HK1202540B

HK1202540B - Heteroaromatic methyl cyclic amine derivative

Info

Publication number: HK1202540B
Application number: HK15103061.1A
Authority: HK
Inventors: Aya Futamura; Yuko Araki; Masahito Abe; Hiroshi Ohta; Ryo Suzuki; Dai Nozawa
Original assignee: 大正制药株式会社
Priority date: 2012-06-15
Filing date: 2013-06-13
Publication date: 2018-02-02

Description

Heteroaromatic methyl cyclic amine derivatives

Technical Field

The present invention relates to a compound having Orexin (OX) receptor antagonistic activity and a pharmaceutically acceptable salt thereof, and a therapeutic or prophylactic agent for diseases such as sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, alzheimer's disease, parkinson's disease, huntington's chorea, eating disorder, headache, migraine, pain, gastrointestinal disease, epilepsy, inflammation, immunological disease, endocrine disease or hypertension, which contains such a compound or salt as an active ingredient.

Background

Orexin (Orexin) is a neuropeptide that is cleaved by Orexin precursors (prepro-Orexin) and is specifically expressed in the lateral hypothalamic region. To date, OX-A consisting of 33 amino acids and OX-B consisting of 28 amino acids have been identified, both of which are involved in regulating sleep-wake patterns and regulating food intake.

Both OX-A and OX-B act on OX receptors. To date, two subtypes of the OX receptor have been cloned, the OX1 and OX2 receptors, both of which are known to be seven transmembrane G-protein coupled receptors expressed primarily in the brain. The OX1 receptor is specifically coupled to Gq in a G protein subclass, while the OX2 receptor is coupled to Gq and Gi/o (see non-patent document 1 and non-patent document 2). The Ox receptor subtype is selectively expressed in the brain, and the Ox1 receptor is expressed at high density in the locus coeruleus, which is the initiation of noradrenergic neurons, while the Ox2 receptor is expressed at high density in the nuclei of papillary, which is the initiation of histaminergic neurons (see non-patent document 3, non-patent document 4, and non-patent document 5). The expression of OX1 receptor and OX2 receptor is found in the nucleus of the midgut, which is the initiation of serotonergic neurons, and in the ventral tegmental area, which is the initiation of dopaminergic neurons (see non-patent document 3). Orexin neurons project to the monoaminergic neuronal system of the brain stem and hypothalamus and have an excitatory effect on these neurons, and in addition, the expression of OX2 receptor is also found in the cholinergic neurons of the brain stem responsible for the regulation of REM sleep and have an effect on the nuclear activity thereof (see non-patent document 3 and non-patent document 4).

In recent years, OX1 and OX2 receptors have focused on the effects of sleep-wake modulation, and the usefulness of OX receptor antagonists has been investigated. When OX-a is intracerebroventricularly administered to rats, an increase in spontaneous motor activity (see non-patent document 6 and non-patent document 7), an increase in stereotypical behavior (see non-patent document 7), an increase in wake-up time (see non-patent document 6), and the like are observed. REM sleep reduction resulting from OX-a administration is completely antagonized by pretreatment with an OX receptor antagonist (see non-patent document 8). In addition, it has been reported that by administering orally available OX1 and OX2 receptor antagonists, the motor activity can be reduced, the sleep latency can be shortened, and the amount of non-REM sleep and REM sleep can be increased (see non-patent document 9 and non-patent document 10).

Patent document 1 discloses a heteroaromatic ring derivative as a compound having an OX receptor antagonistic activity, but does not disclose a compound having a heteroaromatic (heteroaromatic) methylcycloamine skeleton as described in the present application. In addition, for example, compounds having various structures described in non-patent document 11 are generally referred to as OX receptor antagonists, but compounds having heteroaromatic methylcycloamine skeletons described in the present application are not disclosed.

Reference list

Patent document

Patent document 1: WO2003/002559

Non-patent document

Non-patent document 1: zhu Y et al, j. pharmacol. sci., 92, 259-266, 2003.

Non-patent document 2: zeitzer JM et al, Trends Pharmacol. Sci., 27, 368-charge 374, 2006.

Non-patent document 3: marcus JN et al, J.Comp.neurol, 435, 6-25, 2001.

Non-patent document 4: trivedi JP et al, FEBS Lett, 438, 71-75, 1998.

Non-patent document 5: yamanaka A et al, biochem. Biophys. Res. Commun., 290, 1237-.

Non-patent document 6: hagan JJ et al, Proc. Natl. Acad. Sci. USA, 96, 10911-.

Non-patent document 7: nakamura T et al, Brain Res., 873, 181-.

Non-patent document 8: smith MI et al, neurosci. Lett., 341, 256-one 258, 2003.

Non-patent document 9: Brisbare-Roch C et al, nat. Med., 13, 150-.

Non-patent document 10: cox CD et al, j.med.chem., 53, 5320-.

Non-patent document 11: john G et al, ChemMedChem., 5, 1197-.

Summary of The Invention

Technical problem

It is an object of the present invention to find a novel compound having an OX receptor antagonistic activity and to provide a therapeutic or prophylactic agent for diseases such as sleep disorders, depression, anxiety disorders, panic disorders, schizophrenia, drug dependence, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, headache, migraine, pain, gastrointestinal diseases, epilepsy, inflammation, immunological diseases, endocrine diseases or hypertension. More specifically, it is an object of the present invention to provide novel compounds that exhibit good pharmacokinetics and safety as well as good OX receptor antagonistic activity.

Means for solving the problems

The present inventors have conducted extensive studies on novel skeleton compounds having orexin receptor antagonistic activity and found that certain heteroaromatic methylcycloamine derivatives represented by the following formula have good OX receptor antagonistic activity, thereby completing the present invention.

Hereinafter, the present invention is described in detail. Aspects of the present invention (hereinafter referred to as "the present compounds") are as follows.

(1) A compound represented by formula (IA):

[ formula 1]

Wherein the content of the first and second substances,

X¹and X²Identical or different and represents a nitrogen atom or formula CH;

y represents any one of the structures of the following formula (a):

[ formula 2]

n represents 1 or 2;

R¹represents a hydrogen atom, a halogen atom or C_1-6An alkyl group;

R²represents triazolyl, pyridyl or pyrimidinyl;

R³represents a hydrogen atom, a halogen atom or C_1-6Alkyl radical, wherein C_1-6Alkyl groups may be optionally substituted with 1 to 3 halogen atoms; and

R⁴represents a hydrogen atom or C_1-6An alkyl group;

or a pharmaceutically acceptable salt thereof.

(2) A compound according to (1) or a pharmaceutically acceptable salt thereof, wherein, in the above formula (IA),

R²is triazolyl or pyrimidinyl; and

R³is a halogen atom.

(3) The compound according to (1) or (2) or a pharmaceutically acceptable salt thereof, wherein, in the above formula (IA), n is 2.

(4) A compound represented by formula (I):

[ formula 3]

Wherein the content of the first and second substances,

X¹and X²Identical or different and represents a nitrogen atom or formula CH;

Y¹and Y²Either represents a nitrogen atom and the other represents CH;

n represents 1 or 2;

R¹represents a hydrogen atom, a halogen atom or C_1-6An alkyl group;

R²represents triazolyl, pyridyl or pyrimidinyl;

R⁴represents a hydrogen atom or C_1-6An alkyl group;

or a pharmaceutically acceptable salt thereof.

(5) The compound according to (4) or a pharmaceutically acceptable salt thereof, wherein, in the above formula (I),

R²is triazolyl or pyrimidinyl; and

R³is a halogen atom.

(6) The compound according to (4) or (5) wherein, in the above formula (I), n is 2, or a pharmaceutically acceptable salt thereof.

(7) A compound according to (1), or a pharmaceutically acceptable salt thereof, which is one compound, or a mixture of two or more compounds, selected from:

(-) - (2- { [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazolidin-3-yl) [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone,

(-) - (2- { [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazolidin-3-yl) [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone,

(-) - (2- { [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazinan-3-yl) [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone,

(-) - (2- { [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazinan-3-yl) [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone,

(-) - [ (2S,5S) -2- { [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -5-methyl-1, 3-oxazolidin-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone,

(-) - [ (2S,5R) -2- { [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -5-methyl-1, 3-oxazolidin-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone,

[ (2S,4R) -2- { [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -4-methyl-1, 3-oxazolidin-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone,

(-) - [ (2S,4S) -2- { [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -4-methyl-1, 3-oxazolidin-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone,

(±) -2- { [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazolidin-3-yl ] [ 5-methyl-2- (pyrimidin-2-yl) phenyl ] methanone,

(±) - (2- { [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazolidin-3-yl) [ 5-fluoro-2- (pyrimidin-2-yl) phenyl ] methanone,

(±) - (2- { [3- (4-fluorophenyl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazolidin-3-yl) [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone,

(±) - (2- { [4- (4-fluorophenyl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazolidin-3-yl) [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone,

(±) - (2- { [4- (4-fluorophenyl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazolidin-3-yl) [ 5-methyl-2- (pyrimidin-2-yl) phenyl ] methanone,

(-) - (2- { [3- (4-fluorophenyl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazolidin-3-yl) [ 6-methyl-3- (2H-1,2, 3-triazol-2-yl) pyridin-2-yl ] methanone,

(-) - (2- { [3- (4-fluorophenyl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazinan-3-yl) [ 6-methyl-3- (2H-1,2, 3-triazol-2-yl) pyridin-2-yl ] methanone,

(-) - (2- { [3- (4-fluorophenyl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazinan-3-yl) [ 6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl ] methanone,

(-) - (2- { [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazinan-3-yl) [ 5-fluoro-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone,

(-) - (2- { [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazinan-3-yl) [ 5-methyl-2- (pyrimidin-2-yl) phenyl ] methanone,

(-) - (2- { [4- (4-fluorophenyl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazinan-3-yl) [ 6-methyl-3- (2H-1,2, 3-triazol-2-yl) pyridin-2-yl ] methanone,

(-) - (2- { [4- (4-fluorophenyl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazinan-3-yl) [ 6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl ] methanone,

(-) - [2- { [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazinan-3-yl ] [ 5-fluoro-2- (pyrimidin-2-yl) phenyl ] methanone,

(-) - [2- { [4- (4-fluorophenyl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazinan-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone,

(-) - [2- { [5- (5-fluoropyridin-2-yl) -1,2, 4-oxadiazol-3-yl ] methyl } -1, 3-oxazinan-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone,

(-) - [2- { [5- (4-fluorophenyl) -1,2, 4-oxadiazol-3-yl ] methyl } -1, 3-oxazinan-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone,

(-) - [2- { [5- (4-fluorophenyl) -1,2, 4-oxadiazol-3-yl ] methyl } -1, 3-oxazinan-3-yl ] [ 6-methyl-3- (2H-1,2, 3-triazol-2-yl) pyridin-2-yl ] methanone,

[ (2S,4S) -2- { [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -4-methyl-1, 3-oxazinan-3-yl } [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone,

(-) - [ (2S,5S) -2- { [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -5-methyl-1, 3-oxazinan-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone,

(-) - [2- { [3- (4-fluorophenyl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazinan-3-yl ] [ 5-methyl-2- (pyrimidin-2-yl) phenyl ] methanone,

(±) - [2- { [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl ] methyl } -1, 3-oxazinan-3-yl ] [ 5-methyl-2- (pyrimidin-2-yl) phenyl ] methanone,

(-) - [2- { [4- (4-fluorophenyl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazinan-3-yl ] [ 5-methyl-2- (pyrimidin-2-yl) phenyl ] methanone,

(-) - [2- { [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl ] methyl } -1, 3-oxazinan-3-yl ] [ 5-fluoro-2- (pyrimidin-2-yl) phenyl ] methanone,

(-) - [2- { [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl ] methyl } -1, 3-oxazolidin-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone,

(-) - [2- { [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl ] methyl } -1, 3-oxazolidin-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone,

(-) - [2- { [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl ] methyl } -1, 3-oxazinan-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone,

and

(-) - [ (2S,5R) -2- { [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -5-methyl-1, 3-oxazinan-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone.

(8) A pharmaceutical composition containing the compound according to any one of the above (1) to (7) or a pharmaceutically acceptable salt thereof as an active ingredient.

