarboxylate (920 mg, 2.57 mmol) in dehydrated dichloromethane (10 ml) was added dropwise at 0 ° C., followed by stirring at room temperature for 24 hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the solution was extracted twice with dichloromethane. All organic layers were combined, washed successively with 5% aqueous potassium hydrogen sulfate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 70:30 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound 991 mg (75% yield) was obtained as a slightly yellow foam.
Mass spectrum (DUIS, m / z): 513 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 9.78-9.70 (m, 1H), 7.45-7.29 (m, 5H), 5.20-5.08 (m, 2H), 4.63-4.50 (m, 2H) , 4.47-4.37 (m, 2H), 2.58-2.41 (m, 2H), 2.31-2.18 (m, 2H), 1.95-1.80 (m, 2H), 1.67-1.51 (m, 6H), 1.39-1.29 ( m, 3H), 0.12-0.06 (m, 9H).
（参考例４６）
エチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート
Figure JPOXMLDOC01-appb-C000170
 (Reference Example 46)
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate
Figure JPOXMLDOC01-appb-C000170
　参考例４５と同様にして合成した５－ベンジル　２－エチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］ピロロ［３，４－ｃ］ピラゾール－２，５（４Ｈ，６Ｈ）－ジカルボキシラート１５０ｍｇ（０．２９３ｍｍｏｌ）の２－プロパノール４ｍｌ溶液に１０％パラジウム／炭素［Ｎ．Ｅ．ＣＨＥＭＣＡＴ社製、ＰＥ　ｔｙｐｅ、５０％含水］７５ｍｇ、酢酸１ｍｌを室温で順次加えた。水素雰囲気に置換した後、室温で１時間攪拌した。
　反応終了後、反応溶液を酢酸エチルで希釈し、セライトを加え、濾過した。濾液に炭酸水素ナトリウム水溶液を加えて攪拌し、中和した。これを酢酸エチルで２回抽出した。全有機層を合わせ、飽和炭酸水素ナトリウム水溶液で洗浄、無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；１，２－ジクロロエタン：メタノール＝１００：０～８６：１４（Ｖ／Ｖ））に付し目的物を含む画分を減圧濃縮し、標記化合物１０１ｍｇ（収率９１％）を白色泡状物として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：３７９［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：9.86 (s, 1H), 4.52 (q, J = 7.1 Hz, 2H), 4.22 (s, 2H), 2.65 - 2.52 (m, 2H), 2.38 - 2.26 (m, 2H), 2.03 - 1.88 (m, 2H), 1.50 - 1.43 (m, 9H), 0.15 (s, 9H)。 5-Benzyl 2-ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] pyrrolo [3,4-c] pyrazole-2,5 (4H, 6H) synthesized in the same manner as in Reference Example 45 -Dicarboxylate 150 mg (0.293 mmol) in 2-propanol 4 ml solution with 10% palladium / carbon [N. E. CHEMCAT, PE type, 50% water content] 75 mg and acetic acid 1 ml were sequentially added at room temperature. After replacing with a hydrogen atmosphere, the mixture was stirred at room temperature for 1 hour.
After completion of the reaction, the reaction solution was diluted with ethyl acetate, added with celite, and filtered. A sodium bicarbonate aqueous solution was added to the filtrate and stirred to neutralize. This was extracted twice with ethyl acetate. All organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 86:14 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound 101 mg (91% yield) were obtained as a white foam.
Mass spectrum (DUIS, m / z): 379 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 9.86 (s, 1H), 4.52 (q, J = 7.1 Hz, 2H), 4.22 (s, 2H), 2.65-2.52 (m, 2H), 2.38- 2.26 (m, 2H), 2.03-1.88 (m, 2H), 1.50-1.43 (m, 9H), 0.15 (s, 9H).
（参考例４７）
エチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート
Figure JPOXMLDOC01-appb-C000171
 (Reference Example 47)
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate
Figure JPOXMLDOC01-appb-C000171
　参考例２と同様にして合成した５－ｔｅｒｔ－ブチル　２－エチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］ピロロ［３，４－ｃ］ピラゾール－２，５（４Ｈ，６Ｈ）－ジカルボキシラート５７．１ｇ（１１９ｍｍｏｌ）のジクロロメタン５００ｍｌ溶液に、窒素雰囲気下、２，６－ジメチルピリジン２８．０ｍｌ（２４２ｍｍｏｌ）、トリメチルシリル　トリフルオロメタンスルホナート４３．０ｍｌ（２３８ｍｍｏｌ）を０℃で順次滴下し、撹拌しながら０℃で２時間反応させた。
　反応終了後、反応液を飽和炭酸水素ナトリウム水溶液１０００ｍｌに注ぎ入れた後、室温で撹拌し、次いで分液した。水層を酢酸エチル５００ｍｌで２回抽出した後、得られた全有機層を飽和塩化ナトリウム水溶液で洗浄、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。得られた濃縮残渣に、トルエンを加え減圧濃縮する操作を３回行った後、得られた褐色油状物を一晩冷蔵保存し、次いでジエチルエーテル５０ｍｌ及びｎ－ヘキサン１００ｍｌを加え、室温で０．５時間撹拌した。析出した固体を濾取し、ｎ－ヘキサンで洗浄した後、減圧乾燥することにより、標記化合物１７．０ｇ（収率３８％）を白色固体して得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：３７９［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：9.86 (s, 1H), 4.52 (q, J = 7.1 Hz, 2H), 4.23 (s, 2H), 2.64 - 2.52 (m, 2H), 2.38 - 2.27 (m, 2H), 2.03 - 1.89 (m, 2H), 1.53 - 1.42 (m, 9H), 0.14 (s, 9H)。 5-tert-butyl 2-ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] pyrrolo [3,4-c] pyrazole-2,5 (4H, synthesized in the same manner as in Reference Example 2 6H) -dicarboxylate in a solution of 57.1 g (119 mmol) in dichloromethane was added 28.0 ml (242 mmol) of 2,6-dimethylpyridine and 43.0 ml (238 mmol) of trimethylsilyl trifluoromethanesulfonate at 0 ° C. in a nitrogen atmosphere. The solution was added dropwise successively and reacted at 0 ° C. for 2 hours with stirring.
After completion of the reaction, the reaction solution was poured into 1000 ml of a saturated aqueous sodium hydrogen carbonate solution, stirred at room temperature, and then separated. The aqueous layer was extracted twice with 500 ml of ethyl acetate, and then the entire organic layer obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The operation of adding toluene to the obtained concentrated residue and concentrating under reduced pressure was performed three times, and then the resulting brown oil was stored refrigerated overnight, and then 50 ml of diethyl ether and 100 ml of n-hexane were added, and the mixture was stirred at room temperature for 0. Stir for 5 hours. The precipitated solid was collected by filtration, washed with n-hexane, and dried under reduced pressure to obtain 17.0 g (yield 38%) of the title compound as a white solid.
Mass spectrum (DUIS, m / z): 379 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 9.86 (s, 1H), 4.52 (q, J = 7.1 Hz, 2H), 4.23 (s, 2H), 2.64-2.52 (m, 2H), 2.38- 2.27 (m, 2H), 2.03-1.89 (m, 2H), 1.53-1.42 (m, 9H), 0.14 (s, 9H).
（参考例４８）
（Ｓ）－Ｎ－｛５－［３－（ベンジルオキシ）－２－フェニルプロパノイル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド
Figure JPOXMLDOC01-appb-C000172
 (Reference Example 48)
(S) -N- {5- [3- (benzyloxy) -2-phenylpropanoyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3 -Yl} -1- (trimethylsilyl) cyclobutanecarboxamide
Figure JPOXMLDOC01-appb-C000172
　窒素雰囲気下、（Ｓ）－３－（ベンジルオキシ）－２－フェニルプロパン酸［Ｔｅｔｒａｈｅｄｒｏｎ　Ｌｅｔｔ．，２００２（４３），９６９１－９６９３．に記載の方法に準じて合成］１６８ｍｇ（０．６５７ｍｍｏｌ）の脱水ジクロロメタン３ｍｌ溶液に、塩化オキサリル０．１０ｍｌ（１．２ｍｍｏｌ）、脱水ＤＭＦ０．０１０ｍｌ（０．１３ｍｍｏｌ）を０℃で順次加えた後、そのままの温度で３．５時間撹拌した。
　反応終了後、反応液を減圧濃縮することにより濃縮残渣を得た。
　窒素雰囲気下、得られた濃縮残渣の脱水ジクロロメタン１ｍｌ溶液を、参考例４７と同様にして合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１２７ｍｇ（０．３３５ｍｍｏｌ）、ＤＩＰＥＡ０．２３ｍｌ（１．３ｍｍｏｌ）の脱水ジクロロメタン３ｍｌ溶液に０℃で加えた後、そのままの温度で１時間撹拌した。次いで、反応液にトリエチルアミン１．０ｍｌ（７．２ｍｍｏｌ）、メタノール１．０ｍｌ（２５ｍｍｏｌ）を室温で加えた後、そのままの温度で１９時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加えて撹拌し、次いで、ジクロロメタンで３回抽出した。得られた全有機層を無水硫酸マグネシウムで乾燥後、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝８０：２０～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１４２ｍｇ（収率７８％）を微黄色泡状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５４５［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.43 - 7.37 (m, 2H), 7.35 - 7.16 (m, 10H), 4.89 (d, J = 12.0 Hz, 1H), 4.59 (d, J = 12.0 Hz, 1H), 4.50 - 4.39 (m, 2H), 4.19 - 4.12 (m, 1H), 4.05 (dd, J = 5.3, 8.6 Hz, 1H), 3.61 (dd, J = 5.3, 8.8 Hz, 1H), 2.62 - 2.49 (m, 2H), 2.33 - 2.23 (m, 2H), 2.00 - 1.89 (m, 2H), 1.86 (s, 3H), 1.73 (s, 3H), 0.14 (s, 9H)。 Under a nitrogen atmosphere, (S) -3- (benzyloxy) -2-phenylpropanoic acid [Tetrahedron Lett. , 2002 (43), 9691-9963. According to the method described in the above, after adding 0.10 ml (1.2 mmol) of oxalyl chloride and 0.010 ml (0.13 mmol) of dehydrated DMF sequentially to a solution of 168 mg (0.657 mmol) in dehydrated dichloromethane at 0 ° C. The mixture was stirred at the same temperature for 3.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentrated residue.
Under a nitrogen atmosphere, a 1 ml solution of the obtained concentrated residue in dehydrated dichloromethane was synthesized in the same manner as in Reference Example 47, and ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo was synthesized. After adding [3,4-c] pyrazole-2 (4H) -carboxylate (127 mg, 0.335 mmol) and DIPEA (0.23 ml, 1.3 mmol) in dehydrated dichloromethane (3 ml) at 0 ° C., the temperature was left as it was for 1 hour. Stir. Next, 1.0 ml (7.2 mmol) of triethylamine and 1.0 ml (25 mmol) of methanol were added to the reaction solution at room temperature, followed by stirring at the same temperature for 19 hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and stirred, and then extracted with dichloromethane three times. The entire organic layer obtained was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 80: 20 to 50:50 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. By drying under reduced pressure, 142 mg (yield 78%) of the title compound was obtained as a pale yellow foam.
Mass spectrum (CI, m / z): 545 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.43-7.37 (m, 2H), 7.35-7.16 (m, 10H), 4.89 (d, J = 12.0 Hz, 1H), 4.59 (d, J = 12.0 Hz, 1H), 4.50-4.39 (m, 2H), 4.19-4.12 (m, 1H), 4.05 (dd, J = 5.3, 8.6 Hz, 1H), 3.61 (dd, J = 5.3, 8.8 Hz, 1H) , 2.62-2.49 (m, 2H), 2.33-2.23 (m, 2H), 2.00-1.89 (m, 2H), 1.86 (s, 3H), 1.73 (s, 3H), 0.14 (s, 9H).
（参考例４９）
３－（３－メトキシ－２－フェニルプロパノイル）オキサゾリジン－２－オン
Figure JPOXMLDOC01-appb-C000173
 (Reference Example 49)
3- (3-Methoxy-2-phenylpropanoyl) oxazolidine-2-one
Figure JPOXMLDOC01-appb-C000173
　窒素雰囲気下、３－（２－フェニルアセチル）オキサゾリジン－２－オン［Ｔｅｔｒａｈｅｄｒｏｎ，１９９８（５４）２６９７－２７０８．に記載の方法に準じて合成］５０６ｍｇ（２．４６ｍｍｏｌ）の脱水ジクロロメタン１０ｍｌ溶液に、四塩化チタン０．３３ｍｌ（３．０ｍｍｏｌ）を０℃で加えた後、そのままの温度で５分間撹拌した。次いで、ＤＩＰＥＡ０．５２ｍｌ（３．０ｍｍｏｌ）を０℃で加えた後、そのままの温度で１時間撹拌した。次いで、クロロメチルメチルエーテル０．３７ｍｌ（４．９ｍｍｏｌ）を０℃で滴下しながら加えた後、そのままの温度で２時間撹拌した。
　反応終了後、反応液に水を０℃で加えて撹拌し、次いでジクロロメタンで３回抽出した。得られた全有機層を飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７５：２５～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物５２２ｍｇ（収率８５％）を橙色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：２５０［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.44 - 7.38 (m, 2H), 7.35 - 7.27 (m, 3H), 5.38 (dd, J = 4.6, 10.2 Hz, 1H), 4.44 - 4.27 (m, 2H), 4.18 - 4.07 (m, 2H), 3.95 (ddd, J = 6.8, 9.2, 11.0 Hz, 1H), 3.50 (dd, J = 4.6, 9.2 Hz, 1H), 3.37 (s, 3H)。 Under a nitrogen atmosphere, 3- (2-phenylacetyl) oxazolidin-2-one [Tetrahedron, 1998 (54) 2697-2708. According to the method described in 1.] To a solution of 506 mg (2.46 mmol) in 10 ml of dehydrated dichloromethane was added 0.33 ml (3.0 mmol) of titanium tetrachloride at 0 ° C., and the mixture was stirred at that temperature for 5 minutes. Next, 0.52 ml (3.0 mmol) of DIPEA was added at 0 ° C., followed by stirring at the same temperature for 1 hour. Next, 0.37 ml (4.9 mmol) of chloromethyl methyl ether was added dropwise at 0 ° C., and the mixture was stirred at the same temperature for 2 hours.
After completion of the reaction, water was added to the reaction solution at 0 ° C. and stirred, followed by extraction three times with dichloromethane. The obtained all organic layers were washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 75: 25 to 50:50 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure. This gave 522 mg (yield 85%) of the title compound as an orange oil.
Mass spectrum (CI, m / z): 250 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.44-7.38 (m, 2H), 7.35-7.27 (m, 3H), 5.38 (dd, J = 4.6, 10.2 Hz, 1H), 4.44-4.27 (m , 2H), 4.18-4.07 (m, 2H), 3.95 (ddd, J = 6.8, 9.2, 11.0 Hz, 1H), 3.50 (dd, J = 4.6, 9.2 Hz, 1H), 3.37 (s, 3H).
（参考例５０）
３－メトキシ－２－フェニルプロパン酸
Figure JPOXMLDOC01-appb-C000174
 (Reference Example 50)
3-methoxy-2-phenylpropanoic acid
Figure JPOXMLDOC01-appb-C000174
　窒素雰囲気下、参考例４９と同様にして合成した３－（３－メトキシ－２－フェニルプロパノイル）オキサゾリジン－２－オン５１７ｍｇ（２．０７ｍｍｏｌ）のＴＨＦ１２ｍｌ／水４ｍｌ溶液に、過酸化水素水［３０％］１．０ｍｌ（９．７ｍｍｏｌ）を室温で、水酸化リチウム１１１ｍｇ（４．６３ｍｍｏｌ）を０℃で順次加えた後、そのままの温度で２．５時間撹拌した。次いで、１０％チオ硫酸ナトリウム水溶液１０ｍｌ、飽和炭酸水素ナトリウム水溶液１０ｍｌを０℃で少しずつ加えた後、室温で１時間撹拌した。
　反応終了後、反応液を減圧濃縮してＴＨＦを留去した。濃縮残渣をジクロロメタンで２回洗浄した後、６Ｎ塩酸を加えてｐＨ２に調整し、次いでこの溶液を酢酸エチルで３回抽出した。得られた全有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝８０：２０～６５：３５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物３３１ｍｇ（収率８９％）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１８１［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.38 - 7.27 (m, 5H), 4.01 - 3.95 (m, 1H), 3.91 (dd, J = 4.8, 9.2 Hz, 1H), 3.63 (dd, J = 4.8, 8.7 Hz, 1H), 3.39 (s, 3H)。 Under a nitrogen atmosphere, a solution of 517 mg (2.07 mmol) of 3- (3-methoxy-2-phenylpropanoyl) oxazolidine-2-one synthesized in the same manner as in Reference Example 49 in a THF 12 ml / water 4 ml solution with a hydrogen peroxide solution [ 30%] 1.0 ml (9.7 mmol) at room temperature and 111 mg (4.63 mmol) of lithium hydroxide were sequentially added at 0 ° C., followed by stirring at the same temperature for 2.5 hours. Next, 10 ml of a 10% aqueous sodium thiosulfate solution and 10 ml of a saturated aqueous sodium hydrogen carbonate solution were added little by little at 0 ° C., followed by stirring at room temperature for 1 hour.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove THF. The concentrated residue was washed twice with dichloromethane, adjusted to pH 2 by adding 6N hydrochloric acid, and then the solution was extracted three times with ethyl acetate. The obtained all organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 80: 20 to 65:35 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure. This gave 331 mg (89% yield) of the title compound as a colorless oil.
Mass spectrum (CI, m / z): 181 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.38-7.27 (m, 5H), 4.01-3.95 (m, 1H), 3.91 (dd, J = 4.8, 9.2 Hz, 1H), 3.63 (dd, J = 4.8, 8.7 Hz, 1H), 3.39 (s, 3H).
（参考例５１）
ベンジル　４－メトキシ－２－フェニルブタノアート
Figure JPOXMLDOC01-appb-C000175
 (Reference Example 51)
Benzyl 4-methoxy-2-phenylbutanoate
Figure JPOXMLDOC01-appb-C000175
　ベンジル　フェニルアセタート０．４５ｍｌ（２．２ｍｍｏｌ）の脱水ＤＭＦ６ｍｌ溶液に、アルゴン雰囲気下、５５％水素化ナトリウム１３９ｍｇ（３．１９ｍｍｏｌ）を０℃で加えた後、そのままの温度で３０分間撹拌した。次いで、反応液に２－ブロモエチルメチルエーテル０．３５ｍｌ（３．７ｍｍｏｌ）を０℃で加えた後、室温で２時間攪拌した。
　反応終了後、反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。得られた全有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した後、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～９５：５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物５２８ｍｇ（収率８４％）を無色油状物として得た。
マススペクトル（ＥＳＩ，ｍ／ｚ）：２８５［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.34 - 7.21 (m, 10H), 5.15 (d, J = 12.5 Hz, 1H), 5.05 (d, J = 12.5 Hz, 1H), 3.83 (t, J = 7.7 Hz, 1H), 3.38 - 3.30 (m, 1H), 3.29 - 3.20 (m, 4H), 2.45 - 2.34 (m, 1H), 2.06 - 1.95 (m, 1H)。 To a solution of 0.45 ml (2.2 mmol) of benzyl phenylacetate in 6 ml of dehydrated DMF was added 139 mg (3.19 mmol) of 55% sodium hydride at 0 ° C. under an argon atmosphere, and the mixture was stirred at the same temperature for 30 minutes. Then, 0.35 ml (3.7 mmol) of 2-bromoethyl methyl ether was added to the reaction solution at 0 ° C., and the mixture was stirred at room temperature for 2 hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The entire organic layer obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. This gave 528 mg (84% yield) of the title compound as a colorless oil.
Mass spectrum (ESI, m / z): 285 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.34-7.21 (m, 10H), 5.15 (d, J = 12.5 Hz, 1H), 5.05 (d, J = 12.5 Hz, 1H), 3.83 (t, J = 7.7 Hz, 1H), 3.38-3.30 (m, 1H), 3.29-3.20 (m, 4H), 2.45-2.34 (m, 1H), 2.06-1.95 (m, 1H).
（参考例５２）
４－メトキシ－２－フェニルブタン酸
Figure JPOXMLDOC01-appb-C000176
 (Reference Example 52)
4-Methoxy-2-phenylbutanoic acid
Figure JPOXMLDOC01-appb-C000176
　参考例５１と同様にして合成したベンジル　４－メトキシ－２－フェニルブタノアート５２８ｍｇ（１．８６ｍｍｏｌ）のエタノール７ｍｌ溶液に、アルゴン雰囲気下、１０％Ｐｄ－Ｃ（５４．３３％含水、Ｎ．Ｅ．ＣＨＥＭＣＡＴ社製ＰＥ－ｔｙｐｅ）１３０ｍｇを室温で加え、水素雰囲気に置換後、室温で２時間攪拌した。
　反応終了後、反応液をセライト濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル、溶出溶媒；ｎ－ヘキサン：酢酸エチル＝６０：４０～４０：６０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物３０４ｍｇ（収率８４％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１９５［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.37 (br s, 1H), 7.38 - 7.20 (m, 5H), 3.61 (t, J = 7.7 Hz, 1H), 3.29 - 3.16 (m, 5H), 2.26 - 2.14 (m, 1H), 1.88 - 1.77 (m, 1H)。 To a solution of 528 mg (1.86 mmol) of benzyl 4-methoxy-2-phenylbutanoate synthesized in the same manner as in Reference Example 51 in 7 ml of ethanol, 10% Pd—C (54.33% water content, N.P. E. CHEMCAT PE-type (130 mg) was added at room temperature, and the mixture was replaced with a hydrogen atmosphere, followed by stirring at room temperature for 2 hours.
After completion of the reaction, the reaction solution was filtered through Celite and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 60: 40 to 40:60 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. As a result, 304 mg (yield 84%) of the title compound was obtained as a white solid.
Mass spectrum (CI, m / z): 195 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.37 (br s, 1H), 7.38-7.20 (m, 5H), 3.61 (t, J = 7.7 Hz, 1H), 3.29-3.16 (m, 5H), 2.26-2.14 (m, 1H), 1.88-1.77 (m, 1H).
（参考例５３）
（Ｓ）－Ｎ－｛５－［３－（ベンジルオキシ）－２－フェニルプロパノイル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロプロパンカルボキサミド
Figure JPOXMLDOC01-appb-C000177
 (Reference Example 53)
(S) -N- {5- [3- (benzyloxy) -2-phenylpropanoyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3 -Yl} -1- (trimethylsilyl) cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000177
　窒素雰囲気下、（Ｓ）－３－（ベンジルオキシ）－２－フェニルプロパン酸［Ｔｅｔｒａｈｅｄｒｏｎ　Ｌｅｔｔ．，２００２（４３），９６９１－９６９３．に記載の方法に準じて合成］５１．９ｍｇ（０．２０２ｍｍｏｌ）の脱水ジクロロメタン２ｍｌ溶液に、塩化オキサリル０．０４０ｍｌ（０．４７ｍｍｏｌ）、脱水ＤＭＦ０．００５０ｍｌ（０．０６５ｍｍｏｌ）を０℃で順次加えた後、そのままの温度で２．５時間撹拌した。
　反応終了後、反応液を減圧濃縮することにより濃縮残渣を得た。
　窒素雰囲気下、得られた濃縮残渣の脱水ジクロロメタン１ｍｌ溶液を、参考例３８と同様にして合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート４７．０ｍｇ（０．１２９ｍｍｏｌ）、ＤＩＰＥＡ０．１０ｍｌ（０．５７ｍｍｏｌ）の脱水ジクロロメタン１ｍｌ溶液に０℃で加えた後、そのままの温度で２時間撹拌した。次いで、反応液にＮ，Ｎ－ジメチルエタン－１，２－ジアミン０．１０ｍｌ（０．９２ｍｍｏｌ）を０℃で加えた後、室温で３時間撹拌した。
　反応終了後、ジクロロメタンで希釈した反応液を５％硫酸水素カリウム水溶液で洗浄した後、分液した。水層をジクロロメタンで２回抽出した後、得られた全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝８０：２０～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物４８ｍｇ（収率７０％）を微黄色泡状物として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：５３１［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.55 (s, 1H), 7.41 - 7.37 (m, 2H), 7.34 - 7.20 (m, 9H), 4.84 (d, J = 12.0 Hz, 1H), 4.60 (d, J = 12.0 Hz, 1H), 4.47 (d, J = 12.0 Hz, 1H), 4.42 (d, J = 12.0 Hz, 1H), 4.16 (t, J = 8.8 Hz, 1H), 4.02 (dd, J = 5.4, 8.8 Hz, 1H), 3.61 (dd, J = 5.4, 8.8 Hz, 1H), 1.85 (s, 3H), 1.72 (s, 3H), 1.09 - 1.04 (m, 2H), 0.81 - 0.76 (m, 2H), 0.10 (s, 9H)。 Under a nitrogen atmosphere, (S) -3- (benzyloxy) -2-phenylpropanoic acid [Tetrahedron Lett. , 2002 (43), 9691-9963. Synthesis of 51.9 mg (0.202 mmol) in dehydrated dichloromethane (2 ml) was sequentially added at 0 ° C. to 0.040 ml (0.47 mmol) of oxalyl chloride and 0.0050 ml (0.065 mmol) of dehydrated DMF. After that, the mixture was stirred at the same temperature for 2.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentrated residue.
Under nitrogen atmosphere, 1 ml of dehydrated dichloromethane solution of the obtained concentrated residue was synthesized in the same manner as in Reference Example 38. Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -5,6-dihydro After adding pyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate 47.0 mg (0.129 mmol) and DIPEA 0.10 ml (0.57 mmol) in dehydrated dichloromethane 1 ml at 0 ° C. For 2 hours. Next, 0.10 ml (0.92 mmol) of N, N-dimethylethane-1,2-diamine was added to the reaction solution at 0 ° C., and the mixture was stirred at room temperature for 3 hours.
After completion of the reaction, the reaction solution diluted with dichloromethane was washed with 5% aqueous potassium hydrogen sulfate solution, and then separated. The aqueous layer was extracted twice with dichloromethane, and then the entire organic layer obtained was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 80: 20 to 50:50 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. By drying under reduced pressure, 48 mg (yield 70%) of the title compound was obtained as a pale yellow foam.
Mass spectrum (DUIS, m / z): 531 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.55 (s, 1H), 7.41-7.37 (m, 2H), 7.34-7.20 (m, 9H), 4.84 (d, J = 12.0 Hz, 1H), 4.60 (d, J = 12.0 Hz, 1H), 4.47 (d, J = 12.0 Hz, 1H), 4.42 (d, J = 12.0 Hz, 1H), 4.16 (t, J = 8.8 Hz, 1H), 4.02 ( dd, J = 5.4, 8.8 Hz, 1H), 3.61 (dd, J = 5.4, 8.8 Hz, 1H), 1.85 (s, 3H), 1.72 (s, 3H), 1.09-1.04 (m, 2H), 0.81 -0.76 (m, 2H), 0.10 (s, 9H).
（参考例５４）
（Ｒ）－ベンジル　２－エトキシ－２－フェニルアセタート
Figure JPOXMLDOC01-appb-C000178
 (Reference Example 54)
(R) -Benzyl 2-ethoxy-2-phenylacetate
Figure JPOXMLDOC01-appb-C000178
　アルゴン雰囲気下、（Ｒ）－ベンジル　２－ヒドロキシ－２－フェニルアセタート１．０１ｇ（４．１７ｍｏｌ）のヨードエタン２０ｍｌ（０．２５ｍｏｌ）溶液に酸化銀１．９３ｇ（８．３３ｍｍｏｌ）を室温で加え、６０℃で１８時間攪拌した。
　反応終了後、反応液をセライト濾過し、固体成分を酢酸エチルで洗浄した後、ろ液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～８０：２０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物１．０３ｇ（収率９１％）を無色油状物として得た。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.49 - 7.43 (m, 2H), 7.38 - 7.27 (m, 6H), 7.24 - 7.18 (m, 2H), 5.19 (d, J = 12.4 Hz, 1H), 5.11 (d, J = 12.4 Hz, 1H), 4.92 (s, 1H), 3.65 - 3.46 (m, 2H), 1.27 (t, J = 7.0 Hz, 3H)。 Under an argon atmosphere, 1.93 g (8.33 mmol) of silver oxide was added to a solution of 1.01 g (4.17 mol) of (R) -benzyl 2-hydroxy-2-phenylacetate in 20 ml (0.25 mol) of iodoethane at room temperature. And stirred at 60 ° C. for 18 hours.
After completion of the reaction, the reaction solution was filtered through Celite, the solid component was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 80:20 (V / V)), and the fraction containing the target product was concentrated under reduced pressure. The title compound (1.03 g, yield 91%) was obtained as a colorless oil.
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.49-7.43 (m, 2H), 7.38-7.27 (m, 6H), 7.24-7.18 (m, 2H), 5.19 (d, J = 12.4 Hz, 1H ), 5.11 (d, J = 12.4 Hz, 1H), 4.92 (s, 1H), 3.65-3.46 (m, 2H), 1.27 (t, J = 7.0 Hz, 3H).
（参考例５５）
（Ｒ）－２－エトキシ－２－フェニル酢酸
Figure JPOXMLDOC01-appb-C000179
 (Reference Example 55)
(R) -2-Ethoxy-2-phenylacetic acid
Figure JPOXMLDOC01-appb-C000179
　参考例５４と同様にして合成した（Ｒ）－ベンジル　２－エトキシ－２－フェニルアセタート１．０３ｇ（３．８１ｍｍｏｌ）のメタノール２０ｍｌ溶液に、アルゴン雰囲気下、パラジウム／炭素０．１１（ＡＳＣＡ２（商品名），Ｎ．Ｅ．ＣＨＥＭＣＡＴ社製，５４％含水）を加えた後、減圧下水素雰囲気へと置換し、室温で２時間攪拌した。
　反応終了後、反応液をセライト濾過し、固体成分をメタノールで洗浄した後、ろ液を減圧濃縮することにより、標記化合物０．６３ｇ（収率９２％）を薄黄色油状物として得た。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.80 (br s, 1H), 7.44 - 7.28 (m, 5H), 4.84 (s, 1H), 3.60 - 3.50 (m, 1H), 3.47 - 3.20 (m, 1H), 1.15 (t, J = 7.0 Hz, 3H)。 To a 20 ml methanol solution of 1.03 g (3.81 mmol) of (R) -benzyl 2-ethoxy-2-phenyl acetate synthesized in the same manner as in Reference Example 54, palladium / carbon 0.11 (ASCA2 ( (Trade name), manufactured by NE CHEMCAT, containing 54% water), and then replaced with a hydrogen atmosphere under reduced pressure and stirred at room temperature for 2 hours.
After completion of the reaction, the reaction mixture was filtered through Celite, and the solid component was washed with methanol. The filtrate was concentrated under reduced pressure to obtain 0.63 g (yield 92%) of the title compound as a pale yellow oil.
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.80 (br s, 1H), 7.44-7.28 (m, 5H), 4.84 (s, 1H), 3.60-3.50 (m, 1H), 3.47- 3.20 (m, 1H), 1.15 (t, J = 7.0 Hz, 3H).
（参考例５６）
（Ｒ）－ベンジル　２－シクロプロポキシ－２－フェニルアセタート
Figure JPOXMLDOC01-appb-C000180
 (Reference Example 56)
(R) -Benzyl 2-cyclopropoxy-2-phenyl acetate
Figure JPOXMLDOC01-appb-C000180
　１Ｍジエチル亜鉛　ｎ－ヘキサン溶液７．５０ｍｌ（７．５０ｍｍｏｌ）の脱水ジクロロメタン４ｍｌ溶液に、アルゴン雰囲気下で撹拌しながら、ジヨードメタン０．７５０ｍｌ（９．３１ｍｍｏｌ）の脱水ジクロロメタン１ｍｌ溶液を０℃で滴下し、同温度で３０分間撹拌した。次いで、（Ｒ）－ベンジル　２－フェニル－２－（ビニルオキシ）アセタート５００ｍｇ（１．８６ｍｍｏｌ）［Ｊ．　Ａｍ．　Ｃｈｅｍ．　Ｓｏｃ．，２００６，１２８，２５８７－２５９３．に記載の方法に準じて合成］の脱水ジクロロメタン１ｍｌ溶液を撹拌下に、０℃で滴下し、室温で６時間撹拌した。
　反応終了後、反応液に飽和塩化アンモニウム水溶液を加え、ジクロロメタンで抽出した。得られた有機層を飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～８０：２０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物４１６ｍｇ（収率７９％）を無色油状物として得た。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.47 - 7.41 (m, 2H), 7.38 - 7.28 (m, 6H), 7.25 - 7.20 (m, 2H), 5.20 (d, J = 12.5 Hz, 1H), 5.12 (d, J = 12.5 Hz, 1H), 5.01 (s, 1H), 3.43 (tt, J = 3.0, 6.1 Hz, 1H), 0.76 - 0.65 (m, 2H), 0.53 - 0.43 (m, 2H)。 To a solution of 7.50 ml (7.50 mmol) of 1M diethylzinc n-hexane in 4 ml of dehydrated dichloromethane, 0.750 ml (9.31 mmol) of diiodomethane in 1 ml of dehydrated dichloromethane was added dropwise at 0 ° C. with stirring in an argon atmosphere. The mixture was stirred at the same temperature for 30 minutes. Then, (R) -benzyl 2-phenyl-2- (vinyloxy) acetate 500 mg (1.86 mmol) [J. Am. Chem. Soc. 2006, 128, 2587-2593. Of 1 ml of dehydrated dichloromethane was added dropwise at 0 ° C. with stirring and stirred at room temperature for 6 hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 80:20 (V / V)), and the fraction containing the target product was concentrated under reduced pressure. The title compound (416 mg, yield 79%) was obtained as a colorless oil.
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.47-7.41 (m, 2H), 7.38-7.28 (m, 6H), 7.25-7.20 (m, 2H), 5.20 (d, J = 12.5 Hz, 1H ), 5.12 (d, J = 12.5 Hz, 1H), 5.01 (s, 1H), 3.43 (tt, J = 3.0, 6.1 Hz, 1H), 0.76-0.65 (m, 2H), 0.53-0.43 (m, 2H).
（参考例５７）
（Ｒ）－２－シクロプロポキシ－２－フェニル酢酸
Figure JPOXMLDOC01-appb-C000181
 (Reference Example 57)
(R) -2-Cyclopropoxy-2-phenylacetic acid
Figure JPOXMLDOC01-appb-C000181
　参考例５６と同様の方法で合成した（Ｒ）－ベンジル　２－シクロプロポキシ－２－フェニルアセタート４１６ｍｇ（１．４７ｍｍｏｌ）のメタノール２ｍｌ／水２ｍｌ溶液に、水酸化リチウム一水和物９３ｍｇ（２．２ｍｍｏｌ）を室温で加えた後、撹拌しながら室温で２時間反応させた。
　反応終了後、反応液にジエチルエーテルを加えて分液した。水層に２Ｎ塩酸を加えてｐＨ２に調整した後、酢酸エチルで３回抽出した。得られた全有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮することにより、標記化合物２７４ｍｇ（収率９７％）を無色油状物として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：１９１［Ｍ－１］－。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.48 - 7.32 (m, 5H), 4.99 (s, 1H), 3.43 (tt, J = 2.9, 6.0 Hz, 1H), 0.76 - 0.64 (m, 2H), 0.61 - 0.43 (m, 2H)。 To a solution of (R) -benzyl 2-cyclopropoxy-2-phenylacetate (416 mg, 1.47 mmol) synthesized in the same manner as in Reference Example 56 in 2 ml of methanol / 2 ml of water, 93 mg (2 .2 mmol) was added at room temperature, followed by reaction at room temperature for 2 hours with stirring.