(9) A therapeutic or prophylactic agent for a disease such as sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, alzheimer's disease, parkinson's disease, huntington's chorea, eating disorder, headache, migraine, pain, gastrointestinal disease, epilepsy, inflammation, immunological disease, endocrine disease or hypertension, which comprises the compound according to any one of the above (1) to (7) or a pharmaceutically acceptable salt thereof as an active ingredient.

Advantageous effects of the invention

It has been revealed that the heteroaromatic methylcycloamine derivatives of the present invention show affinity for OX receptor and antagonistic activity against receptor stimulation by physiological ligands.

Description of the embodiments

The meanings of the terms used in the present specification are as follows.

"halogen atom" means fluorine atom, chlorine atom, bromine atom and iodine atom.

“C_1-6Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms and examples include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutylA group of the sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, n-hexyl, isohexyl and neohexyl.

"sleep disorder" as used in this specification refers to a condition of disturbed sleep, phase or arousal, including insomnia. In addition, the classification of insomnia includes sleep disorders, sleep arousals, morning awakenings, and deep sleep disorders.

The "pharmaceutically acceptable salt" used in the present specification means a pharmaceutically acceptable acid addition salt and examples of the acid used include salts with inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid and nitric acid; and salts with organic acids such as acetic acid, benzoic acid, oxalic acid, lactic acid, malic acid, tartaric acid, fumaric acid, maleic acid, citric acid, malonic acid, mandelic acid, gluconic acid, galactaric acid, glucoheptonic acid, glycolic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, and naphthalene-2-sulfonic acid. The conversion of the free compound into the above-mentioned salt can be carried out by a conventional method.

Preferred embodiments of the compounds of the present invention are described below.

Wherein R is¹Is a halogen atom or C_1-6Alkyl compounds are preferred, wherein R¹Those which are fluorine atoms or methyl groups are more preferred, and wherein R¹Those which are methyl are further preferred.

Wherein R is²Compounds which are triazolyl or pyrimidinyl are preferred, wherein R is²Those which are 1,2, 3-triazol-2-yl or pyrimidin-2-yl are more preferred.

Wherein R is³Compounds which are halogen atoms are preferred, in which R³Those which are fluorine atoms or chlorine atoms are more preferred, and wherein R³Those which are fluorine atoms are further preferred.

Wherein R is⁴Compounds which are hydrogen atoms or methyl groups are preferred.

Compounds in which n is 2 are preferred.

In addition, when the compounds of the present invention form hydrates or solvates, they are also included in the scope of the present invention. Similarly, pharmaceutically acceptable salts of hydrates or solvates of the compounds of the invention are also included within the scope of the invention.

The compounds of the present invention include all enantiomers, diastereomers, equilibrium compounds, mixtures thereof in any proportion, racemic compounds, and the like.

The compounds according to the invention also include those in which at least one of the hydrogen atom, carbon atom, nitrogen atom, oxygen atom and halogen atom is replaced by a radioisotope or a stable isotope. These labeled compounds are useful for metabolic and pharmacokinetic studies, bioanalysis, etc., as receptor ligands, etc.

The compounds according to the invention can be administered orally or parenterally. The dosage form thereof may be a tablet, a capsule, a granule, a powder, a troche (troche), an ointment, a cream, a paste (plaster), an emulsion, a suspension, a suppository, an injection, etc., and any of them may be prepared by a conventional pharmaceutical preparation technique (for example, a method prescribed in japanese pharmacopoeia 15 th edition, etc.). These dosage forms can be appropriately selected according to the symptoms, age, weight and therapeutic purpose of the patient.

These pharmaceutical preparations can be prepared by adding pharmacologically acceptable carriers, more specifically, excipients (e.g., microcrystalline cellulose, starch, lactose, mannitol), binders (e.g., hydroxypropyl cellulose, polyvinylpyrrolidone), lubricants (e.g., magnesium stearate, talc), disintegrants (e.g., carboxymethylcellulose calcium), and other pharmacologically acceptable various additives to the composition containing the compound of the present invention.

The compounds of the invention may be administered orally or parenterally to adult patients once or several times daily in a single dose of 0.001 to 500 mg. In addition, the dose can be appropriately increased or decreased depending on the type of disease to be treated, age, body weight, symptoms, and the like of the patient.

Typical preparation processes for the compounds (I) of the present invention are shown in schemes A and B below.

The following methods are examples of methods for preparing the compounds of the present invention, and the present invention is not limited thereto. Further, in the examples of the following preparation methods, unless the reaction is affected, the compound may form a salt.

Scheme A

[ formula 4]

Wherein X¹、X²、Y¹、Y²、R¹、R²、R³And R⁴As defined above. A. the¹Represents a halogen atom, a methanesulfonyloxy group (methylsulfonyloxy group), a p-toluenesulfonyloxy group (p-tolylsulfonyloxy group) or a trifluoromethanesulfonyloxy group (trifluoromethanesulfonyloxy group). n is 1 or 2.

Step A-1: the compound (3) can be obtained by a condensation reaction of ethyl glyoxylate (1) and an amine compound (2). The reaction in step A-1 may be carried out under conditions in which a base is reacted with an amine compound or its hydrochloride in a solvent in the presence or absence of a dehydrating agent such as molecular sieve or anhydrous copper sulfate. Examples of the base used in the present reaction include organic amines such as pyridine, triethylamine and diisopropylethylamine, inorganic bases such as sodium hydroxide, potassium hydroxide and sodium hydrogencarbonate, and acetates such as sodium acetate and potassium acetate. Examples of the solvent used in the present reaction include ether solvents such as tetrahydrofuran and 1, 4-dioxane, aprotic polar solvents such as N, N-dimethylformamide and acetonitrile, halogen solvents such as dichloromethane and chloroform, aromatic hydrocarbon solvents such as toluene, ethyl acetate and mixed solvents thereof. The reaction can be carried out at from 0 ℃ to 100 ℃.

Step A-2: the compound (5) can be obtained by a condensation reaction of the compound (3) and the carboxylic acid (4). The reaction in step A-2 can be carried out by a general amidation method of a carboxylic acid. Examples include a method in which a carboxylic acid is converted into a carboxylic acid halide such as carboxylic acid chloride or carboxylic acid bromide and then reacted with (3), and a method in which a carboxylic acid is reacted with (3) in the presence of a dehydration condensation agent. These reactions can be carried out in a solvent in the presence or absence of a base. Examples of the halogenating agent used in the present reaction may include thionyl chloride, oxalyl chloride, phosphorus oxychloride or phosphorus oxybromide. In addition, examples of the dehydration condensing agent used in the present reaction include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC-HCl), [ O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate ] (HATU), propane phosphonic anhydride, dicyclohexylcarbodiimide (DDC), diphenylphosphoryl azide (DPPA), and Carbonyldiimidazole (CDI), and an activating agent such as 1-hydroxybenzotriazole or hydroxysuccinimide may be used as necessary. Examples of the solvent used in the present reaction include ether solvents such as tetrahydrofuran and 1, 4-dioxane, aprotic polar solvents such as N, N-dimethylformamide and acetonitrile, halogen solvents such as dichloromethane and chloroform, aromatic hydrocarbon solvents such as toluene, ethyl acetate or mixed solvents thereof. Examples of the base used in the present reaction include organic amines such as pyridine, triethylamine and diisopropylethylamine and inorganic bases such as potassium carbonate, sodium carbonate and sodium hydrogencarbonate. The reaction can be carried out at from 0 ℃ to 150 ℃ in general, preferably from 0 ℃ to 80 ℃.

Step A-3: the compound (6) can be obtained by reduction of an ester of the compound (5). The reaction in step a-3 may be carried out under conditions in which compound (5) is reacted with a reducing agent such as lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride or lithium borohydride in an alcohol solvent such as methanol or ethanol, an ether solvent such as tetrahydrofuran or 1, 4-dioxane, an aromatic hydrocarbon solvent such as toluene or a mixed solvent thereof. The reaction can be carried out at-80 ℃ to 150 ℃, preferably 0 ℃ to 25 ℃.

Step A-4: the compound (7) can be obtained by converting the hydroxyl group of the compound (6) into a general leaving group. Examples of the reaction in step A-4 include chlorination, bromination, iodination, mesylation (methansulfonylation), and tosylation (p-tolenesulxylation). Examples of the chlorination reaction include a method in which a leaving group is obtained using, for example, methanesulfonyl chloride or the like, followed by substitution with a chlorine atom. Further included are methods using carbon tetrachloride and triphenylphosphine and methods using thionyl chloride or phosphorus oxychloride. During these procedures, a chloride such as sodium chloride or potassium chloride may be added. Examples of the bromination reaction include a method in which carbon tetrabromide and triphenylphosphine are used, for example. Examples of the iodination reaction include methods in which iodine, triphenylphosphine, and imidazole are used, for example. Mesyloxy and p-toluenesulfonyloxy can be achieved using, for example, methanesulfonyl chloride, p-toluenesulfonyl chloride, and the like, respectively. During these reactions, a suitable base may be added. Examples of the base to be added include organic bases such as triethylamine and diisopropylethylamine or inorganic bases such as potassium carbonate. Examples of the reaction solvent include ether solvents such as tetrahydrofuran and 1, 4-dioxane, aprotic polar solvents such as N, N-dimethylformamide and acetonitrile, halogen solvents such as dichloromethane and chloroform, acetonitrile or mixed solvents thereof, and wherein the reaction may be carried out under temperature conditions of about-80 ℃ to about the boiling point of such solvents.

Step A-5: compound (9) can be obtained by the reaction of compound (7) with compound (8). The reaction in step a-5 is carried out in an alcohol solvent such as methanol and ethanol, an ether solvent such as tetrahydrofuran and 1, 4-dioxane, an aprotic polar solvent such as N, N-dimethylformamide and acetonitrile, a halogen solvent such as dichloromethane and chloroform, dimethylsulfoxide, acetonitrile, water or a mixed solvent thereof, in the presence of an inorganic base such as sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate, an alkali metal such as sodium ethoxide or potassium tert-butoxide, or an organic base such as a lower alkoxide of an alkaline earth metal, at a temperature of about-80 ℃ to about the boiling point of such a solvent.

Scheme B

[ formula 5]

Wherein X¹、X²、Y¹、Y²、R¹、R²、R³And R⁴As defined above. R⁵And R⁶Represents an alkoxy group, and A²Represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group.

Step B-1: compound (12) can be obtained by reacting compound (10) with compound (11). The reaction in step B-1 can be carried out under the same reaction conditions as in step A-5.

Step B-2: compound (13) can be obtained from compound (12). The reaction in step B-2 may be carried out under conditions in which compound (12) is reacted with an acid such as hydrochloric acid, trifluoroacetic acid or p-toluenesulfonic acid in an aqueous alcoholic solvent such as aqueous methanol or aqueous ethanol, an ether solvent such as tetrahydrofuran or 1, 4-dioxane, a halogen solvent such as dichloromethane or chloroform, a ketone solvent such as acetone, water or a mixed solvent thereof. The reaction can be carried out at from 0 ℃ to 80 ℃.

Step B-3: the compound (15) can be obtained by a condensation reaction of the compound (13) and the compound (14). The reaction in step B-3 can be carried out under the same reaction conditions as in step A-1.

Step B-4: the compound (16) can be obtained by a condensation reaction of the compound (4) and the compound (15). The reaction in step B-4 can be carried out under the same reaction conditions as in step A-2.

Scheme C

[ formula 6]

Wherein X¹、X²、R¹、R²、R³And R⁴As defined above. R⁵And R⁶Represents an alkoxy group.

Step C-1: compound (19) can be obtained by an amidoximation reaction of compound (17). The reaction in step C-1 may be carried out under conditions in which the nitrile compound (17) is reacted with hydroxylamine (18) or its hydrochloride in an alcohol solvent such as methanol or ethanol. The reaction can be carried out at from 0 ℃ to 100 ℃.

Step C-2: compound (21) can be obtained by an oxadiazole cyclization reaction of compound (19) and compound (20). The reaction in step C-2 may be carried out under conditions in which compound (19) is reacted with carboxylic acid (20) and a dehydration condensation agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC-HCl), dicyclohexylcarbodiimide (DDC), Carbonyldiimidazole (CDI) in an ether solvent such as tetrahydrofuran or 1, 4-dioxane, an aprotic polar solvent such as N, N-dimethylformamide, a halogen solvent such as dichloromethane or chloroform, an aromatic hydrocarbon solvent such as toluene, ethyl acetate, acetonitrile or a mixed solvent thereof.

The reaction is generally carried out at from 0 ℃ to 150 ℃, preferably from 0 ℃ to 90 ℃.

Step C-3: compound (22) can be obtained by acid hydrolysis of compound (21). The reaction in step C-3 may be carried out under the same reaction conditions as in step B-2.

Step C-4: compound (23) can be obtained by a condensation reaction of compound (14) and compound (22). The reaction in step C-4 can be carried out under the same reaction conditions as in step A-1.

Step C-5: the compound (24) can be obtained by a condensation reaction of the compound (4) and the compound (23). The reaction in step C-5 can be carried out under the same reaction conditions as in step A-2.

Scheme D

[ formula 7]

Wherein X¹、X²、R¹、R³And R⁴As defined above. R⁸Represents a triazolyl group, a pyridyl group or a halogen atom, and A³Represents a halogen atom.

Step D-1: compound (27) can be obtained by a nucleophilic reaction or a coupling reaction of compound (25) and compound (26). The reaction in step D-1 may be carried out under the same nucleophilic reaction conditions as in step A-5. The coupling reaction can be carried out by a general method in which the nitrogen atom of the azole compound is substituted with an aromatic ring in the presence of a base using a catalyst and a ligand. Examples include the methods described in Synlett, 2003, 15, 2428 and 2439 or methods according thereto. Examples of the catalyst used in the present reaction include copper catalysts such as copper (O), copper (I) iodide, copper (I) chloride and copper (I) oxide. Examples of the ligand used in this reaction include N, N '-dimethylethylenediamine, N' -dimethylcyclohexane-1, 2-diamine, 2-aminopyridine, 1, 10-phenanthroline, and 2-hydroxybenzaldehyde oxime. Examples of the base used in this reaction include potassium carbonate, potassium phosphate, potassium hydroxide, potassium tert-butoxide, cesium carbonate, sodium hydrogencarbonate, sodium acetate, sodium methoxide and tetrabutylammonium hydroxide. Examples of the solvent used in the present reaction include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and 1, 4-dioxane, aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and acetonitrile, halogen solvents such as dichloromethane and chloroform, aromatic hydrocarbon solvents such as toluene, water or a mixed solvent thereof. The reaction can be carried out generally at from 0 ℃ to 150 ℃, preferably from 25 ℃ to 100 ℃.

Step D-2: compound (28) can be obtained by oxidation reaction of the hydroxyl group of compound (27). The reaction in step D-2 may be carried out under conditions in which compound (27) is reacted with a higher valent iodine compound such as dess-martin reagent or 2-iodoxybenzoic acid, a chromate such as pyridinium chlorochromate or pyridinium dichromate, or an oxidant such as ammonium tetrapropylperruthenate or manganese dioxide in a halogen solvent such as dichloromethane or chloroform, or an aprotic polar solvent such as dimethyl sulfoxide or acetonitrile. The reaction can be carried out at from 0 ℃ to 150 ℃, preferably from 25 ℃ to 80 ℃.

Step D-3: compound (29) can be obtained by a condensation reaction of compound (14) and compound (28). The reaction in step D-3 can be carried out under the same reaction conditions as in step A-1.

Step D-4: compound (31) can be obtained by a condensation reaction of compound (29) and compound (30). The reaction in step D-4 can be carried out under the same reaction conditions as in step A-2.

Step D-5: compound (33) can be obtained by a coupling reaction of compound (31) and compound (32). The reaction in step D-5 can be obtained under the conditions of a Stille coupling reaction using an organotin compound in an aprotic polar solvent such as N, N-dimethylformamide, an aromatic hydrocarbon solvent such as toluene or a mixed solvent thereof. A comprehensive overview of the Stille coupling reaction can be found, for example, in angelw. chem. int. ed., 43, 4704, (2004).

Scheme E

[ formula 8]

Wherein X¹、X²、R¹、R²、R³、R⁴And A³As defined above. R⁷Represent common protecting Groups for carboxylic acids, e.g. Groups described in Protective Groups in Organic Chemistry, by J.F.W.McOmie and in Protective Groups in Organic Synthesis, by T.W.Greene and P.G.M.Wuts, and for example represent C_1-6Alkyl and benzyl.

Step E-1: compound (34) can be obtained by a nucleophilic reaction or a coupling reaction of compound (26) and compound (33). The reaction in step E-1 may be carried out under the same reaction conditions as in step D-1.

Step E-2: compound (35) can be obtained by reduction of an ester of compound (34). The reaction in step E-2 may be carried out under conditions in which compound (34) is reacted with a reducing agent such as lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride or lithium borohydride in an alcohol solvent such as methanol or ethanol, an ether solvent such as tetrahydrofuran or 1, 4-dioxane, an aromatic hydrocarbon solvent such as toluene or a mixed solvent thereof. The reaction can be carried out at-80 ℃ to 150 ℃, preferably 0 ℃ to 25 ℃.

Step E-3: compound (36) can be obtained by oxidation reaction of the hydroxyl group of compound (35). The reaction in step E-3 may be carried out under the same reaction conditions as in step D-2.

Step E-4: compound (38) can be obtained by Wittig reaction of compound (36) and compound (37). The reaction in step E-4 may be carried out under the conditions in which methoxymethyltriphenylphosphonium chloride is treated with a base such as sodium hydride, potassium tert-butoxide, sodium bis (trimethylsilyl) amide or lithium bis (trimethylsilyl) amide in an ether solvent such as tetrahydrofuran or 1, 4-dioxane, an aromatic hydrocarbon solvent such as toluene or a mixed solvent thereof, followed by reaction with an aldehyde. The reaction can be carried out at from 0 ℃ to 120 ℃. The reaction can be carried out under conditions in which the enol ether produced is hydrolysed with a mineral acid such as hydrochloric acid, trifluoroacetic acid or p-toluene sulphonic acid, an organic acid or a lewis acid such as mercury acetate. The reaction can be carried out at from 0 ℃ to 80 ℃.

Step E-5: compound (39) can be obtained by a condensation reaction of compound (14) and compound (38). The reaction in step E-5 can be carried out under the same reaction conditions as in step A-1.

Step E-6: the compound (40) can be obtained by a condensation reaction of the compound (4) and the compound (39). The reaction in step E-6 can be carried out under the same reaction conditions as in step A-2.

Scheme F

[ formula 9]

Wherein X¹、X²、Y¹、Y²、R¹、R²、R³And R⁴As defined above.

Step F-1: compound (9) can be obtained by Mitsunobu reaction of compound (6) and compound (8). The reaction in step F-1 may be carried out under conditions in which the compounds (6) and (8) are reacted with triphenylphosphine/diethyl azodicarboxylate (DEAD), cyanomethylene tributylphosphine (CMBP), or the like in an ether solvent such as tetrahydrofuran or 1, 4-dioxane, a halogen solvent such as dichloromethane or chloroform, or a mixed solvent thereof. The reaction can be carried out at from 0 ℃ to 150 ℃, preferably from 0 ℃ to 80 ℃.

Scheme G

[ formula 10]

Wherein X¹、X²、Y¹、Y²、R¹、R³And R⁴As defined above. A. the⁴Represents a halogen atom.

Step G-1: the compound (42) can be obtained by a condensation reaction of the compound (15) and the compound (41). The reaction in step G-1 can be carried out under the same reaction conditions as in step A-2.

Step G-2: compound (43) can be obtained by a coupling reaction of compound (32) and compound (42). The reaction in step G-2 can be carried out under the same reaction conditions as in step D-5.

Scheme H

[ formula 11]

Wherein X¹、R¹、R²And R⁴As defined above.

Step H-1: compound (45) can be obtained by separating an optical isomer of compound (44). The optical isomers in step H-1 can be directly separated by HPLC equipped with a polysaccharide derivative chiral column, a protein-based chiral column, or the like. In addition, examples include a method using an enzymatic method or a chemical synthesis method and a method in which an optical resolving agent is reacted to separate diastereomers and convert into alcohols. For the method using the enzymatic method, the optically active substance can be prepared by dissolving the compound in a solvent and adding a lipase in the presence of an acid alkenyl ester (acid alkenyl ester) to acylate the alcohol. The lipases used may be those of microbial origin or of animal origin, and examples include porcine pancreatic lipase, and those derived from candida (geneusacandida), Pseudomonas (genus Pseudomonas) and Aspergillus (genus Aspergillus). Examples of alkenyl acid esters include vinyl acetate, vinyl propionate, and vinyl hexanoate. Examples of the reaction solvent include ether solvents such as tetrahydrofuran and 1, 4-dioxane, aprotic polar solvents such as acetonitrile, halogen solvents such as dichloromethane and chloroform, aromatic hydrocarbon solvents such as toluene, water and mixed solvents thereof. The reaction can be carried out at from 20 ℃ to 50 ℃, preferably from 25 ℃ to 35 ℃.

For synthetic methods using chemical methods, optically active substances can be prepared by asymmetric esterification using asymmetric catalysts and esterification agents. Examples of asymmetric catalysts include optically active bisoxazoline-copper complexes. Examples of the optically active bisoxazoline catalyst include (R, R) -2,2' -isopropylidenebis (4-phenyl-2-oxazoline) and (S, S) -2, 6-bis (4-isopropyl-2-oxazoline-2-yl) pyridine, and examples of the copper catalyst include copper halides such as copper (II) trifluoromethanesulfonate, copper (II) chloride and copper (II) bromide. Examples of the esterifying agent include benzoyl chloride and acetyl chloride. Examples of the reaction solvent include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and 1, 4-dioxane, aprotic polar solvents such as acetonitrile, halogen solvents such as dichloromethane and chloroform, aromatic hydrocarbon solvents such as toluene and mixed solvents thereof. The reaction can be carried out at-30 ℃ to 60 ℃, preferably-10 ℃ to 30 ℃.

For the diastereomer separation process, the optically active substance can be prepared by reacting an optical resolving agent containing a chiral carboxylic acid such as (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene or (-) -O-acetyl-D-mandelic acid with the compound, separating the diastereoisomers by fractional crystallization or column chromatography, and subsequently separating the optical resolving agent under conditions of an acid such as hydrochloric acid, trifluoroacetic acid or p-toluenesulfonic acid, or a base such as potassium carbonate, potassium phosphate or potassium hydroxide. The reaction can be carried out at from 0 ℃ to 80 ℃, preferably from 0 ℃ to 30 ℃.

Examples

Hereinafter, the present invention is described in further detail with reference to reference examples, examples and test examples, but is not limited thereto, and may be changed without departing from the scope of the present invention.

In the following reference examples and examples, purification was performed by column chromatography using SNAPCarddge KP-Sil (referred to as "KP-Sil") by Biotage, SNAPCarddge HP-Sil (referred to as "HP-Sil") by Biotage, and SNAPCarddge KP-NH (referred to as "KP NH") by Biotage. For the following reference examples and the working up operations of the examples, the ISOLUTE phase separator of Biotage was used for "ISOLUTE phase separator".

In the following reference examples and examples, thin layer chromatography (PTLC) purification was performed using silica gel 60F254(Merck KGaA).

In the following reference examples and examples, preparative High Performance Liquid Chromatography (HPLC) purification was performed under the following conditions. However, in the case where the compound has a basic functional group, when trifluoroacetic acid is used in the present operation, a neutralization operation or the like may sometimes be carried out to obtain a free form.

Equipment: trilution LC of Gilson

Column: sunfire prep C18 OBD 5.0 μm 30X 50mm from Waters, or YMC-ActusTriant5.0 μm 50X 30mm for YMC

Solvent: a liquid A; water containing 0.1% trifluoroacetic acid, liquid B; acetonitrile containing 0.1% trifluoroacetic acid

Gradient: 0min. (liquid a/liquid B ═ 90/10), 11min. (liquid a/liquid B ═ 20/80), 12 to 13.5min. (liquid a/liquid B ═ 5/95)

Flow rate: 40mL/min.