After completion of the reaction, diethyl ether was added to the reaction solution for liquid separation. The aqueous layer was adjusted to pH 2 by adding 2N hydrochloric acid, and extracted three times with ethyl acetate. The obtained all organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 274 mg (yield 97%) of the title compound as a colorless oil.
Mass spectrum (DUIS, m / z): 191 [M-1] − .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.48-7.32 (m, 5H), 4.99 (s, 1H), 3.43 (tt, J = 2.9, 6.0 Hz, 1H), 0.76-0.64 (m, 2H ), 0.61-0.43 (m, 2H).
（参考例５８）
（Ｒ）－２－イソプロポキシ－２－フェニル酢酸
Figure JPOXMLDOC01-appb-C000182
 (Reference Example 58)
(R) -2-Isopropoxy-2-phenylacetic acid
Figure JPOXMLDOC01-appb-C000182
　アルゴン雰囲気下、（Ｒ）－ベンジル　２－ヒドロキシ－２－フェニルアセタート１．４６ｇ（６．０３ｍｍｏｌ）の２－ヨードプロパン１４．０ｍｌ（１４０ｍｍｏｌ）懸濁液に、酸化銀（Ｉ）２．７９ｇ（１２．０ｍｍｏｌ）を室温で加えた後、撹拌しながら加熱還流下で１４．５時間反応させた。
　反応終了後、反応液を室温まで放冷した後、セライトフィルターを用いて濾過した。濾物を酢酸エチルで洗浄後、全ての濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９５：５～９０：１０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、濃縮残渣６７５ｍｇを得た。
　アルゴン雰囲気下、得られた濃縮残渣のメタノール１０ｍｌ／水２．０ｍｌ溶液に、水酸化リチウム一水和物１７６ｍｇ（４．１９ｍｍｏｌ）を室温で加えた後、撹拌しながら室温で４時間反応させた。
　反応終了後、反応液に水、ジエチルエーテルを加えて撹拌した後、分液した。水層に２Ｎ塩酸を加えてｐＨ２に調整した後、酢酸エチルで３回抽出した。得られた全有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル、溶出溶媒；ｎ－ヘキサン：酢酸エチル＝８５：１５～７０：３０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、濃縮残渣４６７ｍｇを得た。得られた濃縮残渣を分取ＨＰＬＣ（カラム；Ｘ－Ｂｒｉｄｇｅ（商品名）ＯＤＳ，溶出溶媒；１ｖｏｌ％　ギ酸／アセトニトリル：１ｖｏｌ％　ギ酸水溶液＝２０：８０～７０：３０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮してアセトニトリルを留去した。得られた濃縮残渣を酢酸エチルで３回抽出し、次いで全有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮、減圧乾燥することにより、標記化合物３４６ｍｇ（収率３０％［２工程］）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１９５［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.74 (br s, 1H), 7.43 - 7.27 (m, 5H), 4.95 (s, 1H), 3.62 (spt, J = 6.1 Hz, 1H), 1.15 (d, J = 6.1 Hz, 3H), 1.09 (d, J = 6.1 Hz, 3H)。 Under an argon atmosphere, 2.79 g of silver (I) oxide was added to a suspension of 1.46 g (6.03 mmol) of (R) -benzyl 2-hydroxy-2-phenylacetate in 14.0 ml (140 mmol) of 2-iodopropane. (12.0 mmol) was added at room temperature, and the mixture was reacted for 14.5 hours under heating and reflux with stirring.
After completion of the reaction, the reaction solution was allowed to cool to room temperature and then filtered using a celite filter. The filtrate was washed with ethyl acetate, and all the filtrates were concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 95: 5 to 90:10 (V / V)), and the fraction containing the target product was concentrated under reduced pressure and dried under reduced pressure. As a result, 675 mg of a concentrated residue was obtained.
Under an argon atmosphere, 176 mg (4.19 mmol) of lithium hydroxide monohydrate was added at room temperature to a 10 ml methanol / 2.0 ml water solution of the obtained concentrated residue, followed by reaction at room temperature for 4 hours with stirring. .
After completion of the reaction, water and diethyl ether were added to the reaction solution and stirred, followed by liquid separation. The aqueous layer was adjusted to pH 2 by adding 2N hydrochloric acid, and extracted three times with ethyl acetate. The obtained all organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 85: 15 to 70:30 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. As a result, 467 mg of a concentrated residue was obtained. The obtained concentrated residue was subjected to preparative HPLC (column; X-Bridge (trade name) ODS, elution solvent: 1 vol% formic acid / acetonitrile: 1 vol% formic acid aqueous solution = 20: 80 to 70:30 (V / V)). Then, the fraction containing the desired product was concentrated under reduced pressure to distill off acetonitrile. The obtained concentrated residue was extracted three times with ethyl acetate, and the whole organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and dried under reduced pressure to give 346 mg of the title compound (yield) 30% [2 steps]) was obtained as a white solid.
Mass spectrum (CI, m / z): 195 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.74 (br s, 1H), 7.43-7.27 (m, 5H), 4.95 (s, 1H), 3.62 (spt, J = 6.1 Hz, 1H) , 1.15 (d, J = 6.1 Hz, 3H), 1.09 (d, J = 6.1 Hz, 3H).
（参考例５９）
（Ｒ）－エチル　２－フェニル－２－（トリフルオロメトキシ）アセタート
Figure JPOXMLDOC01-appb-C000183
 (Reference Example 59)
(R) -Ethyl 2-phenyl-2- (trifluoromethoxy) acetate
Figure JPOXMLDOC01-appb-C000183
　（Ｒ）－エチル　２－ヒドロキシ－２－フェニルアセタート２５．０ｇ（１３９ｍｍｏｌ）の重クロロホルム１０ｍｌ溶液に、アルゴン雰囲気下で撹拌しながら、４０％　１－トリフルオロメチル－３，３－ジメチル－１，２－ベンゾヨードキソール［Ｔｏｇｎｉ　Ｒｅａｇｅｎｔ　ＩＩ（商品名）、珪藻土混合物、東京化成工業（株）より購入］３．７５ｇ（４．７５ｍｍｏｌ）、ビス（トリフルオロメチルスルホニル）イミド亜鉛（ＩＩ）０．９００ｇ（１．４４ｍｍｏｌ）を室温で加え、室温で８８時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。得られた有機層を飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～６０：４０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物４２１ｍｇ（不純物含む）を黄色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：２４９［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.53 - 7.36 (m, 5H), 5.52 (s, 1H), 4.32 - 4.16 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H)。 While stirring (R) -ethyl 2-hydroxy-2-phenylacetate (25.0 g, 139 mmol) in deuterated chloroform (10 ml) under an argon atmosphere, 40% 1-trifluoromethyl-3,3-dimethyl-1 , 2-Benziodoxol [Togni Reagent II (trade name), diatomaceous earth mixture, purchased from Tokyo Chemical Industry Co., Ltd.] 3.75 g (4.75 mmol), bis (trifluoromethylsulfonyl) imide zinc (II) 0 900 g (1.44 mmol) was added at room temperature and stirred at room temperature for 88 hours.
After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 60:40 (V / V)), and the fraction containing the target product was concentrated under reduced pressure. The title compound (421 mg, including impurities) was obtained as a yellow oil.
Mass spectrum (CI, m / z): 249 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.53-7.36 (m, 5H), 5.52 (s, 1H), 4.32-4.16 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H).
（参考例６０）
（Ｒ）－２－フェニル－２－（トリフルオロメトキシ）酢酸
Figure JPOXMLDOC01-appb-C000184
 (Reference Example 60)
(R) -2-Phenyl-2- (trifluoromethoxy) acetic acid
Figure JPOXMLDOC01-appb-C000184
　参考例５９と同様の方法で合成した（Ｒ）－エチル　２－フェニル－２－（トリフルオロメトキシ）アセタート４２１ｍｇ（不純物含む）のメタノール３ｍｌ／水３ｍｌ溶液に、水酸化リチウム一水和物９３ｍｇ（２．２ｍｍｏｌ）を室温で加えた後、撹拌しながら室温で４時間反応させた。
　反応終了後、反応液にジエチルエーテルを加えて分液した。水層に２Ｎ塩酸を加えてｐＨ２に調整した後、酢酸エチルで３回抽出した。得られた全有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮することにより、標記化合物３９０ｍｇ（不純物含む）を微黄色油状物として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：２１９［Ｍ－１］－。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.52 - 7.37 (m, 5H), 5.57 (s, 1H)。 To a solution of (R) -ethyl 2-phenyl-2- (trifluoromethoxy) acetate (421 mg, including impurities) synthesized in the same manner as in Reference Example 59 in 3 ml of methanol / 3 ml of water, 93 mg of lithium hydroxide monohydrate ( 2.2 mmol) was added at room temperature, followed by reaction at room temperature for 4 hours with stirring.
After completion of the reaction, diethyl ether was added to the reaction solution for liquid separation. The aqueous layer was adjusted to pH 2 by adding 2N hydrochloric acid, and extracted three times with ethyl acetate. The obtained all organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 390 mg (including impurities) of the title compound as a pale yellow oil.
Mass spectrum (DUIS, m / z): 219 [M−1] − .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.52-7.37 (m, 5H), 5.57 (s, 1H).
（参考例６１）
（Ｒ）－ベンジル　２－フェニル－２－プロポキシアセタート
Figure JPOXMLDOC01-appb-C000185
 (Reference Example 61)
(R) -Benzyl 2-phenyl-2-propoxyacetate
Figure JPOXMLDOC01-appb-C000185
　アルゴン雰囲気下、（Ｒ）－ベンジル　２－ヒドロキシ－２－フェニルアセタート１．５８ｇ（６．５２ｍｍｏｌ）の１－ヨードプロパン１４．５ｍｌ（１４９ｍｍｏｌ）懸濁液に、酸化銀（Ｉ）３．０３ｇ（１３．１ｍｍｏｌ）を室温で加えた後、撹拌しながら８０℃で１４時間反応させた。
　反応終了後、反応液を室温まで放冷した後、セライトフィルターを用いて濾過した。濾物を酢酸エチルで洗浄後、全ての濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９７：３～９０：１０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１．２３ｇ（収率６６％）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：２８５［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：7.43 - 7.27 (m, 8H), 7.26 - 7.20 (m, 2H), 5.13 (s, 2H), 5.06 (s, 1H), 3.46 (td, J = 6.6, 9.0 Hz, 1H), 3.40 - 3.28 (m, 1H), 1.60 - 1.49 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H)。 Under an argon atmosphere, a suspension of 1.58 g (6.52 mmol) of (R) -benzyl 2-hydroxy-2-phenylacetate in 14.5 ml (149 mmol) of 1-iodopropane was charged with 3.03 g of silver (I) oxide. (13.1 mmol) was added at room temperature, followed by reaction at 80 ° C. for 14 hours with stirring.
After completion of the reaction, the reaction solution was allowed to cool to room temperature and then filtered using a celite filter. The filtrate was washed with ethyl acetate, and all the filtrates were concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 97: 3 to 90:10 (V / V)), and the fraction containing the target product was concentrated under reduced pressure and dried under reduced pressure. As a result, 1.23 g (yield 66%) of the title compound was obtained as a colorless oil.
Mass spectrum (CI, m / z): 285 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 7.43-7.27 (m, 8H), 7.26-7.20 (m, 2H), 5.13 (s, 2H), 5.06 (s, 1H), 3.46 (td , J = 6.6, 9.0 Hz, 1H), 3.40-3.28 (m, 1H), 1.60-1.49 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H).
（参考例６２）
（Ｒ）－２－フェニル－２－プロポキシ酢酸
Figure JPOXMLDOC01-appb-C000186
 (Reference Example 62)
(R) -2-Phenyl-2-propoxyacetic acid
Figure JPOXMLDOC01-appb-C000186
　アルゴン雰囲気下、参考例６１と同様にして合成した（Ｒ）－ベンジル　２－フェニル－２－プロポキシアセタート１．２３ｇ（４．３３ｍｍｏｌ）のエタノール１５ｍｌ溶液に、１０％パラジウム／炭素［ＰＥ　ｔｙｐｅ（商品名），Ｎ．Ｅ．ＣＨＥＭＣＡＴ社製，５４％含水］２７４ｍｇを室温で加えた後、減圧下水素雰囲気へと置換し、撹拌しながら室温で１．５時間反応させた。
　反応終了後、反応容器内を減圧下アルゴン雰囲気へと置換した。反応液をセライトフィルターを用いて濾過し、除去した固体をエタノールで洗浄した後、濾液を減圧濃縮、減圧乾燥することにより、標記化合物８９２ｍｇ（不純物を含む）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１９５［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：12.78 (br s, 1H), 7.42 - 7.29 (m, 5H), 4.83 (s, 1H), 3.47 (td, J = 6.6, 9.0 Hz, 1H), 3.40 - 3.25 (m, 1H), 1.61 - 1.49 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H)。 Under an argon atmosphere, 10% palladium / carbon [PE type] was added to a solution of 1.23 g (4.33 mmol) of (R) -benzyl 2-phenyl-2-propoxyacetate synthesized in the same manner as in Reference Example 61 in 15 ml of ethanol. Product name), N.M. E. 274 mg of CHEMCAT, 54% water content] was added at room temperature, and the mixture was replaced with a hydrogen atmosphere under reduced pressure. The mixture was reacted at room temperature for 1.5 hours with stirring.
After completion of the reaction, the inside of the reaction vessel was replaced with an argon atmosphere under reduced pressure. The reaction mixture was filtered using a celite filter, and the removed solid was washed with ethanol. The filtrate was concentrated under reduced pressure and dried under reduced pressure to give 892 mg (including impurities) of the title compound as a colorless oil.
Mass spectrum (CI, m / z): 195 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 12.78 (br s, 1H), 7.42-7.29 (m, 5H), 4.83 (s, 1H), 3.47 (td, J = 6.6, 9.0 Hz, 1H), 3.40-3.25 (m, 1H), 1.61-1.49 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H).
（参考例６３）
メチル　２－（４－フルオロフェニル）－２－メトキシアセタート
Figure JPOXMLDOC01-appb-C000187
 (Reference Example 63)
Methyl 2- (4-fluorophenyl) -2-methoxyacetate
Figure JPOXMLDOC01-appb-C000187
　４－フルオロマンデル酸８００ｍｇ（４．７０ｍｍｏｌ）の脱水ＤＭＦ２０ｍｌ溶液に、アルゴン雰囲気下で撹拌しながら、５５％水素化ナトリウム４５０ｍｇ（１０．３ｍｍｏｌ）を０℃で分割添加し、同温度で１時間撹拌した。次いで、ヨードメタン０．７３２ｍｌ（１１．８ｍｍｏｌ）を０℃で滴下した後、室温で２時間撹拌した。さらにヨードメタン０．７３２ｍｌ（１１．８ｍｍｏｌ）を０℃で滴下した後、室温で２時間撹拌した。
　反応終了後、反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。得られた有機層を飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～７０：３０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物２４７ｍｇ（収率２７％）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１９９［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.46 - 7.38 (m, 2H), 7.11 - 7.02 (m, 2H), 4.76 (s, 1H), 3.73 (s, 3H), 3.40 (s, 3H)。 To a solution of 800 mg (4.70 mmol) of 4-fluoromandelic acid in 20 ml of dehydrated DMF, 450 mg (10.3 mmol) of 55% sodium hydride was added in portions at 0 ° C. with stirring in an argon atmosphere, and stirred at the same temperature for 1 hour. did. Next, 0.732 ml (11.8 mmol) of iodomethane was added dropwise at 0 ° C., followed by stirring at room temperature for 2 hours. Further, 0.732 ml (11.8 mmol) of iodomethane was added dropwise at 0 ° C., followed by stirring at room temperature for 2 hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 70:30 (V / V)), and the fraction containing the target product was concentrated under reduced pressure. The title compound (247 mg, yield 27%) was obtained as a colorless oil.
Mass spectrum (CI, m / z): 199 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.46-7.38 (m, 2H), 7.11-7.02 (m, 2H), 4.76 (s, 1H), 3.73 (s, 3H), 3.40 (s, 3H ).
（参考例６４）
２－（４－フルオロフェニル）－２－メトキシ酢酸
Figure JPOXMLDOC01-appb-C000188
 (Reference Example 64)
2- (4-Fluorophenyl) -2-methoxyacetic acid
Figure JPOXMLDOC01-appb-C000188
　参考例６３と同様にして合成したメチル　２－（４－フルオロフェニル）－２－メトキシアセタート２４７ｍｇ（１．２５ｍｍｏｌ）のＴＨＦ５ｍｌ溶液に、撹拌しながら、１Ｎ水酸化ナトリウム水溶液２．０ｍｌ（２．０ｍｍｏｌ）を室温で加え、同温度で１６時間撹拌した。
　反応終了後、反応液に１Ｎ塩酸を加えてｐＨを２に調整し、酢酸エチルで抽出した。得られた有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥し、濾過、濾液を減圧濃縮、減圧乾燥することにより、標記化合物２６０ｍｇ（不純物含む）を茶色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１８５［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.49 - 7.36 (m, 2H), 7.13 - 7.03 (m, 2H), 4.77 (s, 1H), 3.43 (s, 3H)。 To a solution of 247 mg (1.25 mmol) of methyl 2- (4-fluorophenyl) -2-methoxyacetate synthesized in the same manner as in Reference Example 63 in 5 ml of THF, 2.0 ml (2. 0 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 16 hours.
After completion of the reaction, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried under reduced pressure to obtain 260 mg (including impurities) of the title compound as a brown oil.
Mass spectrum (CI, m / z): 185 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.49-7.36 (m, 2H), 7.13-7.03 (m, 2H), 4.77 (s, 1H), 3.43 (s, 3H).
（参考例６５）
エチル　２－（３－フルオロフェニル）－２－ヒドロキシアセタート
Figure JPOXMLDOC01-appb-C000189
 (Reference Example 65)
Ethyl 2- (3-fluorophenyl) -2-hydroxyacetate
Figure JPOXMLDOC01-appb-C000189
　３－フルオロフェニルボロン酸１．００ｇ（７．１５ｍｍｏｌ）の脱水トルエン３０ｍｌ懸濁液に、アルゴン雰囲気下で撹拌しながら、５０％エチル　オキソアセタート　トルエン溶液［Ａｐｏｌｌｏ　ｓｃｉｅｎｔｉｆｉｃ　ｌｉｍｉｔｅｄより購入］２．２０ｇ（１０．８ｍｍｏｌ）、２－（ジ－ｔｅｒｔ－ブチルホスフィノ）ビフェニル１０７ｍｇ（０．３５９ｍｍｏｌ）を室温で加え、減圧下窒素雰囲気へと置換した。次いで、トリス（ジベンジリデンアセトン）ジパラジウム（０）９２．０ｍｇ（０．１００ｍｍｏｌ）を撹拌下に室温で加え、８０℃で９時間反応させた。
　反応液をセライトフィルターを用いて濾過し、ろ液に水を加えて酢酸エチルで抽出した。得られた有機層を飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～６０：４０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物２６３ｍｇ（収率１９％）を微黄色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１９９［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.38 - 7.29 (m, 1H), 7.25 - 7.20 (m, 1H), 7.19 - 7.13 (m, 1H), 7.06 - 6.98 (m, 1H), 5.15 (d, J = 5.4 Hz, 1H), 4.34 - 4.14 (m, 2H), 3.50 (d, J = 5.4 Hz, 1H), 1.25 (t, J = 7.2 Hz, 3H)。 2. A solution of 1.00 g (7.15 mmol) of 3-fluorophenylboronic acid in 30 ml of dehydrated toluene with stirring in an argon atmosphere, 50% ethyl oxoacetate in toluene [purchased from Apollo scientific limited] 2.20 g (10. 8 mmol) and 2- (di-tert-butylphosphino) biphenyl (107 mg, 0.359 mmol) were added at room temperature, and the atmosphere was replaced with a nitrogen atmosphere under reduced pressure. Subsequently, 92.0 mg (0.100 mmol) of tris (dibenzylideneacetone) dipalladium (0) was added at room temperature with stirring, and the mixture was reacted at 80 ° C. for 9 hours.
The reaction mixture was filtered using a celite filter, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 60:40 (V / V)), and the fraction containing the target product was concentrated under reduced pressure. The title compound (263 mg, yield 19%) was obtained as a pale yellow oil.
Mass spectrum (CI, m / z): 199 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.38-7.29 (m, 1H), 7.25-7.20 (m, 1H), 7.19-7.13 (m, 1H), 7.06-6.98 (m, 1H), 5.15 (d, J = 5.4 Hz, 1H), 4.34-4.14 (m, 2H), 3.50 (d, J = 5.4 Hz, 1H), 1.25 (t, J = 7.2 Hz, 3H).
（参考例６６）
エチル　２－（３－フルオロフェニル）－２－メトキシアセタート
Figure JPOXMLDOC01-appb-C000190
 (Reference Example 66)
Ethyl 2- (3-fluorophenyl) -2-methoxyacetate
Figure JPOXMLDOC01-appb-C000190
　アルゴン雰囲気下、参考例６５と同様の方法で合成したエチル　２－（３－フルオロフェニル）－２－ヒドロキシアセタート２６３ｍｇ（１．３３ｍｍｏｌ）のヨードメタン８．０ｍｌ（１３０ｍｍｏｌ）溶液に、酸化銀６１５ｍｇ（２．６５ｍｍｏｌ）を室温で加え、同温度で撹拌しながら３時間反応させた。
　反応終了後、セライトフィルターを用いて濾過し、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～６０：４０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物１５５ｍｇ（収率５５％）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：２１３［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.37 - 7.29 (m, 1H), 7.25 - 7.15 (m, 2H), 7.07 - 7.00 (m, 1H), 4.75 (s, 1H), 4.28 - 4.12 (m, 2H), 3.43 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H)。 In a solution of 263 mg (1.33 mmol) of ethyl 2- (3-fluorophenyl) -2-hydroxyacetate synthesized in the same manner as in Reference Example 65 under an argon atmosphere, 8.0 ml (130 mmol) of iodomethane was added to 615 mg of silver oxide ( 2.65 mmol) was added at room temperature, and the mixture was reacted at the same temperature for 3 hours with stirring.
After completion of the reaction, the reaction mixture was filtered using a celite filter, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 60:40 (V / V)), and the fraction containing the target product was concentrated under reduced pressure. 155 mg (55% yield) of the title compound were obtained as a colorless oil.
Mass spectrum (CI, m / z): 213 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.37-7.29 (m, 1H), 7.25-7.15 (m, 2H), 7.07-7.00 (m, 1H), 4.75 (s, 1H), 4.28-4.12 (m, 2H), 3.43 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H).
（参考例６７）
２－（３－フルオロフェニル）－２－メトキシ酢酸
Figure JPOXMLDOC01-appb-C000191
 (Reference Example 67)
2- (3-Fluorophenyl) -2-methoxyacetic acid
Figure JPOXMLDOC01-appb-C000191
　参考例６６と同様にして合成したエチル　２－（３－フルオロフェニル）－２－メトキシアセタート１５５ｍｇ（０．７３０ｍｍｏｌ）のＴＨＦ５ｍｌ溶液に、撹拌しながら、１Ｎ水酸化ナトリウム水溶液１．０ｍｌ（１．０ｍｍｏｌ）を室温で加え、同温度で２０時間撹拌した。
　反応終了後、反応液に１Ｎ塩酸を加えてｐＨを２に調整し、酢酸エチルで抽出した。得られた有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥し、濾過、濾液を減圧濃縮することにより、標記化合物１４４ｍｇ（不純物含む）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１８５［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.41 - 7.32 (m, 1H), 7.25 - 7.20 (m, 1H), 7.19 - 7.13 (m, 1H), 7.10 - 7.03 (m, 1H), 4.79 (s, 1H), 3.46 (s, 3H)。 While stirring in a solution of ethyl 2- (3-fluorophenyl) -2-methoxyacetate (155 mg, 0.730 mmol) in THF (5 ml) synthesized in the same manner as in Reference Example 66, 1.0 ml (1. 0 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 20 hours.
After completion of the reaction, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 144 mg (including impurities) of the title compound as a colorless oil.
Mass spectrum (CI, m / z): 185 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.41-7.32 (m, 1H), 7.25-7.20 (m, 1H), 7.19-7.13 (m, 1H), 7.10-7.03 (m, 1H), 4.79 (s, 1H), 3.46 (s, 3H).
（参考例６８）
（Ｒ）－メチル　２－（２－フルオロフェニル）－２－メトキシアセタート
Figure JPOXMLDOC01-appb-C000192
 (Reference Example 68)
(R) -Methyl 2- (2-fluorophenyl) -2-methoxyacetate
Figure JPOXMLDOC01-appb-C000192
　（Ｒ）－２－（２－フルオロフェニル）－２－ヒドロキシ酢酸［Ｃｏｍｂｉ－Ｂｌｏｃｋｓより購入］１．００ｇ（５．８８ｍｍｏｌ）の脱水ＤＭＦ２０ｍｌ溶液に、アルゴン雰囲気下で撹拌しながら、５５％水素化ナトリウム３１０ｍｇ（７．１０ｍｍｏｌ）を０℃で分割添加し、同温度で１時間撹拌した。次いで、ヨードメタン０．８４２ｍｌ（１３．５ｍｍｏｌ）を０℃で滴下した後、室温で４時間撹拌した。
　反応終了後、反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。得られた有機層を飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～７０：３０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物８５８ｍｇ（収率７４％）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１９９［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.50 - 7.42 (m, 1H), 7.38 - 7.30 (m, 1H), 7.21 - 7.14 (m, 1H), 7.13 - 7.05 (m, 1H), 5.14 (s, 1H), 3.43 (s, 3H)。 (R) -2- (2-Fluorophenyl) -2-hydroxyacetic acid [purchased from Combi-Blocks] 55% hydrogenated with stirring in 1.00 g (5.88 mmol) of dehydrated DMF in 20 ml under argon atmosphere Sodium 310 mg (7.10 mmol) was added in portions at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. Next, 0.842 ml (13.5 mmol) of iodomethane was added dropwise at 0 ° C., followed by stirring at room temperature for 4 hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 70:30 (V / V)), and the fraction containing the target product was concentrated under reduced pressure. The title compound (858 mg, yield 74%) was obtained as a colorless oil.
Mass spectrum (CI, m / z): 199 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.50-7.42 (m, 1H), 7.38-7.30 (m, 1H), 7.21-7.14 (m, 1H), 7.13-7.05 (m, 1H), 5.14 (s, 1H), 3.43 (s, 3H).
（参考例６９）
（Ｒ）－２－（２－フルオロフェニル）－２－メトキシ酢酸
Figure JPOXMLDOC01-appb-C000193
 (Reference Example 69)
(R) -2- (2-Fluorophenyl) -2-methoxyacetic acid
Figure JPOXMLDOC01-appb-C000193
　参考例６８と同様にして合成した（Ｒ）－メチル　２－（２－フルオロフェニル）－２－メトキシアセタート８５８ｍｇ（４．３３ｍｍｏｌ）のＴＨＦ１０ｍｌ溶液に、撹拌しながら、１Ｎ水酸化ナトリウム水溶液５．２ｍｌ（５．２ｍｍｏｌ）を室温で加え、５０℃で３時間撹拌した。
　反応終了後、室温まで放冷した後、反応液に１Ｎ塩酸を加えてｐＨを２に調整し、酢酸エチルで抽出した。得られた有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥し、濾過、濾液を減圧濃縮することにより、標記化合物３９０ｍｇ（収率４９％）を茶色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１８５［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.46 - 7.32 (m, 2H), 7.22 - 7.05 (m, 2H), 5.11 (s, 1H), 3.43 (s, 3H)。 Into a 10 ml THF solution of 858 mg (4.33 mmol) (R) -methyl 2- (2-fluorophenyl) -2-methoxyacetate synthesized in the same manner as in Reference Example 68, a 1N aqueous sodium hydroxide solution was added. 2 ml (5.2 mmol) was added at room temperature and stirred at 50 ° C. for 3 hours.
After the completion of the reaction, the mixture was allowed to cool to room temperature, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 2, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (390 mg, yield 49%) as a brown oil.
Mass spectrum (CI, m / z): 185 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.46-7.32 (m, 2H), 7.22-7.05 (m, 2H), 5.11 (s, 1H), 3.43 (s, 3H).
（参考例７０）
エチル　２－ヒドロキシ－２－（チオフェン－２－イル）アセタート
Figure JPOXMLDOC01-appb-C000194
 (Reference Example 70)
Ethyl 2-hydroxy-2- (thiophen-2-yl) acetate
Figure JPOXMLDOC01-appb-C000194
　チオフェン－２－ボロン酸１．００ｇ（７．８２ｍｍｏｌ）の脱水トルエン３０ｍｌ懸濁液に、アルゴン雰囲気下で撹拌しながら、５０％エチル　オキソアセタート　トルエン溶液［Ａｐｏｌｌｏ　ｓｃｉｅｎｔｉｆｉｃ　ｌｉｍｉｔｅｄより購入］２．４０ｇ（１１．８ｍｍｏｌ）、２－（ジ－ｔｅｒｔ－ブチルホスフィノ）ビフェニル１１７ｍｇ（０．３９２ｍｍｏｌ）を室温で加え、減圧下窒素雰囲気へと置換した。次いで、トリス（ジベンジリデンアセトン）ジパラジウム（０）１０１ｍｇ（０．１１０ｍｍｏｌ）を撹拌下に室温で加え、８０℃で９時間反応させた。
　反応液をセライトフィルターを用いて濾過し、ろ液に水を加えて酢酸エチルで抽出した。得られた有機層を飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥、濾過、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～６０：４０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物８６ｍｇ（収率６％）を黄色油状物として得た。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.29 (dd, J = 1.2, 5.1 Hz, 1H), 7.13 - 7.09 (m, 1H), 7.00 (dd, J = 3.6, 5.1 Hz, 1H), 5.43 - 5.37 (m, 1H), 4.37 - 4.22 (m, 2H), 3.48 (d, J = 6.4 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H)。 To a suspension of 1.00 g (7.82 mmol) of thiophene-2-boronic acid in 30 ml of dehydrated toluene with stirring under an argon atmosphere, 50% ethyl oxoacetate in toluene [purchased from Apollo scientific limited] 2.40 g (11. 8 mmol) and 117 mg (0.392 mmol) of 2- (di-tert-butylphosphino) biphenyl were added at room temperature, and the atmosphere was replaced with a nitrogen atmosphere under reduced pressure. Next, 101 mg (0.110 mmol) of tris (dibenzylideneacetone) dipalladium (0) was added at room temperature with stirring, and the mixture was reacted at 80 ° C. for 9 hours.
The reaction mixture was filtered using a celite filter, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 60:40 (V / V)), and the fraction containing the target product was concentrated under reduced pressure. The title compound (86 mg, yield 6%) was obtained as a yellow oil.
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.29 (dd, J = 1.2, 5.1 Hz, 1H), 7.13-7.09 (m, 1H), 7.00 (dd, J = 3.6, 5.1 Hz, 1H), 5.43-5.37 (m, 1H), 4.37-4.22 (m, 2H), 3.48 (d, J = 6.4 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H).
（参考例７１）
エチル　２－メトキシ－２－（チオフェン－２－イル）アセタート
Figure JPOXMLDOC01-appb-C000195
 (Reference Example 71)
Ethyl 2-methoxy-2- (thiophen-2-yl) acetate
Figure JPOXMLDOC01-appb-C000195
　アルゴン雰囲気下、参考例７０と同様の方法で合成したエチル　２－ヒドロキシ－２－（チオフェン－２－イル）アセタート８６ｍｇ（０．４６ｍｍｏｌ）のヨードメタン４．０ｍｌ（６４ｍｍｏｌ）溶液に、酸化銀２１４ｍｇ（０．９２３ｍｍｏｌ）を室温で加え、同温度で撹拌しながら３時間反応させた。
　反応終了後、セライトフィルターを用いて濾過し、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～６０：４０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物６８．５ｍｇ（収率７４％）を無色油状物として得た。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.33 (dd, J = 1.2, 5.1 Hz, 1H), 7.16 - 7.10 (m, 1H), 7.00 (dd, J = 3.5, 5.1 Hz, 1H), 5.02 (s, 1H), 4.33 - 4.17 (m, 2H), 3.44 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H)。 In an argon atmosphere, a solution of 86 mg (0.46 mmol) of ethyl 2-hydroxy-2- (thiophen-2-yl) acetate synthesized in the same manner as in Reference Example 70 was added to 4.0 ml (64 mmol) of iodomethane, and 214 mg of silver oxide ( 0.923 mmol) was added at room temperature, and the mixture was reacted for 3 hours while stirring at the same temperature.
After completion of the reaction, the reaction mixture was filtered using a celite filter, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 60:40 (V / V)), and the fraction containing the target product was concentrated under reduced pressure. The title compound (68.5 mg, yield 74%) was obtained as a colorless oil.