The detection method comprises the following steps: UV 254 nm.

In the following reference examples and examples, high performance liquid chromatography mass spectrometry (HPLC) was determined by the following 2 conditions.

Condition 1

The measuring instrument is as follows: agilent 2900 and Agilent 6150 from Agilent

Column: acquity CSH C181.7 μm 2.1 x 50mm from Waters

Solvent: a liquid A; water containing 0.1% formic acid, liquid B; acetonitrile containing 0.1% formic acid

Gradient: 0min. (liquid a/liquid B ═ 80/20), 1.2 to 1.4min. (liquid a/liquid B ═ 1/99)

Flow rate: 0.8mL/min, detection method: UV 254nm

An ionization method comprises the following steps: electron impact ionization (ESI: electrospray ionization)

Condition 2

The measuring instrument is as follows: LCMS-2010EV of SHIMADZU

Column: shim-pack XR-ODS 2.2 μm 2.0mm I.D. x 30mm of SHIMADZU

Gradient: 0min. (liquid a/liquid B ═ 90/10), 1min. (liquid a/liquid B ═ 60/40), 2min. (liquid a/liquid B ═ 0/100), 2.5min. (liquid a/liquid B ═ 0/100)

Flow rate: 0.6mL/min, detection method: UV 254nm

An ionization method comprises the following steps: electron impact ionization (ESI: electrospray ionization) and atmospheric pressure chemical ionization (APCI: atmospheric pressure chemical ionization) Mass Spectrometry (MS) was measured under the following conditions in the following reference examples and examples.

An MS measuring instrument: LCMS-2010EV from SHIMADZU or Platform LC from micromass.

In the following examples, analysis of racemic compounds was performed by any of the following 13 conditions.

Condition 1

The measuring instrument is as follows: agilent 1100 of Agilent

Column: CHIRALPAKAD-3(Daicel corporation, 4.6 mm. about.250 mm)

Flow rate: 1.0mL/min

Mobile phase: hexane/ethanol 30/70

Condition 2

The measuring instrument is as follows: waters 2695 and 2998 of Waters

Column: CHIRALPAK IB (Daicel corporation, 4.6 mm. 250mm)

Flow rate: 1.0mL/min

Mobile phase: hexane/ethanol 90/10

Condition 3

The measuring instrument is as follows: waters 2695 and 2998 of Waters

Column: CHIRALPAK IB (Daicel corporation, 4.6 mm. 250mm)

Flow rate: 1.0mL/min

Mobile phase: hexane/2-propanol-30/70

Condition 4

The measuring instrument is as follows: agilent 1100 of Agilent

Column: CHIRALPAKAD-3(Daicel corporation, 4.6 mm. about.150 mm)

Flow rate: 1.0mL/min

Mobile phase: hexane/ethanol 20/80

Condition 5

The measuring instrument is as follows: agilent 1100 of Agilent

Column: CHIRALPAK IB-3(Daicel corporation, 4.6 mm. about.150 mm)

Flow rate: 1.0mL/min

Mobile phase: hexane/ethanol 50/50

Condition 6

The measuring instrument is as follows: waters 996 and 2795 from Waters

Column: CHIRALPAK AD-3(Daicel corporation, 4.6 mm. about.150 mm)

Flow rate: 1.0mL/min

Mobile phase: hexane/2-propanol-0/100

Condition 7

The measuring instrument is as follows: agilent 1100 of Agilent

Column: CHIRALPAK IB-3(Daicel corporation, 4.6 mm. about.150 mm)

Flow rate: 1.0mL/min

Mobile phase: hexane/ethanol 70/30

Condition 8

The measuring instrument is as follows: waters 996 and 2795 from Waters

Column: CHIRALPAK IB-3(Daicel corporation, 4.6 mm. about.150 mm)

Flow rate: 1.0mL/min

Mobile phase: hexane/2-propanol-30/70

Condition 9

The measuring instrument is as follows: agilent 1100 of Agilent

Column: CHIRALPAK AD-3(Daicel corporation, 4.6 mm. about.150 mm)

Flow rate: 1.0mL/min

Mobile phase: hexane/ethanol 30/70

Condition 10

The measuring instrument is as follows: agilent 1100 of Agilent

Column: CHIRALPAK IB-3(Daicel corporation, 4.6 mm. about.150 mm)

Flow rate: 1.0mL/min

Mobile phase: hexane/ethanol 90/10

Condition 11

The measuring instrument is as follows: agilent 1100 of Agilent

Column: CHIRALPAK IB-3(Daicel corporation, 4.6 mm. about.150 mm)

Flow rate: 1.0mL/min

Mobile phase: hexane/ethanol 80/20

Condition 12

The measuring instrument is as follows: waters 996 and 2795 from Waters

Column: CHIRALPAK ID-3(Daicel corporation, 4.6 mm. about.150 mm)

Flow rate: 1.0mL/min

Mobile phase: hexane/2-propanol-50/50

Condition 13

The measuring instrument is as follows: waters 996 and 2795 from Waters

Column: CHIRALPAK IA-3(Daicel corporation, 4.6 mm. about.150 mm)

Flow rate: 1.0mL/min

Mobile phase: hexane/2-propanol-20/80.

In the following examples, optical rotation analysis was measured under the following conditions.

The measuring instrument is as follows: JASCO P-2300 of JASCO.

In the following reference examples and examples, an initiator (biotage ab) was used as the microwave synthesizer.

In the following reference examples and examples, compounds are named according to ACD/Name (ACD/Labs 12.01, advanced chemistry development Inc.).

In the reference examples and examples, the following terms and reactants are as follows.

Na₂SO₄(anhydrous sodium sulfate), MgSO₄(magnesium sulfate Anhydrous), Cs₂CO₃(Cesium carbonate), NaHCO₃(sodium bicarbonate), TFA (trifluoroacetic acid), THF (tetrahydrofuran), DMF (N, N-dimethylformamide), NMP (N-methyl-2-pyrrolidinone), EtOAc (ethyl acetate), CHCl₃(chloroform), HATU [ O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate]DIPEA (N, N-diisopropylethylamine), TEA (triethylamine), MsCl (methanesulfonyl chloride), NaBH₄(sodium borohydride), LiBH₄(lithium borohydride).

Reference example 1: (±) -3- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoyl ] -1, 3-oxazolidine-2-carboxylic acid ethyl ester

[ formula 12]

To a solution of ethyl glyoxylate (polymeric, 47% in toluene) (13.4mL, 63.5mol) in CHCl₃(260mL), activated molecular sieves 4A (200g) and 2-aminoethanol (4.0mL, 66.1mmol) were added and the resulting mixture was allowed to warm to room temperatureStirred for 24 hours. By passingMolecular sieve 4A was filtered off, and then the solvent was distilled off under reduced pressure to obtain a pale yellow oil. To 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoic acid (2.7g, 13.2mmol) in CHCl₃To the solution in (130mL), thionyl chloride (1.4mL, 19.8mmol) was added dropwise and stirred at 75 ℃ for 5 hours. The reaction mixture was cooled to room temperature, and then the solvent and excess thionyl chloride were distilled off under reduced pressure. The residue obtained was taken up in CHCl with ice water cooling₃(100mL) to a solution of TEA (3.7mL, 26.4mmol) and the pale yellow oil obtained in the above reaction in CHCl₃(30mL), and the resulting mixture was warmed to room temperature and stirred for 3 hours. Water was added to the reaction mixture followed by CHCl₃And (4) extracting. The organic layer was washed with saturated aqueous sodium chloride solution and then with Na₂SO₄Drying is then carried out, the drying agent is filtered off and the solvent is then distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 150g, hexane/EtOAc 88/12 to 0/100) to obtain the title compound (3.6g) (light yellow oil).

MS(ESI/APCI Dual pos.)m/z：331[M+H]⁺

Reference example 2: (±) - [2- (hydroxymethyl) -1, 3-oxazolidin-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone

[ formula 13]

To the (. + -.) -3- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoyl group obtained in reference example 1 was added under ice water cooling]-1, 3-oxazolidine-2-carboxylic acid ethyl ester (4.0g, 12.1mmol) in MeOH (60mL) and NaBH was added gradually₄(4.6g, 121mmol) and stirred for 1 hour. The resulting mixture was warmed to room temperature and stirred for 1 hour. The solvent was distilled off under reduced pressure, and saturated ammonium chloride was dissolved in waterAdding the solution to the reaction mixture with CHCl₃And (4) extracting. The organic layer was washed with saturated aqueous sodium chloride solution and then with Na₂SO₄Drying is then carried out, the drying agent is filtered off and the solvent is then distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 100g, hexane/EtOAc 88/12 to 0/100) to obtain the title compound (3.6g) (colorless oil).

MS(ESI/APCI Dual pos.)m/z：289[M+H]⁺

Reference example 3: (±) -3- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoyl ] -1, 3-oxazinane-2-carboxylic acid ethyl ester

[ formula 14]

The same procedures as in reference example 1 were carried out by using ethyl glyoxylate (polymeric, 47% toluene solution) (4.3mL, 20.4mol), 3-aminopropan-1-ol (1.6mL, 20.4mmol) and 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoic acid (1.0g, 4.9mmol) to obtain the title compound (1.3g) (colorless solid).

MS(ESI pos.)m/z：367[M+Na]⁺

Reference example 4: (±) [2- (hydroxymethyl) -1, 3-oxazinane-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone

[ formula 15]

To the (. + -.) -3- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoyl group obtained in reference example 3]To a solution of ethyl (0.50g, 1.5mmol) 1, 3-oxazinane-2-carboxylate in THF (5mL) was added LiBH₄A solution in THF (0.97mL, 2.9mmol) was stirred at room temperature for 2 h. Adding water to the reaction mixture, followed byWith CHCl₃And (4) extracting. The organic layer was washed with saturated aqueous sodium chloride solution and then with Na₂SO₄Drying is then carried out, the drying agent is filtered off and the solvent is then distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25g, hexane/EtOAc 88/12 to 0/100) to obtain the title compound (0.34g) (colorless oil).

MS(ESI pos.)m/z：303[M+H]⁺

Reference example 5: (2RS,5S) -5-methyl-3- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoyl ] -1, 3-oxazolidine-2-carboxylic acid ethyl ester

[ formula 16]

The same procedures as in reference example 1 were carried out by using ethyl glyoxylate (polymeric, 47% in toluene) (0.5mL, 2.4mmol), (2S) -1-aminopropan-2-ol (0.18mL, 2.4mmol) and 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoic acid (0.20g, 0.98mmol) to obtain the title compound (0.11g) as a colorless oil.

MS(ESI/APCI Dual pos.)m/z：345[M+H]⁺

Reference example 6: (2RS,5R) -5-methyl-3- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoyl ] -1, 3-oxazolidine-2-carboxylic acid ethyl ester

[ formula 17]

The same procedures as in reference example 1 were carried out by using ethyl glyoxylate (polymeric, 47% in toluene) (0.5mL, 2.4mmol), (2R) -1-aminopropan-2-ol (0.18mL, 2.4mmol) and 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoic acid (0.20g, 0.98mmol) to obtain the title compound (0.14g) as a colorless oil.

MS(ESI/APCI Dual pos.)m/z：345[M+H]⁺

Reference example 7: [ (2S,4R) -2- (hydroxymethyl) -4-methyl-1, 3-oxazolidin-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone

[ formula 18]

The same procedures as in reference example 1 were carried out by using ethyl glyoxylate (polymeric, 47% in toluene) (2.0mL, 9.5mmol), (2R) -2-aminopropan-1-ol (0.73mL, 9.5mmol) and 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoic acid (1.0g, 4.9mmol) to obtain a diastereomeric mixture of ethyl (2RS,4R) -4-methyl-3- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoyl ] -1, 3-oxazolidine-2-carboxylate. The obtained mixture of diastereomers was purified by thin layer chromatography (1mm, hexane/EtOAc ═ 66/34) to obtain ethyl (2S,4R) -4-methyl-3- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoyl ] -1, 3-oxazolidine-2-carboxylate (colorless oil). The same procedures as in reference example 4 were carried out by using the obtained colorless oil as a starting material to obtain the title compound (0.041g) (colorless oil).

MS(ESI pos.)m/z：303[M+H]⁺

Reference example 8: [ (2S,4S) -2- (hydroxymethyl) -4-methyl-1, 3-oxazolidin-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone

[ formula 19]

The same procedures as in reference example 1 were carried out by using ethyl glyoxylate (polymeric, 47% in toluene) (2.0mL, 9.5mmol), (2S) -2-aminopropan-1-ol (0.73mL, 9.5mmol) and 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoic acid (1.0g, 4.9mmol) to obtain a diastereomeric mixture of ethyl (2RS,4S) -4-methyl-3- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoyl ] -1, 3-oxazolidine-2-carboxylate. The obtained mixture of diastereomers was purified by thin layer chromatography (1mm, hexane/EtOAc ═ 66/34) to obtain (2S,4S) -4-methyl-3- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoyl ] -1, 3-oxazolidine-2-carboxylic acid ethyl ester (colorless oil). The same procedures as in reference example 4 were carried out by using the obtained colorless oil as a starting material to obtain the title compound (0.19g) (colorless solid).

MS(ESI pos.)m/z：303[M+H]⁺

Reference example 9: 5-fluoro-2- [1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl ] pyridine

[ formula 20]

To 1- (tetrahydro-2H-pyran-2-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (100.5g, 0.36mol), 2-bromo-5-fluoropyridine (56.5g, 0.33mol) and Pd (PPh)₃)₄(38.0g, 32.6mmol) in a mixed solution of ethanol (300mL) and toluene (300mL) was added 2M Na₂CO₃Aqueous solution (0.49L, 0.99mol) and the resulting mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, then water and EtOAc were added thereto, and the resulting mixture was stirred at room temperature for 30 minutes, followed by extraction with EtOAc. The organic layer was washed with saturated aqueous sodium chloride solution and MgSO₄After drying, the drying agent was filtered off, NH silica gel (400g) was then added thereto, and the resulting mixture was stirred for 15 hours. The mixture was filtered through acidic silica gel (eluted with n-hexane: AcOEt ═ 1: 1 → AcOEt) and the solvent was distilled off under reduced pressure to obtain the title compound (100g) (pale yellow oil).

MS(ESI pos.)m/z：248[M+H]+

Reference example 10: 5-fluoro-2- (1H-pyrazol-3-yl) pyridine

[ formula 21]

To 5-fluoro-2- [1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl group obtained in reference example 9]To a solution of pyridine (81.2g, 0.33mol) in methanol (250mL) was added 4M HCl-EtOAc solution (0.25L, 0.96mol) and the resulting mixture was stirred at room temperature for 16 h. The solvent was distilled off under reduced pressure, then EtOAc (500mL) was added to the residue and the resulting mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and then cooled with ice, and then the precipitate was filtered off and dried to obtain the hydrochloride salt of the title compound (colorless solid). Water (700mL) and EtOAc (350mL) were added to the obtained hydrochloride salt, and the resulting mixture was stirred for 30 minutes, then separated. The organic layer obtained was extracted three times with 1.2M hydrochloric acid (100 mL). The aqueous layers were combined, the pH adjusted to 12 with 8M aqueous NaOH, then with CHCl₃The organic layer was extracted. The extracted organic layer was passed through an ISOLUTE phase separator, and the solvent was distilled off under reduced pressure. Diisopropyl ether (300mL) was added to the residue obtained and the resulting mixture was heated to reflux for 2 hours. The reaction mixture was cooled at room temperature, then cooled with ice, and then the precipitate was filtered off and dried to obtain the title compound (44.9g) (pale pink solid).

MS(ESI pos.)m/z：164[M+H]+

Reference example 11: 5-fluoro-2- (1H-pyrazol-4-yl) pyridine

[ formula 22]

To 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolaneTo a solution of tert-butyl (15.4g, 52.5mmol) and 2-bromo-5-fluoropyridine (8.4g, 47.7mmol) in 1, 4-dioxane (100mL) of-2-yl) -1H-pyrazole-1-carboxylate was added Pd (PPh)₃)₄(5.5g, 4.77mmol) and 2MNa₂CO₃Aqueous solution (71.6mL, 0.14mol) and the resulting mixture was then stirred at 100 ℃ for 3 hours and then at room temperature for 72 hours. Water was added to the reaction mixture, followed by extraction with EtOAc. The organic layer was washed with saturated aqueous sodium chloride solution and MgSO₄Drying is then carried out, the drying agent is filtered off and the solvent is then distilled off under reduced pressure. A small amount of EtOAc was added to the obtained residue, and the resulting mixture was filtered off and dried to obtain the title compound (4.9g) (colorless solid).

MS(ESI pos.)m/z：164[M+H]+

Reference example 12: 2- [1- (2, 2-diethoxyethyl) -1H-pyrazol-3-yl ] -5-fluoropyridine

[ formula 23]

To a solution of 5-fluoro-2- (1H-pyrazol-3-yl) pyridine (11.7g, 58.6mmol) obtained in reference example 10 in DMF (195mL) was added Cs₂CO₃(57.3g, 0.18mol) and 2-bromo-1, 1-diethoxyethane (11.5mL, 76.2mmol) and stirred at 80 ℃ for 18 h. The reaction mixture was cooled to room temperature, then water was added thereto, followed by extraction with EtOAc. The organic layer was washed with saturated aqueous sodium chloride solution and MgSO₄Drying is then carried out, the drying agent is filtered off and the solvent is then distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50g, hexane/EtOAc 88/12 to 35/65) to obtain the title compound (8.2g) (colorless oil).

MS(ESI pos.)m/z：280[M+H]⁺

Reference examples 13 to 15 were obtained by the same procedures as in reference example 12. The structural formula, name and MS data of the obtained compound are shown in table 1.

[ Table 1]

Reference example 16: (2S,4S) -4-methyl-3- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoyl) -1, 3-oxazinane-2-carboxylic acid ethyl ester

[ formula 24]

To a solution of (3R) -3-aminobutyric acid (1.0g, 9.7mmol) in THF (10mL) under cooling in an ice bath was added dropwise a 0.9mol/L borane-THF solution (32.3mL, 29.1mmol) over 1 hour, and the resulting mixture was stirred at room temperature for 20 minutes. The resulting mixture was heated to 80 ℃ and stirred under heating for a further 6 hours. Methanol was added thereto under ice-bath cooling, and the reaction mixture was stirred for 30 minutes and then concentrated under reduced pressure. The same procedures as in reference example 1 were carried out by using the obtained (3R) -3-aminobutan-1-ol, ethyl glyoxylate (polymeric, 47% in toluene) (2.0mL, 9.7mmol) and 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoic acid (0.50g, 2.5mmol) to obtain a diastereomer mixture (colorless oil). The obtained mixture of diastereomers was purified by column chromatography (HP-Sil 10g, hexane/EtOAc ═ 90/10 to 0/100) to obtain the title compound (0.37g) as a low polar compound (colorless oil).

MS(ESI pos.)m/z：359[M+H]⁺

Reference example 17: [ (2S,4S) -2- (hydroxymethyl) -4-methyl-1, 3-oxazinan-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone

[ formula 25]

The same procedures as in reference example 2 were carried out by using ethyl (2S,4S) -4-methyl-3- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoyl) -1, 3-oxazinane-2-carboxylate (0.37g, 1.0mmol) obtained in reference example 16 to obtain the title compound (0.068g) (colorless solid).

MS(ESI pos.)m/z：317[M+H]⁺

Reference example 18: (2RS,5RS) -5-methyl-3- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoyl ] -1, 3-oxazinane-2-carboxylic acid ethyl ester

[ formula 26]

The same procedures as in reference example 1 were carried out by using 3-amino-2-methylpropan-1-ol (0.10g, 1.1mmol), ethyl glyoxylate (polymeric, 47% in toluene) (2.0mL, 9.7mmol) and 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoic acid (0.5g, 2.5mmol) to obtain the title compound (0.13g) (colorless oil).

MS(ESI pos.)m/z：359[M+H]⁺

Reference example 19: n-hydroxy-3, 3-dimethoxypropionamidine

[ formula 27]

To a solution of hydroxylamine monohydrochloride (3.2g, 45.6mmol) in MeOH (70mL) was added NaHCO₃(3.8g, 45.6mmol) and stirred at room temperature for 30 minutes, then a solution of 3, 3-dimethoxypropionitrile (5.0g, 43.4mmol) in MeOH (30mL) was added dropwise thereto. The reaction mixture was stirred at 80 ℃ for 15 hours. Cooling the mixture toAt room temperature, the resulting salt was filtered off and the solvent was distilled off under reduced pressure. The residue obtained is purified by column chromatography (HP-Sil 100g, CHCl)₃MeOH 99/1 to 90/10) to obtain the title compound (4.5g) (light yellow oil).

MS(ESI pos.)m/z：171[M+Na]⁺

Reference example 20: 2- [3- (2, 2-Dimethoxyethyl) -1,2, 4-oxadiazol-5-yl ] -5-fluoropyridine

[ formula 28]

A solution of N-hydroxy-3, 3-dimethoxypropionamidine (1.0g, 6.8mmol) obtained in reference example 19 in DMF (3mL) was added to a solution of 5-fluoropyridine-2-carboxylic acid (1.0g, 7.1mmol) and carbonyldiimidazole (1.3g, 8.1mmol) in DMF (4mL), which was stirred at 40 ℃ for 1 hour, and the mixture was stirred for 30 minutes. The reaction solution was heated to 90 ℃ and stirred for 15 hours. Water was added to the reaction mixture, followed by extraction with EtOAc. The organic layer was washed with water and saturated aqueous sodium chloride solution, and then with Na₂SO₄Drying is then carried out, the drying agent is filtered off and the solvent is then distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25g, hexane/EtOAc 75/25 to 0/100) to obtain the title compound (1.2g) (colorless solid).

MS(ESI pos.)m/z：254[M+H]⁺

Reference example 21: 3- (2, 2-Dimethoxyethyl) -5- (4-fluorophenyl) -1,2, 4-oxadiazole

[ formula 29]

The same procedures as in reference example 20 were carried out by using N-hydroxy-3, 3-dimethoxypropionamidine (1.0g, 6.8mmol) obtained in reference example 19 and 4-fluorobenzoic acid (0.99g, 7.1mmol) as starting materials to obtain the title compound (1.4g) (colorless oil).

MS(ESI pos.)m/z：253[M+H]⁺

Reference example 22: 2- [1- (5-Fluoropyridin-2-yl) -1H-pyrazol-4-yl ] ethanol

[ formula 30]

To a solution of 2- (1H-pyrazol-4-yl) ethanol (1.0g, 8.9mmol) and 2, 5-difluoropyridine (0.89mL, 9.8mmol) in acetonitrile (45mL) was added Cs₂CO₃(9.7g, 17.8mmol) and the resulting mixture was stirred at 80 ℃ for 3 hours. The reaction mixture was cooled, then water was added thereto, followed by extraction with EtOAc. The organic layer was washed with saturated aqueous sodium chloride solution and then with Na₂SO₄Drying is then carried out, the drying agent is filtered off and the solvent is then distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25g, hexane/EtOAc 90/10 to 30/70) to obtain the title compound (0.63g) (colorless solid).