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.33 (dd, J = 1.2, 5.1 Hz, 1H), 7.16-7.10 (m, 1H), 7.00 (dd, J = 3.5, 5.1 Hz, 1H), 5.02 (s, 1H), 4.33-4.17 (m, 2H), 3.44 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H).
（参考例７２）
２－メトキシ－２－（チオフェン－２－イル）酢酸
Figure JPOXMLDOC01-appb-C000196
 (Reference Example 72)
2-Methoxy-2- (thiophen-2-yl) acetic acid
Figure JPOXMLDOC01-appb-C000196
　参考例７１と同様にして合成したエチル　２－メトキシ－２－（チオフェン－２－イル）アセタート６８ｍｇ（０．３４ｍｍｏｌ）のＴＨＦ３ｍｌ溶液に、撹拌しながら、１Ｎ水酸化ナトリウム水溶液０．５ｍｌ（０．５ｍｍｏｌ）を室温で加え、同温度で１６時間撹拌した。
　反応終了後、反応液に１Ｎ塩酸を加えてｐＨを２に調整し、酢酸エチルで抽出した。得られた有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥し、濾過、濾液を減圧濃縮、減圧乾燥することにより、標記化合物６０ｍｇ（不純物含む）を微黄色油状物として得た。
マススペクトル（ＤＵＩＳ，ｍ／ｚ）：１７１［Ｍ－１］－。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.36 (dd, J = 1.2, 5.1 Hz, 1H), 7.19 - 7.14 (m, 1H), 7.02 (dd, J = 3.5, 5.1 Hz, 1H), 5.07 (s, 1H), 3.48 (s, 3H)。 While stirring in a solution of ethyl 2-methoxy-2- (thiophen-2-yl) acetate 68 mg (0.34 mmol) in THF 3 ml synthesized in the same manner as in Reference Example 71, 0.5 ml (0. 5 mmol) was added at room temperature and stirred at the same temperature for 16 hours.
After completion of the reaction, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried under reduced pressure to obtain 60 mg (including impurities) of the title compound as a pale yellow oil.
Mass spectrum (DUIS, m / z): 171 [M-1] − .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.36 (dd, J = 1.2, 5.1 Hz, 1H), 7.19-7.14 (m, 1H), 7.02 (dd, J = 3.5, 5.1 Hz, 1H), 5.07 (s, 1H), 3.48 (s, 3H).
（参考例７３）
２－エチル　５－（トリクロロメチル）　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］ピロロ［３，４－ｃ］ピラゾール－２，５（４Ｈ，６Ｈ）－ジカルボキラート、および、エチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラートの混合物
Figure JPOXMLDOC01-appb-C000197
 (Reference Example 73)
2-ethyl 5- (trichloromethyl) 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] pyrrolo [3,4-c] pyrazole-2,5 (4H, 6H) -dicarboxylate, and Of ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate blend
Figure JPOXMLDOC01-appb-C000197
　アルゴン雰囲気下、参考例４７と同様にして合成したエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート８．０３ｇ（２１．２ｍｍｏｌ）の脱水ジクロロメタン１００ｍｌ溶液にＤＩＰＥＡ１２．９ｍｌ（７４．１ｍｍｏｌ）を室温で加えた。次いで、ビス（トリクロロメチル）カルボナート４．４０ｇ（１４．８ｍｍｏｌ）の脱水ジクロロメタン１０ｍｌ溶液を－７８℃で滴下しながら加えた後、そのままの温度で１．５時間撹拌した。
　反応終了後、反応液に飽和炭酸水素ナトリウム水溶液とジクロロメタンを加えた後、成り行きで室温まで昇温させながら１時間撹拌した。反応液を分液後、水層を酢酸エチルで２回抽出した。全有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝８５：１５→７５：２５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた濃縮残渣にｎ－ヘキサンを加え、室温で１０分間撹拌した後に冷凍庫で１５分間静置した。析出した固体を濾別し、取り除いた固体をｎ－ヘキサンで洗浄することにより得られた濾液を減圧濃縮、減圧乾燥することにより、２－エチル　５－（トリクロロメチル）　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］ピロロ［３，４－ｃ］ピラゾール－２，５（４Ｈ，６Ｈ）－ジカルボキラート２．９０ｇ（収率２５％）とエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１．７５ｇ（収率１９％）の混合物を白色泡状物として得た。
マススペクトル（ＥＳＩ，ｍ／ｚ）：５３９［Ｍ＋１］＋，４４１［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：9.99 - 9.84 (m, total 1H), 4.97 (s, 0.85H), 4.84 - 4.79 (m, total 1.15H), 4.59 - 4.51 (m, total 2H), 2.64 - 2.53 (m, total 2H), 2.39 - 2.28 (m, total 2H), 2.03 - 1.92 (m, total 2H), 1.82 - 1.75 (m, total 6H), 1.51 - 1.44 (m, total 3H), 0.19 - 0.13 (m, total 9H)。 Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) synthesized as in Reference Example 47 under an argon atmosphere ) -Carboxylate (12.9 ml, 74.1 mmol) was added to a solution of 8.03 g (21.2 mmol) in dehydrated dichloromethane (100 ml) at room temperature. Next, a solution of 4.40 g (14.8 mmol) of bis (trichloromethyl) carbonate in 10 ml of dehydrated dichloromethane was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 1.5 hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added to the reaction solution, and the mixture was stirred for 1 hour while gradually raising the temperature to room temperature. After separating the reaction solution, the aqueous layer was extracted twice with ethyl acetate. All organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 85: 15 → 75: 25 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. N-Hexane was added to the resulting concentrated residue, stirred at room temperature for 10 minutes, and then allowed to stand in a freezer for 15 minutes. The precipitated solid was separated by filtration, and the filtrate obtained by washing the removed solid with n-hexane was concentrated under reduced pressure and dried under reduced pressure to give 2-ethyl 5- (trichloromethyl) 6,6-dimethyl-3. -[1- (trimethylsilyl) cyclobutanecarboxamide] pyrrolo [3,4-c] pyrazole-2,5 (4H, 6H) -dicarboxylate 2.90 g (25% yield) and ethyl 5- (chlorocarbonyl)- 1.75 g (19% yield) of 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate The mixture was obtained as a white foam.
Mass spectrum (ESI, m / z): 539 [M + 1] + , 441 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 9.99-9.84 (m, total 1H), 4.97 (s, 0.85H), 4.84-4.79 (m, total 1.15H), 4.59-4.51 (m, total 2H ), 2.64-2.53 (m, total 2H), 2.39-2.28 (m, total 2H), 2.03-1.92 (m, total 2H), 1.82-1.75 (m, total 6H), 1.51-1.44 (m, total 3H ), 0.19-0.13 (m, total 9H).
（参考例７４）
｛１－［アミノ（フェニル）メチル］シクロブチル｝メタノール
Figure JPOXMLDOC01-appb-C000198
 (Reference Example 74)
{1- [Amino (phenyl) methyl] cyclobutyl} methanol
Figure JPOXMLDOC01-appb-C000198
　アルゴン雰囲気下、カルバミン酸エチル２．０７ｇ（２３．２ｍｍｏｌ）のトルエン２０ｍｌ溶液に、ベンズアルデヒド２．３６ｍｌ（２３．２ｍｍｏｌ）、ｐ－トルエンスルホン酸一水和物２３５ｍｇ（１．２３ｍｍｏｌ）を室温で順次加えた後、室温で５分間撹拌した。次いで、シクロブタンカルボアルデヒド１．８０ｍｌ（２３．２ｍｍｏｌ）を室温で加えた後、６０℃で４時間撹拌した。
　反応終了後、反応液を飽和炭酸水素ナトリウム水溶液に注ぎ入れた後、室温で撹拌した。分液した後、水層をトルエンで１回抽出した。得られた全有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９０：１０～６０：４０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、濃縮残渣２．２０ｇを得た。
　アルゴン雰囲気下、得られた濃縮残渣のエタノール１０ｍｌ溶液に、水素化ホウ素ナトリウム１９９ｍｇ（５．２６ｍｍｏｌ）を０℃で分割添加した後、０℃で０．５時間、更に室温で２．５時間撹拌した。次いで、反応液に水酸化カリウム９９０ｍｇ（１７．７ｍｍｏｌ）、水５．０ｍｌを室温で加えた後、加熱還流下で２．５時間撹拌した。
　反応終了後、反応液を減圧濃縮してエタノールを留去した。濃縮残渣に２Ｎ塩酸を加えた後、ジエチルエーテルで洗浄した。分液して得られた水層に２Ｎ水酸化ナトリウム水溶液を加えてｐＨ＞１０に調整した後、ジクロロメタンで３回抽出した。得られた全有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。得られた濃縮残渣を１，２－ジクロロエタンに溶解させた後、ｎ－ヘキサンを加えて析出させた固体を濾取し、ｎ－ヘキサンで洗浄してから減圧乾燥することにより、標記化合物８５９ｍｇ（収率１９％［２工程］）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１９２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：7.36 - 7.25 (m, 4H), 7.24 - 7.16 (m, 1H), 3.97 (s, 1H), 3.41 (d, J = 10.7 Hz, 1H), 3.25 (d, J = 10.7 Hz, 1H), 2.06 - 1.92 (m, 2H), 1.79 - 1.63 (m, 2H), 1.61 - 1.50 (m, 1H), 1.47 - 1.37 (m, 1H)。 Under an argon atmosphere, 2.07 g (23.2 mmol) of ethyl carbamate in 20 ml of toluene, 2.36 ml (23.2 mmol) of benzaldehyde and 235 mg (1.23 mmol) of p-toluenesulfonic acid monohydrate were sequentially added at room temperature. After the addition, the mixture was stirred at room temperature for 5 minutes. Next, 1.80 ml (23.2 mmol) of cyclobutanecarbaldehyde was added at room temperature, followed by stirring at 60 ° C. for 4 hours.
After completion of the reaction, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and then stirred at room temperature. After liquid separation, the aqueous layer was extracted once with toluene. The obtained all organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 60:40 (V / V)), and the fraction containing the target product was concentrated under reduced pressure and dried under reduced pressure. As a result, 2.20 g of a concentrated residue was obtained.
Under an argon atmosphere, 199 mg (5.26 mmol) of sodium borohydride was added portionwise at 0 ° C. to a 10 ml solution of the obtained concentrated residue in ethanol, and then stirred at 0 ° C. for 0.5 hours and further at room temperature for 2.5 hours. did. Next, 990 mg (17.7 mmol) of potassium hydroxide and 5.0 ml of water were added to the reaction solution at room temperature, followed by stirring for 2.5 hours under heating and reflux.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to distill off ethanol. 2N hydrochloric acid was added to the concentrated residue, followed by washing with diethyl ether. The aqueous layer obtained by liquid separation was adjusted to pH> 10 by adding a 2N aqueous sodium hydroxide solution, and then extracted three times with dichloromethane. The obtained all organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was dissolved in 1,2-dichloroethane, then n-hexane was added, and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to give 859 mg of the title compound ( Yield 19% [2 steps]) was obtained as a white solid.
Mass spectrum (CI, m / z): 192 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 7.36-7.25 (m, 4H), 7.24-7.16 (m, 1H), 3.97 (s, 1H), 3.41 (d, J = 10.7 Hz, 1H ), 3.25 (d, J = 10.7 Hz, 1H), 2.06-1.92 (m, 2H), 1.79-1.63 (m, 2H), 1.61-1.50 (m, 1H), 1.47-1.37 (m, 1H).
（参考例７５）
（Ｒ）－Ｎ－［２－（１－ヒドロキシシクロプロピル）－１－フェニルエチル］－２，２，２－トリフルオロアセタミド
Figure JPOXMLDOC01-appb-C000199
 (Reference Example 75)
(R) -N- [2- (1-hydroxycyclopropyl) -1-phenylethyl] -2,2,2-trifluoroacetamide
Figure JPOXMLDOC01-appb-C000199
　アルゴン雰囲気下、参考例２０と同様にして合成した（Ｒ）－メチル　３－フェニル－３－（２，２，２－トリフルオロアセタミド）プロパノアート１．０１ｇ（３．６７ｍｍｏｌ）の脱水ＴＨＦ１０ｍｌ溶液にオルトチタン酸テトライソプロピル０．２２ｍｌ（０．７５ｍｍｏｌ）を０℃で加えた後、１Ｍエチルマグネシウムブロミド／ＴＨＦ溶液１１．０ｍｌ（１１．０ｍｍｏｌ）を０℃で１時間かけて滴下しながら加えた後、そのままの温度で３時間、次いで室温に昇温して１．５時間撹拌した。
　反応終了後、反応液に飽和塩化アンモニウム水溶液を加えて撹拌した後、不溶物をセライトフィルターを用いて濾別した。ろ取した固体を酢酸エチルで洗浄した後、濾液を分液した。水層を酢酸エチルで１回抽出した後、全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９５：５～７５：２５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物４８９ｍｇ（収率４９％）を微黄色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：２７４［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：9.67 (br s, 1H), 7.37 - 7.30 (m, 4H), 7.30 - 7.21 (m, 1H), 5.33 - 5.05 (m, 2H), 2.01 (dd, J = 5.2, 14.2 Hz, 1H), 1.93 (dd, J = 9.2, 14.2 Hz, 1H), 0.57 - 0.46 (m, 2H), 0.45 - 0.37 (m, 1H), 0.11 - 0.04 (m, 1H)。 Under an argon atmosphere, a solution of 1.01 g (3.67 mmol) of (R) -methyl 3-phenyl-3- (2,2,2-trifluoroacetamide) propanoate synthesized in the same manner as in Reference Example 20 in a 10 ml solution of dehydrated THF. After adding 0.22 ml (0.75 mmol) of tetraisopropyl orthotitanate at 0 ° C., 11.0 ml (11.0 mmol) of 1M ethylmagnesium bromide / THF solution was added dropwise at 0 ° C. over 1 hour. The mixture was kept at the same temperature for 3 hours, then warmed to room temperature and stirred for 1.5 hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction mixture and stirred, and then insoluble matter was filtered off using a celite filter. The solid collected by filtration was washed with ethyl acetate, and the filtrate was separated. The aqueous layer was extracted once with ethyl acetate, and then the entire organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 95: 5 to 75:25 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure. As a result, 489 mg (yield 49%) of the title compound was obtained as a slightly yellow solid.
Mass spectrum (CI, m / z): 274 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 9.67 (br s, 1H), 7.37-7.30 (m, 4H), 7.30-7.21 (m, 1H), 5.33-5.05 (m, 2H), 2.01 (dd, J = 5.2, 14.2 Hz, 1H), 1.93 (dd, J = 9.2, 14.2 Hz, 1H), 0.57-0.46 (m, 2H), 0.45-0.37 (m, 1H), 0.11-0.04 ( m, 1H).
（参考例７６）
（Ｒ）－１－（２－アミノ－２－フェニルエチル）シクロプロパノール
Figure JPOXMLDOC01-appb-C000200
 (Reference Example 76)
(R) -1- (2-Amino-2-phenylethyl) cyclopropanol
Figure JPOXMLDOC01-appb-C000200
　アルゴン雰囲気下、参考例７５と同様にして合成した（Ｒ）－Ｎ－［２－（１－ヒドロキシシクロプロピル）－１－フェニルエチル］－２，２，２－トリフルオロアセタミド４１２ｍｇ（１．５１ｍｍｏｌ）のエタノール７ｍｌ溶液に、水素化ホウ素ナトリウム１７４ｍｇ（４．６０ｍｍｏｌ）を室温で加えた後、室温で１４．５時間撹拌した。 Under an argon atmosphere, 412 mg of (R) -N- [2- (1-hydroxycyclopropyl) -1-phenylethyl] -2,2,2-trifluoroacetamide synthesized in the same manner as in Reference Example 75 (1. 51 mmol) in 7 ml of ethanol was added 174 mg (4.60 mmol) of sodium borohydride at room temperature, followed by stirring at room temperature for 14.5 hours.
　反応終了後、反応液に飽和塩化アンモニウム水溶液を０℃で加えた後、室温で撹拌した。水を追加して不溶物を溶解した後、ジクロロメタンで２回抽出した。全有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７５：２５～６０：４０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物２５９ｍｇ（不純物を含む）を微黄色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１７８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：7.38 - 7.24 (m, 4H), 7.21 - 7.14 (m, 1H), 4.15 (dd, J = 4.0, 9.4 Hz, 1H), 1.82 (ddd, J = 1.3, 9.4, 13.9 Hz, 1H), 1.51 - 1.44 (m, 1H), 0.58 - 0.51 (m, 1H), 0.49 - 0.42 (m, 1H), 0.41 - 0.34 (m, 1H), 0.21 - 0.14 (m, 1H)。 After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution at 0 ° C., followed by stirring at room temperature. Water was added to dissolve insoluble matters, and the mixture was extracted twice with dichloromethane. All organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 75: 25 to 60:40 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. By drying under reduced pressure, 259 mg (including impurities) of the title compound was obtained as a slightly yellow solid.
Mass spectrum (CI, m / z): 178 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 7.38-7.24 (m, 4H), 7.21-7.14 (m, 1H), 4.15 (dd, J = 4.0, 9.4 Hz, 1H), 1.82 (ddd , J = 1.3, 9.4, 13.9 Hz, 1H), 1.51-1.44 (m, 1H), 0.58-0.51 (m, 1H), 0.49-0.42 (m, 1H), 0.41-0.34 (m, 1H), 0.21 -0.14 (m, 1H).
（参考例７７）
（Ｒ）－Ｎ－（３－エチル－３－ヒドロキシ－１－フェニルペンチル）－２，２，２－トリフルオロアセタミド
Figure JPOXMLDOC01-appb-C000201
 (Reference Example 77)
(R) -N- (3-Ethyl-3-hydroxy-1-phenylpentyl) -2,2,2-trifluoroacetamide
Figure JPOXMLDOC01-appb-C000201
　参考例２０と同様にして合成した（Ｒ）－メチル　３－フェニル－３－（２，２，２－トリフルオロアセタミド）プロパノアート７００ｍｇ（２．５４ｍｍｏｌ）の脱水ＴＨＦ１０ｍｌ溶液に、アルゴン雰囲気下、１Ｍエチルマグネシウムブロミド－ＴＨＦ溶液７．６３ｍｌ（７．６３ｍｍｏｌ）を０℃で滴下した後、室温で６時間撹拌した。
　反応終了後、反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。得られた全有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した後、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～９０：１０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物７１４ｍｇ（不純物を含む）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：３０４［Ｍ＋１］＋。 To a solution of 700 mg (2.54 mmol) of (R) -methyl 3-phenyl-3- (2,2,2-trifluoroacetamide) propanoate synthesized in the same manner as in Reference Example 20 in 10 ml of dehydrated THF, 1M After dropwise addition of 7.63 ml (7.63 mmol) of ethylmagnesium bromide-THF solution at 0 ° C., the mixture was stirred at room temperature for 6 hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The entire organic layer obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 90:10 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure. This gave 714 mg (including impurities) of the title compound as a colorless oil.
Mass spectrum (CI, m / z): 304 [M + 1] + .
（参考例７８）
（Ｒ）－１－アミノ－３－エチル－１－フェニルペンタン－３－オール
Figure JPOXMLDOC01-appb-C000202
 (Reference Example 78)
(R) -1-Amino-3-ethyl-1-phenylpentane-3-ol
Figure JPOXMLDOC01-appb-C000202
　参考例７７にて合成した（Ｒ）－Ｎ－（３－エチル－３－ヒドロキシ－１－フェニルペンチル）－２，２，２－トリフルオロアセタミド７１４ｍｇ（不純物を含む）の水１ｍｌ／メタノール５ｍｌ溶液に、アルゴン雰囲気下、炭酸カリウム６５１ｍｇ（４．７１ｍｍｏｌ）を室温で加えた後、そのままの温度で２０時間撹拌した。
　反応終了後、反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。得られた全有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した後、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７５：２５～６０：４０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１２０ｍｇ（収率２３％［２工程］）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：２０８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：7.38 - 7.25 (m, 4H), 7.22 - 7.15 (m, 1H), 4.01 (dd, J = 2.6, 10.9 Hz, 1H), 1.66 - 1.41 (m, 4H), 1.38 - 1.25 (m, 2H), 0.86 - 0.71 (m, 6H)。 714 mg (including impurities) of (R) -N- (3-ethyl-3-hydroxy-1-phenylpentyl) -2,2,2-trifluoroacetamide synthesized in Reference Example 77 (1 ml) water / methanol (5 ml) To the solution, 651 mg (4.71 mmol) of potassium carbonate was added at room temperature under an argon atmosphere, followed by stirring at the same temperature for 20 hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The entire organic layer obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 75: 25 to 60:40 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure. As a result, 120 mg (yield 23% [2 steps]) of the title compound was obtained as a colorless oil.
Mass spectrum (CI, m / z): 208 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 7.38-7.25 (m, 4H), 7.22-7.15 (m, 1H), 4.01 (dd, J = 2.6, 10.9 Hz, 1H), 1.66-1.41 (m, 4H), 1.38-1.25 (m, 2H), 0.86-0.71 (m, 6H).
（参考例７９）
（Ｅ）－メチル　３－（４－フルオロフェニル）アクリラート
Figure JPOXMLDOC01-appb-C000203
 (Reference Example 79)
(E) -Methyl 3- (4-fluorophenyl) acrylate
Figure JPOXMLDOC01-appb-C000203
　４－フルオロベンズアルデヒド２．０ｇ（１６ｍｍｏｌ）の脱水ＴＨＦ２０ｍｌ溶液に、アルゴン雰囲気下、メチル　２－（トリフェニルホスホラニリデン）アセタート６．４７ｇ（１９．４ｍｍｏｌ）を室温で加えた後、そのままの温度で２０時間撹拌した。
　反応終了後、反応液を減圧濃縮した。得られた濃縮残渣にＴＢＭＥ２０ｍｌを加えて濾過し、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～９０：１０（ｖ／ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物２．７４ｇ（収率９４％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１８１［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.66 (d, J = 16.0 Hz, 1H), 7.55 - 7.47 (m, 2H), 7.13 - 7.03 (m, 2H), 6.41 - 6.33 (m, 1H), 3.81 (s, 3H)。 To a solution of 2.0 g (16 mmol) of 4-fluorobenzaldehyde in 20 ml of dehydrated THF, 6.47 g (19.4 mmol) of methyl 2- (triphenylphosphoranylidene) acetate was added at room temperature under an argon atmosphere. Stir for 20 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. To the obtained concentrated residue, 20 ml of TBME was added and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 90:10 (v / v)), and the fraction containing the target product was concentrated under reduced pressure and dried under reduced pressure. As a result, 2.74 g (yield 94%) of the title compound was obtained as a white solid.
Mass spectrum (CI, m / z): 181 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.66 (d, J = 16.0 Hz, 1H), 7.55-7.47 (m, 2H), 7.13-7.03 (m, 2H), 6.41-6.33 (m, 1H ), 3.81 (s, 3H).
（参考例８０）
（Ｒ）－メチル　３－｛ベンジル［（Ｓ）－１－フェニルエチル］アミノ｝－３－（４－フルオロフェニル）プロパノアート
Figure JPOXMLDOC01-appb-C000204
 (Reference Example 80)
(R) -methyl 3- {benzyl [(S) -1-phenylethyl] amino} -3- (4-fluorophenyl) propanoate
Figure JPOXMLDOC01-appb-C000204
　（Ｓ）－Ｎ－ベンジル－１－フェニルエタンアミン２．７９ｍｌ（１３．３ｍｍｏｌ）の脱水ＴＨＦ３０ｍｌ溶液に、アルゴン雰囲気下、１．６Ｍ　ｎ－ブチルリチウム　ｎ－ヘキサン溶液７．８０ｍｌ（１２．５ｍｍｏｌ）を－７８℃で滴下した後、そのままの温度で３０分間撹拌した。次いで、参考例７９と同様にして合成した（Ｅ）－メチル　３－（４－フルオロフェニル）アクリラート１．５ｇ（８．３ｍｍｏｌ）のＴＨＦ５ｍｌ溶液を－７８℃で加えた後、そのままの温度で１時間撹拌した。
　反応終了後、反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。得られた有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した後、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～９５：５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物１．５３ｇ（収率４７％）を微黄色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：３９２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.43 - 7.16 (m, 12H), 7.08 - 6.96 (m, 2H), 4.42 (dd, J = 5.4, 9.7 Hz, 1H), 3.97 (q, J = 6.9 Hz, 1H), 3.72 (d, J = 14.7 Hz, 1H), 3.65 (d, J = 14.7 Hz, 1H), 3.47 (s, 3H), 2.65 (dd, J = 5.4, 14.9 Hz, 1H), 2.52 (dd, J = 9.7, 14.9 Hz, 1H), 1.27 - 1.21 (m, 3H)。 (S) -N-benzyl-1-phenylethanamine 2.79 ml (13.3 mmol) in 30 ml of dehydrated THF was added under argon atmosphere, 1.6M n-butyllithium n-hexane solution 7.80 ml (12.5 mmol) Was added dropwise at −78 ° C., followed by stirring at the same temperature for 30 minutes. Next, a solution of 1.5 g (8.3 mmol) of (E) -methyl 3- (4-fluorophenyl) acrylate synthesized in the same manner as in Reference Example 79 in 5 ml of THF was added at −78 ° C. Stir for hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The title compound (1.53 g, yield 47%) was obtained as a pale yellow oil.
Mass spectrum (CI, m / z): 392 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.43-7.16 (m, 12H), 7.08-6.96 (m, 2H), 4.42 (dd, J = 5.4, 9.7 Hz, 1H), 3.97 (q, J = 6.9 Hz, 1H), 3.72 (d, J = 14.7 Hz, 1H), 3.65 (d, J = 14.7 Hz, 1H), 3.47 (s, 3H), 2.65 (dd, J = 5.4, 14.9 Hz, 1H ), 2.52 (dd, J = 9.7, 14.9 Hz, 1H), 1.27-1.21 (m, 3H).
（参考例８１）
（Ｒ）－４－｛ベンジル［（Ｓ）－１－フェニルエチル］アミノ｝－４－（４－フルオロフェニル）－２－メチルブタン－２－オール
Figure JPOXMLDOC01-appb-C000205
 (Reference Example 81)
(R) -4- {Benzyl [(S) -1-phenylethyl] amino} -4- (4-fluorophenyl) -2-methylbutan-2-ol
Figure JPOXMLDOC01-appb-C000205
　参考例８０と同様にして合成した（Ｒ）－メチル　３－｛ベンジル［（Ｓ）－１－フェニルエチル］アミノ｝－３－（４－フルオロフェニル）プロパノアート１．３５ｇ（３．４５ｍｍｏｌ）の脱水ＴＨＦ２０ｍｌ溶液に、アルゴン気流下、１Ｍメチルマグネシウムブロミド－ＴＨＦ溶液１０．４ｍｌ（１０．４ｍｍｏｌ）を０℃で滴下した後、室温で２０時間撹拌した。
　反応終了後、反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。得られた有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した後、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９５：５～８５：１５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物８５０ｍｇ（収率６３％）を無色油状物として得た。
マススペクトル（ＥＳＩ，ｍ／ｚ）：３９２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：7.48 - 7.09 (m, 14H), 4.21 (s, 1H), 4.09 - 3.98 (m, 1H), 3.92 - 3.85 (m, 1H), 3.74 (d, J = 15.1 Hz, 1H), 3.63 (d, J = 15.1 Hz, 1H), 2.10 (dd, J = 9.2, 13.9 Hz, 1H), 2.02 - 1.93 (m, 1H), 0.93 (d, J = 6.8 Hz, 3H), 0.82 (s, 3H), 0.69 (s, 3H)。 Dehydration of 1.35 g (3.45 mmol) of (R) -methyl 3- {benzyl [(S) -1-phenylethyl] amino} -3- (4-fluorophenyl) propanoate synthesized as in Reference Example 80 To a 20 ml THF solution, 10.4 ml (10.4 mmol) of a 1M methylmagnesium bromide-THF solution was added dropwise at 0 ° C. under an argon stream, followed by stirring at room temperature for 20 hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 95: 5 to 85:15 (V / V)), and the fraction containing the target product was concentrated under reduced pressure and dried under reduced pressure. This gave 850 mg (yield 63%) of the title compound as a colorless oil.
Mass spectrum (ESI, m / z): 392 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 7.48-7.09 (m, 14H), 4.21 (s, 1H), 4.09-3.98 (m, 1H), 3.92-3.85 (m, 1H), 3.74 (d, J = 15.1 Hz, 1H), 3.63 (d, J = 15.1 Hz, 1H), 2.10 (dd, J = 9.2, 13.9 Hz, 1H), 2.02-1.93 (m, 1H), 0.93 (d, J = 6.8 Hz, 3H), 0.82 (s, 3H), 0.69 (s, 3H).
（参考例８２）
（Ｒ）－４－アミノ－４－（４－フルオロフェニル）－２－メチルブタン－２－オール
Figure JPOXMLDOC01-appb-C000206
 (Reference Example 82)
(R) -4-Amino-4- (4-fluorophenyl) -2-methylbutan-2-ol
Figure JPOXMLDOC01-appb-C000206
　参考例８１と同様にして合成した（Ｒ）－４－｛ベンジル［（Ｓ）－１－フェニルエチル］アミノ｝－４－（４－フルオロフェニル）－２－メチルブタン－２－オール８５０ｍｇ（２．１７ｍｍｏｌ）のメタノール１０ｍｌ溶液に、アルゴン気流下、２０％水酸化パラジウム／炭素（５０％含水）４２５ｍｇを室温で加え、水素雰囲気に置換後、室温で７時間撹拌した。
　反応終了後、反応液を酢酸エチルで希釈し、セライト濾過した。濾液を減圧濃縮し、得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬ，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７５：２５～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物２４８ｍｇ（不純物を含む）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１９８［Ｍ＋１］＋。 850 mg of (R) -4- {benzyl [(S) -1-phenylethyl] amino} -4- (4-fluorophenyl) -2-methylbutan-2-ol synthesized in the same manner as in Reference Example 81 (2. 17%) in 10 ml of methanol was added 425 mg of 20% palladium hydroxide / carbon (containing 50% water) at room temperature under an argon stream, and after replacing with a hydrogen atmosphere, the mixture was stirred at room temperature for 7 hours.
After completion of the reaction, the reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was concentrated under reduced pressure, and the resulting concentrated residue was subjected to silica gel column chromatography (DIOL, elution solvent; n-hexane: ethyl acetate = 75: 25 to 50:50 (V / V)) to contain the desired product. The fraction was concentrated under reduced pressure to obtain 248 mg (including impurities) of the title compound as a colorless oil.
Mass spectrum (CI, m / z): 198 [M + 1] + .
（参考例８３）
（Ｅ）－メチル　３－（３－フルオロフェニル）アクリラート
Figure JPOXMLDOC01-appb-C000207
 (Reference Example 83)
(E) -Methyl 3- (3-fluorophenyl) acrylate
Figure JPOXMLDOC01-appb-C000207
　３－フルオロベンズアルデヒド１．２７ｍｌ（１２．１ｍｍｏｌ）の脱水ＴＨＦ２５ｍｌ溶液に、アルゴン気流下、メチル　２－（トリフェニルホスホラニリデン）アセタート５．２５ｇ（１５．７ｍｍｏｌ）を室温で加えた後、そのままの温度で１６時間撹拌した。
　反応終了後、反応液を減圧濃縮した。得られた濃縮残渣にＴＢＭＥ２０ｍｌを加え、不溶物を濾別し、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～９０：１０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物１．７５ｇ（収率８０％）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１８１［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.65 (d, J = 16.1 Hz, 1H), 7.40 - 7.33 (m, 1H), 7.32 - 7.27 (m, 1H), 7.25 - 7.19 (m, 1H), 7.12 - 7.05 (m, 1H), 6.44 (d, J = 16.1 Hz, 1H), 3.82 (s, 3H)。 To a solution of 1.27 ml (12.1 mmol) of 3-fluorobenzaldehyde in 25 ml of dehydrated THF, 5.25 g (15.7 mmol) of methyl 2- (triphenylphosphoranylidene) acetate was added at room temperature under a stream of argon. Stir at temperature for 16 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. To the resulting concentrated residue, 20 ml of TBME was added, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 90:10 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The title compound (1.75 g, yield 80%) was obtained as a colorless oil.
Mass spectrum (CI, m / z): 181 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.65 (d, J = 16.1 Hz, 1H), 7.40-7.33 (m, 1H), 7.32-7.27 (m, 1H), 7.25-7.19 (m, 1H ), 7.12-7.05 (m, 1H), 6.44 (d, J = 16.1 Hz, 1H), 3.82 (s, 3H).
（参考例８４）
（Ｒ）－メチル　３－｛ベンジル［（Ｓ）－１－フェニルエチル］アミノ｝－３－（３－フルオロフェニル）プロパノアート
Figure JPOXMLDOC01-appb-C000208
 (Reference Example 84)
(R) -methyl 3- {benzyl [(S) -1-phenylethyl] amino} -3- (3-fluorophenyl) propanoate
Figure JPOXMLDOC01-appb-C000208
　（Ｓ）－Ｎ－ベンジル－１－フェニルエタンアミン３．２５ｍｌ（１５．５ｍｍｏｌ）の脱水ＴＨＦ３０ｍｌ溶液に、アルゴン雰囲気下、１．６Ｍ　ｎ－ブチルリチウム　ｎ－ヘキサン溶液９．１１ｍｌ（１４．６ｍｍｏｌ）を－７８℃で滴下した後、そのままの温度で１時間撹拌した。次いで、参考例８３と同様にして合成した（Ｅ）－メチル　３－（３－フルオロフェニル）アクリラート１．７５ｇ（９．７１ｍｍｏｌ）のＴＨＦ５ｍｌ溶液を－７８℃で加えた後、そのままの温度で１時間撹拌した。