MS(ESI pos.)m/z：208[M+H]⁺

Reference example 23: (±) - (2- { [3- (4-fluorophenyl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazinan-3-yl) (2-iodo-5-methylphenyl) methanone

[ formula 31]

To 1- (2, 2-diethoxyethyl) -3- (4-fluorophenyl) -1H-pyrazole obtained in reference example 14 (0.16g, 0.57mmol) in CHCl₃To a solution in (3mL) was added TFA (0.42mL, 5.7mmol), and the resulting mixture was stirred at 35 ℃ for 6 h. Then, the product is processedTFA (0.14mL, 0.19mmol) was added and the mixture was stirred at 35 ℃ for 6 h. The reaction mixture was cooled to room temperature and then NaHCO was added₃The aqueous solution was added to the reaction mixture followed by CHCl₃And (4) extracting. The organic layer was washed with saturated aqueous sodium chloride solution and then with Na₂SO₄Dried and the drying agent filtered off. The solvent was distilled off under reduced pressure to obtain a colorless oil. To the colorless oil obtained in CHCl₃To a solution in (3mL) was added activated molecular sieve 4A (0.60g) and 3-aminopropan-1-ol (0.044mL, 0.57mmol) and the resulting mixture was stirred at room temperature for 24 h. By passingMolecular sieve 4A was filtered off, and then the solvent was distilled off under reduced pressure to obtain a pale yellow oil. To 2-iodo-5-methylbenzoyl chloride (0.19g, 0.69mmol) in CHCl was added under ice water cooling₃(5mL) to a solution, TEA (0.20mL, 1.4mmol) and the pale yellow oil obtained in the above reaction in CHCl were added₃(2mL) and the resulting mixture was warmed to room temperature and stirred for 15 hours. Water was added to the reaction mixture followed by CHCl₃And (4) extracting. The organic layer was washed with saturated aqueous sodium chloride solution and then with Na₂SO₄Drying is then carried out, the drying agent is filtered off and the solvent is then distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50g, hexane/EtOAc 80/20 to 0/100) to obtain the title compound (0.19g) (light yellow oil).

MS(ESI pos.)m/z：506[M+H]⁺

Reference example 24: (±) - (2- { [4- (4-fluorophenyl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazinan-3-yl) (2-iodo-5-methylphenyl) methanone

[ formula 32]

The same procedures as in reference example 23 were carried out by using 1- (2, 2-diethoxyethyl) -4- (4-fluorophenyl) -1H-pyrazole (1.0g, 3.6mmol) obtained in reference example 15 as a starting material to obtain the title compound (1.2g) (colorless oil).

MS(ESI pos.)m/z：506[M+H]⁺

Reference example 25: (±) - (2- { [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl ] methyl } -1, 3-oxazinan-3-yl) (2-iodo-5-methylphenyl) methanone

[ formula 33]

To 2- [1- (5-Fluoropyridin-2-yl) -1H-pyrazol-4-yl group obtained in reference example 22]To a solution of ethanol (0.21g, 1.0mmol) in dimethyl sulfoxide (5mL) was added 2-iodoxybenzoic acid (0.50g, 1.1mmol), and the resulting mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, followed by extraction with EtOAc. The organic layer was washed with water and saturated aqueous sodium chloride solution, and then with Na₂SO₄Dried, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure to obtain a colorless oil. The same procedures as in reference example 23 were carried out by using the obtained colorless oil as a starting material to obtain the title compound (0.16g) (pale yellow oil).

MS(ESI pos.)m/z：507[M+H]⁺

Reference example 26: (±) - (5-fluoro-2-iodophenyl) (2- { [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl ] methyl } -1, 3-oxazinan-3-yl) methanone

[ formula 34]

The same procedures as in reference example 25 were carried out by using 2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl ] ethanol (0.21g, 1.0mmol) obtained in reference example 22 and 5-fluoro-2-iodobenzoic acid (0.16g, 0.60mmol) to obtain the title compound (0.15g) (pale yellow oil).

MS(ESI pos.)m/z：511[M+H]⁺

Reference example 27: 1- (5-Fluoropyridin-2-yl) -1H-pyrazole-3-carboxylic acid ethyl ester

[ formula 35]

To a solution of 1H-pyrazole-3-carboxylic acid ethyl ester (25.0g, 178.4mmol) and 2-bromo-5-fluoropyridine (47.1g, 267.6mmol) in DMF (300mL) were added copper (I) iodide (8.5g, 44.6mmol), rac-trans-N, N' -dimethylcyclohexane-1, 2-diamine (28.1mL, 178.4mmol) and Cs₂CO₃(116.2g, 356.8mmol) and the resulting mixture was stirred at 90 ℃ for 7 h. The reaction mixture was cooled to room temperature, then water and EtOAc were added, followed byAnd (5) filtering. The organic layer was removed from the filtrate, washed with saturated aqueous sodium chloride solution and then with Na₂SO₄Drying is then carried out, the drying agent is filtered off and the solvent is then distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50g, hexane/EtOAc: 70/30 to 0/100). The obtained solid was stirred and washed in hexane/EtOAc ═ 4/1 and filtered off to obtain the title compound (29.0g) (colorless solid).

MS(ESI pos.)m/z：236[M+H]⁺

Reference example 28: [1- (5-Fluoropyridin-2-yl) -1H-pyrazol-3-yl ] methanol

[ formula 36]

To a solution of ethyl 1- (5-fluoropyridin-2-yl) -1H-pyrazole-3-carboxylate (10.0g, 42.5mmol) obtained in reference example 27 in THF (50mL) was added diisobutylaluminum hydride (1.01mol/L toluene solution, 105.2mL, 106.3mmol) with cooling at-78 ℃, and after dropwise addition, the resulting mixture was heated to 0 ℃ and stirred for 2 hours. Aqueous potassium sodium tartrate (Rochelle salt) was added to the reaction mixture under ice cooling, followed by extraction with EtOAc. The organic layer was washed with saturated aqueous sodium chloride solution and MgSO₄After drying, the drying agent was filtered off, and then the solvent was distilled off under reduced pressure to obtain the title compound (8.0g) (colorless solid).

MS(ESI pos.)m/z：194[M+H]⁺

Reference example 29: 1- (5-Fluoropyridin-2-yl) -1H-pyrazole-3-carbaldehyde

[ formula 37]

To [1- (5-Fluoropyridin-2-yl) -1H-pyrazol-3-yl group obtained in reference example 28]Methanol (8.0g, 34.0mmol) in CHCl₃To the suspension in (100mL) was added 85% manganese dioxide (29.6g, 0.34mol) and the resulting mixture was stirred at 60 ℃ for 3 hours. By passingThe reaction mixture was filtered and washed with CHCl₃The solid was washed and the filtrate was concentrated under reduced pressure. The resulting residue was washed with diethyl ether and filtered off to obtain the title compound (5.3g) (light brown solid).

MS(ESI pos.)m/z：192[M+H]⁺

Reference example 30: [1- (5-Fluoropyridin-2-yl) -1H-pyrazol-3-yl ] acetaldehyde

[ formula 38]

To a solution of methoxymethyltriphenylphosphonium chloride (5.4g, 15.7mmol) in THF (50mL) was added n-butyllithium (2.6mol/L hexane solution, 6.3mL, 16.5mmol) under cooling at-78 deg.C, and the resulting mixture was stirred for 30 minutes. The reaction mixture was heated to 0 ℃, a solution of 1- (5-fluoropyridin-2-yl) -1H-pyrazole-3-carbaldehyde obtained in reference example 29 (1.5g, 7.9mmol) and hexamethylphosphoric triamide (0.5mL) in THF (50mL) was added thereto, and the resulting mixture was stirred for 3 hours, then heated to room temperature and stirred for 15 hours. To the reaction mixture, EtOAc and saturated aqueous sodium chloride solution were added under cooling in an ice bath and stirred to separate an organic layer. The organic layer was MgSO₄Dried, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure to obtain a brown oil. To the brown oil obtained, aqueous hydrochloric acid (1.2mol/L, 10mL) was added, and the resulting mixture was heated to reflux and stirred for 2 hours. The reaction mixture was cooled at room temperature, then water was added thereto, followed by extraction with EtOAc. The organic layer was washed with saturated aqueous sodium chloride solution and MgSO₄Drying is then carried out, the drying agent is filtered off and the solvent is then distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25g, hexane/EtOAc 80/20 to 20/80) to obtain the title compound (1.0g) (light yellow oil).

MS(ESI pos.)m/z：206[M+H]⁺

Reference example 31: [2- (hydroxymethyl) -1, 3-oxazinan-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone

[ formula 39]

To (. + -.) - [2- (hydroxymethyl) -1,3-Oxazinan-3-yl][ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl]To a solution of methanone (1.7g, 5.7mmol) in toluene (29mL) were added pyridinium p-toluenesulfonate (0.14g, 0.57mol) and (S) -5-allyl-2-oxabicyclo [3.3.0]Oct-8-ene (1.0g, 6.9mmol) and stirred at an oil bath temperature of 70 ℃. The reaction mixture was cooled to room temperature and then NaHCO was added₃Saturated aqueous solution was added thereto, followed by extraction with EtOAc. The organic layer was washed with water and saturated aqueous sodium chloride solution, and then with Na₂SO₄Drying is then carried out, the drying agent is filtered off and the solvent is then distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 160g, hexane/EtOAc 75/25 to 40/60) to obtain 2 diastereomeric mixtures of low polarity compounds (0.89g) (colorless solid). To the obtained solution of the colorless solid diastereomer in MeOH (40mL) was added toluenesulfonic acid monohydrate (0.075g, 0.4mmol) and the resulting mixture was stirred at room temperature for 15 h. NaHCO is added₃Saturated aqueous solution was added to the reaction mixture followed by CHCl₃And (4) extracting. The organic layer was washed with saturated aqueous sodium chloride solution and then with Na₂SO₄Drying is then carried out, the drying agent is filtered off and the solvent is then distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10g, hexane/EtOAc ═ 75/25 to 0/100), (KP-NH 10g, hexane/EtOAc ═ 75/25 to 0/100) to obtain the title compound (0.58g, 94% ee) (colorless oil). The optical purity was analyzed based on the analysis conditions of the racemic compound described previously (condition 10, Rt)¹＝10.2min，Rt²11.6min) to obtain a solution with a short relative retention time (Rt)¹10.2min) was added.

MS(ESI pos.)m/z：303[M+H]⁺

The title compound may be synthesized instead by different methods as follows.

To (. + -.) [2- (hydroxymethyl) -1, 3-oxazinan-3-yl group obtained in reference example 4][ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl]To a solution of methanone (1.0mg, 0.0033mmol), vinyl acetate (0.05mL) and tert-butyl methyl ether (1mL) was added porcine pancreatic-derived lipase (9).5mg, trade name Lipase, derived from porcine pancreas type II, manufactured by SIGMA Chemical Company) and stirred in a screw-top flask (screen visual) at 35 ℃ for 24 hours with shaking at 250 rpm. The reaction solution was filtered using EKICRODISK 13CR (manufactured by Pall Corporation). The filtrate was concentrated under reduced pressure, and the obtained residue was subjected to HPLC analysis under the above racemic compound analysis conditions 10, and {3- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoyl group was obtained]-1, 3-oxazinan-2-yl } methyl acetate (54.5%, 81.2% ee, with Rt¹＝7.3min，Rt²The compound with longer retention time of 8.9min was in excess, a colorless oil) and the title compound (45.5%,>99.9% ee, having Rt¹＝10.2min，Rt²The shorter retention time compound was in excess, colorless oil, 11.6 min).

MS(ESI pos.)m/z：303[M+H]⁺

The title compound may be synthesized instead by different methods as follows.

To a solution of copper (II) trifluoromethanesulfonate (0.013g, 0.040mmol) and (R, R) -2,2' -isopropylidenebis (4-phenyl-2-oxazoline) (0.012g, 0.040mmol) in THF (1.5mL) was added (. + -.) - [2- (hydroxymethyl) -1, 3-oxazinan-3-yl group obtained in reference example 4][ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl]Methanone (0.36g, 1.2mmol), potassium carbonate (0.16g, 1.2mmol) and benzoyl chloride (0.069g, 0.59mmol) and the resulting mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture followed by CHCl₃And (4) extracting. The organic layer was washed with saturated aqueous sodium chloride solution and then with Na₂SO₄Drying is then carried out, the drying agent is filtered off and the solvent is then distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10g, hexane/EtOAc ═ 75/25 to 0/100) to obtain {3- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoyl group]Methyl-1, 3-oxazinan-2-yl } benzoate (0.16g, 55% ee) (colorless oil). Based on the racemic Compound analysis conditions described previously (Condition 10, Rt)¹＝6.9min，Rt²7.9min), optical purity was analyzed to obtain a sample with a short relative retention time (Rt)¹6.9min) ofThe compound is in excess. To a solution of the obtained colorless oil (0.020g, 0.049mmol) in MeOH (0.5mL) was added potassium carbonate (0.010g, 0.074mmol), and the resulting mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with EtOAc. The organic layer was washed with saturated aqueous sodium chloride solution and then with Na₂SO₄Drying is then carried out, the drying agent is filtered off and the solvent is then distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10g, hexane/EtOAc 75/25 to 0/100) to obtain the title compound (0.011g, 55% ee) (colorless oil). Based on the racemic Compound analysis conditions described previously (Condition 10, Rt)¹＝10.2min，Rt²11.6min), the optical purity was analyzed to obtain a sample with a short relative retention time (Rt)¹10.2min) was added.