　反応終了後、反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。得られた有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した後、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～９５：５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物２．２２ｇ（収率５８％）を微黄色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：３９２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.45 - 7.09 (m, 13H), 7.00 - 6.91 (m, 1H), 4.44 (dd, J = 5.4, 9.4 Hz, 1H), 3.98 (q, J = 6.9 Hz, 1H), 3.73 (d, J = 14.6 Hz, 1H), 3.66 (d, J = 14.6 Hz, 1H), 3.49 (s, 3H), 2.63 (dd, J = 5.4, 15.2 Hz, 1H), 2.54 (dd, J = 9.4, 15.2 Hz, 1H), 1.25 (d, J = 6.9 Hz, 3H)。 (S) -N-benzyl-1-phenylethanamine 3.25 ml (15.5 mmol) in 30 ml of dehydrated THF was added to 9.11 ml (14.6 mmol) of 1.6 M n-butyllithium n-hexane solution in an argon atmosphere. Was added dropwise at −78 ° C., followed by stirring at the same temperature for 1 hour. Next, a solution of 1.75 g (9.71 mmol) of (E) -methyl 3- (3-fluorophenyl) acrylate synthesized in the same manner as in Reference Example 83 in 5 ml of THF was added at −78 ° C. Stir for hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The title compound (2.22 g, yield 58%) was obtained as a pale yellow oil.
Mass spectrum (CI, m / z): 392 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.45-7.09 (m, 13H), 7.00-6.91 (m, 1H), 4.44 (dd, J = 5.4, 9.4 Hz, 1H), 3.98 (q, J = 6.9 Hz, 1H), 3.73 (d, J = 14.6 Hz, 1H), 3.66 (d, J = 14.6 Hz, 1H), 3.49 (s, 3H), 2.63 (dd, J = 5.4, 15.2 Hz, 1H ), 2.54 (dd, J = 9.4, 15.2 Hz, 1H), 1.25 (d, J = 6.9 Hz, 3H).
（参考例８５）
（Ｒ）－４－｛ベンジル［（Ｓ）－１－フェニルエチル］アミノ｝－４－（３－フルオロフェニル）－２－メチルブタン－２－オール
Figure JPOXMLDOC01-appb-C000209
 (Reference Example 85)
(R) -4- {Benzyl [(S) -1-phenylethyl] amino} -4- (3-fluorophenyl) -2-methylbutan-2-ol
Figure JPOXMLDOC01-appb-C000209
　参考例８４と同様にして合成した（Ｒ）－メチル　３－｛ベンジル［（Ｓ）－１－フェニルエチル］アミノ｝－３－（３－フルオロフェニル）プロパノアート２．２２ｇ（５．６７ｍｍｏｌ）の脱水ＴＨＦ２０ｍｌ溶液に、アルゴン雰囲気下、１Ｍメチルマグネシウムブロミド－ＴＨＦ溶液１７．０ｍｌ（１７．０ｍｍｏｌ）を０℃で滴下した後、室温で１７時間撹拌した。
　反応終了後、反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。得られた有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した後、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９５：５～８５：１５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物１．９５ｇ（収率８８％）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：３９２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.42 - 7.22 (m, 11H), 7.20 - 7.15 (m, 1H), 7.13 - 7.07 (m, 1H), 7.06 - 6.99 (m, 1H), 5.45 (s, 1H), 4.32 - 4.20 (m, 2H), 4.17 - 4.05 (m, 1H), 3.61 (d, J = 13.2 Hz, 1H), 2.39 (dd, J = 10.6, 14.7 Hz, 1H), 1.40 (dd, J = 3.4, 14.7 Hz, 1H), 1.12 (s, 3H), 1.03 (d, J = 7.0 Hz, 3H), 0.62 (s, 3H)。 Dehydration of 2.22 g (5.67 mmol) of (R) -methyl 3- {benzyl [(S) -1-phenylethyl] amino} -3- (3-fluorophenyl) propanoate synthesized in the same manner as in Reference Example 84 To a 20 ml THF solution, 17.0 ml (17.0 mmol) of a 1M methylmagnesium bromide-THF solution was added dropwise at 0 ° C. in an argon atmosphere, followed by stirring at room temperature for 17 hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 95: 5 to 85:15 (V / V)), and the fraction containing the target product was concentrated under reduced pressure. 1.95 g (88% yield) of the title compound was obtained as a colorless oil.
Mass spectrum (CI, m / z): 392 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.42-7.22 (m, 11H), 7.20-7.15 (m, 1H), 7.13-7.07 (m, 1H), 7.06-6.99 (m, 1H), 5.45 (s, 1H), 4.32-4.20 (m, 2H), 4.17-4.05 (m, 1H), 3.61 (d, J = 13.2 Hz, 1H), 2.39 (dd, J = 10.6, 14.7 Hz, 1H), 1.40 (dd, J = 3.4, 14.7 Hz, 1H), 1.12 (s, 3H), 1.03 (d, J = 7.0 Hz, 3H), 0.62 (s, 3H).
（参考例８６）
（Ｒ）－４－アミノ－４－（３－フルオロフェニル）－２－メチルブタン－２－オール
Figure JPOXMLDOC01-appb-C000210
 (Reference Example 86)
(R) -4-Amino-4- (3-fluorophenyl) -2-methylbutan-2-ol
Figure JPOXMLDOC01-appb-C000210
　参考例８５と同様にして合成した（Ｒ）－４－｛ベンジル［（Ｓ）－１－フェニルエチル］アミノ｝－４－（３－フルオロフェニル）－２－メチルブタン－２－オール１．１ｇ（２．８ｍｍｏｌ）のメタノール１０ｍｌ溶液に、アルゴン気流下、２０％水酸化パラジウム／炭素（５０％含水）２００ｍｇを室温で加え、水素雰囲気に置換後、室温で６時間撹拌した。次いで、アルゴン雰囲気に置換後、ぎ酸アンモニウム０．３５４ｇ（５．６１ｍｍｏｌ）を室温で加え、６０℃で２時間攪拌した。
　反応終了後、反応液を酢酸エチルで希釈した後セライト濾過し、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬ，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７５：２５～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物２７６ｍｇ（収率５０％）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１９８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：7.37 - 7.28 (m, 1H), 7.25 - 7.14 (m, 2H), 7.03 - 6.95 (m, 1H), 4.08 (dd, J = 3.0, 10.5 Hz, 1H), 1.63 (dd, J = 10.5, 13.9 Hz, 1H), 1.52 (dd, J = 3.0, 13.9 Hz, 1H), 1.22 (s, 3H), 1.09 (s, 3H)。 1.1 g of (R) -4- {benzyl [(S) -1-phenylethyl] amino} -4- (3-fluorophenyl) -2-methylbutan-2-ol synthesized in the same manner as in Reference Example 85 2.8 mmol) in 10 ml of methanol was added 200 mg of 20% palladium hydroxide / carbon (containing 50% water) at room temperature under an argon stream, and after replacing with a hydrogen atmosphere, the mixture was stirred at room temperature for 6 hours. Next, after replacing with an argon atmosphere, 0.354 g (5.61 mmol) of ammonium formate was added at room temperature, and the mixture was stirred at 60 ° C. for 2 hours.
After completion of the reaction, the reaction mixture was diluted with ethyl acetate and filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel column chromatography (DIOL, elution solvent; n-hexane: ethyl acetate = 75: 25 to 50:50 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure. This gave 276 mg (yield 50%) of the title compound as a colorless oil.
Mass spectrum (CI, m / z): 198 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 7.37-7.28 (m, 1H), 7.25-7.14 (m, 2H), 7.03-6.95 (m, 1H), 4.08 (dd, J = 3.0, 10.5 Hz, 1H), 1.63 (dd, J = 10.5, 13.9 Hz, 1H), 1.52 (dd, J = 3.0, 13.9 Hz, 1H), 1.22 (s, 3H), 1.09 (s, 3H).
（参考例８７）
（Ｒ）－エチル　５－｛［１－（３－フルオロフェニル）－３－ヒドロキシ－３－メチルブチル］カルバモイル｝－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート
Figure JPOXMLDOC01-appb-C000211
 (Reference Example 87)
(R) -ethyl 5-{[1- (3-fluorophenyl) -3-hydroxy-3-methylbutyl] carbamoyl} -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6 Dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate
Figure JPOXMLDOC01-appb-C000211
　参考例８６と同様にして合成した（Ｒ）－４－アミノ－４－（３－フルオロフェニル）－２－メチルブタン－２－オール７０ｍｇ（０．３５ｍｍｏｌ）の１，４－ジオキサン５ｍｌ溶液に、アルゴン気流下撹拌しながらＤＩＰＥＡ０．３１ｍｌ（１．８ｍｏｌ）、参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１７２ｍｇ（０．３９０ｍｍｏｌ）を室温で順次加え、９０℃で２時間撹拌した。
　反応終了後、室温まで放冷した反応溶液に飽和塩化アンモニウム水溶液を加え、その混合液から酢酸エチルで抽出した。有機層は飽和塩化ナトリウム水溶液で洗浄、無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７０：３０～２７：７３（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物１４９ｍｇ（収率７０％）を白色泡状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：６０２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：9.78 (s, 1H), 7.36 - 7.26 (m, 1H), 7.19 - 7.12 (m, 2H), 7.01 - 6.93 (m, 1H), 6.71 (d, J = 6.2 Hz, 1H), 4.96 - 4.88 (m, 1H), 4.67 - 4.60 (m, 2H), 4.54 (d, J = 13.6 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 2.59 - 2.42 (m, 2H), 2.29 - 2.21 (m, 2H), 2.02 - 1.84 (m, 3H), 1.66 (dd, J = 3.2, 14.2 Hz, 1H), 1.59 (s, 3H), 1.54 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H), 1.14 (s, 3H), 1.13 (s, 3H), 0.11 (s, 9H)。 To a solution of 70 mg (0.35 mmol) of (R) -4-amino-4- (3-fluorophenyl) -2-methylbutan-2-ol synthesized in the same manner as in Reference Example 86 in 5 ml of 1,4-dioxane, argon was added. DIPEA 0.31 ml (1.8 mol) with stirring under an air stream, ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5 synthesized in the same manner as in Reference Example 3 , 6-Dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate 172 mg (0.390 mmol) was sequentially added at room temperature and stirred at 90 ° C. for 2 hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution which had been allowed to cool to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 70: 30 to 27:73 (V / V)), and the fraction containing the target product was concentrated under reduced pressure. 149 mg (70% yield) of the title compound were obtained as a white foam.
Mass spectrum (CI, m / z): 602 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 9.78 (s, 1H), 7.36-7.26 (m, 1H), 7.19-7.12 (m, 2H), 7.01-6.93 (m, 1H), 6.71 (d, J = 6.2 Hz, 1H), 4.96-4.88 (m, 1H), 4.67-4.60 (m, 2H), 4.54 (d, J = 13.6 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 2.59-2.42 (m, 2H), 2.29-2.21 (m, 2H), 2.02-1.84 (m, 3H), 1.66 (dd, J = 3.2, 14.2 Hz, 1H), 1.59 (s, 3H) , 1.54 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H), 1.14 (s, 3H), 1.13 (s, 3H), 0.11 (s, 9H).
（参考例８８）
（Ｅ）－メチル　３－（２－フルオロフェニル）アクリラート
Figure JPOXMLDOC01-appb-C000212
 (Reference Example 88)
(E) -Methyl 3- (2-fluorophenyl) acrylate
Figure JPOXMLDOC01-appb-C000212
　２－フルオロベンズアルデヒド１．２６ｍｌ（１２．１ｍｍｏｌ）の脱水ＴＨＦ２５ｍｌ溶液に、アルゴン気流下、メチル　２－（トリフェニルホスホラニリデン）アセタート５．２５ｇ（１５．７ｍｍｏｌ）を室温で加えた後、そのままの温度で１７時間撹拌した。
　反応終了後、反応液を減圧濃縮した。得られた濃縮残渣にＴＢＭＥ２０ｍｌを加え、不溶物を濾別し、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～９０：１０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物１．５８ｇ（収率７３％）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１８１［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.83 (d, J = 16.3 Hz, 1H), 7.57 - 7.50 (m, 1H), 7.40 - 7.33 (m, 1H), 7.20 - 7.07 (m, 2H), 6.55 (d, J = 16.3 Hz, 1H), 3.82 (s, 3H)。 To a solution of 1.26 ml (12.1 mmol) of 2-fluorobenzaldehyde in 25 ml of dehydrated THF, 5.25 g (15.7 mmol) of methyl 2- (triphenylphosphoranylidene) acetate was added at room temperature under a stream of argon. Stir at temperature for 17 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. To the resulting concentrated residue, 20 ml of TBME was added, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 90:10 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The title compound (1.58 g, yield 73%) was obtained as a colorless oil.
Mass spectrum (CI, m / z): 181 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.83 (d, J = 16.3 Hz, 1H), 7.57-7.50 (m, 1H), 7.40-7.33 (m, 1H), 7.20-7.07 (m, 2H ), 6.55 (d, J = 16.3 Hz, 1H), 3.82 (s, 3H).
（参考例８９）
（Ｒ）－メチル　３－｛ベンジル［（Ｓ）－１－フェニルエチル］アミノ｝－３－（２－フルオロフェニル）プロパノアート
Figure JPOXMLDOC01-appb-C000213
 (Reference Example 89)
(R) -methyl 3- {benzyl [(S) -1-phenylethyl] amino} -3- (2-fluorophenyl) propanoate
Figure JPOXMLDOC01-appb-C000213
　（Ｓ）－Ｎ－ベンジル－１－フェニルエタンアミン２．９４ｍｌ（１４．１ｍｍｏｌ）の脱水ＴＨＦ３０ｍｌ溶液に、アルゴン気流下、１．６Ｍ　ｎ－ブチルリチウム　ｎ－ヘキサン溶液８．２２ｍｌ（１３．２ｍｍｏｌ）を－７８℃で滴下した後、そのままの温度で１時間撹拌した。次いで、参考例８８と同様にして合成した（Ｅ）－メチル　３－（２－フルオロフェニル）アクリラート１．５８ｇ（８．７７ｍｍｏｌ）のＴＨＦ５ｍｌ溶液を－７８℃で滴下した後、そのままの温度で１時間撹拌した。
　反応終了後、反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。得られた有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した後、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～９５：５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物１．２７ｇ（収率３７％）を微黄色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：３９２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.45 - 7.03 (m, 14H), 4.75 (dd, J = 6.8, 8.9 Hz, 1H), 4.05 (q, J = 6.9 Hz, 1H), 3.81 (d, J = 14.6 Hz, 1H), 3.65 (d, J = 14.6 Hz, 1H), 3.44 (s, 3H), 2.79 (dd, J = 6.8, 14.9 Hz, 1H), 2.65 (dd, J = 8.9, 14.9 Hz, 1H), 1.20 (d, J = 6.9 Hz, 3H)。 (S) -N-Benzyl-1-phenylethanamine 2.94 ml (14.1 mmol) in a dehydrated THF 30 ml solution under a stream of argon, 8.2M ml (13.2 mmol) of 1.6 M n-butyllithium n-hexane solution Was added dropwise at −78 ° C., followed by stirring at the same temperature for 1 hour. Next, a solution of 1.58 g (8.77 mmol) of (E) -methyl 3- (2-fluorophenyl) acrylate synthesized in the same manner as in Reference Example 88 was added dropwise at −78 ° C. Stir for hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The title compound (1.27 g, yield 37%) was obtained as a pale yellow oil.
Mass spectrum (CI, m / z): 392 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.45-7.03 (m, 14H), 4.75 (dd, J = 6.8, 8.9 Hz, 1H), 4.05 (q, J = 6.9 Hz, 1H), 3.81 ( d, J = 14.6 Hz, 1H), 3.65 (d, J = 14.6 Hz, 1H), 3.44 (s, 3H), 2.79 (dd, J = 6.8, 14.9 Hz, 1H), 2.65 (dd, J = 8.9 , 14.9 Hz, 1H), 1.20 (d, J = 6.9 Hz, 3H).
（参考例９０）
（Ｒ）－４－｛ベンジル［（Ｓ）－１－フェニルエチル］アミノ｝－４－（２－フルオロフェニル）－２－メチルブタン－２－オール
Figure JPOXMLDOC01-appb-C000214
 (Reference Example 90)
(R) -4- {benzyl [(S) -1-phenylethyl] amino} -4- (2-fluorophenyl) -2-methylbutan-2-ol
Figure JPOXMLDOC01-appb-C000214
　参考例８９と同様にして合成した（Ｒ）－メチル　３－｛ベンジル［（Ｓ）－１－フェニルエチル］アミノ｝－３－（２－フルオロフェニル）プロパノアート１．２７ｇ（３．２４ｍｍｏｌ）の脱水ＴＨＦ１５ｍｌ溶液に、アルゴン気流下、１Ｍメチルマグネシウムブロミド－ＴＨＦ溶液９．７３ｍｌ（９．７３ｍｍｏｌ）を０℃で滴下した後、室温で１７時間撹拌した。
　反応終了後、反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。得られた有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した後、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９５：５～８５：１５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物１．１０ｇ（収率８７％）を微黄色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：３９２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＣＤＣｌ３）δ：7.51 - 7.08 (m, 14H), 5.58 (s, 1H), 4.72 (dd, J = 3.1, 11.3 Hz, 1H), 4.31 (d, J = 12.9 Hz, 1H), 4.16 - 4.05 (m, 1H), 3.55 (d, J = 12.9 Hz, 1H), 2.47 (dd, J = 11.3, 14.6 Hz, 1H), 1.32 (dd, J = 3.1, 14.6 Hz, 1H), 1.11 (s, 3H), 1.06 (d, J = 7.0 Hz, 3H), 0.53 (s, 3H)。 Dehydration of 1.27 g (3.24 mmol) of (R) -methyl 3- {benzyl [(S) -1-phenylethyl] amino} -3- (2-fluorophenyl) propanoate synthesized in the same manner as in Reference Example 89 To a 15 ml THF solution, 9.73 ml (9.73 mmol) of a 1M methylmagnesium bromide-THF solution was added dropwise at 0 ° C. under an argon stream, followed by stirring at room temperature for 17 hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 95: 5 to 85:15 (V / V)), and the fraction containing the target product was concentrated under reduced pressure. The title compound (1.10 g, yield 87%) was obtained as a pale yellow oil.
Mass spectrum (CI, m / z): 392 [M + 1] + .
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ: 7.51-7.08 (m, 14H), 5.58 (s, 1H), 4.72 (dd, J = 3.1, 11.3 Hz, 1H), 4.31 (d, J = 12.9 Hz, 1H), 4.16-4.05 (m, 1H), 3.55 (d, J = 12.9 Hz, 1H), 2.47 (dd, J = 11.3, 14.6 Hz, 1H), 1.32 (dd, J = 3.1, 14.6 Hz , 1H), 1.11 (s, 3H), 1.06 (d, J = 7.0 Hz, 3H), 0.53 (s, 3H).
（参考例９１）
（Ｒ）－４－アミノ－４－（２－フルオロフェニル）－２－メチルブタン－２－オール
Figure JPOXMLDOC01-appb-C000215
 (Reference Example 91)
(R) -4-Amino-4- (2-fluorophenyl) -2-methylbutan-2-ol
Figure JPOXMLDOC01-appb-C000215
　参考例９０と同様にして合成した（Ｒ）－４－｛ベンジル［（Ｓ）－１－フェニルエチル］アミノ｝－４－（２－フルオロフェニル）－２－メチルブタン－２－オール１．１ｇ（２．８ｍｍｏｌ）のメタノール１０ｍｌ溶液に、アルゴン気流下、２０％水酸化パラジウム／炭素（５０％含水）２００ｍｇを室温で加え、水素雰囲気に置換後、室温で６時間撹拌した。次いで、アルゴン雰囲気に置換後、ギ酸アンモニウム３５４ｍｇ（５．６１ｍｍｏｌ）を室温で加え、６０℃で２時間攪拌した。
　反応終了後、反応液を酢酸エチルで希釈した後セライト濾過し、濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬ，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７５：２５～５０：５０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物２６５ｍｇ（収率４８％）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１９８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：7.61 - 7.55 (m, 1H), 7.28 - 7.21 (m, 1H), 7.20 - 7.14 (m, 1H), 7.13 - 7.06 (m, 1H), 4.39 (dd, J = 2.7, 10.4 Hz, 1H), 1.64 (dd, J = 10.4, 13.8 Hz, 1H), 1.52 (dd, J = 2.7, 13.8 Hz, 1H), 1.22 (s, 3H), 1.09 (s, 3H)。 1.1 g of (R) -4- {benzyl [(S) -1-phenylethyl] amino} -4- (2-fluorophenyl) -2-methylbutan-2-ol synthesized in the same manner as in Reference Example 90 2.8 mmol) in 10 ml of methanol was added 200 mg of 20% palladium hydroxide / carbon (containing 50% water) at room temperature under an argon stream, and after replacing with a hydrogen atmosphere, the mixture was stirred at room temperature for 6 hours. Subsequently, after replacing with an argon atmosphere, 354 mg (5.61 mmol) of ammonium formate was added at room temperature, and the mixture was stirred at 60 ° C. for 2 hours.
After completion of the reaction, the reaction mixture was diluted with ethyl acetate and filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL, elution solvent; n-hexane: ethyl acetate = 75: 25 to 50:50 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. By drying under reduced pressure, 265 mg (yield 48%) of the title compound was obtained as a colorless oil.
Mass spectrum (CI, m / z): 198 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 7.61-7.55 (m, 1H), 7.28-7.21 (m, 1H), 7.20-7.14 (m, 1H), 7.13-7.06 (m, 1H) , 4.39 (dd, J = 2.7, 10.4 Hz, 1H), 1.64 (dd, J = 10.4, 13.8 Hz, 1H), 1.52 (dd, J = 2.7, 13.8 Hz, 1H), 1.22 (s, 3H), 1.09 (s, 3H).
（参考例９２）
（Ｒ）－エチル　５－｛［１－（２－フルオロフェニル）－３－ヒドロキシ－３－メチルブチル］カルバモイル｝－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート
Figure JPOXMLDOC01-appb-C000216
 (Reference Example 92)
(R) -Ethyl 5-{[1- (2-fluorophenyl) -3-hydroxy-3-methylbutyl] carbamoyl} -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6 Dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate
Figure JPOXMLDOC01-appb-C000216
　参考例９１と同様にして合成した（Ｒ）－４－アミノ－４－（２－フルオロフェニル）－２－メチルブタン－２－オール７０ｍｇ（０．３５ｍｍｏｌ）の１，４－ジオキサン５ｍｌ溶液に、アルゴン気流下撹拌しながらＤＩＰＥＡ０．３０９ｍｌ（１．７７ｍｏｌ）、参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート２３５ｍｇ（０．５３３ｍｍｏｌ）を室温で順次加え、９０℃で２時間撹拌した。
　反応終了後、室温まで放冷した反応溶液に飽和塩化アンモニウム水溶液を加え、その混合液から酢酸エチルで抽出した。有機層は飽和塩化ナトリウム水溶液で洗浄、無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝６５：３５～２９：７１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１５０ｍｇ（収率７０％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：６０２［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：9.79 (s, 1H), 7.54 - 7.46 (m, 1H), 7.27 - 7.07 (m, 3H), 6.70 (d, J = 5.8 Hz, 1H), 5.24 - 5.16 (m, 1H), 4.71 - 4.54 (m, 3H), 4.42 (q, J = 7.2 Hz, 2H), 2.58 - 2.44 (m, 2H), 2.32 - 2.22 (m, 2H), 2.02 - 1.87 (m, 3H), 1.67 - 1.57 (m, 4H), 1.53 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H), 1.19 - 1.14 (m, 6H), 0.13 (s, 9H)。 To a solution of 70 mg (0.35 mmol) of (R) -4-amino-4- (2-fluorophenyl) -2-methylbutan-2-ol synthesized in the same manner as in Reference Example 91 in 5 ml of 1,4-dioxane, argon was added. DIPEA 0.309 ml (1.77 mol) with stirring under an air stream, ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5 synthesized in the same manner as in Reference Example 3 , 6-Dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate (235 mg, 0.533 mmol) was sequentially added at room temperature, and the mixture was stirred at 90 ° C. for 2 hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution which had been allowed to cool to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 65: 35 to 29:71 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure. As a result, 150 mg (yield 70%) of the title compound was obtained as a white solid.
Mass spectrum (CI, m / z): 602 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 9.79 (s, 1H), 7.54-7.46 (m, 1H), 7.27-7.07 (m, 3H), 6.70 (d, J = 5.8 Hz, 1H ), 5.24-5.16 (m, 1H), 4.71-4.54 (m, 3H), 4.42 (q, J = 7.2 Hz, 2H), 2.58-2.44 (m, 2H), 2.32-2.22 (m, 2H), 2.02-1.87 (m, 3H), 1.67-1.57 (m, 4H), 1.53 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H), 1.19-1.14 (m, 6H), 0.13 (s, 9H).
（参考例９３）
（Ｒ）－メチル　３－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－４－メチルペンタノアート
Figure JPOXMLDOC01-appb-C000217
 (Reference Example 93)
(R) -methyl 3-[(tert-butoxycarbonyl) amino] -4-methylpentanoate
Figure JPOXMLDOC01-appb-C000217
　（Ｒ）－３－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－４－メチルペンタン酸６００ｍｇ（２．５９ｍｍｏｌ）のジクロロメタン６ｍｌ溶液に、アルゴン気流下撹拌しながら４－ジメチルアミノピリジン６３ｍｇ（０．５２ｍｍｏｌ）、メタノール０．５３ｍｌ（１３ｍｍｏｌ）を室温で順次加えた。
　次いで、１－（３－ジメチルアミノプロピル）－３－エチルカルボジイミド　塩酸塩７４６ｍｇ（３．８９ｍｍｏｌ）を撹拌下に０℃で一度に加え、室温で２時間撹拌した。
　反応終了後、反応溶液に水を加え、その混合液から酢酸エチルで２回抽出した。有機層は飽和塩化ナトリウム水溶液で洗浄、無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～８０：２０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物６３０ｍｇ（収率９９％）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：２４６［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：6.72 & 6.37 (br d, J = 9.2 Hz, total 1H), 3.71 - 3.61 (m, 1H), 3.60 - 3.52 (m, 3H), 2.44 (dd, J = 4.6, 15.0 Hz, 1H), 2.30 (dd, J = 9.4, 15.0 Hz, 1H), 1.71 - 1.58 (m, 1H), 1.36 (s, 9H), 0.86 - 0.73 (m, 6H)。 While stirring (R) -3-[(tert-butoxycarbonyl) amino] -4-methylpentanoic acid 600 mg (2.59 mmol) in 6 ml of dichloromethane while stirring under an argon stream, 63 mg (0.52 mmol) of 4-dimethylaminopyridine. , 0.53 ml (13 mmol) of methanol was sequentially added at room temperature.
Next, 746 mg (3.89 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added in one portion at 0 ° C. with stirring, and the mixture was stirred at room temperature for 2 hours.
After completion of the reaction, water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 80:20 (V / V)), and the fraction containing the target product was concentrated under reduced pressure. The title compound was obtained as a colorless oil (630 mg, yield 99%).
Mass spectrum (CI, m / z): 246 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 6.72 & 6.37 (br d, J = 9.2 Hz, total 1H), 3.71-3.61 (m, 1H), 3.60-3.52 (m, 3H), 2.44 (dd, J = 4.6, 15.0 Hz, 1H), 2.30 (dd, J = 9.4, 15.0 Hz, 1H), 1.71-1.58 (m, 1H), 1.36 (s, 9H), 0.86-0.73 (m, 6H ).
（参考例９４）
（Ｒ）－ｔｅｒｔ－ブチル　（５－ヒドロキシ－２，５－ジメチルヘキサン－３－イル）カルバマート
Figure JPOXMLDOC01-appb-C000218
 (Reference Example 94)
(R) -tert-butyl (5-hydroxy-2,5-dimethylhexane-3-yl) carbamate
Figure JPOXMLDOC01-appb-C000218
　参考例９３と同様にして合成した（Ｒ）－メチル　３－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－４－メチルペンタノアート６３０ｍｇ（２．５７ｍｍｏｌ）の脱水ＴＨＦ６ｍｌ溶液に、アルゴン気流下撹拌しながら１Ｍメチルマグネシウムブロミド－ＴＨＦ溶液７．７ｍｌ（７．７ｍｏｌ）を０℃で滴下し、室温で４時間撹拌した。
　反応終了後、反応液に飽和塩化アンモニウム水溶液を加え、その混合液から酢酸エチルで抽出した。有機層は飽和塩化ナトリウム水溶液で洗浄、無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮した。得られた残渣を得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９１：９～７０：３０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物１３３ｍｇ（収率２１％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：２４６［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：6.53 & 6.14 (br d, J = 8.9 Hz, total 1H), 4.09 (s, 1H), 3.47 - 3.39 (m, 1H), 1.63 - 1.50 (m, 1H), 1.42 - 1.33 (m, 11H), 1.06 (s, 3H), 1.05 (s, 3H), 0.80 - 0.74 (m, 6H)。 A solution of 630 mg (2.57 mmol) of (R) -methyl 3-[(tert-butoxycarbonyl) amino] -4-methylpentanoate synthesized in the same manner as in Reference Example 93 in 6 ml of dehydrated THF was stirred under an argon stream. 7.7 ml (7.7 mol) of 1M methylmagnesium bromide-THF solution was added dropwise at 0 ° C. and stirred at room temperature for 4 hours.
After completion of the reaction, saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue obtained was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 91: 9 to 70:30 (V / V)), and the fraction containing the desired product was obtained. Concentration under reduced pressure gave 133 mg (yield 21%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 246 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 6.53 & 6.14 (br d, J = 8.9 Hz, total 1H), 4.09 (s, 1H), 3.47-3.39 (m, 1H), 1.63-1.50 (m, 1H), 1.42-1.33 (m, 11H), 1.06 (s, 3H), 1.05 (s, 3H), 0.80-0.74 (m, 6H).
（参考例９５）
（Ｒ）－４－アミノ－２，５－ジメチルヘキサン－２－オール　塩酸塩
Figure JPOXMLDOC01-appb-C000219
 (Reference Example 95)
(R) -4-Amino-2,5-dimethylhexane-2-ol hydrochloride
Figure JPOXMLDOC01-appb-C000219
　参考例９４と同様にして合成した（Ｒ）－ｔｅｒｔ－ブチル　（５－ヒドロキシ－２，５－ジメチルヘキサン－３－イル）カルバマート１３３ｍｇ（０．５４２ｍｍｏｌ）の１，４－ジオキサン２ｍｌ溶液に、アルゴン気流下撹拌しながら４Ｎ塩化水素／１，４－ジオキサン０．６７８ｍｌ（２．７１ｍｏｌ）を室温で一度に加え、室温で３時間撹拌した。次いで、４Ｎ塩化水素／１，４－ジオキサン０．６７８ｍｌ（２．７１ｍｏｌ）を撹拌下に室温で一度に加え、室温で１５時間撹拌した。
　反応終了後、反応溶液を濃縮した。そこにｎ－ヘキサン５ｍｌを加えて室温で２時間撹拌した。析出した固体を濾取、ｎ－ヘキサンで洗浄、減圧乾燥することで標記化合物５８ｍｇ（収率５９％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１４６［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：8.25 - 4.63 (m, 3H), 3.16 - 3.04 (m, 1H), 1.96 - 1.82 (m, 1H), 1.58 (dd, J = 2.0, 15.0 Hz, 1H), 1.49 (dd, J = 9.8, 15.0 Hz, 1H), 1.21 (s, 3H), 1.17 (s, 3H), 0.91 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H)。 To a solution of 133 mg (0.542 mmol) of (R) -tert-butyl (5-hydroxy-2,5-dimethylhexane-3-yl) carbamate synthesized in the same manner as in Reference Example 94 in 2 ml of 1,4-dioxane, argon was added. While stirring under a stream of air, 0.678 ml (2.71 mol) of 4N hydrogen chloride / 1,4-dioxane was added all at once at room temperature, and the mixture was stirred at room temperature for 3 hours. Subsequently, 0.678 ml (2.71 mol) of 4N hydrogen chloride / 1,4-dioxane was added all at once at room temperature with stirring, and the mixture was stirred at room temperature for 15 hours.
After completion of the reaction, the reaction solution was concentrated. Thereto was added 5 ml of n-hexane, followed by stirring at room temperature for 2 hours. The precipitated solid was collected by filtration, washed with n-hexane, and dried under reduced pressure to obtain 58 mg (yield 59%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 146 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 8.25-4.63 (m, 3H), 3.16-3.04 (m, 1H), 1.96-1.82 (m, 1H), 1.58 (dd, J = 2.0, 15.0 Hz, 1H), 1.49 (dd, J = 9.8, 15.0 Hz, 1H), 1.21 (s, 3H), 1.17 (s, 3H), 0.91 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H).
（参考例９６）
（Ｒ）－エチル　５－［（５－ヒドロキシ－２，５－ジメチルヘキサン－３－イル）カルバモイル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート
Figure JPOXMLDOC01-appb-C000220
 (Reference Example 96)
(R) -ethyl 5-[(5-hydroxy-2,5-dimethylhexane-3-yl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydro Pyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate
Figure JPOXMLDOC01-appb-C000220
　参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート２６０ｍｇ（０．５９０ｍｍｏｌ）の１，４－ジオキサン４ｍｌ溶液に、アルゴン気流下撹拌しながらＤＩＰＥＡ０．３４２ｍｌ（１．９６ｍｏｌ）、参考例９５と同様にして合成した（Ｒ）－４－アミノ－２，５－ジメチルヘキサン－２－オール　塩酸塩５７ｍｇ（０．３１ｍｍｏｌ）を室温で順次加え、９０℃で１．５時間撹拌した。
　反応終了後、室温まで放冷した反応溶液に飽和塩化アンモニウム水溶液を加え、その混合液から酢酸エチルで抽出した。有機層は飽和塩化ナトリウム水溶液で洗浄、無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７０：３０～３０：７０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物９９ｍｇ（収率５７％）を白色泡状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５５０［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：9.78 (s, 1H), 5.83 (d, J = 7.7 Hz, 1H), 4.55 (d, J = 13.6 Hz, 1H), 4.47 (d, J = 13.6 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 4.30 (s, 1H), 3.73 - 3.62 (m, 1H), 2.58 - 2.43 (m, 2H), 2.31 - 2.21 (m, 2H), 1.96 - 1.82 (m, 2H), 1.75 - 1.57 (m, 8H), 1.50 - 1.42 (m, 1H), 1.34 (t, J = 7.1 Hz, 3H), 1.10 (s, 3H), 1.08 (s, 3H), 0.89 - 0.78 (m, 6H), 0.15 - 0.08 (m, 9H)。 Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole- synthesized as in Reference Example 3 Synthesis was performed in the same manner as in Reference Example 95, with DIPEA 0.342 ml (1.96 mol) in a 4 ml 1,4-dioxane solution of 260 mg (0.590 mmol) of 2 (4H) -carboxylate and stirring under an argon stream (R). -4-Amino-2,5-dimethylhexane-2-ol hydrochloride 57 mg (0.31 mmol) was sequentially added at room temperature, followed by stirring at 90 ° C. for 1.5 hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution which had been allowed to cool to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 70: 30 to 30:70 (V / V)), and the fraction containing the target product was concentrated under reduced pressure and dried under reduced pressure. This gave 99 mg (57% yield) of the title compound as a white foam.
Mass spectrum (CI, m / z): 550 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 9.78 (s, 1H), 5.83 (d, J = 7.7 Hz, 1H), 4.55 (d, J = 13.6 Hz, 1H), 4.47 (d, J = 13.6 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 4.30 (s, 1H), 3.73-3.62 (m, 1H), 2.58-2.43 (m, 2H), 2.31-2.21 (m , 2H), 1.96-1.82 (m, 2H), 1.75-1.57 (m, 8H), 1.50-1.42 (m, 1H), 1.34 (t, J = 7.1 Hz, 3H), 1.10 (s, 3H), 1.08 (s, 3H), 0.89-0.78 (m, 6H), 0.15-0.08 (m, 9H).
（参考例９７）
エチル　［１－（４－フルオロフェニル）－２，２－ジメチル－３－オキソプロピル］カルバマート
Figure JPOXMLDOC01-appb-C000221
 (Reference Example 97)
Ethyl [1- (4-fluorophenyl) -2,2-dimethyl-3-oxopropyl] carbamate
Figure JPOXMLDOC01-appb-C000221
　カルバミン酸エチル２．６３ｇ（２９．５ｍｍｏｌ）のトルエン２５ｍｌ溶液に、アルゴン気流下撹拌しながら４－フルオロベンズアルデヒド３．１ｍｌ（２９ｍｍｏｌ）、ｐ－トルエンスルホン酸一水和物０．２８１ｇ（１．４８ｍｍｏｌ）を室温で順次加え、室温で５分間撹拌した。次いで、イソブチルアルデヒド２．６８ｍｌ（２９．５ｍｍｏｌ）を撹拌下に室温で滴下し、６０℃で３時間撹拌した。
　反応終了後、反応液を飽和炭酸水素ナトリウム水溶液に注ぎ入れ、次いで室温で５分間撹拌した。有機層と水層を分液した後、分けた水層をトルエンで１回抽出した。得られた全有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで脱水、ろ過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９０：１０～６９：３１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物３．８５ｇ（収率４９％）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：２６８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：9.59 (s, 1H), 7.95 (d, J = 10.1 Hz, 1H), 7.43 - 7.33 (m, 2H), 7.21 - 7.12 (m, 2H), 5.04 (d, J = 10.1 Hz, 1H), 4.01 - 3.93 (m, 2H), 1.15 (t, J = 7.1 Hz, 3H), 0.94 (s, 3H), 0.87 (s, 3H)。 To a solution of 2.63 g (29.5 mmol) of ethyl carbamate in a 25 ml toluene solution, 3.1 ml (29 mmol) of 4-fluorobenzaldehyde and 0.281 g (1.48 mmol) of p-toluenesulfonic acid monohydrate were stirred under a stream of argon. ) Were sequentially added at room temperature and stirred at room temperature for 5 minutes. Next, 2.68 ml (29.5 mmol) of isobutyraldehyde was added dropwise at room temperature with stirring, and the mixture was stirred at 60 ° C. for 3 hours.
After completion of the reaction, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and then stirred at room temperature for 5 minutes. After the organic layer and the aqueous layer were separated, the separated aqueous layer was extracted once with toluene. The obtained all organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 69:31 (V / V)), and the fraction containing the target product was concentrated under reduced pressure and dried under reduced pressure. As a result, 3.85 g (yield 49%) of the title compound was obtained as a colorless oil.
Mass spectrum (CI, m / z): 268 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 9.59 (s, 1H), 7.95 (d, J = 10.1 Hz, 1H), 7.43-7.33 (m, 2H), 7.21-7.12 (m, 2H ), 5.04 (d, J = 10.1 Hz, 1H), 4.01-3.93 (m, 2H), 1.15 (t, J = 7.1 Hz, 3H), 0.94 (s, 3H), 0.87 (s, 3H).
（参考例９８）
３－アミノ－３－（４－フルオロフェニル）－２，２－ジメチルプロパン－１－オール
Figure JPOXMLDOC01-appb-C000222
 (Reference Example 98)
3-Amino-3- (4-fluorophenyl) -2,2-dimethylpropan-1-ol
Figure JPOXMLDOC01-appb-C000222
　参考例９７と同様にして合成したエチル　［１－（４－フルオロフェニル）－２，２－ジメチル－３－オキソプロピル］カルバマート３．８４ｇ（１４．４ｍｍｏｌ）のエタノール２０ｍｌ溶液に、アルゴン気流下撹拌しながら水素化ホウ素ナトリウム０．３２６ｇ（８．６２ｍｍｏｌ）を０℃で分割添加し、室温で１時間撹拌した。次いで、水酸化カリウム１．６１ｇ（２８．７ｍｍｏｌ）、水（１０ｍｌ）を撹拌下に室温で加えた後、加熱還流下で２時間撹拌した。
　反応終了後、放冷した反応液を減圧濃縮してエタノールを留去した。濃縮残渣に２Ｎ塩酸を加えてｐＨ２とし、ジエチルエーテルで洗浄した。水層に１Ｎ水酸化ナトリウム水溶液を加えて塩基性（ｐＨ９）にした後、ジクロロメタンで３回抽出した。得られた全有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで脱水、ろ過、減圧濃縮、減圧乾燥を行うことにより、標記化合物１．９３ｇ（収率６８％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１９８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：7.38 - 7.29 (m, 2H), 7.15 - 7.03 (m, 2H), 3.81 (s, 1H), 3.25 (d, J = 10.5 Hz, 1H), 3.13 (d, J = 10.5 Hz, 1H), 0.74 (s, 3H), 0.65 (s, 3H)。 Ethyl [1- (4-fluorophenyl) -2,2-dimethyl-3-oxopropyl] carbamate synthesized in the same manner as in Reference Example 97 was stirred in a 20 ml ethanol solution in 3.84 g (14.4 mmol) under an argon stream. While adding 0.326 g (8.62 mmol) of sodium borohydride in portions at 0 ° C., the mixture was stirred at room temperature for 1 hour. Next, 1.61 g (28.7 mmol) of potassium hydroxide and water (10 ml) were added at room temperature with stirring, and then the mixture was stirred for 2 hours with heating under reflux.
After completion of the reaction, the cooled reaction solution was concentrated under reduced pressure to distill off ethanol. The concentrated residue was adjusted to pH 2 by adding 2N hydrochloric acid and washed with diethyl ether. The aqueous layer was made basic (pH 9) by adding a 1N aqueous sodium hydroxide solution, and extracted three times with dichloromethane. The obtained all organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried under reduced pressure to obtain 1.93 g (yield 68%) of the title compound as a white solid. .
Mass spectrum (CI, m / z): 198 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 7.38-7.29 (m, 2H), 7.15-7.03 (m, 2H), 3.81 (s, 1H), 3.25 (d, J = 10.5 Hz, 1H ), 3.13 (d, J = 10.5 Hz, 1H), 0.74 (s, 3H), 0.65 (s, 3H).
（参考例９９）
エチル　［１－（３－フルオロフェニル）－２，２－ジメチル－３－オキソプロピル］カルバマート
Figure JPOXMLDOC01-appb-C000223
 (Reference Example 99)
Ethyl [1- (3-fluorophenyl) -2,2-dimethyl-3-oxopropyl] carbamate
Figure JPOXMLDOC01-appb-C000223
　アルゴン雰囲気下、カルバミン酸エチル２．６３ｇ（２９．５ｍｍｏｌ）のトルエン２５ｍｌ溶液に、３－フルオロベンズアルデヒド３．１０ｍｌ（２９．５ｍｍｏｌ）、ｐ－トルエンスルホン酸一水和物２８８ｍｇ（１．５１ｍｍｏｌ）を室温で順次加えた後、室温で５分間撹拌した。次いで、イソブチルアルデヒド２．７０ｍｌ（２９．７ｍｍｏｌ）を室温で加えた後、Ｄｅａｎ－Ｓｔａｒｋ装置を装着して加熱還流下で３時間撹拌した。次いで、イソブチルアルデヒド２．７０ｍｌ（２９．７ｍｍｏｌ）を追加した後、加熱還流下で更に３時間撹拌した。
　反応終了後、反応液を飽和炭酸水素ナトリウム水溶液に注ぎ入れた後、室温で撹拌した。分液した後、水層をトルエンで１回抽出した。得られた全有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９０：１０～６０：４０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物４．６１ｇ（収率５９％）を微黄色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：２６８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：9.59 (s, 1H), 7.95 (br d, J = 10.2 Hz, 1H), 7.36 (dt, J = 6.2, 7.9 Hz, 1H), 7.27 - 7.06 (m, 3H), 5.07 (d, J = 10.2 Hz, 1H), 4.06 - 3.89 (m, 2H), 1.18 - 1.12 (m, 3H), 0.94 (s, 3H), 0.88 (s, 3H)。 Under an argon atmosphere, 2.63 g (29.5 mmol) of ethyl carbamate in 25 ml of toluene was charged with 3.10 ml (29.5 mmol) of 3-fluorobenzaldehyde and 288 mg (1.51 mmol) of p-toluenesulfonic acid monohydrate. After sequential addition at room temperature, the mixture was stirred at room temperature for 5 minutes. Next, 2.70 ml (29.7 mmol) of isobutyraldehyde was added at room temperature, and a Dean-Stark apparatus was attached, followed by stirring for 3 hours under heating and reflux. Next, 2.70 ml (29.7 mmol) of isobutyraldehyde was added, and the mixture was further stirred for 3 hours under reflux with heating.
After completion of the reaction, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and then stirred at room temperature. After liquid separation, the aqueous layer was extracted once with toluene. The obtained all organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 60:40 (V / V)), and the fraction containing the target product was concentrated under reduced pressure and dried under reduced pressure. As a result, 4.61 g (yield 59%) of the title compound was obtained as a slightly yellow oily substance.
Mass spectrum (CI, m / z): 268 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 9.59 (s, 1H), 7.95 (br d, J = 10.2 Hz, 1H), 7.36 (dt, J = 6.2, 7.9 Hz, 1H), 7.27 -7.06 (m, 3H), 5.07 (d, J = 10.2 Hz, 1H), 4.06-3.89 (m, 2H), 1.18-1.12 (m, 3H), 0.94 (s, 3H), 0.88 (s, 3H ).
（参考例１００）
３－アミノ－３－（３－フルオロフェニル）－２，２－ジメチルプロパン－１－オール
Figure JPOXMLDOC01-appb-C000224
 (Reference Example 100)
3-Amino-3- (3-fluorophenyl) -2,2-dimethylpropan-1-ol
Figure JPOXMLDOC01-appb-C000224
　アルゴン雰囲気下、参考例９９と同様にして合成したエチル　［１－（３－フルオロフェニル）－２，２－ジメチル－３－オキソプロピル］カルバマート４．７５ｇ（１７．８ｍｍｏｌ）のエタノール１２ｍｌ溶液に、撹拌しながら水素化ホウ素ナトリウム３５２ｍｇ（９．３０ｍｍｏｌ）を０℃で分割添加した後、室温で４時間撹拌した。
　反応終了後、反応液を減圧濃縮し、残渣にジクロロメタン７５ｍｌを加えた。この溶液を飽和塩化アンモニウム水溶液５０ｍｌに注ぎ入れ、発泡が収まるまで室温で撹拌した後、分液した。水層をジクロロメタン２５ｍｌで抽出し、全有機層を無水硫酸マグネシウムで乾燥し、ろ過後、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７８：２２～５７：４３（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。
　得られた残渣（３．９１ｇ）にエタノール１２ｍｌ、８５％水酸化カリウム２．４５ｇ（３７．１ｍｍｏｌ）を加え、４時間加熱還流した。
　放冷後、減圧濃縮し、水５０ｍｌ、ジクロロメタン５０ｍｌを加え、室温で撹拌した。分液した後、水層をジクロロメタン５０ｍｌで２回抽出した。全有機層を無水硫酸ナトリウムで乾燥後、ろ過、ろ液を減圧濃縮することにより、標記化合物２．５８ｇ（収率７４％）を微黄色粘稠液体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１９８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：7.36 - 7.25 (m, 1H), 7.19 - 7.08 (m, 2H), 7.06 - 6.97 (m, 1H), 5.00 (br s, 1H), 3.81 (s, 1H), 3.25 (d, J = 10.5 Hz, 1H), 3.14 (d, J = 10.5 Hz, 1H), 1.99 (br s, 2H), 0.77 (s, 3H), 0.66 (s, 3H)。 In an argon atmosphere, a solution of ethyl [1- (3-fluorophenyl) -2,2-dimethyl-3-oxopropyl] carbamate synthesized in the same manner as in Reference Example 99 in a solution of ethanol (12 ml) in 12 ml of ethanol was added. While stirring, 352 mg (9.30 mmol) of sodium borohydride was added in portions at 0 ° C., followed by stirring at room temperature for 4 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and 75 ml of dichloromethane was added to the residue. The solution was poured into 50 ml of a saturated aqueous ammonium chloride solution, stirred at room temperature until foaming stopped, and then separated. The aqueous layer was extracted with 25 ml of dichloromethane, and the entire organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 78: 22 to 57:43 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure.
To the obtained residue (3.91 g), 12 ml of ethanol and 2.45 g (37.1 mmol) of 85% potassium hydroxide were added and heated under reflux for 4 hours.
After cooling, the mixture was concentrated under reduced pressure, 50 ml of water and 50 ml of dichloromethane were added, and the mixture was stirred at room temperature. After liquid separation, the aqueous layer was extracted twice with 50 ml of dichloromethane. The whole organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2.58 g (yield 74%) of the title compound as a slightly yellow viscous liquid.
Mass spectrum (CI, m / z): 198 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 7.36-7.25 (m, 1H), 7.19-7.08 (m, 2H), 7.06-6.97 (m, 1H), 5.00 (br s, 1H), 3.81 (s, 1H), 3.25 (d, J = 10.5 Hz, 1H), 3.14 (d, J = 10.5 Hz, 1H), 1.99 (br s, 2H), 0.77 (s, 3H), 0.66 (s, 3H).
（参考例１０１）
３－アミノ－３－（２－フルオロフェニル）－２，２－ジメチルプロパン－１－オール
Figure JPOXMLDOC01-appb-C000225
 (Reference Example 101)
3-Amino-3- (2-fluorophenyl) -2,2-dimethylpropan-1-ol
Figure JPOXMLDOC01-appb-C000225
　アルゴン雰囲気下、カルバミン酸エチル２．６２ｇ（２９．４ｍｍｏｌ）のトルエン２５ｍｌ溶液に、２－フルオロベンズアルデヒド３．０５ｍｌ（２９．２ｍｍｏｌ）、ｐ－トルエンスルホン酸一水和物２８６ｍｇ（１．５１ｍｍｏｌ）を室温で順次加えた後、室温で５分間反応させた。次いで、イソブチルアルデヒド２．７０ｍｌ（２９．７ｍｍｏｌ）を６０℃で加えた後、同温度で５．５時間反応させた。
　反応終了後、反応液を飽和炭酸水素ナトリウム水溶液に注ぎ入れ、室温で５分間撹拌した。分液した後、水層をトルエンで１回抽出した。得られた全有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥、ろ過、減圧濃縮を行った。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９０：１０～６０：４０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより濃縮残渣を得た。
　得られた残渣６．２３ｇのエタノール１５ｍｌ溶液に、アルゴン雰囲気下、撹拌しながら、水素化ホウ素ナトリウム４７８ｍｇ（１２．６ｍｍｏｌ）を０℃で分割添加した後、室温で４時間撹拌した。
　反応終了後、反応液を減圧濃縮し、残渣にジクロロメタン７５ｍｌを加えた。この溶液を飽和塩化アンモニウム水溶液５０ｍｌに注ぎ入れ、発泡が収まるまで室温で撹拌した後、分液した。水層をジクロロメタン２５ｍｌで抽出し、全有機層を無水硫酸マグネシウムで脱水し、ろ過後、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル，溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７７：２３～５６：４４（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。
　得られた残渣５．０３ｇにエタノール１５ｍｌ、８５％水酸化カリウム３．０８ｇ（４６．７ｍｍｏｌ）を加え、５時間加熱還流した。
　放冷後、減圧濃縮し、水５０ｍｌ、ジクロロメタン１００ｍｌを加え、室温で撹拌した後、分液し、水層をジクロロメタン５０ｍｌで２回抽出した。得られた全有機層の濁りが解消するまでジエチルエーテルを加えた後、無水硫酸ナトリウムで乾燥、ろ過、ろ液を減圧濃縮することにより、標記化合物３．６０ｇ（収率６３％）を微黄色粘稠液体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１９８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：7.55 - 7.49 (m, 1H), 7.30 - 7.21 (m, 1H), 7.20 - 7.13 (m, 1H), 7.12 - 7.03 (m, 1H), 5.03 (br s, 1H), 4.15 (s, 1H), 3.35 (d, J=10.5 Hz, 1H), 3.21 (d, J=10.5 Hz, 1H), 2.01 (br s, 2H), 0.73 (s, 3H), 0.71 - 0.66 (m, 3H)。 Under an argon atmosphere, to a solution of 2.62 g (29.4 mmol) of ethyl carbamate in 25 ml of toluene, 3.05 ml (29.2 mmol) of 2-fluorobenzaldehyde and 286 mg (1.51 mmol) of p-toluenesulfonic acid monohydrate were added. After adding sequentially at room temperature, it was made to react at room temperature for 5 minutes. Subsequently, 2.70 ml (29.7 mmol) of isobutyraldehyde was added at 60 ° C., and the mixture was reacted at the same temperature for 5.5 hours.
After completion of the reaction, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and stirred at room temperature for 5 minutes. After liquid separation, the aqueous layer was extracted once with toluene. The obtained all organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 60:40 (V / V)), and the fraction containing the target product was concentrated under reduced pressure and dried under reduced pressure. As a result, a concentrated residue was obtained.
To a solution of 6.23 g of the resulting residue in 15 ml of ethanol, 478 mg (12.6 mmol) of sodium borohydride was added in portions at 0 ° C. with stirring in an argon atmosphere, and then stirred at room temperature for 4 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and 75 ml of dichloromethane was added to the residue. The solution was poured into 50 ml of a saturated aqueous ammonium chloride solution, stirred at room temperature until foaming stopped, and then separated. The aqueous layer was extracted with 25 ml of dichloromethane, and the entire organic layer was dehydrated with anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 77: 23 to 56:44 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure.
To 5.03 g of the obtained residue, 15 ml of ethanol and 3.08 g (46.7 mmol) of 85% potassium hydroxide were added and heated to reflux for 5 hours.
After allowing to cool, the mixture was concentrated under reduced pressure, added with 50 ml of water and 100 ml of dichloromethane, stirred at room temperature, separated, and the aqueous layer was extracted twice with 50 ml of dichloromethane. Diethyl ether was added until the turbidity of the entire organic layer was eliminated, and then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 3.60 g (yield 63%) of the title compound as slightly yellow. Obtained as a viscous liquid.
Mass spectrum (CI, m / z): 198 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 7.55-7.49 (m, 1H), 7.30-7.21 (m, 1H), 7.20-7.13 (m, 1H), 7.12-7.03 (m, 1H) , 5.03 (br s, 1H), 4.15 (s, 1H), 3.35 (d, J = 10.5 Hz, 1H), 3.21 (d, J = 10.5 Hz, 1H), 2.01 (br s, 2H), 0.73 ( s, 3H), 0.71-0.66 (m, 3H).
（参考例１０２）
エチル　（２，２，４－トリメチル－１－オキソペンタン－３－イル）カルバマート
Figure JPOXMLDOC01-appb-C000226
 (Reference Example 102)
Ethyl (2,2,4-trimethyl-1-oxopentan-3-yl) carbamate
Figure JPOXMLDOC01-appb-C000226
　アルゴン雰囲気下、カルバミン酸エチル２．０６ｇ（２３．１ｍｍｏｌ）のトルエン２０ｍｌ溶液に、イソブチルアルデヒド６．００ｍｌ（６６．１ｍｍｏｌ）、ｐ－トルエンスルホン酸一水和物２２４ｍｇ（１．１８ｍｍｏｌ）を室温で順次加えた後、室温で５分間、６０℃で４時間撹拌した。
　反応終了後、反応液を飽和炭酸水素ナトリウム水溶液に注ぎ入れた後、室温で撹拌した。分液した後、水層をトルエンで１回抽出した。得られた全有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９０：１０～６０：４０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１．５５ｇ（収率３１％）を微黄色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：２１６［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：9.55 (s, 1H), 7.11 (br d, J = 10.4 Hz, 1H), 4.01 (q, J = 7.1 Hz, 2H), 3.67 (dd, J = 6.2, 10.4 Hz, 1H), 1.80 - 1.66 (m, 1H), 1.17 (t, J = 7.1 Hz, 3H), 0.98 (s, 3H), 0.90 (s, 3H), 0.80 (d, J = 6.8 Hz, 3H), 0.75 (d, J = 6.8 Hz, 3H)。 Under an argon atmosphere, 6.00 ml (66.1 mmol) of isobutyraldehyde and 224 mg (1.18 mmol) of p-toluenesulfonic acid monohydrate at room temperature were added to a solution of 2.06 g (23.1 mmol) of ethyl carbamate in 20 ml of toluene. After sequential addition, the mixture was stirred at room temperature for 5 minutes and at 60 ° C. for 4 hours.
After completion of the reaction, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and then stirred at room temperature. After liquid separation, the aqueous layer was extracted once with toluene. The obtained all organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 60:40 (V / V)), and the fraction containing the target product was concentrated under reduced pressure and dried under reduced pressure. As a result, 1.55 g (yield 31%) of the title compound was obtained as a slightly yellow oily substance.
Mass spectrum (CI, m / z): 216 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 9.55 (s, 1H), 7.11 (br d, J = 10.4 Hz, 1H), 4.01 (q, J = 7.1 Hz, 2H), 3.67 (dd , J = 6.2, 10.4 Hz, 1H), 1.80-1.66 (m, 1H), 1.17 (t, J = 7.1 Hz, 3H), 0.98 (s, 3H), 0.90 (s, 3H), 0.80 (d, J = 6.8 Hz, 3H), 0.75 (d, J = 6.8 Hz, 3H).
（参考例１０３）
３－アミノ－２，２，４－トリメチルペンタン－１－オ－ル
Figure JPOXMLDOC01-appb-C000227
 (Reference Example 103)
3-Amino-2,2,4-trimethylpentane-1-ol
Figure JPOXMLDOC01-appb-C000227
　アルゴン雰囲気下、参考例１０２と同様にして合成したエチル　（２，２，４－トリメチル－１－オキソペンタン－３－イル）カルバマート１．５５ｇ（７．２０ｍｍｏｌ）のエタノール１０ｍｌ溶液に、水素化ホウ素ナトリウム１７６ｍｇ（４．６６ｍｍｏｌ）を０℃で分割添加した後、０℃で１時間、更に室温で１３．５時間撹拌した。次いで、反応液に水酸化カリウム８５３ｍｇ（１５．２ｍｍｏｌ）、水５．０ｍｌを室温で加えた後、加熱還流下で３時間撹拌した。
　反応終了後、反応液を減圧濃縮してエタノールを留去した。濃縮残渣に２Ｎ塩酸を加えた後、ジエチルエーテルで洗浄した。分液して得られた水層に１Ｎ水酸化ナトリウム水溶液を加えてｐＨ＞１０に調整した後、ジクロロメタンで３回抽出した。得られた全有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ＤＩＯＬシリカゲル、溶出溶媒；１，２－ジクロロエタン：ｎ－ヘキサン＝３０：７０～１００：０→１，２－ジクロロエタン：メタノール＝９５：５（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物５７７ｍｇ（収率５５％）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１４６［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：3.23 (d, J = 10.4 Hz, 1H), 3.15 (d, J = 10.4 Hz, 1H), 2.36 (d, J = 1.8 Hz, 1H), 1.87 (dspt, J = 1.8, 6.8 Hz, 1H), 0.88 (d, J = 6.8 Hz, 3H), 0.81 - 0.76 (m, 9H)。 Under an argon atmosphere, borohydride was added to a solution of 1.55 g (7.20 mmol) of ethyl (2,2,4-trimethyl-1-oxopentan-3-yl) carbamate synthesized in the same manner as in Reference Example 102 in 10 ml of ethanol. After 176 mg (4.66 mmol) of sodium was added in portions at 0 ° C., the mixture was stirred at 0 ° C. for 1 hour and further at room temperature for 13.5 hours. Next, 853 mg (15.2 mmol) of potassium hydroxide and 5.0 ml of water were added to the reaction solution at room temperature, and the mixture was stirred for 3 hours under reflux with heating.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to distill off ethanol. 2N hydrochloric acid was added to the concentrated residue, followed by washing with diethyl ether. The aqueous layer obtained by liquid separation was adjusted to pH> 10 by adding 1N aqueous sodium hydroxide solution, and extracted three times with dichloromethane. The obtained all organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: n-hexane = 30: 70 to 100: 0 → 1,2-dichloroethane: methanol = 95: 5 (V / V )), And the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure to obtain 577 mg (yield 55%) of the title compound as a colorless oil.
Mass spectrum (CI, m / z): 146 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 3.23 (d, J = 10.4 Hz, 1H), 3.15 (d, J = 10.4 Hz, 1H), 2.36 (d, J = 1.8 Hz, 1H) , 1.87 (dspt, J = 1.8, 6.8 Hz, 1H), 0.88 (d, J = 6.8 Hz, 3H), 0.81-0.76 (m, 9H).
（参考例１０４）
（Ｒ）－ベンジル　２－ブトキシ－２－フェニルアセタート
Figure JPOXMLDOC01-appb-C000228
 (Reference Example 104)
(R) -Benzyl 2-butoxy-2-phenylacetate
Figure JPOXMLDOC01-appb-C000228
　アルゴン雰囲気下、（Ｒ）－ベンジル　２－ヒドロキシ－２－フェニルアセタート２．３４ｇ（９．６６ｍｍｏｌ）の１－ヨードブタン２５．０ｍｌ（２１９ｍｍｏｌ）懸濁液に、酸化銀（Ｉ）４．５５ｇ（１９．６ｍｍｏｌ）を室温で加えた後、撹拌しながら８０℃で１０．５時間反応させた。
　反応終了後、反応液を室温まで放冷した後 、セライトフィルターを用いて濾過した。濾物を酢酸エチルで洗浄後、全ての濾液を減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９７：３～９３：７（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮、減圧乾燥することにより、標記化合物１．６５ｇ（収率５７％）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：２９９［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：7.45 - 7.17 (m, 10H), 5.18 - 5.09 (m, 2H), 5.05 (s, 1H), 3.50 (td, J = 6.4, 9.2 Hz, 1H), 3.40 (td, J = 6.4, 9.2 Hz, 1H), 1.58 - 1.46 (m, 2H), 1.38 - 1.26 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H)。 Under an argon atmosphere, a suspension of (R) -benzyl 2-hydroxy-2-phenylacetate (2.34 g, 9.66 mmol) in 1-iodobutane (25.0 ml, 219 mmol) and silver (I) (4.55 g, 19.6 mmol) was added at room temperature, followed by reaction at 80 ° C. for 10.5 hours with stirring.
After completion of the reaction, the reaction solution was allowed to cool to room temperature and then filtered using a celite filter. The filtrate was washed with ethyl acetate, and all the filtrates were concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 97: 3 to 93: 7 (V / V)), and the fraction containing the target product was concentrated under reduced pressure and dried under reduced pressure. This gave 1.65 g (57% yield) of the title compound as a colorless oil.
Mass spectrum (CI, m / z): 299 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 7.45-7.17 (m, 10H), 5.18-5.09 (m, 2H), 5.05 (s, 1H), 3.50 (td, J = 6.4, 9.2 Hz , 1H), 3.40 (td, J = 6.4, 9.2 Hz, 1H), 1.58-1.46 (m, 2H), 1.38-1.26 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H).
（参考例１０５）
ｔｅｒｔ－ブチル　（３－ヒドロキシ－２，２－ジメチル－１－フェニルプロピル）カルバマート
Figure JPOXMLDOC01-appb-C000229
 (Reference Example 105)
tert-Butyl (3-hydroxy-2,2-dimethyl-1-phenylpropyl) carbamate
Figure JPOXMLDOC01-appb-C000229
　アルゴン気流下、３－アミノ－２，２－ジメチル－３－フェニルプロパン－１－オール［Ｓｙｎｔｈｅｔｉｃ　Ｃｏｍｍｕｎｉｃａｔｉｏｎｓ，　１９９４，２４（７），８９９－９０６．に記載の方法に準じて合成］１．００ｇ（５．５８ｍｍｏｌ）のジクロロメタン５ｍｌ溶液に、トリエチルアミン２．３４ｍｌ（１６．８ｍｍｏｌ）、ジ－ｔｅｒｔ－ブチル　ジカーボネート２．５６ｍｌ（１１．１　ｍｍｏｌ）を室温で順次加え、室温で２時間撹拌した。
　反応終了後、反応溶液に飽和塩化アンモニウム水溶液を加え、その混合液から酢酸エチルで抽出した。有機層は飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９１：９～７０：３０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物１．４５ｇ（収率９３％）を白色固体として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：２８０［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：7.37 - 7.18 (m, 6H), 4.97 - 4.75 (m, 1H), 4.62 - 4.32 (m, 1H), 3.22 - 3.08 (m, 1H), 3.05 - 2.90 (m, 1H), 1.40 - 1.29 (m, 9H), 0.83 - 0.73 (m, 6H)。 Under an argon stream, 3-amino-2,2-dimethyl-3-phenylpropan-1-ol [Synthetic Communications, 1994, 24 (7), 899-906. Synthesis of 1.00 g (5.58 mmol) in dichloromethane (5 ml) with triethylamine (2.34 ml, 16.8 mmol) and di-tert-butyl dicarbonate (2.56 ml, 11.1 mmol). Sequentially added at room temperature and stirred at room temperature for 2 hours.
After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 91: 9 to 70:30 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. 1.45 g (93% yield) of the title compound was obtained as a white solid.
Mass spectrum (CI, m / z): 280 [M + 1] +.
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 7.37-7.18 (m, 6H), 4.97-4.75 (m, 1H), 4.62-4.32 (m, 1H), 3.22-3.08 (m, 1H) , 3.05-2.90 (m, 1H), 1.40-1.29 (m, 9H), 0.83-0.73 (m, 6H).
（参考例１０６）
ｔｅｒｔ－ブチル　（３－メトキシ－２，２－ジメチル－１－フェニルプロピル）カルバマート
Figure JPOXMLDOC01-appb-C000230
 (Reference Example 106)
tert-Butyl (3-methoxy-2,2-dimethyl-1-phenylpropyl) carbamate
Figure JPOXMLDOC01-appb-C000230
　参考例１０５と同様にして合成したｔｅｒｔ－ブチル　（３－ヒドロキシ－２，２－ジメチル－１－フェニルプロピル）カルバマート６００ｍｇ（２．１５ｍｍｏｌ）のジクロロメタン６ｍｌ溶液に、アルゴン気流下撹拌しながら水酸化カリウム３７０ｍｇ（６．５９ｍｍｏｌ）を０℃で一度に加え、０℃で１５分間撹拌した。次いで、ジメチル硫酸０．４０７ｍｌ（４．２９ｍｍｏｌ）を０℃で滴下し、室温で８時間撹拌した。
　反応終了後、反応溶液に水を加え、その混合液からジクロロメタンで抽出した。有機層は飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥し、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１００：０～８７：１３（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物１１４ｍｇ（収率１８％）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：２９４［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：7.35 - 7.16 & 6.95 - 6.82 (m, total 6H), 4.67 - 4.37 (m, 1H), 3.28 - 3.19 (m, 3H), 3.08 - 2.91 (m, 1H), 2.88 - 2.76 (m, 1H), 1.43 - 1.13 (m, 9H), 0.90 - 0.82 (m, 3H), 0.81 - 0.70 (m, 3H)。 To a solution of tert-butyl (3-hydroxy-2,2-dimethyl-1-phenylpropyl) carbamate 600 mg (2.15 mmol) synthesized in the same manner as in Reference Example 105 in 6 ml of dichloromethane, potassium hydroxide with stirring under an argon stream 370 mg (6.59 mmol) was added in one portion at 0 ° C. and stirred at 0 ° C. for 15 minutes. Next, 0.407 ml (4.29 mmol) of dimethyl sulfate was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 8 hours.
After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 87:13 (V / V)), and the fraction containing the target product was concentrated under reduced pressure. The title compound (114 mg, 18% yield) was obtained as a colorless oil.
Mass spectrum (CI, m / z): 294 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 7.35-7.16 & 6.95-6.82 (m, total 6H), 4.67-4.37 (m, 1H), 3.28-3.19 (m, 3H), 3.08-2.91 (m, 1H), 2.88-2.76 (m, 1H), 1.43-1.13 (m, 9H), 0.90-0.82 (m, 3H), 0.81-0.70 (m, 3H).
（参考例１０７）
３－メトキシ－２，２－ジメチル－１－フェニルプロパン－１－アミン
Figure JPOXMLDOC01-appb-C000231
 (Reference Example 107)
3-methoxy-2,2-dimethyl-1-phenylpropan-1-amine
Figure JPOXMLDOC01-appb-C000231
　参考例１０６と同様にして合成したｔｅｒｔ－ブチル　（３－メトキシ－２，２－ジメチル－１－フェニルプロピル）カルバマート１１４ｍｇ（０．３８９ｍｍｏｌ）の１，４－ジオキサン２ｍｌ溶液に、アルゴン気流下撹拌しながら４Ｎ塩化水素／１，４－ジオキサン０．４８６ｍｌ（１．９４ｍｍｏｌ）を室温で一度に加え、室温で２０時間撹拌した。
　反応終了後、反応溶液を濃縮した。水を加えて残渣を溶かした後、飽和炭酸水素ナトリウム水溶液を加えてｐＨ８とし、酢酸エチルで２回抽出した。有機層を無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮することにより、標記化合物７１ｍｇ（収率９５％）を無色油状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：１９４［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：7.34 - 7.16 (m, 5H), 3.78 (s, 1H), 3.23 (s, 3H), 3.13 (d, J = 8.8 Hz, 1H), 2.92 (d, J = 8.8 Hz, 1H), 1.82 (br s, 2H), 0.83 (s, 3H), 0.70 (s, 3H)。 To a solution of 114 mg (0.389 mmol) of tert-butyl (3-methoxy-2,2-dimethyl-1-phenylpropyl) carbamate synthesized in the same manner as in Reference Example 106 in 2 ml of 1,4-dioxane, the mixture was stirred under an argon stream. While adding 0.486 ml (1.94 mmol) of 4N hydrogen chloride / 1,4-dioxane at room temperature, the mixture was stirred at room temperature for 20 hours.