MS(ESI pos.)m/z：303[M+H]⁺

Reference example 32: [2- (chloromethyl) -1, 3-oxazinan-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone

[ formula 40]

To the [2- (hydroxymethyl) -1, 3-oxazinan-3-yl group obtained in reference example 31 was added under ice water cooling][ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl]Methanone (1.8g, 5.8mmol, 86.3% ee) and TEA (1.2mL, 8.7mmol) in CHCl₃To the solution in (30mL) was added MsCl (0.54mL, 7.0 mmol). The resulting mixture was warmed to room temperature and then stirred for 3 hours. Water was added to the reaction mixture followed by CHCl₃And (4) extracting. The organic layer was washed with saturated aqueous sodium chloride solution and then with Na₂SO₄Drying is then carried out, the drying agent is filtered off and the solvent is then distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10g, hexane/EtOAc: 88/12 to 0/100). EtOAc (10mL) was added to the obtained residue, and the resulting mixture was stirred for 30 minutes under ice bath cooling,and the solid was filtered off to obtain the title compound (0.81g, 84.2% ee) (colorless solid). Based on the racemic Compound analysis conditions described previously (Condition 12, Rt)¹＝7.7min，Rt²11.9min), the optical purity was analyzed to obtain a sample containing a peptide having a long relative retention time (Rt)²11.9min) was added.

MS(ESI pos.)m/z：321[M+H]⁺

Reference example 33: (2RS,5SR) -5-methyl-3- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoyl ] -1, 3-oxazinane-2-carboxylic acid ethyl ester

[ formula 41]

To (2RS,5RS) -5-methyl-3- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoyl group obtained in reference example 18]To a solution of ethyl (2.1g, 6.0mmol) 1, 3-oxazinane-2-carboxylate in ethanol (60mL) was added potassium carbonate (7.4g, 53.8mmol) and the resulting mixture was stirred at 75 ℃ for 7 h. The reaction mixture was cooled to room temperature, then water was added thereto, and the solvent was concentrated under reduced pressure, followed by extraction with EtOAc. The organic layer was washed with water and saturated aqueous sodium chloride solution, and then with Na₂SO₄Drying is then carried out, the drying agent is filtered off and the solvent is then distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 120g, hexane/EtOAc 90/10 to 30/70) to obtain the title compound (0.72g) (colorless oil).

MS(ESI pos.)m/z：359[M+H]⁺

Reference example 34: [ (2RS,5SR) -2- (hydroxymethyl) -5-methyl-1, 3-oxazinan-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone

[ formula 42]

The same procedures as in reference example 2 were carried out by using (2RS,5SR) -5-methyl-3- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoyl) -1, 3-oxazinane-2-carboxylic acid ethyl ester (0.72g, 2.0mmol) obtained in reference example 33 as a starting material to obtain the title compound (0.59g) (colorless oil).

MS(ESI pos.)m/z：317[M+H]⁺

Reference example 35: (2RS,5SR) - [2- (chloromethyl) -5-methyl-1, 3-oxazinan-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone

[ formula 43]

The same procedures as in reference example 32 were carried out by using [ (2RS,5SR) -2- (hydroxymethyl) -5-methyl-1, 3-oxazinan-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone (0.59g, 1.9mmol) obtained in reference example 34 as a starting material to obtain the title compound (0.52g) (colorless oil).

MS(ESI pos.)m/z：335[M+H]⁺

Example 1: (-) - (2- { [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazolidin-3-yl) [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone

[ formula 44]

[2- (hydroxymethyl) -1, 3-oxazolidin-3-yl group obtained in reference example 2 was added under ice water cooling][ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl]Methanone (1.7g, 5.9mmol) and TEA (1.2mL, 8.8mmol) in CHCl₃To a solution in (30mL) was added MsCl (0.55mL, 7.1mmol), and the resulting mixture was stirred for 1 hour. Water was added to the reaction mixture with ice water cooling, followed by CHCl₃And (4) extracting. The organic layer was washed with saturated aqueous sodium chloride solution and then with Na₂SO₄Drying is then carried out, the drying agent is filtered off and the solvent is then distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50g, hexane/EtOAc ═ 88/12 to 0/100) to obtain {3- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoyl group]-1, 3-oxazolidin-2-yl } methanesulfonic acid methyl ester (light yellow oil). 5-fluoro-2- (1H-pyrazol-3-yl) pyridine (1.3g, 8.1mmol) and Cs₂CO₃(4.8g, 14.7mmol) was added to the obtained pale yellow oil in DMF (30mL) and the resulting mixture was stirred at 90 ℃ oil bath temperature for 24 h. The reaction mixture was cooled to room temperature, then water was added thereto, followed by extraction with EtOAc, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 150g, hexane/EtOAc 88/12 to 0/100) to obtain a racemic mixture of the title compound (1.2g) (light yellow oil). Based on the racemic Compound analysis conditions described previously (Condition 1, Rt)¹＝3.6min，Rt²7.0min) to obtain a racemic mixture with short relative retention time (Rt) using a semi-preparative column separation¹3.6min) of the title compound (0.39g) (colorless solid).

LCMS retention time: 0.90 min.

MS(ESI pos.)m/z：434[M+H]⁺

[α]_D ²⁵＝-71.0(c＝0.0994，CHCl₃)

Examples 2 to 4 were obtained by the same procedure as in example 1. The structural formula, name, LCMS data and specific optical rotation of the obtained compound are shown in Table 2.

[ Table 2]

Example 5: (-) - [ (2S,5S) -2- { [4- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -5-methyl-1, 3-oxazolidin-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone

[ formula 45]

By using (2RS,5S) -5-methyl-3- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoyl group obtained in reference example 5]-1, 3-oxazolidin-2-carboxylic acid ethyl ester (0.11g, 0.33mmol) as a starting material, the same procedure as in reference example 2 was carried out to obtain [2- (hydroxymethyl) -5-methyl-1, 3-oxazolidin-3-yl group][ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl]Diastereomeric mixtures of methanones (colorless oils). The obtained mixture of diastereomers was purified by thin layer chromatography (1mm, hexane/EtOAc ═ 50/50) to obtain [ (2S,5S) -2- (hydroxymethyl) -5-methyl-1, 3-oxazolidin-3-yl group][ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl]Methanone (colorless oil). To the obtained [ (2S,5S) -2- (hydroxymethyl) -5-methyl-1, 3-oxazolidin-3-yl group was added under ice water cooling][ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl]Methanone (30.2mg, 0.10mmol) and TEA (0.021mL, 0.15mmol) in CHCl₃(0.8mL), MsCl (0.011mL, 0.15mmol) was added and the resulting mixture was stirred for 1 hour. Water was added to the reaction mixture with ice water cooling, followed by CHCl₃And (4) extracting. The organic layer was washed with saturated aqueous sodium chloride solution and then with Na₂SO₄Drying is then carried out, the drying agent is filtered off and the solvent is then distilled off under reduced pressure. 5-fluoro-2- (1H-pyrazol-4-yl) pyridine (0.033g, 0.20mmol) and Cs₂CO₃(0.065g, 0.20mmol) was added to the obtained residue solution (0.5 mL). The resulting mixture was reacted at 120 ℃ for 1 hour under microwave irradiation. Will be provided withThe reaction mixture was cooled, water was added thereto, followed by CHCl₃Extraction, the extract was passed through an ISOLUTE phase separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by HPLC to obtain the title compound (0.020g) (colorless oil).

LCMS retention time: 0.92 min.

MS(ESI pos.)m/z：448[M+H]⁺

[α]_D ²⁵＝-80.4(c＝0.0828，CHCl₃)

Examples 6 to 10 were obtained by the same procedure as in example 5. The structural formula, name, LCMS data and specific optical rotation of the obtained compound are shown in Table 3.

[ Table 3]

Example 11: (±) - (2- { [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazolidin-3-yl) [2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone

[ formula 46]

To 2- [1- (2, 2-diethoxyethyl) -1H-pyrazol-3-yl group obtained in reference example 12]-5-fluoropyridine (4.0g, 14.3mmol) in CHCl₃To a solution in (72mL) was added TFA (6.4mL, 85.9mmol), and the resulting mixture was stirred at 35 ℃ for 6 h. TFA (6.4mL, 85.9mmol) was added and the mixture was stirred at 35 ℃ for 3 h. The reaction mixture was cooled to room temperature and then NaHCO was added₃The aqueous solution is added to the reaction mixturePost-use CHCl₃And (4) extracting. The organic layer was washed with saturated aqueous sodium chloride solution and MgSO₄Dried and the drying agent filtered off. The solvent was distilled off under reduced pressure to obtain [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl]Acetaldehyde (colorless oil). To [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl]Acetaldehyde in CHCl₃To a solution in (36mL) was added activated molecular sieve 4A (29g) and 2-aminoethanol (1.1mL, 14.3mmol), and the resulting mixture was stirred at room temperature for 48 hours. By passingMolecular sieve 4A was filtered off, and then the solvent was distilled off under reduced pressure to obtain a colorless oil. To a solution of the obtained colorless oil (0.10g, 0.40mmol) and 2- (2H-1,2, 3-triazol-2-yl) benzoic acid (76mg, 0.40mmol) in DMF (0.4mL) were added DIPEA (0.21mL, 1.2mmol) and HATU (0.16g, 0.48mmol), and the resulting mixture was stirred at room temperature for 48 hours. The reaction mixture was purified by HPLC to obtain the title compound (40.8mg) (colorless solid).

LCMS retention time: 0.83 min.

MS(ESI pos.)m/z：420[M+H]⁺

Examples 12 to 38 were obtained by the same procedure as in example 11. Examples 26 to 32 and examples 34 to 38 were optically separated by the same procedure as in example 1. The structural formula, name, LCMS data and specific optical rotation of the obtained compound are shown in tables 4-1 to 4-4.

[ Table 4-1]

[ tables 4-2]

[ tables 4 to 3]

[ tables 4 to 4]

Example 39: [ (2S,4S) -2- { [4- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -4-methyl-1, 3-oxazinan-3-yl } [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone

[ formula 47]

To a solution of [ (2S,4S) -2- (hydroxymethyl) -4-methyl-1, 3-oxazinan-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone (0.070g, 0.22mmol) obtained in reference example 17 in toluene (1mL) were added 5-fluoro-2- (1H-pyrazol-4-yl) pyridine (0.040g, 0.24mmol) obtained in reference example 11 and cyanomethylenetributylphosphine (0.087mL, 0.33mmol), and the resulting mixture was stirred at 100 ℃ for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (KP-NH12g, hexane/EtOAc ═ 80/20 to 0/100) (HP-Sil 10g, hexane/EtOAc ═ 80/20 to 0/100) to obtain the title compound (0.11g) (colorless oil).

LCMS retention time: 0.96 min.

MS(ESI pos.)m/z：462[M+H]⁺

Example 40: (-) - [ (2S,5S) -2- { [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -5-methyl-1, 3-oxazinan-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone

[ formula 48]

The same procedures as in reference example 2 were carried out by using ethyl (2RS,5RS) -5-methyl-3- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoyl) -1, 3-oxazinan-2-carboxylate (0.13g, 0.36mmol) obtained in reference example 18 as a starting material to obtain [ (2RS,5RS) -2- (hydroxymethyl) -5-methyl-1, 3-oxazinan-3-yl][ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl]Methanone (0.098g) (colorless oil). The same procedures as in example 39 were carried out by using the obtained colorless oil (0.098g, 0.31mmol) and 5-fluoro-2- (1H-pyrazol-4-yl) pyridine (0.056g, 0.34mmol) obtained in reference example 11 as starting materials to obtain a racemic mixture (0.11g) of the title compound. Based on the racemic Compound analysis conditions described previously (Condition 7, Rt)¹＝4.3min，Rt²4.8min) the resulting racemic mixture was separated using a semi-preparative column to obtain the title compound (0.44g) (Rt) with short relative retention time¹4.3min) (colorless oil).

LCMS retention time: 0.94 min.

MS(ESI pos.)m/z：462[M+H]⁺

[α]_D ²³＝-44.1(c＝0.0704，CHCl₃)

Example 41: (-) - [2- { [3- (4-fluorophenyl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazinan-3-yl ] [ 5-methyl-2- (pyrimidin-2-yl) phenyl ] methanone

[ formula 49]

To (. + -.) - (2- { [3- (4-fluorophenyl) -1H-pyrazol-1-yl) obtained in reference example 23 was added]To a solution of methyl } -1, 3-oxazinan-3-yl) (2-iodo-5-methylphenyl) methanone (0.19g, 0.38mmol) and (tributylstannyl) pyrimidine (0.15mL, 0.46mmol) in toluene (4mL) was added Pd (PPh)₃)₄(0.044g, 0.04mmol), copper iodide (0.0070g, 0.040mmol) and cesium fluoride (0.12g, 0.76mmol), and the resulting mixture was stirred under microwave irradiation at 130 ℃ for 0.5 hours. Aqueous potassium fluoride solution was added to the reaction mixture followed by CHCl₃And (4) extracting. The organic layer was washed with an aqueous potassium fluoride solution, water and a saturated aqueous sodium chloride solution. The organic layer was washed with Na₂SO₄Dry, filter off the drying agent and then concentrate under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10g, hexane/EtOAc ═ 80/20 to 0/100) (KP-NH12g, hexane/EtOAc ═ 80/20 to 0/100) to obtain a racemic mixture of the title compound (0.099g) (colorless oil). Based on the racemic Compound analysis conditions described previously (Condition 4, Rt)¹＝3.9min，Rt²13.7min) using a semi-preparative column to obtain a racemic mixture with short relative retention time (Rt)¹3.9min) of the title compound (0.036g) (colorless oil).

LCMS retention time: 1.0 min.

MS(ESI pos.)m/z：458[M+H]+

[α]_D ²³＝-34.1(c＝0.0914，CHCl₃)

Examples 42 to 44 were obtained by the same procedure as in example 41. The structural formulae, names, LCMS data and specific optical rotations of examples 42 to 44 are shown in Table 5.

[ Table 5]

Example 45: (-) - [2- { [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl ] methyl } -1, 3-oxazolidin-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone

[ formula 50]

By using [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl group obtained in reference example 30]Acetaldehyde (0.80g, 3.9mmol), the same procedure as in example 11 was conducted to obtain a racemic mixture (0.063g) (pale yellow solid). Based on the racemic Compound analysis conditions described previously (Condition 9, Rt)¹＝4.6min，Rt²13.8min) using a semi-preparative column to obtain a racemic mixture with short relative retention time (Rt)¹4.6min) of the title compound (0.017g) (colourless solid).

LCMS retention time: 1.0 min.

MS(ESI pos.)m/z：434[M+H]+

[α]_D ²³＝-104.0(c＝0.0566，CHCl₃)

Example 46: (-) - [2- { [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl ] methyl } -1, 3-oxazolidin-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone

[ formula 51]

By using 2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl group obtained in reference example 22]Ethanol (0.30g, 1.5mmol) asThe same procedures as in reference example 25 were carried out to obtain a racemic mixture (0.039g) of the title compound as a starting material (colorless oil). Based on the racemic Compound analysis conditions described previously (Condition 2, Rt)¹＝16.3min，Rt²19.2min) the racemic mixture obtained was separated using a semi-preparative column to obtain a solid phase with a short relative retention time (Rt)¹16.3min) of the title compound (0.0076g) (colorless solid).

LCMS retention time: 0.97 min.

MS(ESI pos.)m/z：434[M+H]⁺

[α]_D ²³＝-80.9(c＝0.0478，CHCl₃)

Example 47: (-) - [2- { [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl ] methyl } -1, 3-oxazinan-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone

[ formula 52]

By using 2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl group obtained in reference example 22]Ethanol (0.30g, 1.5mmol) was used as a starting material, and the same procedures as in reference example 25 were carried out to obtain a racemic mixture (0.19g) of the title compound as a colorless solid. Based on the racemic Compound analysis conditions described previously (Condition 11, Rt)¹＝9.9min，Rt²11.5min) the racemic mixture obtained was separated using a semi-preparative column to obtain a solid phase with a short relative retention time (Rt)¹9.9min) of the title compound (0.0095g) (colorless solid).

LCMS retention time: 0.97 min.

MS(ESI pos.)m/z：448[M+H]⁺

[α]_D ²³＝-21.4(c＝0.109，CHCl₃)

Example 48: (-) - (2- { [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazinan-3-yl) [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone

[ formula 53]

To a solution of 5-fluoro-2- (1H-pyrazol-3-yl) pyridine (0.36g, 2.2mmol) obtained in reference example 10 in DMF (9mL) was added sodium hydride (55%, 0.12g, 2.7mmol), and the resulting mixture was stirred at room temperature for 30 minutes. A solution of [2- (chloromethyl) -1, 3-oxazinan-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone (0.79g, 2.5mmol, 84.2% ee) obtained in reference example 32 in DMF (3mL) was added dropwise thereto. The reaction mixture was stirred at 90 ℃ for 1 hour. The reaction mixture was cooled to room temperature, then water was added thereto, followed by extraction with EtOAc.

The organic layer was washed with water and saturated aqueous sodium chloride solution, and then with Na₂SO₄Drying is then carried out, the drying agent is filtered off and the solvent is then distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 40g, hexane/EtOAc: 70/30 to 0/100). EtOH (10mL) was added thereto, and the resulting mixture was stirred under cooling in an ice bath for 1 hour, and then filtered off to obtain the title compound (0.60g,>99.9% ee, same stereochemistry as in example 3) (colorless solid). Based on the racemic Compound analysis conditions described previously (Condition 9, Rt)¹＝4.3min，Rt²6.7min) to obtain a sample with a short relative retention time (Rt)¹4.3min) was added.

LCMS retention time: 0.90 min.

MS(ESI pos.)m/z：448[M+H]⁺

Example 49: (-) - [ (2S,5R) -2- { [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -5-methyl-1, 3-oxazinan-3-yl ] [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone

[ formula 54]

By using (2RS,5SR) - [2- (chloromethyl) -5-methyl-1, 3-oxazinan-3-yl group obtained in reference example 35][ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl]Methanone (0.52g, 1.5mmol) and 5-fluoro-2- (1H-pyrazol-4-yl) pyridine (0.23g, 1.4mmol) obtained in reference example 11 were subjected to the same procedures as in example 48 to obtain the title compound (0.44 g). Based on the racemic Compound analysis conditions described previously (Condition 13, Rt)¹＝6.6min，Rt²12.4min) the racemic mixture obtained was separated using a semi-preparative column (0.070g) to obtain a column with a short relative retention time (Rt)¹6.6min) of the title compound (0.030g) (colourless oil).

LCMS retention time: 0.95 min.

MS(ESI pos.)m/z：462[M+H]⁺

[α]_D ²⁵＝-14.1(c＝0.0870，CHCl₃)

Test example (measurement of orexin antagonistic Activity)

Antagonistic activity of the test compounds against the human orexin-1 receptor (hOX1R) and the orexin-2 receptor (hOX2R) was determined by modifying the methods described in the literature (Toshikatsu Okumura et al, Biochemical and biophysical research Communications280, 976-981, 2001). Chinese Hamster Ovary (CHO) cells forced (forcedly) to express hOX1R and hOX2R were seeded at 20,000 cells per well onto 96-well black transparent plates (Nunc) which were 5% at 37%CO₂In Ham's F-12 medium containing 0.1mM MEM non-essential amino acids, 0.5mg/mL G418, 10% fetal bovine serum (all from Invitrogen) for 16 hours. After removal of the medium, 100. mu.L of 0.5. mu.M Fluo-4AM ester (Dojin) assay buffer (25mM HEPES (Dojin), Hank's Balanced salt solution (Invitrogen), 0.1% bovine serum albumin, 2.5mM probenecid, 200. mu.g/ml Amararth (all from Sigma-Aldrich), pH7.4) was added and the cells were incubated at 37 ℃ with 5% CO₂And incubated for 60 minutes. After removal of assay buffer containing fluo-3AM ester, test compounds were dissolved in dimethyl sulfoxide to 10mM and diluted with assay buffer, 150 μ L thereof was added and incubated for 30 min.

The 2 amino acid substituted ligand Peptide of human orexin-A (Pyr-Pro-Leu-Pro-Asp-Ala-Cys-Arg-Gln-Lys-Thr-Ala-Ser-Cys-Arg-Leu-Tyr-Glu-Leu-Leu-His-Gly-Ala-Gly-Asn-His-Ala-Gly-Ile-Leu-Thr-Leu-NH 2; Peptide Institute, Inc.) was diluted with assay buffer to give a final concentration of 300pM for hOX1R and 3nM for hOX2R and 50. mu.L of ligand solution was added to start the reaction. The fluorescence intensity of the reaction of each well was measured every second using a Functional Drug Screening System (FDSS; Hamamatsu photonics K.K.) for 3 minutes, and the maximum fluorescence intensity was used as intracellular Ca²⁺Concentration of the indicator to determine antagonist activity. The antagonistic activity of the test compound was calculated when the fluorescence intensity of the well to which only the dilution buffer was added was 100% and the fluorescence intensity of the well to which the buffer containing no ligand or compound was added was 0%, and the 50% Inhibitory Concentration (IC) was determined from the fluorescence intensity when several concentrations of the compound were added₅₀Value).

IC of the Compounds of the invention₅₀The values are shown in Table 6.

[ Table 6]

INDUSTRIAL APPLICABILITY

The compounds of the present invention have been shown to have OX receptor antagonistic activity. Accordingly, the compound of the present invention or a pharmaceutically acceptable salt thereof can be used as a therapeutic or prophylactic agent for diseases modulated by OX receptor antagonistic activity, such as sleep disorders, depression, anxiety disorders, panic disorders, schizophrenia, drug dependence, alzheimer's disease, parkinson's disease, huntington's chorea, eating disorders, headache, migraine, pain, gastrointestinal diseases, epilepsy, inflammation, immunological diseases, endocrine diseases and hypertension.

Claims

1. A compound represented by formula (IA):

[ formula 1]

Wherein the content of the first and second substances,

X¹and X²Identical or different and represents a nitrogen atom or formula CH;

y represents any one of the following formulae (a):

[ formula 2]

n represents 1 or 2;

R¹represents a hydrogen atom, a halogen atom or C_1-6An alkyl group;

R²represents triazolyl, pyridyl or pyrimidinyl;

R⁴represents a hydrogen atom or C_1-6An alkyl group;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof,

wherein, in the above formula (IA),

R²is triazolyl or pyrimidinyl; and

R³is a halogen atom.

3. The compound according to claim 1 or 2, wherein n is 2 in the above formula (IA), or a pharmaceutically acceptable salt thereof.

4. A compound represented by formula (I):

[ formula 3]

Wherein the content of the first and second substances,

X¹and X²Identical or different and represents a nitrogen atom or formula CH;

Y¹and Y²Either represents a nitrogen atom and the other represents CH;

n represents 1 or 2;

R¹represents a hydrogen atom, a halogen atom or C_1-6An alkyl group;

R²represents triazolyl, pyridyl or pyrimidinyl;

R⁴represents a hydrogen atom or C_1-6An alkyl group;

or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 4 or a pharmaceutically acceptable salt thereof,

wherein, in the above formula (I),

R²is triazolyl or pyrimidinyl; and

R³is a halogen atom.

6. The compound according to claim 4 or 5, wherein n is 2 in the above formula (I), or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is one compound, or a mixture of two or more compounds, selected from:

8. A pharmaceutical composition containing a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient.

9. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of sleep disorders, depression, anxiety disorders, panic disorders, schizophrenia, drug dependence, alzheimer's disease, parkinson's disease, huntington's chorea, eating disorders, pain, gastrointestinal disorders, epilepsy, inflammation, immunological disorders, endocrine disorders or hypertension.

10. Use according to claim 9, wherein the pain is headache.

11. Use according to claim 10, wherein the headache is migraine.