After completion of the reaction, the reaction solution was concentrated. Water was added to dissolve the residue, saturated aqueous sodium hydrogen carbonate solution was added to adjust to pH 8, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 71 mg (yield 95%) of the title compound as a colorless oil.
Mass spectrum (CI, m / z): 194 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 7.34-7.16 (m, 5H), 3.78 (s, 1H), 3.23 (s, 3H), 3.13 (d, J = 8.8 Hz, 1H), 2.92 (d, J = 8.8 Hz, 1H), 1.82 (br s, 2H), 0.83 (s, 3H), 0.70 (s, 3H).
（参考例１０８）
エチル　５－［（３－メトキシ－２，２－ジメチル－１－フェニルプロピル）カルバモイル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ[３，４－ｃ]ピラゾール－２（４Ｈ）－カルボキシラート
Figure JPOXMLDOC01-appb-C000232
 (Reference Example 108)
Ethyl 5-[(3-methoxy-2,2-dimethyl-1-phenylpropyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3 4-c] pyrazole-2 (4H) -carboxylate
Figure JPOXMLDOC01-appb-C000232
　参考例１０７と同様にして合成した３－メトキシ－２，２－ジメチル－１－フェニルプロパン－１－アミン７０ｍｇ（０．３６ｍｍｏｌ）の１，４－ジオキサン５ｍｌ溶液に、アルゴン気流下撹拌しながらＤＩＰＥＡ０．３１５ｍｌ（１．８１ｍｏｌ）、参考例３と同様にして合成したエチル　５－（クロロカルボニル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－５，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－２（４Ｈ）－カルボキシラート１７６ｍｇ（０．３９９ｍｍｏｌ）を室温で順次加え、９０℃で２時間撹拌した。
　反応終了後、室温まで放冷した反応液に飽和塩化アンモニウム水溶液を加え、その混合液から酢酸エチルで抽出した。有機層は飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥し、濾過、減圧濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝６１：３９～４０：６０（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物１３１ｍｇ（収率６１％）を白色泡状物として得た。
マススペクトル（ＣＩ，ｍ／ｚ）：５９８［Ｍ＋１］＋。
１Ｈ－ＮＭＲスペクトル（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：9.75 (s, 1H), 7.38 - 7.20 (m, 5H), 6.78 (d, J = 8.3 Hz, 1H), 4.64 - 4.50 (m, 3H), 4.42 (q, J = 7.1 Hz, 2H), 3.40 (s, 3H), 3.15 (d, J = 9.2 Hz, 1H), 2.93 (d, J = 9.2 Hz, 1H), 2.57 - 2.45 (m, 2H), 2.32 - 2.23 (m, 2H), 1.97 - 1.82 (m, 2H), 1.61 (s, 3H), 1.52 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H), 1.13 (s, 3H), 0.68 (s, 3H), 0.13 (s, 9H)。 To a solution of 70 mg (0.36 mmol) of 3-methoxy-2,2-dimethyl-1-phenylpropan-1-amine synthesized in the same manner as in Reference Example 107 in 5 ml of 1,4-dioxane, DIPEA0 was stirred under an argon stream. 315 ml (1.81 mol), ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo synthesized in the same manner as in Reference Example 3 176 mg (0.399 mmol) of 3,4-c] pyrazole-2 (4H) -carboxylate was sequentially added at room temperature, followed by stirring at 90 ° C. for 2 hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution which had been allowed to cool to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 61: 39 to 40:60 (V / V)), and the fraction containing the target product was concentrated under reduced pressure. The title compound (131 mg, 61% yield) was obtained as a white foam.
Mass spectrum (CI, m / z): 598 [M + 1] + .
1 H-NMR spectrum (400 MHz, DMSO-d 6 ) δ: 9.75 (s, 1H), 7.38-7.20 (m, 5H), 6.78 (d, J = 8.3 Hz, 1H), 4.64-4.50 (m, 3H ), 4.42 (q, J = 7.1 Hz, 2H), 3.40 (s, 3H), 3.15 (d, J = 9.2 Hz, 1H), 2.93 (d, J = 9.2 Hz, 1H), 2.57-2.45 (m , 2H), 2.32-2.23 (m, 2H), 1.97-1.82 (m, 2H), 1.61 (s, 3H), 1.52 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H), 1.13 ( s, 3H), 0.68 (s, 3H), 0.13 (s, 9H).
［試験例１］
ＣＤＫ７酵素阻害試験
　緩衝液の調製は、Ｎ－２－ヒドロキシエチルピペラジン－Ｎ’－２－エタンスルホン酸緩衝液（ＨＥＰＥＳ緩衝液）（ｐＨ７．４）、ジチオスレイトール（ＤＴＴ）、ＴｒｉｔｏｎＸ－１００、塩化マグネシウム（ＭｇＣｌ２）を混和して行った。５００μＭ［γ－３３Ｐ］ＡＴＰ溶液は、１０ｍＭ　ＡＴＰ溶液と市販の［γ－３３Ｐ］ＡＴＰ溶液（Ｐｅｒｋｉｎ　Ｅｌｍｅｒ社製　Ｃｏｄｅ　Ｎｏ．ＮＥＧ－３０２Ｈ）を緩衝液で希釈して用いた。ＣＤＫ７溶液は、市販のＣＤＫ７（Ｃａｒｎａ　ｂｉｏｓｃｉｅｎｃｅｓ社製　Ｃａｔａｌｏｇ　Ｎｏ．０４－１０８）を緩衝液で希釈して用いた。基質溶液は、Ｍｙｅｌｉｎ　Ｂａｓｉｃ　Ｐｒｏｔｅｉｎ（ＭＢＰ）を緩衝液で希釈して用いた。反応溶液の調製は、４℃にて緩衝液、５００μＭ［γ－３３Ｐ］ＡＴＰ溶液、ＣＤＫ７溶液、基質溶液を混和して反応溶液とした。
　ＣＤＫ７酵素反応は、１．５ｍＬマイクロチューブに、４℃にて１０％ジメチルスルホキシド（ＤＭＳＯ）／９０％注射用蒸留水で調製した被験化合物溶液を５μＬ、反応溶液を４５μＬ加え、マイクロチューブをウォーターバスインキュベーターにて３０℃で２０分間反応させて行った。反応後４℃に冷却しながら、各マイクロチューブに１０％トリクロロ酢酸（ＴＣＡ）水溶液を加えて、混和し反応を停止した。４℃にて１０分静置後、遠心機で遠心し、上清を廃棄した。次に２％ＴＣＡ水溶液を加え、混和後、遠心機で遠心し上清を廃棄した。この洗浄操作を２回行った。洗浄後、沈殿を１Ｎ水酸化ナトリウム（ＮａＯＨ）水溶液で溶解し、液体シンチレーションカウンターにより、反応生成物のエネルギー量（放射活性）を測定した。
　ＣＤＫ７に対する被験化合物の阻害活性の算出は、ＭＢＰに結合する３３Ｐの量を５０％阻害する被験化合物濃度（ＩＣ５０値）として、ＥＸＳＵＳ（バージョン８．０．０又はバージョン８．０．１、ＣＡＣエクシケア社製）を用いて行った。
　Ｋｉ値の算出は、以下の計算式に従って行った。Ｓは反応溶液中に含まれるＡＴＰ濃度を、ＫｍはＭｉｃｈａｅｌｉｓ－Ｍｅｎｔｅｎ定数を表す。
Ｋｉ＝ＩＣ５０／（１＋Ｓ／Ｋｍ） [Test Example 1]
CDK7 enzyme inhibition test Buffers were prepared using N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid buffer (HEPES buffer) (pH 7.4), dithiothreitol (DTT), Triton X-100, Magnesium chloride (MgCl 2 ) was mixed. As the 500 μM [γ- 33 P] ATP solution, a 10 mM ATP solution and a commercially available [γ- 33 P] ATP solution (Code No. NEG-302H, manufactured by Perkin Elmer) were diluted with a buffer solution. As the CDK7 solution, commercially available CDK7 (Catalog No. 04-108 manufactured by Carna biosciences) was diluted with a buffer solution. As the substrate solution, Myelin Basic Protein (MBP) was diluted with a buffer solution. The reaction solution was prepared by mixing a buffer solution, 500 μM [γ- 33 P] ATP solution, CDK7 solution, and substrate solution at 4 ° C.
For the CDK7 enzyme reaction, add 5 μL of a test compound solution prepared with 10% dimethyl sulfoxide (DMSO) / 90% distilled water for injection at 4 ° C. and 45 μL of the reaction solution to a 1.5 mL microtube. The reaction was carried out at 30 ° C. for 20 minutes in an incubator. After the reaction, while cooling to 4 ° C., a 10% trichloroacetic acid (TCA) aqueous solution was added to each microtube and mixed to stop the reaction. After standing at 4 ° C. for 10 minutes, the mixture was centrifuged with a centrifuge and the supernatant was discarded. Next, a 2% TCA aqueous solution was added, mixed, and centrifuged with a centrifuge to discard the supernatant. This washing operation was performed twice. After washing, the precipitate was dissolved in a 1N sodium hydroxide (NaOH) aqueous solution, and the amount of energy (radioactivity) of the reaction product was measured with a liquid scintillation counter.
Calculation of the inhibitory activity of a test compound against CDK7 was carried out using EXSUS (version 8.0.0 or version 8.0.1, as the test compound concentration (IC 50 value) that inhibits the amount of 33 P binding to MBP by 50%. CAC Excicare).
The Ki value was calculated according to the following calculation formula. S represents the ATP concentration contained in the reaction solution, and Km represents the Michaelis-Menten constant.
Ki = IC 50 / (1 + S / Km)
　本試験において本発明の化合物は優れたＣＤＫ７阻害活性を示し、例えば化合物番号ＩＩ－１３、ＩＩ－１４、ＩＩＩ－１１、ＩＩＩ－１４、ＩＩＩ－１７、ＩＩＩ－２２、ＩＩＩ－２５、ＩＩＩ－３１、ＩＶ－１、ＩＶ－１８、ＩＶ－２０、ＩＶ－２１、ＩＶ－２５、ＩＶ－３４、ＩＶ－４９、ＩＶ－６４、ＩＶ－６７、ＩＶ－７０、ＩＶ－８９、ＩＶ－９５のナトリウム塩、ＩＶ－１０１、ＩＶ－１０３、ＩＶ－１０５、ＩＶ－１０７、ＩＶ－１１１、ＩＶ－１１３，ＩＶ－１１５、ＩＶ－１１９、ＩＶ－１２５、ＩＶ－１２６、ＩＶ－１２７、ＩＶ－１４２、ＩＶ－２００、ＩＶ－２２１、ＩＶ－２２５、ＩＶ－２２７、ＩＶ－２５４、ＩＶ－２６０、ＩＶ－２７２、ＩＶ－２８６、ＩＶ－３０６、ＩＶ－３３１、ＩＶ－３３２、ＩＶ－３３４、ＩＶ－３３６、ＩＶ－３４４、ＩＶ－３５２、ＩＶ－３６０、ＩＶ－３６４、ＩＶ－３８５、ＩＶ－３８９、ＩＶ－３９４、ＩＶ－３９９、および、ＩＶ－４００のＫｉ値は５０ｎＭ以下であった。 In this test, the compounds of the present invention show excellent CDK7 inhibitory activity, for example, compound numbers II-13, II-14, III-11, III-14, III-17, III-22, III-25, III-31. IV-1, IV-18, IV-20, IV-21, IV-25, IV-34, IV-49, IV-64, IV-67, IV-70, IV-89, IV-95 sodium Salt, IV-101, IV-103, IV-105, IV-107, IV-111, IV-113, IV-115, IV-119, IV-125, IV-126, IV-127, IV-142, IV-200, IV-221, IV-225, IV-227, IV-254, IV-260, IV-272, IV-286, IV-306, IV-331, IV-332, I -334, IV-336, IV-344, IV-352, IV-360, IV-364, IV-385, IV-389, IV-394, IV-399, and IV-400 have a Ki value of 50 nM or less Met.
［試験例２］
ＣＤＫ２酵素阻害試験
　緩衝液の調製は、ＨＥＰＥＳ緩衝液（ｐＨ７．４）、ＤＴＴ、ＴｒｉｔｏｎＸ－１００、ＭｇＣｌ２を混和して行った。５００μＭ［γ－３３Ｐ］ＡＴＰ溶液は、１０ｍＭ　ＡＴＰ溶液と市販の［γ－３３Ｐ］ＡＴＰ溶液（Ｐｅｒｋｉｎ　Ｅｌｍｅｒ社製　Ｃｏｄｅ　Ｎｏ．ＮＥＧ－３０２Ｈ）を緩衝液で希釈して用いた。ＣＤＫ２溶液は、市販のＣＤＫ２（Ｉｎｖｉｔｒｏｇｅｎ社製　Ｃａｔａｌｏｇ　Ｎｏ．ＰＶ３２６７）を緩衝液で希釈して用いた。基質溶液は、ＭＢＰを緩衝液で希釈して用いた。反応溶液の調製は、４℃にて緩衝液、５００μＭ［γ－３３Ｐ］ＡＴＰ溶液、ＣＤＫ２溶液、基質溶液を混和して反応溶液とした。
　ＣＤＫ２酵素反応は、１．５ｍＬマイクロチューブ中において、４℃にて１０％ＤＭＳＯ／９０％注射用蒸留水に調製した被験化合物溶液を５μＬ、反応溶液を４５μＬ加え、マイクロチューブをウォーターバスインキュベーターにて３０℃で２０分間反応させて行った。反応後４℃に冷却しながら、各マイクロチューブに１０％ＴＣＡ水溶液を加えて、混和し反応を停止した。４℃にて１０分静置後、遠心機で遠心し、上清を廃棄した。次に２％ＴＣＡ水溶液を加え混和後、遠心機で遠心し上清を廃棄した。この洗浄操作を２回行った。洗浄後、沈殿を１ＮのＮａＯＨ水溶液で溶解し、液体シンチレーションカウンターにより、放射活性を測定した。
　ＣＤＫ２に対する被験化合物の阻害活性の算出は、ＭＢＰに結合する３３Ｐの量を５０％阻害する被験化合物濃度（ＩＣ５０値）として、ＥＸＳＵＳ（バージョン８．０．０又はバージョン８．０．１、ＣＡＣエクシケア社製）を用いて行った。
　Ｋｉ値の算出は、以下の計算式に従って行った。Ｓは反応溶液中に含まれるＡＴＰ濃度を、ＫｍはＭｉｃｈａｅｌｉｓ－Ｍｅｎｔｅｎ定数を表す。
Ｋｉ＝ＩＣ５０／（１＋Ｓ／Ｋｍ） [Test Example 2]
Preparation of CDK2 enzyme inhibition test buffer, HEPES buffer (pH7.4), DTT, was performed by mixing the TritonX-100, MgCl 2. As the 500 μM [γ- 33 P] ATP solution, a 10 mM ATP solution and a commercially available [γ- 33 P] ATP solution (Code No. NEG-302H, manufactured by Perkin Elmer) were diluted with a buffer solution. As the CDK2 solution, commercially available CDK2 (Catalog No. PV3267 manufactured by Invitrogen) was diluted with a buffer solution. As the substrate solution, MBP was diluted with a buffer solution. The reaction solution was prepared by mixing a buffer solution, 500 μM [γ- 33 P] ATP solution, CDK2 solution and substrate solution at 4 ° C.
For the CDK2 enzyme reaction, 5 μL of a test compound solution prepared in 10% DMSO / 90% distilled water for injection at 4 ° C. and 45 μL of the reaction solution were added in a 1.5 mL microtube at a water bath incubator. The reaction was carried out at 30 ° C. for 20 minutes. After the reaction, while cooling to 4 ° C., a 10% TCA aqueous solution was added to each microtube and mixed to stop the reaction. After standing at 4 ° C. for 10 minutes, the mixture was centrifuged with a centrifuge and the supernatant was discarded. Next, 2% TCA aqueous solution was added and mixed, and then centrifuged with a centrifuge to discard the supernatant. This washing operation was performed twice. After washing, the precipitate was dissolved with 1N NaOH aqueous solution, and the radioactivity was measured with a liquid scintillation counter.
Calculation of the inhibitory activity of the test compound against CDK2 was performed using EXSUS (version 8.0.0 or version 8.0.1, as the test compound concentration (IC 50 value) that inhibits the amount of 33 P binding to MBP by 50%. CAC Excicare).
The Ki value was calculated according to the following calculation formula. S represents the ATP concentration contained in the reaction solution, and Km represents the Michaelis-Menten constant.
Ki = IC 50 / (1 + S / Km)
　本試験において本発明の化合物、例えば化合物番号ＩＩ－１３、ＩＩ－１４、ＩＩＩ－１１、ＩＩＩ－２２、ＩＩＩ－２５、ＩＶ－１、ＩＶ－１８、ＩＶ－２０、ＩＶ－２１、ＩＶ－３４、ＩＶ－４９、ＩＶ－６４、ＩＶ－６７、ＩＶ－７０、ＩＶ－９５のナトリウム塩、ＩＶ－１０１、ＩＶ－１０３、ＩＶ－１０５、ＩＶ－１１５、ＩＶ－１２５、ＩＶ－１７９、ＩＶ－２００、ＩＶ－２２５、ＩＶ－２３６、ＩＶ－２４０、ＩＶ－２５４、ＩＶ－２７２、ＩＶ－２７６、ＩＶ－３４０、ＩＶ－３５２、および、ＩＶ－３６０のＣＤＫ２阻害活性のＫｉ値は１０００ｎＭ以上であり、ＣＤＫ２阻害活性に対してＣＤＫ７阻害活性が高い選択性を有していた。 In this test, the compounds of the present invention, such as compound numbers II-13, II-14, III-11, III-22, III-25, IV-1, IV-18, IV-20, IV-21, IV-34 IV-49, IV-64, IV-67, IV-70, IV-95 sodium salt, IV-101, IV-103, IV-105, IV-115, IV-125, IV-179, IV- The Ki value of CDK2 inhibitory activity of 200, IV-225, IV-236, IV-240, IV-254, IV-272, IV-276, IV-340, IV-352, and IV-360 is 1000 nM or more. And CDK7 inhibitory activity was highly selective with respect to CDK2 inhibitory activity.
［試験例３］
ＰＡＫ４酵素阻害試験
　緩衝液の調製は、トリスヒドロキシアミノメタン緩衝液（Ｔｒｉｓ緩衝液）（ｐＨ７．５）、ＤＴＴ、ＴｒｉｔｏｎＸ－１００、ＭｇＣｌ２、エチレングリコールビス（β－アミノエチルエーテル）－Ｎ，Ｎ，Ｎ’，Ｎ’－四酢酸（ＥＧＴＡ）、β－グリセロールホスファート、オルトバナジン（Ｖ）酸ナトリウムを混和して行った。４０μＭ［γ－３３Ｐ］ＡＴＰ溶液は、１０ｍＭ　ＡＴＰ溶液と市販の［γ－３３Ｐ］ＡＴＰ溶液（Ｐｅｒｋｉｎ　Ｅｌｍｅｒ社製　Ｃｏｄｅ　Ｎｏ．ＮＥＧ－３０２Ｈ）を緩衝液で希釈して用いた。ＰＡＫ４溶液は、市販のＰＡＫ４（Ｉｎｖｉｔｒｏｇｅｎ社製　Ｃａｔａｌｏｇ　Ｎｏ．ＰＶ４２１２）を緩衝液で希釈して用いた。基質溶液は、ＭＢＰを緩衝液で希釈して用いた。反応溶液の調製は、４℃にて緩衝液、４０μＭ［γ－３３Ｐ］ＡＴＰ溶液、ＰＡＫ４溶液、基質溶液を混和して反応溶液とした。
　ＰＡＫ４酵素反応は、１．５ｍＬマイクロチューブ内において、４℃にて１０％ＤＭＳＯ／９０％注射用蒸留水に調製した被験化合物溶液を５μＬ、反応溶液を４５μＬ加え、マイクロチューブをウォーターバスインキュベーターにて３０℃で２０分間反応させて行った。反応後４℃に冷却しながら、各マイクロチューブに１０％ＴＣＡ水溶液を加えて、混和し反応を停止した。４℃にて１０分静置後、遠心機で遠心し、上清を廃棄する。次に２％ＴＣＡ水溶液を加え混和後、遠心機で遠心し上清を廃棄した。この洗浄操作を２回行った。洗浄後、沈殿を１ＮのＮａＯＨ水溶液で溶解し、液体シンチレーションカウンターにより、放射活性を測定した。
　ＰＡＫ４に対する被験化合物の阻害活性の算出は、ＭＢＰに結合する３３Ｐの量を５０％阻害する被験化合物濃度（ＩＣ５０値）として、ＥＸＳＵＳ（バージョン８．０．０又はバージョン８．０．１、ＣＡＣエクシケア社製）を用いて行った。
　Ｋｉ値の算出は、以下の計算式に従って行った。Ｓは反応溶液中に含まれるＡＴＰ濃度を、ＫｍはＭｉｃｈａｅｌｉｓ－Ｍｅｎｔｅｎ定数を表す。
Ｋｉ＝ＩＣ５０／（１＋Ｓ／Ｋｍ） [Test Example 3]
PAK4 enzyme inhibition test The buffer was prepared by trishydroxyaminomethane buffer (Tris buffer) (pH 7.5), DTT, Triton X-100, MgCl 2 , ethylene glycol bis (β-aminoethyl ether) -N, N , N ′, N′-tetraacetic acid (EGTA), β-glycerol phosphate and sodium orthovanadate (V) were mixed. As a 40 μM [γ- 33 P] ATP solution, a 10 mM ATP solution and a commercially available [γ- 33 P] ATP solution (Code No. NEG-302H manufactured by Perkin Elmer) were diluted with a buffer solution. As the PAK4 solution, commercially available PAK4 (Catalog No. PV4212 manufactured by Invitrogen) was diluted with a buffer solution. As the substrate solution, MBP was diluted with a buffer solution. The reaction solution was prepared by mixing a buffer solution, 40 μM [γ- 33 P] ATP solution, PAK4 solution and substrate solution at 4 ° C.
In the PAK4 enzyme reaction, 5 μL of a test compound solution prepared in 10% DMSO / 90% distilled water for injection at 4 ° C. and 45 μL of the reaction solution are added in a 1.5 mL microtube, and the microtube is added in a water bath incubator. The reaction was carried out at 30 ° C. for 20 minutes. After the reaction, while cooling to 4 ° C., a 10% TCA aqueous solution was added to each microtube and mixed to stop the reaction. After leaving at 4 ° C. for 10 minutes, centrifuge in a centrifuge and discard the supernatant. Next, 2% TCA aqueous solution was added and mixed, and then centrifuged with a centrifuge to discard the supernatant. This washing operation was performed twice. After washing, the precipitate was dissolved with 1N NaOH aqueous solution, and the radioactivity was measured with a liquid scintillation counter.
Calculation of the inhibitory activity of a test compound against PAK4 was performed using EXSUS (version 8.0.0 or version 8.0.1, as the test compound concentration (IC 50 value) that inhibits the amount of 33 P binding to MBP by 50%. CAC Excicare).
The Ki value was calculated according to the following calculation formula. S represents the ATP concentration contained in the reaction solution, and Km represents the Michaelis-Menten constant.
Ki = IC 50 / (1 + S / Km)
　本試験において本発明の化合物、例えば化合物番号ＩＩ－１３、ＩＩ－１４、ＩＩＩ－１１、ＩＩＩ－２２、ＩＩＩ－２５、ＩＶ－１、ＩＶ－１８、ＩＶ－２０、ＩＶ－２１、ＩＶ－３４、ＩＶ－４９、ＩＶ－６４、ＩＶ－６７、ＩＶ－７０、ＩＶ－９５のナトリウム塩、ＩＶ－１０１、ＩＶ－１０３、ＩＶ－１０５、ＩＶ－１１５、ＩＶ－１２５、ＩＶ－１４２、ＩＶ－１７９、ＩＶ－２００、ＩＶ－２２５、ＩＶ－２３６、ＩＶ－２５４、ＩＶ－２５８、ＩＶ－２７６、ＩＶ－３４０、ＩＶ－３６０、ＩＶ－３６４、ＩＶ－３８５、ＩＶ－３８９、および、ＩＶ－３９９のＰＡＫ４阻害活性のＫｉ値は５００ｎＭ以上であり、ＰＡＫ４阻害活性に対してＣＤＫ７阻害活性が高い選択性を有していた。 In this test, the compounds of the present invention, such as compound numbers II-13, II-14, III-11, III-22, III-25, IV-1, IV-18, IV-20, IV-21, IV-34 IV-49, IV-64, IV-67, IV-70, IV-95 sodium salt, IV-101, IV-103, IV-105, IV-115, IV-125, IV-142, IV- 179, IV-200, IV-225, IV-236, IV-254, IV-258, IV-276, IV-340, IV-360, IV-364, IV-385, IV-389, and IV- The Ki value of the PAK4 inhibitory activity of 399 was 500 nM or more, and the CDK7 inhibitory activity was highly selective with respect to the PAK4 inhibitory activity.
［試験例４］
ヒトＰＢＭＣ各種刺激剤カクテル誘発ＩＬ－１７産生抑制試験
　健常成人よりヘパリン下採血した血液よりＦｉｃｏｌｌ－Ｐａｑｕｅ（ＧＥ　Ｈｅａｌｔｈｃａｒｅ社製　１７－１４４０－０２）を用い、ＰＢＭＣを分離し回収した。回収したＰＢＭＣを更にフラスコで一定時間培養後、上清の非接着細胞を回収し、Ｔ－ｃｅｌｌ浮遊液とした。Ｔ　ｃｅｌｌ　Ａｃｔｉｖａｔｉｏｎ　Ｐｌａｔｅ　Ａｎｔｉ－Ｈｕｍａｎ　ＣＤ３　９６ｗｅｌｌプレート（Ｃｏｒｎｉｎｇ社製　ＲＥＦ．３５４７２５）に、ＤＭＳＯに溶解した被験化合物、および終濃度２μｇ／ｍＬ　ＣＤ２８抗体（ＢｉｏＬｅｇｅｎｄ社製　Ｃａｔ．Ｎｏ．３０２９１４）、終濃度１０μｇ／ｍＬ　ヒトＩＦＮ－γ抗体（ＢＤ　Ｂｉｏｓｃｉｅｎｃｅｓ社製　Ｃａｔ．Ｎｏ．５５４６９８）、終濃度１０μｇ／ｍＬ　ヒトＩＬ－４抗体（ＢＤ　Ｂｉｏｓｃｉｅｎｃｅｓ社製　Ｃａｔ．Ｎｏ．５５４４８１）、終濃度２０ｎｇ／ｍＬ　ヒトＩＬ－６（ＢｉｏＬｅｇｅｎｄ社製　Ｃａｔ．Ｎｏ．５７０８０２）、終濃度１０ｎｇ／ｍＬ　ヒトＩＬ－２３（ＢｉｏＬｅｇｅｎｄ社製　Ｃａｔ．Ｎｏ．５７４１０２）、終濃度１０ｎｇ／ｍＬ　ヒトＩＬ－１β（ＰＥＰＲＯＴＥＣＨ社製　Ｃａｔ．Ｎｏ．２００－０１Ｂ）、終濃度１０ｎｇ／ｍＬ　ヒトＴＧＦ－β（ＢｉｏＬｅｇｅｎｄ社製　Ｃａｔ．Ｎｏ．５８０７０２）を含む１０％ＦＢＳ（ＧＩＢＣＯ社製　ＲＥＦ．１００８２）、１％ペニシリン／ストレプトマイシン／アンホテルシンＢ（ＧＩＢＣＯ社製　ＲＥＦ．１５２４０－０９６）、１％ｎｏｎ　ｅｓｓｅｎｔｉａｌ　ａｍｉｎｏ　ａｃｉｄ（ＧＩＢＣＯ社製　ＲＥＦ．１１１４０－０５０）、１％ピルビン酸（ＧＩＢＣＯ社製　ＲＥＦ．１１１４０）含有ＲＰＭＩ１６４０培地（ＧＩＢＣＯ社製　ＲＥＦ．１１８７５）を１００μＬずつ添加した。次いで２×１０５ｃｅｌｌｓ／ｍＬに調整したＴ－ｃｅｌｌ浮遊液を各ウェルに１００μＬ添加した（ＤＭＳＯ終濃度　０．１％）。被験化合物を添加しないウェルには、ＤＭＳＯのみを添加した。炭酸ガスインキュベーター内で５日間インキュベートした後に、培養上清を回収し、ＩＬ－１７含量測定まで－２０℃に保存した。
　培養上清中ＩＬ－１７含量測定にはサンドイッチＥＬＩＳＡキット（Ｑｕａｎｔｉｋｉｎｅ　Ｈｕｍａｎ　ＩＬ－１７、Ｒ＆Ｄ　Ｓｙｓｔｅｍｓ社製）を用いた。各サンプルのＩＬ－１７含量は、キット付属のＳｔａｎｄａｒｄ　ＩＬ－１７の標準曲線から算出した。ＤＭＳＯのみ添加の場合の各種刺激剤カクテルによるＩＬ－１７産生量を１００％とし、被験化合物各濃度におけるＩＬ－１７産生抑制率を算出した。添加した被験化合物の濃度と被験化合物のＩＬ－１７産生抑制率から、ＩＬ－１７産生を５０％抑制するのに必要な被験化合物の濃度（ＩＣ５０値）をＥＸＳＵＳ（バージョン８．０．０又はバージョン８．０．１、ＣＡＣエクシケア社製）を用いて算出した。 [Test Example 4]
Human PBMC Stimulator Cocktail Induced IL-17 Production Inhibition Test PBMC were separated and collected from blood collected under heparin from healthy adults using Ficoll-Paque (GE Healthcare 17-1440-02). The recovered PBMC was further cultured in a flask for a certain period of time, and then the supernatant non-adherent cells were recovered and used as a T-cell suspension. A test compound dissolved in DMSO on a T cell Activation Plate Anti-Human CD3 96-well plate (Corning REF.354725) and a final concentration of 2 μg / mL CD28 antibody (BioLegend Cat. No. 302914), a final concentration of 10 μg / mL human IFN-γ antibody (BD Biosciences Cat. No. 554698), final concentration 10 μg / mL human IL-4 antibody (BD Biosciences Cat. No. 554481), final concentration 20 ng / mL human IL-6 ( BioLegend Cat. No. 570802), final concentration of 10 ng / mL human IL-23 (BioLegend Cat. No. 574102), final concentration of 10 ng / mL human IL-1. β (PEPROTECH Cat. No. 200-01B), final concentration 10 ng / mL human TGF-β (BioLegend Cat. No. 580702) 10% FBS (GIBCO REF. 10082), 1% penicillin / Streptomycin / Anhotelsin B (GIBCO REF.15240-096), 1% non essential amino acid (GIBCO REF.11140-050), 1% pyruvic acid (GIBCO REF.11140) -containing RPMI1640 medium (GIBCO REF. 11875) was added in an amount of 100 μL. Next, 100 μL of a T-cell suspension adjusted to 2 × 10 5 cells / mL was added to each well (DMSO final concentration 0.1%). Only DMSO was added to wells to which no test compound was added. After incubating in a carbon dioxide incubator for 5 days, the culture supernatant was collected and stored at −20 ° C. until measurement of IL-17 content.
A sandwich ELISA kit (Quantikine Human IL-17, manufactured by R & D Systems) was used to measure the IL-17 content in the culture supernatant. The IL-17 content of each sample was calculated from the standard IL-17 standard curve supplied with the kit. The IL-17 production inhibition rate at each concentration of the test compound was calculated with the IL-17 production amount by various stimulant cocktails when only DMSO was added as 100%. Based on the concentration of the test compound added and the IL-17 production inhibition rate of the test compound, the concentration of the test compound (IC 50 value) required to inhibit the IL-17 production by 50% is expressed as EXSUS (version 8.0.0 or Version 8.0.1, manufactured by CAC Excicare).
　本試験において本発明の化合物は優れたＩＬ－１７産生抑制活性を示し、例えば、化合物番号ＩＶ－７０、ＩＶ－８５、ＩＶ－１４２、ＩＶ－１７９、ＩＶ－２００、ＩＶ－２５４、ＩＶ－２５８、ＩＶ－２７２、ＩＶ－２７６、ＩＶ－３３１、ＩＶ－３３４、ＩＶ－３３６、ＩＶ－３４０、ＩＶ－３４４、ＩＶ－３５２、ＩＶ－３６０、ＩＶ－３６４、ＩＶ－３８５、ＩＶ－３８９、および、ＩＶ－３９９のＩＣ５０値は５０ｎＭ以下であった。 In this test, the compound of the present invention exhibits excellent IL-17 production inhibitory activity. For example, Compound Nos. IV-70, IV-85, IV-142, IV-179, IV-200, IV-254, IV-258 IV-272, IV-276, IV-331, IV-334, IV-336, IV-340, IV-344, IV-352, IV-360, IV-364, IV-385, IV-389, and IV-399 had an IC 50 value of 50 nM or less.
［試験例５］
オキサゾロン（ＯＸＡ）誘発マウス遅延型過敏性皮膚炎モデルにおける腫脹抑制試験
　２％に調整したＯＸＡ（ＳＩＧＭＡ社製　ＲＥＦ．Ｅ０７５３－１０Ｇ）のエタノール溶液０．０５ｍＬを、除毛クリームで除毛したＢＡＬＢ／ｃマウス（雌、日本エスエルシー社供給）の腹部に、２日間連続で塗布し、感作動物とした。また、２％ＯＸＡのかわりにエタノールを塗布したマウスを非感作動物とした。
　塗布から５日後、被験化合物塗布群では、感作動物の右耳の両側（耳介前面及び耳介後面）に、１％に調整した被験化合物のエタノール溶液を０．０１ｍＬずつ塗布した。対照群では、非感作動物の右耳の両側に、エタノールを０．０１ｍＬずつ塗布した。Ｖｅｈｉｃｌｅ群では、感作動物の右耳の両側に、エタノールを０．０１ｍＬずつ塗布した。１時間後、各群のマウスの右耳の両側に２％ＯＸＡのエタノール溶液を右耳の両側に０．０１５ｍＬずつ塗布した。翌日、右耳の厚さをシックネスゲージ（テクロック社製）で測定し、抑制率を下記の式で算出した。
　抑制率（％）＝（１－（被験化合物塗布群の耳厚－対照群の耳厚）／（Ｖｅｈｉｃｌｅ群の耳厚－対照群の耳厚））×１００ [Test Example 5]
BALB / c It was applied to the abdomen of a mouse (female, supplied by Japan SLC Co., Ltd.) for 2 consecutive days to obtain a sensitive working product. In addition, mice in which ethanol was applied instead of 2% OXA were used as non-sensitive animals.
Five days after application, in the test compound application group, 0.01 mL each of an ethanol solution of the test compound adjusted to 1% was applied to both sides (anterior surface of the pinna and the back surface of the pinna) of the right ear of the sensitized animal. In the control group, 0.01 mL of ethanol was applied to both sides of the right ear of the non-sensitized animal. In the Vehicle group, 0.01 mL of ethanol was applied to both sides of the right ear of the sensitized animal. After 1 hour, 0.015 mL of a 2% OXA ethanol solution was applied to both sides of the right ear of each group of mice. The next day, the thickness of the right ear was measured with a thickness gauge (manufactured by Teclock), and the inhibition rate was calculated by the following formula.
Inhibition rate (%) = (1− (ear thickness of test compound application group−ear thickness of control group) / (ear thickness of vehicle group−ear thickness of control group)) × 100
　本試験において、本発明の化合物は優れた腫脹抑制作用を示し、例えば、１％エタノール溶液の塗布で化合物番号ＩＶ－１４２、ＩＶ－２７２、ＩＶ－３３１、ＩＶ－３４０、ＩＶ－３６０、ＩＶ－３６４、および、ＩＶ－４００は５０％以上の抑制率を示した。 In this test, the compound of the present invention exhibits an excellent anti-tumor action. For example, compound Nos. IV-142, IV-272, IV-331, IV-340, IV-360, IV- 364 and IV-400 showed an inhibition rate of 50% or more.
［試験例６］
ヒト肝臓ミクロソーム画分を用いた代謝試験
　ヒト肝臓ミクロソーム（Ｘｅｎｏｔｅｃｈ社製　ＣａｔＮｏ．Ｈ６１０）２ｍｇタンパク相当を懸濁させた反応組成液（ＮＡＤＰＨ産生系溶液Ａ（Ｃｏｒｎｉｎｇ社製　ＲＥＦ．４５１２２０）５０μＬ、ＮＡＤＰＨ産生系溶液Ｂ（Ｃｏｒｎｉｎｇ社製　ＲＥＦ．４５１２００）１０μＬ、２５０ｍＭ　ＵＤＰ－グルクロン酸４０μＬ、ＵＧＴ　Ｒｅａｃｔｉｏｎ　Ｍｉｘ溶液Ｂ（Ｃｏｒｎｉｎｇ社製　ＲＥＦ．４５１３２０）２００μＬ、蒸留水５９０μＬ）に、ＤＭＳＯ（和光純薬工業株式会社製　ＣｏｄｅＮｏ．０４３－０７２１６）に溶解した被験化合物（一般式（Ｖ）または（ＶＩ）で表されるプロドラッグ）１０μＬ（ＤＭＳＯ終濃度　１．０％）を加え、３７℃で５分間インキュベートした。
　高速液体クロマトグラフィー（島津製作所社製　型式ＬＣ－２０Ａシリーズ）にて被験化合物（一般式（Ｖ）または（ＶＩ）で表されるプロドラッグ）及び生成した薬理活性体であるアルコール体のピーク面積（測定ＵＶ波長２４５ｎｍ）を算出した。
ＨＰＬＣ条件；カラム：Ｐｈｅｎｏｍｅｎｅｘ　Ｋｉｎｅｔｅｘ　Ｃ１８（Ｐｈｅｎｏｍｅｎｅｘ社製　ＰａｒｔＮｏ．００Ｄ－４４６２－ＡＮ），２．１ｍｍ×１００ｍｍ，２．６μｍ，カラム温度４０℃、溶離液；Ａ液：０．１％ギ酸（和光純薬工業株式会社製　ＣｏｄｅＮｏ．０６３－０４１９２）、
Ｂ液：アセトニトリル（和光純薬工業株式会社製　ＣｏｄｅＮｏ．０１９－０８６３１）／メタノール（和光純薬工業株式会社製　ＣｏｄｅＮｏ．１３８－０６４７３）／ギ酸＝５００／５００／１，グラジエント条件；０→３分：Ａ液９０％、３→１１分：Ａ液２０％→５％、１１→１５分：Ａ液５％、分析時間２０分） [Test Example 6]
Metabolism test using human liver microsome fraction Human liver microsome (Xenotech CatNo. H610) 50 μL of reaction composition solution (NADPH production system solution A (Corning REF.451220) 50 μL, NADPH production DMSO (manufactured by Wako Pure Chemical Industries, Ltd.) was added to a system solution B (Corning REF.451200) 10 μL, 250 mM UDP-glucuronic acid 40 μL, UGT Reaction Mix solution B (Corning REF.451320) 200 μL, distilled water 590 μL. 10 μL (DMSO final concentration 1.0%) of a test compound (prodrug represented by the general formula (V) or (VI)) dissolved in Code No. 043-07216) was added and incubated at 37 ° C. for 5 minutes.
Peak area of the test compound (prodrug represented by the general formula (V) or (VI)) and the produced pharmacologically active alcohol in high performance liquid chromatography (model LC-20A series, manufactured by Shimadzu Corporation) The measurement UV wavelength (245 nm) was calculated.
HPLC conditions; Column: Phenomenex Kinex C18 (Part No. 00D-4462-AN manufactured by Phenomenex), 2.1 mm × 100 mm, 2.6 μm, column temperature 40 ° C., eluent; A solution: 0.1% formic acid (Wako Pure) Yakuhin Kogyo Code No.063-04192),
Liquid B: acetonitrile (Code No. 019-08631 manufactured by Wako Pure Chemical Industries, Ltd.) / Methanol (Code No. 138-06473 manufactured by Wako Pure Chemical Industries, Ltd.) / Formic acid = 500/500/1, gradient condition: 0 → 3 minutes : Solution A 90%, 3 → 11 minutes: Solution A 20% → 5%, 11 → 15 minutes: Solution A 5%, analysis time 20 minutes)
　本試験において、例えば、化合物番号Ｖ－８６は、５分インキュベート後では、生成するアルコール体である化合物番号ＩＶ－１８のピークのみが検出された。 In this test, for example, with Compound No. V-86, only the peak of Compound No. IV-18, which is an alcohol form, was detected after 5 minutes of incubation.
　本試験において、本発明のプロドラッグは、速やかに薬理活性体に変換された。 In this test, the prodrug of the present invention was quickly converted to a pharmacologically active form.
　前記試験例１乃至６の結果より、本発明の化合物は、それ自体が優れたＣＤＫ７阻害活性と高い選択性を有するか、優れたＣＤＫ７阻害活性と高い選択性を有する化合物のプロドラッグとして機能し、例えば、アトピー性皮膚炎の治療薬および／または予防薬として有用といえる。 From the results of Test Examples 1 to 6, the compound of the present invention itself has excellent CDK7 inhibitory activity and high selectivity, or functions as a prodrug of a compound having excellent CDK7 inhibitory activity and high selectivity. For example, it can be said that it is useful as a therapeutic agent and / or preventive agent for atopic dermatitis.
　本発明の一般式（Ｉ）で表される特定の構造を有する新規な置換ジヒドロピロロピラゾール化合物またはその薬理上許容される塩は、それ自体が優れたＣＤＫ７阻害活性を有するか、または、優れたＣＤＫ７阻害活性を有する化合物のプロドラッグとして機能しうるものであり、一般式（Ｉ）で表される化合物またはその薬理上許容される塩を含む医薬組成物は、アトピー性皮膚炎の治療薬および／または予防薬として有用である。 The novel substituted dihydropyrrolopyrazole compound or a pharmacologically acceptable salt thereof having a specific structure represented by the general formula (I) of the present invention itself has an excellent CDK7 inhibitory activity or an excellent A pharmaceutical composition comprising a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof, which can function as a prodrug of a compound having CDK7 inhibitory activity, comprises a therapeutic agent for atopic dermatitis and It is useful as a preventive agent.

Claims (33)

  1. 　一般式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
     ［式中、
    　２つのＲは、それぞれ独立にＣ１－３アルキル基を示す、または、互いに結合してＣ２－５アルキレン基を形成している基を示し、
    　Ｌ２は、単結合、酸素原子、または、－ＮＨ－で表される２価のアミノ基を示し、
    　Ｌ３は、単結合、または、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基を示し、
    　Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ１－４アルキル基を示し、
    　Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示し、
    　Ｒ５は、水素原子、置換されていてもよい直鎖もしくは分岐Ｃ１－１６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示す］
    で表される化合物またはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。     Formula (I):
    Figure JPOXMLDOC01-appb-C000001
     [Where:
    Two R's each independently represent a C 1-3 alkyl group, or a group bonded to each other to form a C 2-5 alkylene group;
    L 2 represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—,
    L 3 represents a single bond or a linear or branched C 1-6 alkylene group which may be substituted,
    R 1 , R 2 and R 3 each independently represents an optionally substituted linear or branched C 1-4 alkyl group;
    R 4 is an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-10 aryl group, or And represents an optionally substituted heterocyclic group,
    R 5 represents a hydrogen atom, an optionally substituted linear or branched C 1-16 alkyl group, an optionally substituted C 3-6 cycloalkyl group, or an optionally substituted C 6-10 aryl group. Or a heterocyclic group which may be substituted]
    A pharmaceutical composition for treating or preventing atopic dermatitis, comprising a compound represented by the formula: or a pharmacologically acceptable salt thereof.
  2. 　一般式（ＩＩ）：
    Figure JPOXMLDOC01-appb-C000002
     ［式中、
    　Ｌ２は、単結合、酸素原子、または、－ＮＨ－で表される２価のアミノ基を示し、
    　Ｌ３は、単結合、または、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基を示し、
    　Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ１－４アルキル基を示し、
    　Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示し、
    　Ｒ５は、水素原子、置換されていてもよい直鎖もしくは分岐Ｃ１－１６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示す］
    で表される化合物またはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。     General formula (II):
    Figure JPOXMLDOC01-appb-C000002
     [Where:
    L 2 represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—,
    L 3 represents a single bond or a linear or branched C 1-6 alkylene group which may be substituted,
    R 1 , R 2 and R 3 each independently represents an optionally substituted linear or branched C 1-4 alkyl group;
    R 4 is an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-10 aryl group, or And represents an optionally substituted heterocyclic group,
    R 5 represents a hydrogen atom, an optionally substituted linear or branched C 1-16 alkyl group, an optionally substituted C 3-6 cycloalkyl group, or an optionally substituted C 6-10 aryl group. Or a heterocyclic group which may be substituted]
    A pharmaceutical composition for treating or preventing atopic dermatitis, comprising a compound represented by the formula: or a pharmacologically acceptable salt thereof.
  3. 　Ｌ２およびＬ３が、単結合を示す、請求項２記載の医薬組成物。 The pharmaceutical composition according to claim 2, wherein L 2 and L 3 represent a single bond.
  4. 　Ｌ２が、－ＮＨ－で表される２価のアミノ基を示し、Ｌ３が、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基を示す、請求項２記載の医薬組成物。 L 2 is a divalent group represented by -NH-, L 3 indicates a straight chain may be substituted or branched C 1-6 alkylene group, a pharmaceutical composition according to claim 2, wherein .
  5. 　一般式（ＩＩＩ）：
    Figure JPOXMLDOC01-appb-C000003
     ［式中、
    　Ｌ２は、単結合、酸素原子、または、－ＮＨ－で表される２価のアミノ基を示し、
    　Ｌ３は、単結合、または、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基を示し、
    　Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ１－４アルキル基を示し、
    　Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示し、
    　Ｒ５は、水素原子、置換されていてもよい直鎖もしくは分岐Ｃ１－１６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示す］
    で表される化合物またはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。     General formula (III):
    Figure JPOXMLDOC01-appb-C000003
     [Where:
    L 2 represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—,
    L 3 represents a single bond or a linear or branched C 1-6 alkylene group which may be substituted,
    R 1 , R 2 and R 3 each independently represents an optionally substituted linear or branched C 1-4 alkyl group;
    R 4 is an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-10 aryl group, or And represents an optionally substituted heterocyclic group,
    R 5 represents a hydrogen atom, an optionally substituted linear or branched C 1-16 alkyl group, an optionally substituted C 3-6 cycloalkyl group, or an optionally substituted C 6-10 aryl group. Or a heterocyclic group which may be substituted]
    A pharmaceutical composition for treating or preventing atopic dermatitis, comprising a compound represented by the formula: or a pharmacologically acceptable salt thereof.
  6. 　Ｌ２およびＬ３が、単結合を示す、請求項５記載の医薬組成物。 The pharmaceutical composition according to claim 5, wherein L 2 and L 3 represent a single bond.
  7. 　Ｌ２が、－ＮＨ－で表される２価のアミノ基を示し、Ｌ３が、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基を示す、請求項５記載の医薬組成物。 L 2 is a divalent group represented by -NH-, L 3 indicates a straight chain may be substituted or branched C 1-6 alkylene group, 5. A pharmaceutical composition according .
  8. 　一般式（ＩＶ）：
    Figure JPOXMLDOC01-appb-C000004
     ［式中、
    　Ｌ２は、単結合、酸素原子、または、－ＮＨ－で表される２価のアミノ基を示し、
    　Ｌ３は、単結合、または、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基を示し、
    　Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ１－４アルキル基を示し、
    　Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示し、
    　Ｒ５は、水素原子、置換されていてもよい直鎖もしくは分岐Ｃ１－１６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示す］
    で表される化合物またはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。     Formula (IV):
    Figure JPOXMLDOC01-appb-C000004
     [Where:
    L 2 represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—,
    L 3 represents a single bond or a linear or branched C 1-6 alkylene group which may be substituted,
    R 1 , R 2 and R 3 each independently represents an optionally substituted linear or branched C 1-4 alkyl group;
    R 4 is an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-10 aryl group, or And represents an optionally substituted heterocyclic group,
    R 5 represents a hydrogen atom, an optionally substituted linear or branched C 1-16 alkyl group, an optionally substituted C 3-6 cycloalkyl group, or an optionally substituted C 6-10 aryl group. Or a heterocyclic group which may be substituted]
    A pharmaceutical composition for treating or preventing atopic dermatitis, comprising a compound represented by the formula: or a pharmacologically acceptable salt thereof.
  9. 　Ｌ２およびＬ３が、単結合を示す、請求項８記載の医薬組成物。 The pharmaceutical composition according to claim 8, wherein L 2 and L 3 represent a single bond.
  10. 　Ｌ２が、－ＮＨ－で表される２価のアミノ基を示し、Ｌ３が、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基を示す、請求項８記載の医薬組成物。 L 2 is a divalent group represented by -NH-, L 3 indicates the optionally substituted straight or branched C 1-6 alkylene group, a pharmaceutical composition according to claim 8 .
  11. 　一般式（Ｖ）もしくは（ＶＩ）：
    Figure JPOXMLDOC01-appb-C000005
     ［式中、
    　２つのＲは、それぞれ独立にＣ１－３アルキル基を示す、または、互いに結合してＣ２－５アルキレン基を形成している基を示し、
    　Ｌ２は、単結合、酸素原子、または、－ＮＨ－で表される２価のアミノ基を示し、
    　Ｌ３は、単結合、または、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基を示し、
    　Ｒ１、Ｒ２およびＲ３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ１－４アルキル基を示し、
    　Ｒ４は、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示し、
    　Ｒ６は、水素原子、置換されていてもよい直鎖もしくは分岐Ｃ１－１６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ１－６アルコキシ基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示し、
    　Ｒ７は、置換されていてもよい直鎖もしくは分岐Ｃ１－１６アルキル基、置換されていてもよいＣ３－６シクロアルキル基、置換されていてもよいＣ６－１０アリール基、または、置換されていてもよい複素環基を示し、
    　Ｒ８およびＲ９は、それぞれ独立に、水素原子またはＣ１－４アルキル基を示す］
    で表される化合物またはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。     Formula (V) or (VI):
    Figure JPOXMLDOC01-appb-C000005
     [Where:
    Two R's each independently represent a C 1-3 alkyl group, or a group bonded to each other to form a C 2-5 alkylene group;
    L 2 represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—,
    L 3 represents a single bond or a linear or branched C 1-6 alkylene group which may be substituted,
    R 1 , R 2 and R 3 each independently represents an optionally substituted linear or branched C 1-4 alkyl group;
    R 4 is an optionally substituted linear or branched C 1-6 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-10 aryl group, or And represents an optionally substituted heterocyclic group,
    R 6 is a hydrogen atom, an optionally substituted linear or branched C 1-16 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 1-6 alkoxy group , An optionally substituted C 6-10 aryl group or an optionally substituted heterocyclic group;
    R 7 is an optionally substituted linear or branched C 1-16 alkyl group, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted C 6-10 aryl group, or And represents an optionally substituted heterocyclic group,
    R 8 and R 9 each independently represents a hydrogen atom or a C 1-4 alkyl group]
    A pharmaceutical composition for treating or preventing atopic dermatitis, comprising a compound represented by the formula: or a pharmacologically acceptable salt thereof.
  12. 　Ｌ２が、－ＮＨ－で表される２価のアミノ基を示し、Ｌ３が、置換されていてもよい直鎖もしくは分岐Ｃ１－６アルキレン基を示す、請求項１１記載の医薬組成物。 L 2 is a divalent group represented by -NH-, L 3 indicates a straight chain may be substituted or branched C 1-6 alkylene group, pharmaceutical composition according to claim 11 wherein .
  13. 　（Ｓ）－Ｎ－（２－ヒドロキシ－１－フェニルエチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｓ）－Ｎ－（２－ヒドロキシ－１－フェニルエチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｓ）－Ｎ－（２－ヒドロキシ－１－フェニルエチル）－６，６－ジメチル－３－［２－メチル－２－（トリメチルシリル）プロパンアミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｓ）－３－［１－（エチルジメチルシリル）シクロブタンカルボキサミド］－Ｎ－（２－ヒドロキシ－１－フェニルエチル）－６，６－ジメチル－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｓ）－３－［２－（エチルジメチルシリル）－２－メチルプロパンアミド］－Ｎ－（２－ヒドロキシ－１－フェニルエチル）－６，６－ジメチル－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｓ）－２－［（２－メトキシプロパン－２－イル）オキシ］－１－フェニルエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキシラート、
    （Ｓ）－２－ヒドロキシ－１－フェニルエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキシラート、
    ２－メトキシ－１－フェニルエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキシラート、
    （Ｒ）－Ｎ－（３－ヒドロキシ－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｒ）－Ｎ－（３－ヒドロキシ－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｒ）－Ｎ－（４－ヒドロキシ－１－フェニルブチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｒ）－Ｎ－（５－ヒドロキシ－１－フェニルペンチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｓ）－Ｎ－（２－ヒドロキシ－２－メチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｓ）－Ｎ－（２－ヒドロキシ－２－メチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    Ｎ－（３－ヒドロキシ－２，２－ジメチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｒ）－Ｎ－（３－ヒドロキシ－３－メチル－１－フェニルブチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｓ）－Ｎ－（２－メトキシ－１－フェニルエチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｓ）－Ｎ－［２－（ジフルオロメトキシ）－１－フェニルエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｓ）－Ｎ－（２－エトキシ－１－フェニルエチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｒ）－Ｎ－（３－メトキシ－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４．５．６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニル酢酸ナトリウム、
    Ｎ－［１－（２－フルオロフェニル）－２－ヒドロキシエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｓ）－Ｎ－［１－（３－フルオロフェニル）－２－ヒドロキシエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｓ）－Ｎ－［１－（４－フルオロフェニル）－２－ヒドロキシエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    Ｎ－［２－ヒドロキシ－１－（ピリジン－２－イル）エチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    Ｎ－［２－ヒドロキシ－１－（ピリジン－３－イル）エチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｓ）－Ｎ－（１－シクロヘキシル－２－ヒドロキシエチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｓ）－Ｎ－（１－ヒドロキシ－３－メチルブタン－２－イル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｓ）－Ｎ－（１－ヒドロキシプロパン－２－イル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　アセタート、
    （Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　プロピオナート、
    （Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　ブタノアート、
    （Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　ペンタノアート、
    （Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　オクタノアート、
    （Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　ドデカノアート、
    （Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　パルミタート、
    （Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　イソブタノアート、
    （Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　ピバラート、
    （Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　３－メチルブタノアート、
    （Ｓ）－２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエチル　ベンゾアート、
    （Ｓ）－４－（２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエトキシ）－４－オキソブタン酸ナトリウム、
    （Ｓ）－（２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルエトキシ）メチル　ピバラート、
    （Ｓ）－２－アセトキシ－１－フェニルエチル　６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキシラート、
    （Ｓ）－ベンジル　２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルアセタート、
    （Ｓ）－メチル　２－｛６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－５－カルボキサミド｝－２－フェニルアセタート、
    Ｎ－（２，２－ジフルオロ－３－ヒドロキシ－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｓ）－Ｎ－［１－（２－クロロフェニル）－２－ヒドロキシエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｓ）－Ｎ－［２－ヒドロキシ－１－（ｏ－トリル）エチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｓ）－Ｎ－（１－ヒドロキシ－３－フェニルプロパン－２－イル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    Ｎ－［５－（３－ヒドロキシ－２－フェニルプロパノイル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
    （Ｓ）－Ｎ－［５－（３－ヒドロキシ－２－フェニルプロパノイル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
    （Ｒ）－Ｎ－［５－（２－メトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
    （Ｓ）－Ｎ－［５－（２－メトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
    Ｎ－［５－（３－メトキシ－２－フェニルプロパノイル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
    Ｎ－［５－（４－メトキシ－２－フェニルブタノイル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
    （Ｓ）－Ｎ－［５－（３－ヒドロキシ－２－フェニルプロパノイル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロプロパンカルボキサミド、
    （Ｒ）－Ｎ－［５－（２－メトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロプロパンカルボキサミド、
    （Ｒ）－Ｎ－｛５－［２－（ジフルオロメトキシ）－２－フェニルアセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
    （Ｒ）－Ｎ－［５－（２－エトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
    （Ｒ）－１－（エチルジメチルシリル）－Ｎ－［５－（２－メトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］シクロブタンカルボキサミド、
    （Ｒ）－Ｎ－［５－（２－シクロプロポキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
    （Ｒ）－Ｎ－［５－（２－イソプロポキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
    （Ｒ）－Ｎ－｛６，６－ジメチル－５－［２－フェニル－２－（トリフルオロメトキシ）アセチル］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
    （Ｒ）－Ｎ－［６，６－ジメチル－５－（２－フェニル－２－プロポキシアセチル）－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、
    Ｎ－｛５－［２－（４－フルオロフェニル）－２－メトキシアセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
    Ｎ－｛５－［２－（３－フルオロフェニル）－２－メトキシアセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
    （Ｒ）－Ｎ－｛５－［２－（２－フルオロフェニル）－２－メトキシアセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
    Ｎ－｛５－［２－メトキシ－２－（チオフェン－２－イル）アセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
    （－）－Ｎ－｛５－［２－メトキシ－２－（チオフェン－２－イル）アセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
    （＋）－Ｎ－｛５－［２－メトキシ－２－（チオフェン－２－イル）アセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミド、
    Ｎ－｛［１－（ヒドロキシメチル）シクロブチル］（フェニル）メチル｝－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｒ）－Ｎ－［２－（１－ヒドロキシシクロプロピル）－１－フェニルエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｒ）－Ｎ－（３－エチル－３－ヒドロキシ－１－フェニルペンチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｒ）－Ｎ－［１－（４－フルオロフェニル）－３－ヒドロキシ－３－メチルブチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｒ）－Ｎ－［１－（３－フルオロフェニル）－３－ヒドロキシ－３－メチルブチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｒ）－Ｎ－［１－（２－フルオロフェニル）－３－ヒドロキシ－３－メチルブチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｒ）－Ｎ－（５－ヒドロキシ－２，５－ジメチルヘキサン－３－イル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    Ｎ－［１－（４－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    Ｎ－［１－（３－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （－）－Ｎ－［１－（３－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （＋）－Ｎ－［１－（３－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    Ｎ－［１－（２－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    Ｎ－（１－ヒドロキシ－２，２，４－トリメチルペンタン－３－イル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｒ）－Ｎ－（３－ヒドロキシ－３－メチル－１－フェニルブチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    Ｎ－（３－ヒドロキシ－２，２－ジメチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （－）－Ｎ－（３－ヒドロキシ－２，２－ジメチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （＋）－Ｎ－（３－ヒドロキシ－２，２－ジメチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド、
    （Ｒ）－Ｎ－［５－（２－ブトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミド、および
    Ｎ－（３－メトキシ－２，２－ジメチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミド
    からなる化合物群から選択される化合物またはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。     (S) -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
    (S) -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide,
    (S) -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-3- [2-methyl-2- (trimethylsilyl) propanamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
    (S) -3- [1- (Ethyldimethylsilyl) cyclobutanecarboxamide] -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
    (S) -3- [2- (Ethyldimethylsilyl) -2-methylpropanamide] -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-4,6-dihydropyrrolo [3 4-c] pyrazole-5 (1H) -carboxamide,
    (S) -2-[(2-Methoxypropan-2-yl) oxy] -1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxylate,
    (S) -2-Hydroxy-1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H)- Carboxylate,
    2-methoxy-1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxylate,
    (R) -N- (3-hydroxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
    (R) -N- (3-hydroxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide,
    (R) -N- (4-hydroxy-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
    (R) -N- (5-hydroxy-1-phenylpentyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
    (S) -N- (2-hydroxy-2-methyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
    (S) -N- (2-hydroxy-2-methyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide,
    N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
    (R) -N- (3-hydroxy-3-methyl-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
    (S) -N- (2-methoxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
    (S) -N- [2- (Difluoromethoxy) -1-phenylethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c Pyrazole-5 (1H) -carboxamide,
    (S) —N- (2-Ethoxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
    (R) -N- (3-methoxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
    (S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4.5.6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Sodium phenylacetate,
    N- [1- (2-Fluorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide,
    (S) -N- [1- (3-Fluorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide,
    (S) -N- [1- (4-Fluorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide,
    N- [2-hydroxy-1- (pyridin-2-yl) ethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
    N- [2-hydroxy-1- (pyridin-3-yl) ethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
    (S) -N- (1-cyclohexyl-2-hydroxyethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
    (S) -N- (1-Hydroxy-3-methylbutan-2-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c Pyrazole-5 (1H) -carboxamide,
    (S) -N- (1-hydroxypropan-2-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
    (S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl acetate,
    (S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl propionate,
    (S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl butanoate,
    (S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl pentanoate,
    (S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl octanoate,
    (S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl dodecanoate,
    (S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl palmitate,
    (S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl isobutanoate,
    (S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl pivalate,
    (S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl 3-methylbutanoate,
    (S) -2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl benzoate,
    (S) -4- (2- {6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide } -2-Phenylethoxy) -4-oxobutanoic acid sodium,
    (S)-(2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide}- 2-phenylethoxy) methyl pivalate,
    (S) -2-Acetoxy-1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H)- Carboxylate,
    (S) -Benzyl 2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide}- 2-phenyl acetate,
    (S) -Methyl 2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide}- 2-phenyl acetate,
    N- (2,2-difluoro-3-hydroxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
    (S) —N- [1- (2-chlorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
    (S) -N- [2-hydroxy-1- (o-tolyl) ethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
    (S) -N- (1-hydroxy-3-phenylpropan-2-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
    N- [5- (3-Hydroxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- ( Trimethylsilyl) cyclobutanecarboxamide,
    (S) -N- [5- (3-Hydroxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclobutanecarboxamide,
    (R) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide,
    (S) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide,
    N- [5- (3-Methoxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- ( Trimethylsilyl) cyclobutanecarboxamide,
    N- [5- (4-Methoxy-2-phenylbutanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- ( Trimethylsilyl) cyclobutanecarboxamide,
    (S) -N- [5- (3-Hydroxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclopropanecarboxamide,
    (R) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclopropanecarboxamide,
    (R) -N- {5- [2- (Difluoromethoxy) -2-phenylacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3- Yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
    (R) -N- [5- (2-Ethoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide,
    (R) -1- (Ethyldimethylsilyl) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c ] Pyrazol-3-yl] cyclobutanecarboxamide,
    (R) -N- [5- (2-Cyclopropoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclobutanecarboxamide,
    (R) -N- [5- (2-Isopropoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclobutanecarboxamide,
    (R) -N- {6,6-dimethyl-5- [2-phenyl-2- (trifluoromethoxy) acetyl] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3 -Yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
    (R) -N- [6,6-Dimethyl-5- (2-phenyl-2-propoxyacetyl) -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide,
    N- {5- [2- (4-Fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
    N- {5- [2- (3-Fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
    (R) -N- {5- [2- (2-Fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole- 3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
    N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl } -1- (Trimethylsilyl) cyclobutanecarboxamide,
    (-)-N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole -3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
    (+)-N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole -3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
    N-{[1- (hydroxymethyl) cyclobutyl] (phenyl) methyl} -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide,
    (R) -N- [2- (1-hydroxycyclopropyl) -1-phenylethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 4-c] pyrazole-5 (1H) -carboxamide,
    (R) -N- (3-Ethyl-3-hydroxy-1-phenylpentyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
    (R) -N- [1- (4-Fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [ 3,4-c] pyrazole-5 (1H) -carboxamide,
    (R) -N- [1- (3-Fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [ 3,4-c] pyrazole-5 (1H) -carboxamide,
    (R) -N- [1- (2-Fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [ 3,4-c] pyrazole-5 (1H) -carboxamide,
    (R) -N- (5-hydroxy-2,5-dimethylhexane-3-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 4-c] pyrazole-5 (1H) -carboxamide,
    N- [1- (4-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxamide,
    N- [1- (3-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxamide,
    (−) — N- [1- (3-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- Dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide,
    (+)-N- [1- (3-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- Dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide,
    N- [1- (2-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxamide,
    N- (1-hydroxy-2,2,4-trimethylpentan-3-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] pyrazole-5 (1H) -carboxamide,
    (R) -N- (3-hydroxy-3-methyl-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide,
    N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c Pyrazole-5 (1H) -carboxamide,
    (−) — N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3, 4-c] pyrazole-5 (1H) -carboxamide,
    (+)-N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 4-c] pyrazole-5 (1H) -carboxamide,
    (R) -N- [5- (2-Butoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide and N- (3-methoxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- A pharmaceutical composition for treating or preventing atopic dermatitis, comprising a compound selected from the group consisting of dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof object.
  14. 　（Ｒ）－Ｎ－［１－（４－フルオロフェニル）－３－ヒドロキシ－３－メチルブチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。 (R) -N- [1- (4-Fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [ A pharmaceutical composition for treating or preventing atopic dermatitis, comprising 3,4-c] pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof.
  15. 　（－）－Ｎ－（３－ヒドロキシ－２，２－ジメチル－１－フェニルプロピル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロプロパン－１－カルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。 (-)-N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropane-1-carboxamide] -4,6-dihydro A pharmaceutical composition for treating or preventing atopic dermatitis, comprising pyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof.
  16. 　（Ｒ）－Ｎ－［５－（２－メトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。 (R) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- A pharmaceutical composition for treating or preventing atopic dermatitis, comprising 1- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.
  17. 　（Ｒ）－Ｎ－［６，６－ジメチル－５－（２－フェニル－２－プロポキシアセチル）－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。 (R) -N- [6,6-Dimethyl-5- (2-phenyl-2-propoxyacetyl) -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- A pharmaceutical composition for treating or preventing atopic dermatitis, comprising 1- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.
  18. 　（Ｒ）－Ｎ－｛５－［２－（２－フルオロフェニル）－２－メトキシアセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。 (R) -N- {5- [2- (2-Fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole- A pharmaceutical composition for treating or preventing atopic dermatitis, comprising 3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide or a pharmaceutically acceptable salt thereof.
  19. 　（Ｒ）－Ｎ－［５－（２－エトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。 (R) -N- [5- (2-Ethoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- A pharmaceutical composition for treating or preventing atopic dermatitis, comprising 1- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.
  20. 　（Ｒ）－Ｎ－［５－（２－シクロプロポキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。 (R) -N- [5- (2-Cyclopropoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] A pharmaceutical composition for treating or preventing atopic dermatitis, comprising 1- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.
  21. 　（Ｒ）－Ｎ－［５－（２－イソプロポキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロブタンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。 (R) -N- [5- (2-Isopropoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] A pharmaceutical composition for treating or preventing atopic dermatitis, comprising 1- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.
  22. 　（＋）－Ｎ－｛５－［２－メトキシ－２－（チオフェン－２－イル）アセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。 (+)-N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole A pharmaceutical composition for treating or preventing atopic dermatitis, comprising -3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide or a pharmaceutically acceptable salt thereof.
  23. 　（－）－Ｎ－［１－（３－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。 (−) — N- [1- (3-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- A pharmaceutical composition for treating or preventing atopic dermatitis, comprising dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof.
  24. 　Ｎ－｛５－［２－（３－フルオロフェニル）－２－メトキシアセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。 N- {5- [2- (3-Fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl} A pharmaceutical composition for treating or preventing atopic dermatitis, comprising 1- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.
  25. 　Ｎ－［１－（４－フルオロフェニル）－３－ヒドロキシ－２，２－ジメチルプロピル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。 N- [1- (4-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof, a pharmaceutical composition for treating or preventing atopic dermatitis.
  26. 　（Ｒ）－Ｎ－［１－（３－フルオロフェニル）－３－ヒドロキシ－３－メチルブチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。 (R) -N- [1- (3-Fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [ A pharmaceutical composition for treating or preventing atopic dermatitis, comprising 3,4-c] pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof.
  27. 　（Ｒ）－Ｎ－｛６，６－ジメチル－５－［２－フェニル－２－（トリフルオロメトキシ）アセチル］－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。 (R) -N- {6,6-dimethyl-5- [2-phenyl-2- (trifluoromethoxy) acetyl] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3 -Il} -1- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof, a pharmaceutical composition for treating or preventing atopic dermatitis.
  28. 　（Ｒ）－Ｎ－［２－（１－ヒドロキシシクロプロピル）－１－フェニルエチル］－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。 (R) -N- [2- (1-hydroxycyclopropyl) -1-phenylethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 4-c] A pharmaceutical composition for treating or preventing atopic dermatitis, comprising pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof.
  29. 　（Ｒ）－Ｎ－（３－ヒドロキシ－３－メチル－１－フェニルブチル）－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。 (R) -N- (3-hydroxy-3-methyl-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 c] A pharmaceutical composition for treating or preventing atopic dermatitis, comprising pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof.
  30. 　（Ｒ）－Ｎ－［５－（２－メトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］－１－（トリメチルシリル）シクロプロパンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。 (R) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- A pharmaceutical composition for treating or preventing atopic dermatitis, comprising 1- (trimethylsilyl) cyclopropanecarboxamide or a pharmacologically acceptable salt thereof.
  31. 　（Ｒ）－Ｎ－｛５－［２－（ジフルオロメトキシ）－２－フェニルアセチル］－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル｝－１－（トリメチルシリル）シクロブタンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。 (R) -N- {5- [2- (Difluoromethoxy) -2-phenylacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3- IL} -1- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof, a pharmaceutical composition for treating or preventing atopic dermatitis.
  32. 　（Ｒ）－１－（エチルジメチルシリル）－Ｎ－［５－（２－メトキシ－２－フェニルアセチル）－６，６－ジメチル－１，４，５，６－テトラヒドロピロロ［３，４－ｃ］ピラゾール－３－イル］シクロブタンカルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。 (R) -1- (Ethyldimethylsilyl) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c ] A pharmaceutical composition for treating or preventing atopic dermatitis, comprising pyrazol-3-yl] cyclobutanecarboxamide or a pharmaceutically acceptable salt thereof.
  33. 　Ｎ－｛［１－（ヒドロキシメチル）シクロブチル］（フェニル）メチル｝－６，６－ジメチル－３－［１－（トリメチルシリル）シクロブタンカルボキサミド］－４，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（１Ｈ）－カルボキサミドまたはその薬理上許容される塩を含む、アトピー性皮膚炎を治療または予防するための医薬組成物。 N-{[1- (hydroxymethyl) cyclobutyl] (phenyl) methyl} -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole A pharmaceutical composition for treating or preventing atopic dermatitis, comprising -5 (1H) -carboxamide or a pharmacologically acceptable salt thereof.
PCT/JP2017/016701 2016-04-28 2017-04-27 Pharmaceutical composition for treatment or prevention of atopic dermatitis WO2017188369A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2016091334A JP2019112305A (en) 2016-04-28 2016-04-28 Pharmaceutical composition for treating and/or preventing atopic dermatitis
JP2016-091334 2016-04-28

Publications (1)

Publication Number Publication Date
WO2017188369A1 true WO2017188369A1 (en) 2017-11-02

Family

ID=60159958

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2017/016701 WO2017188369A1 (en) 2016-04-28 2017-04-27 Pharmaceutical composition for treatment or prevention of atopic dermatitis

Country Status (2)

Country Link
JP (1) JP2019112305A (en)
WO (1) WO2017188369A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190256531A1 (en) * 2015-06-15 2019-08-22 Ube Industries, Ltd. Substituted dihydropyrrolopyrazole derivative
WO2020100944A1 (en) 2018-11-14 2020-05-22 宇部興産株式会社 Dihydropyrrolopyrazole derivative

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006514026A (en) * 2002-12-19 2006-04-27 ファルマシア・イタリア・エス・ピー・エー Pyrrolo-pyrazole substituted derivatives as kinase inhibitors
JP2010505905A (en) * 2006-10-11 2010-02-25 ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ Substituted pyrrolo-pyrazole derivatives as kinase inhibitors
US20130084275A1 (en) * 2011-04-26 2013-04-04 Technische Universitat Dresden Methods and Compositions for Reducing Interleukin-4 or Interleukin-13 Signaling
WO2016068287A1 (en) * 2014-10-31 2016-05-06 宇部興産株式会社 Substituted dihydropyrrolopyrazole compound

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006514026A (en) * 2002-12-19 2006-04-27 ファルマシア・イタリア・エス・ピー・エー Pyrrolo-pyrazole substituted derivatives as kinase inhibitors
JP2010505905A (en) * 2006-10-11 2010-02-25 ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ Substituted pyrrolo-pyrazole derivatives as kinase inhibitors
US20130084275A1 (en) * 2011-04-26 2013-04-04 Technische Universitat Dresden Methods and Compositions for Reducing Interleukin-4 or Interleukin-13 Signaling
WO2016068287A1 (en) * 2014-10-31 2016-05-06 宇部興産株式会社 Substituted dihydropyrrolopyrazole compound

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190256531A1 (en) * 2015-06-15 2019-08-22 Ube Industries, Ltd. Substituted dihydropyrrolopyrazole derivative
US10894798B2 (en) * 2015-06-15 2021-01-19 Ube Industries, Ltd. Substituted dihydropyrrolopyrazole derivative
WO2020100944A1 (en) 2018-11-14 2020-05-22 宇部興産株式会社 Dihydropyrrolopyrazole derivative

Also Published As

Publication number Publication date
JP2019112305A (en) 2019-07-11

Similar Documents

Publication Publication Date Title
JP6690543B2 (en) Substituted dihydropyrrolopyrazole compound
WO2017188357A1 (en) Substituted dihydropyrrolopyrazole compound, and pharmaceutical composition for dosing in combination with other psoriasis treatment drug
ES2461967T3 (en) Pyrrolo [2,3-d] pyrimidine compounds
EP3733673B1 (en) Oxy-fluoropiperidine derivative as kinase inhibitor
KR102588426B1 (en) Substituted dihydropyrrolopyrazole derivatives
US10975068B2 (en) 6-aminopyridin-3-yl thiazoles as modulators of RORγT
EP3939979A1 (en) Jak kinase inhibitor, preparation method for same, and applications thereof in field of medicine
EP4032890A1 (en) Heterocyclic amide compound, pharmaceutically acceptable salt thereof, and preparation method therefor and use thereof
JP2023508772A (en) JAK inhibitor compounds and uses thereof
WO2017188369A1 (en) Pharmaceutical composition for treatment or prevention of atopic dermatitis
WO2017188358A1 (en) Pharmaceutical composition for treatment or prevention of chronic obstructive pulmonary disease
WO2019235553A1 (en) Azetidine derivative, and prodrug thereof
WO2020100944A1 (en) Dihydropyrrolopyrazole derivative
US20220274983A1 (en) Jak kinase inhibitor and use thereof
RU2712269C2 (en) Pyrrolo[2,3-d]pyrimidine compound or salt thereof
US11780843B2 (en) Compounds active towards nuclear receptors
US11613532B2 (en) Compounds active towards nuclear receptors
EP3932923B1 (en) Pyrazolopyrimidine compound, pharmaceutical composition, and application therefor
JP2020186182A (en) Proteolysis targeting compound
BR112017026994B1 (en) COMPOUND, AND, PHARMACEUTICAL COMPOSITION.
BR112018001695B1 (en) PYRROLO[2,3-d]PYRIMIDINE COMPOUND, JAK3 INHIBITOR, PHARMACEUTICAL COMPOSITION, AGENT, USES OF SAID COMPOUND AND METHOD FOR PRODUCING THE SAME

Legal Events

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

Ref country code: DE

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

Ref document number: 17789651

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 17789651

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP