WO2018117166A1

WO2018117166A1 - Thiazole derivative or pharmacologically acceptable salt of same

Info

Publication number: WO2018117166A1
Application number: PCT/JP2017/045770
Authority: WO
Inventors: 文也棚田; 秀明平澤; 陽輔務台; 喜朗木島; 小林　淳一
Original assignee: キッセイ薬品工業株式会社
Priority date: 2016-12-21
Filing date: 2017-12-20
Publication date: 2018-06-28
Also published as: JPWO2018117166A1

Abstract

The present invention addresses the problem of providing: a novel thiazole derivative or a pharmacologically acceptable salt thereof; a pharmaceutical composition which contains the thiazole derivative or a pharmacologically acceptable salt thereof; and a pharmaceutical use of the pharmaceutical composition. The present invention provides a compound represented by formula (I), which has TRPM 8 inhibitory activity, or a pharmacologically acceptable salt of the compound. (In the formula, ring A represents thiazole or the like; ring B represents a C_6-10 aryl or the like; each of R^2a and R^2b independently represents a hydrogen atom or the like; R³ represents a hydrogen atom or the like; R^4arepresents a hydrogen atom or the like; R^4b represents a hydrogen atom or the like; R⁵ represents a hydrogen atom or the like; R⁶ represents a hydrogen atom or the like; R^7a represents a hydrogen atom or the like; R^7b represents a hydrogen atom or the like; and n represents 0 or 1.) In addition, a compound represented by formula (I) or a pharmacologically acceptable salt of the compound is able to be used as a therapeutic or prophylactic agent for diseases or conditions associated with hyperexcitement or disorder of afferent nerves.

Description

Thiazole derivative or pharmacologically acceptable salt thereof

The present invention relates to a thiazole derivative useful as a pharmaceutical product, or a pharmacologically acceptable salt thereof, a pharmaceutical composition containing the same, and a pharmaceutical use thereof.

Transient Receptor Potential (TRP) channels are non-selective cation channels that are activated by various stimuli such as temperature and chemicals. TRPM, TRPA, TRPV, TRPC, TRPP, TRPML Divided into the TRPN family. Furthermore, TRPM1, TRPM2, TRPM3, TRPM4a, TRPM4b, TRPM5, TRPM6, TRPM7, and TRPM8 are known in the TRPM family (see, for example, Non-Patent Document 1).
TRPM8 is the 8th channel of the TRPM family cloned in 2002 (see, for example, Non-Patent Document 2) and is also known as CMR1 (cold and menthol sensitive receptor-1). It is activated by a chemical substance (menthol or Icilin) that causes stimulation or low-temperature sensation (see, for example, Non-Patent Documents 1 and 2). TRPM8 is expressed in primary afferent nerve (Aδ fiber and C fiber) and trigeminal nerve, taste papillae, vascular endothelium, aorta, pulmonary artery, prostate, male genital organ (see Non-Patent Document 3, for example), human bladder It is also expressed in nerve fibers that control the epithelium (for example, see Non-Patent Document 4), prostate cancer (for example, see Non-Patent Document 5), oral squamous cell carcinoma (for example, see Non-Patent Document 6), etc. It has been reported.
In TRPM8 knockout mice, lack of cold perception, lack of hypersensitivity to cold stimulation after neuropathy or inflammation, etc. (see, for example, Non-Patent Document 3).
In nervous system diseases, expression of TRPM8 is increased in sciatic nerve disorder model rats, and it has been reported that it is involved in cold hyperalgesia (see, for example, Non-Patent Document 7). It has also been shown that TRPM8 expression is increased in rats and mice due to peripheral neuropathy caused by oxaliplatin, and that TRPM8 is involved in cold hyperalgesia due to oxaliplatin (for example, Non-patent Document 8 and 9). TRPM8 is also involved in peripheral neuropathic pain caused by oxaliplatin in humans, as in rodents, because patients taking oxaliplatin have increased responsiveness to menthol compared to healthy individuals (For example, refer nonpatent literature 10).
Regarding urinary system diseases, it has been reported that TRPM8 is involved in frequent urination symptoms caused by low temperature in rats (see, for example, Non-Patent Document 11). In rats, TRPM8 is expressed in nerves that doubly control skin and bladder in rats, and is considered to be involved in the feeling of urination urgency caused by low temperature (for example, see Non-Patent Document 12). In patients with upper central nervous disease such as cats, stroke, and spinal cord injury, infusion of a small amount of cold water into the bladder induces an unusual micturition reflex, which is enhanced by menthol (e.g., menthol) Non-patent documents 13 and 14). Further, in cats, this micturition reflex is reduced by desensitization of C fibers, and therefore, it is considered that menthol-sensitive C fibers are involved (see, for example, Non-Patent Document 13).
In addition, an increase in TRPM8 expression was confirmed in nerve fibers in the subepithelial bladder of patients with idiopathic detrusor overactivity / bladder pain syndrome, and TRPM8 expression was correlated with urination frequency and pain score. (See, for example, Non-Patent Document 15) TRPM8 may play an important role in urine storage in the bladder afferent.
Therefore, by inhibiting TRPM8, treatment or prevention of diseases or symptoms resulting from TRPM8 activation is expected.

Thiazole derivatives are described in Patent Documents 1 to 7.

However, the compounds described in the above documents differ in structure from the compounds of the present invention, and there is no description or suggestion of a TRPM8 inhibitor.

International Publication No. 2010/094755 Pamphlet International Publication No. 2013/106761 Pamphlet International Publication No. 2012/129562 International Publication No. 2008/106202 Pamphlet International Publication No. 2005/000300 Pamphlet International Publication No. 2003/097047 Pamphlet International Publication No. 2016/161268 Pamphlet

An object of the present invention is to provide a novel thiazole derivative, or a pharmacologically acceptable salt thereof, a pharmaceutical composition containing the same, and a pharmaceutical use thereof.

The present inventors diligently studied to find a novel thiazole derivative. As a result, the present inventors have found that the compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof has a potent TRPM8 inhibitory action, and has made the present invention.

That is, the means for solving the above problems are as follows.
[1] Compound represented by formula (I):

[Where,
Ring A is a group selected from the group consisting of the following (a) to (d):

((**) represents the bonding position with the benzene ring, and (***) represents the bonding position with the ring B);
R ¹ is a hydrogen atom, hydroxy, amino, C _1-6 alkyl or hydroxy C _1-6 alkyl;
Ring B is C _6-10 aryl or heterocycle;
R ^2a and R ^2b each independently represent a hydrogen atom, a halogen atom, hydroxy, amino, C _1-6 alkyl, C _1-6 alkoxy, hydroxy C _1-6 alkyl, haloC _1-6 alkyl or haloC _1-6 alkoxy;
R ³ is a hydrogen atom, a halogen atom, C _1-6 alkyl, C _1-6 alkoxy or haloC _1-6 alkyl;
R ^4a is a hydrogen atom or CR ⁸ R ⁹ R ¹⁰ ;
R ^4b is a hydrogen atom or C _1-6 alkyl;
R ⁵ is a hydrogen atom or C _1-6 alkyl;
Ring C is a group selected from C _6-10 aryl or the group consisting of: pyridyl, pyrimidyl, thiazolyl, pyrazinyl, pyrazolyl, imidazolyl, pyridazinyl, triazolyl, indolyl, isoquinolyl and tetrazolyl;
R ⁶ represents a hydrogen atom, a halogen atom, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, cyano, hydroxy C _1-6 alkyl, hydroxy C _1-6 alkoxy, halo C _1-6 alkyl, halo C _{1 -6} alkoxy, amino, C _1-6 alkoxy C _1-6 alkoxy, carbamoyl or C _1-6 alkoxy C _1-6 alkyl;
R ^7a is a hydrogen atom, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, hydroxy C _1-6 alkyl, hydroxy C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, fluorine atom or amino C _1-6 alkyl;
R ^7b is a hydrogen atom, a fluorine atom or C _1-6 alkyl;
However, R ⁵ and R ^7b together are the following groups:

May be formed;
R ⁸ , R ⁹ and R ¹⁰ are each independently a hydrogen atom, hydroxy, C _1-6 alkyl, amino, NR ¹¹ R ¹² C _1-6 alkyl, C _1-6 alkoxy, hydroxy C _1-6 alkyl C _1-6 alkoxy C _1-6 alkyl, fluorine atom, carbamoyl, fluoro C _1-6 alkyl or dihydroxy C _1-6 alkyl;
R ¹¹ and R ¹² are each independently a hydrogen atom, C _1-6 alkyl or (C _1-6 alkyl) carbonyl;
R ¹³ is hydroxy C _1-6 alkyl;
n is 0 or 1] or a pharmacologically acceptable salt thereof.

[2] The compound according to [1] above:
Ring A is a group represented by the following formula:

((**), (***) and R ¹ have the same meanings as [1] above);
Or a pharmacologically acceptable salt thereof.
[3] The compound according to [1] or [2] above:
Ring B is C _6-10 aryl;
R ^2a and R ^2b are each independently a hydrogen atom, a halogen atom, hydroxy, amino, C _1-6 alkyl, C _1-6 alkoxy or hydroxy C _1-6 alkyl;
R ³ is a hydrogen atom or a halogen atom;
R ^4b is a hydrogen atom;
Ring C is C _6-10 aryl or a group selected from: pyridyl, pyrimidyl, pyrazolyl and triazolyl;
R ⁶ is a hydrogen atom, a halogen atom, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, cyano, hydroxy C _1-6 alkyl or hydroxy C _1-6 alkoxy;
R ^7a is a hydrogen atom, hydroxy, C _1-6 alkyl, C _1-6 alkoxy or hydroxy C _1-6 alkyl;
R ⁸ , R ⁹ and R ¹⁰ are each independently a hydrogen atom, hydroxy, C _1-6 alkyl, amino, C _1-6 alkoxy, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 A compound or a pharmaceutically acceptable salt thereof, which is an alkyl or fluorine atom.
[4] The compound according to any one of [1] to [3] above:
Ring B is phenyl;
A compound or a pharmaceutically acceptable salt thereof, wherein n is 1.
[5] The compound according to any one of [1] to [4] above:
R ⁵ is a hydrogen atom;
R ^7a is a hydrogen atom, hydroxy, C _1-6 alkyl or C _1-6 alkoxy;
A compound or a pharmaceutically acceptable salt thereof, wherein R ^7b is a hydrogen atom.
[6] The compound according to any one of [1] to [5] above:
R ^4a is CR ⁸ R ⁹ R ¹⁰ (R ⁸ , R ⁹ and R ¹⁰ have the same meanings as defined in [3] above);
Or a pharmacologically acceptable salt thereof.

[7] The compound according to any one of [1] to [6] above:
Ring A is a group represented by the following formula:

((**), (***) and R ¹ have the same meanings as [1] above);
Or a pharmaceutically acceptable salt thereof.
[8] The compound according to any one of [1] to [7] above:
R ¹ is a hydrogen atom, hydroxy or amino;
Ring C is a group selected from the group consisting of: pyridyl, pyrimidyl, pyrazolyl and triazolyl;
A compound or a pharmaceutically acceptable salt thereof, wherein R ⁶ is a hydrogen atom, hydroxy or halogen atom.

[9] The compound according to [1], represented by formula (II):

[Where
R ^2c and R ^2d are each independently a hydrogen atom, a halogen atom or C _1-6 alkoxy (however, they are not simultaneously a hydrogen atom);
Ring C ′ is a group selected from C _6-10 aryl or the group consisting of: pyridyl, pyrimidyl, pyrazolyl and triazolyl;
R ^3a is a hydrogen atom, a halogen atom, C _1-6 alkyl or C _1-6 alkoxy;
R ^4c is a group represented by the following formula:

R ^6a is a hydrogen atom or a halogen atom;
R ^7c is a hydrogen atom, hydroxy, C _1-6 alkyl or C _1-6 alkoxy;
R ^9a and R ^10a are each independently a hydrogen atom, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, hydroxy C _1-6 alkyl or a fluorine atom] or a pharmaceutically acceptable salt thereof salt.
[10] The compound according to [9] above:
R ^3a is a hydrogen atom or a halogen atom;
R ^4c is a group represented by the following formula:

(Wherein R ^9a and R ^10a have the same meanings as [9] above);
Or a pharmaceutically acceptable salt thereof.
[11] A pharmaceutical composition comprising the compound according to any one of [1] to [10] above or a pharmacologically acceptable salt thereof, and a pharmaceutical additive.
[12] The pharmaceutical composition according to [11] above, which is a pharmaceutical composition for treating or preventing a disease or symptom caused by hyperexcitability or disorder of afferent nerves.

As another embodiment, means for solving the above problems are the following [13] and [14].

[13] A disease caused by hyperexcitation or disorder of afferent nerves, comprising administering an effective amount of the compound according to any one of [1] to [10] above or a pharmacologically acceptable salt thereof, How to treat or prevent symptoms.
[14] The compound according to any one of [1] to [10] above or a drug thereof for producing a pharmaceutical composition for treating or preventing a disease or symptom caused by hyperexcitability or disorder of afferent nerves The use of a physically acceptable salt.

The compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof is, for example, an Icilin-induced wet-dog shake inhibitory action confirmation test according to the method described in International Publication No. 2009/012430. Showed a strong inhibitory action. Therefore, the compound represented by the formula (I) of the present invention, or a pharmacologically acceptable salt thereof, is useful as a therapeutic or prophylactic agent for a disease or symptom caused by hyperexcitation or disorder of afferent nerve. .

The terms used in this specification will be explained.

“Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferably it is a fluorine atom or a chlorine atom.

“C _1-6 alkyl” means an optionally branched alkyl having 1 to 6 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2- Examples include dimethylpropyl, n-hexyl, isohexyl and the like.

“C _1-6 alkoxy” means an optionally branched alkoxy having 1 to 6 carbon atoms. Examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.

“Halo C _1-6 alkyl” means the above C _1-6 alkyl substituted with 1 to 5 of the same or different halogen atoms. For example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 2,2,2-tri Fluoroethyl, 1,1,2,2,2-pentafluoroethyl, 2,2,2-trichloroethyl, 3-fluoropropyl, 2-fluoropropyl, 1-fluoropropyl, 3,3-difluoropropyl, 2, Examples include 2-difluoropropyl, 1,1-difluoropropyl, 1-fluorobutyl, 1-fluoropentyl, 1-fluorohexyl and the like.

“Halo C _1-6 alkoxy” means the above C _1-6 alkoxy substituted with 1 to 5 of the same or different halogen atoms. For example, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-chloroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 1,1-difluoroethoxy, 1,2-difluoroethoxy, 2,2,2- Trifluoroethoxy, 1,1,2,2,2-pentafluoroethoxy, 2,2,2-trichloroethoxy, 3-fluoropropoxy, 2-fluoropropoxy, 1-fluoropropoxy, 3,3-difluoropropoxy, 2 , 2-difluoropropoxy, 1,1-difluoropropoxy, 4-fluorobutoxy, 5-fluoropentyloxy, 6-fluorohexyloxy and the like.

“Hydroxy C _1-6 alkyl” means the above C _1-6 alkyl substituted with 1 to 5 hydroxy. Preferably, it is monohydroxy C _1-6 alkyl or dihydroxy C _1-6 alkyl. For example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, 3-hydroxypropyl, 1,2-dihydroxyethyl, 1,3-dihydroxy And propyl.

“Hydroxy C _1-6 alkoxy” means the above C _1-6 alkoxy substituted with 1 to 5 hydroxy. Examples include hydroxymethoxy, 1-hydroxyethoxy, 2-hydroxypropan-2-yloxy, 2-hydroxyethoxy, 2-hydroxy-2-methylpropoxy, 3-hydroxypropoxy and the like.

“C _1-6 alkoxy C _1-6 alkyl” means the above C _1-6 alkyl substituted with the above C _1-6 alkoxy.

“C _1-6 alkoxy C _1-6 alkoxy” means the above C _1-6 alkoxy substituted by the above C _1-6 alkoxy.

“C _6-10 aryl” refers to phenyl or naphthyl.

“Amino C _1-6 alkyl” means the above C _1-6 alkyl substituted with amino.

“(C _1-6 alkyl) carbonyl” means a carbonyl substituted with the above C _1-6 alkyl. Examples thereof include acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, isobutylcarbonyl, butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, hexylcarbonyl and the like.

“Heterocycle” refers to a 5- or 6-membered heterocycle containing 1 to 4 heteroatoms selected from sulfur, oxygen, and nitrogen, and includes, for example, furyl, thienyl, pyrrolyl, pyrazolyl, Imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, 1-oxidepyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furazanyl and other aromatic heterocycles, pyrrolinyl, imidazolinyl , Pyrazolinyl, dihydropyranyl, dihydrothiopyranyl, dihydropyridyl, dihydropyrimidinyl and the like, and morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piper Piperazinyl, it can be mentioned saturated heterocyclic ring such as tetrahydrofuranyl. The “heterocycle” may be condensed with another cyclic group, for example, isobenzofuranyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, chromenyl, chromanonyl. , Xanthenyl, phenoxathiinyl, indolizinyl, isoindolidinyl, indolyl, indazolyl, purinyl, quinolidinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, carbazolyl, carbolinyl, acridinyl, isoindolinyl, 2,3-dihydrobenzofuran Nyl, imidazo [1,2-a] pyridyl, imidazo [1,2-a] pyrazinyl, benzo [1,3] dioxolyl, benzothienyl, 5,6,7,8-tetrahydroimidazo [1,2-a] Pyrazinyl, azaindori Mention may be made of a nil or the like.

The “heterocycle” of ring B is preferably pyridyl, benzo [1,3] dioxolyl or thienyl.

Hereinafter, the present invention will be described in more detail.

The compound represented by the formula (I) of the present invention includes stereoisomers such as optical isomers, geometric isomers and the like.
The optical isomer of the compound represented by the formula (I) of the present invention may have any configuration of R configuration or S configuration at each asymmetric carbon atom. In addition, any optical isomer is included in the present invention, and a mixture of these optical isomers is also included. Furthermore, a racemate consisting of an equal amount of each optical isomer in a mixture of optically active substances is also included in the scope of the present invention. When the compound represented by the formula (I) of the present invention is a racemic solid or crystal, a racemic compound, a racemic mixture and a racemic solid solution are also included in the scope of the present invention.
In the compound represented by the formula (I) of the present invention, when a geometric isomer exists, the present invention includes any of the geometric isomers.
Moreover, in the compound represented by the formula (I) of the present invention, when a tautomer exists, the present invention includes any of the tautomers.

The compound represented by the formula (I) of the present invention can be converted into a pharmacologically acceptable salt thereof according to a conventional method as necessary. Examples of such salts include acid addition salts and salts with bases.

Acid addition salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, Acid addition with organic acids such as p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid A salt etc. can be mentioned.

Examples of salts with bases include salts with inorganic bases such as sodium salts, potassium salts, calcium salts and magnesium salts, and salts with organic bases such as piperidine, morpholine, pyrrolidine, arginine and lysine.

Further, the compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof includes solvates with pharmaceutically acceptable solvents such as hydrates and ethanol.

TRPM8 is a cation channel that is expressed in dorsal root ganglia and trigeminal ganglia. A TRPM8 inhibitor decreases the amount of cation inflow into cells via TRPM8 and suppresses an increase in intracellular cation concentration. Based on this action, TRPM8 inhibitors are useful as therapeutic or preventive agents for symptoms such as lower urinary tract symptoms (LUTS), especially overactive bladder (OAB), by suppressing overexcited afferent nerve activity. is there.
In addition, the TRPM8 inhibitory action can be evaluated by the efficacy of suppressing the wet-dog shake action induced by administration of Icilin, which is a TRPM8 agonist. Furthermore, an effect on overactive bladder (OAB) can be evaluated by a test for confirming an extension effect on the urination interval of acetic acid-induced detrusor overactive bladder according to the method described in J.Urol., 2001, 166, 1142. .

Another embodiment of the compound represented by the formula (II) of the present invention is as follows. Each symbol has the same meaning as described above.
R ^2c and R ^2d are each independently a hydrogen atom, a halogen atom or C _1-6 alkoxy (however, they are not simultaneously a hydrogen atom);
Ring C ′ is a group selected from the group consisting of: pyridyl, pyrimidyl, pyrazolyl and triazolyl;
R ^3a is a hydrogen atom, a halogen atom, C _1-6 alkyl or C _1-6 alkoxy;
R ^4c is a group represented by the following formula:

R ^6a is a hydrogen atom or a halogen atom;
R ^7c is a hydrogen atom, hydroxy, C _1-6 alkyl or C _1-6 alkoxy;
R ^9a and R ^10a are each independently a hydrogen atom, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, hydroxy C _1-6 alkyl or a fluorine atom.

Another embodiment of the compound represented by the formula (II) of the present invention is as follows. Each symbol has the same meaning as described above.
R ^2c and R ^2d are each independently a hydrogen atom, a halogen atom or C _1-6 alkoxy (however, they are not simultaneously a hydrogen atom);
Ring C ′ is a group selected from the group consisting of: pyridyl, pyrimidyl, pyrazolyl and triazolyl;
R ^3a is a hydrogen atom or a halogen atom;
R ^4c is a group represented by the following formula:

Method for Producing Compound Represented by Formula (I) of the Present Invention The compound represented by formula (I) of the present invention or a pharmacologically acceptable salt thereof is a method detailed below or a modification thereof. It can be produced according to a method, a method described in other literature, or a method analogous thereto.

Compound (7) can be produced, for example, by the method shown in Scheme 1 (Scheme 1).

(Wherein ring B, R ^2a , R ^2b and R ³ are as defined above; G is B (OH) ₂ or pinacolatoboryl; Ra is C _1-6 alkyl)

Process 1-1
Compound (3) can be produced by reacting compound (1) and compound (2) in a solvent in the presence of a base and a palladium catalyst.
Examples of the solvent used include N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, ethanol, water And a mixed solvent thereof. Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium fluoride, cesium fluoride, triethylamine, pyridine, N, N-diisopropylethylamine, 2,6- Lutidine, 1,8-diazabicyclo [5,4,0] -7-undecene and the like. Examples of the palladium catalyst include palladium (II) acetate, bis (triphenylphosphine) palladium (II) dichloride, 1,1′-bis (diphenylphosphino) ferrocene palladium (II) dichloride, tetrakis (triphenylphosphine) palladium. (0), bis {ditert-butyl (4-dimethylaminophenyl) phosphine} palladium (II) dichloride, and the like. The reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 30 minutes to 7 days, although it varies depending on the raw material used, the solvent, the reaction temperature, and the like.
The above reaction can also be performed using a microwave reactor. When the reaction is performed using a microwave reactor, the pressure range is 1 to 30 bar, the output range is 1 to 400 W, the reaction temperature is room temperature to 300 ° C., the reaction time, although it varies depending on the raw material, solvent, and model to be used. The reaction can be carried out under conditions of 1 minute to 1 day.
Compound (1) and compound (2) can be produced according to methods described in the literature or a method analogous thereto, in addition to using commercially available products.

Process 1-2
Compound (4) can be produced by reacting compound (3) with a brominating agent in a solvent. Examples of the solvent used include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran and the like. Examples of the brominating agent include N-bromosuccinimide, tribromoisocyanuric acid, bromine and the like. The reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 1 hour to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.

Process 1-3
Compound (6) can be produced from compound (4) and compound (5) by the same method as in step 1-1.
Compound (5) can be produced according to a method described in the literature or a method analogous thereto, in addition to using a commercially available product.

Process 1-4
Compound (7) can be produced by hydrolyzing compound (6) in a solvent using a base. Examples of the solvent to be used include methanol, ethanol, acetonitrile, tetrahydrofuran, 1,4-dioxane, water, a mixed solvent thereof and the like. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. The reaction temperature is from room temperature to solvent reflux temperature, and the reaction time is usually from 30 minutes to 3 days, although it varies depending on the raw material used, solvent, reaction temperature and the like. In addition, this process can also use acid hydrolysis and hydrogenolysis as needed. M.M. Examples include a method described in Wuts, “Greene's Protective Groups in Organic Synthesis”, fifth edition, Wiley-Interscience, 2014.

Compound (11) can be produced, for example, by the method shown in Scheme 2 (Scheme 2).

(Wherein, ring B, R ^2a , R ^2b , R ³ , G, and Ra are as defined above)

Process 2-1 (process2-1)
Compound (8) can be produced from compound (1) and compound (5) by the same method as in step 1-1.

Process 2-2
Compound (9) can be produced from compound (8) and a brominating agent by the same method as in Step 1-2.

Process 2-3 (process2-3)
Compound (10) can be produced from compound (9) and compound (2) by the same method as in step 1-1.

Process 2-4 (process2-4)
Compound (11) can be produced from compound (10) by the same method as in Step 1-4.

Compound (19) can be produced, for example, by the method shown in Scheme 3 (Scheme 3).

(Wherein, ring B, R ^2a , R ^2b , R ³ , G and Ra are as defined above)

Process 3-1 (process3-1)
Compound (13) can be produced from compound (12) and compound (2) by the same method as in step 1-1.
Compound (12) can be produced according to a method described in the literature or a method analogous thereto, in addition to using a commercially available product.

Deprotection
Compound (14) can be produced by deprotecting compound (13) according to a conventional method.

Process 3-2 (process3-2)
Compound (15) can be produced by reacting compound (14) with a nitrite and a brominating agent in a solvent. Examples of the solvent used include acetonitrile, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide and the like. Examples of the nitrite ester include amyl nitrite, ethyl nitrite, and isobutyl nitrite. Examples of the brominating agent include copper (II) bromide. The reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 1 hour to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.

Process 3-3 (process3-3)
Compound (16) can be produced from compound (15) by the same method as in Step 1-4.

Process 3-4 (process3-4)
Compound (17) can be produced by reacting compound (16) with a base and an azide reagent in tert-butyl alcohol. Examples of the base include triethylamine, N, N-diisopropylethylamine and the like. Examples of the azidating reagent include diphenyl phosphoryl azide. The reaction temperature is from room temperature to the solvent reflux temperature, and the reaction time is usually from 1 hour to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.

Process 3-5 (process3-5)
Compound (18) can be produced from compound (17) and compound (5) by the same method as in Step 1-1.

Process 3-6 (process3-6)
Compound (19) can be produced from compound (18) by the same method as in Step 1-4.

Compound (25) can be produced, for example, by the method shown in Scheme 4 (Scheme 4).

(Wherein, ring B, R ^2a , R ^2b , R ³ and Ra are as defined above; U is a bromine atom, an iodine atom, etc .; R ^1a is C _1-6 alkyl)

Process 4-1
Compound (21) can be produced by reacting compound (20) with a brominating agent in the presence of a radical initiator in a solvent. Examples of the solvent used include tetrachloromethane, chloroform, dichloromethane, dichloroethane, and benzene. Examples of the radical initiator include azobisisobutyronitrile, 1,1′-azobis (cyclohexanecarbonitrile), benzoyl peroxide, di-tert-butyl peroxide, and the like. Examples of the brominating agent include N-bromosuccinimide, tribromoisocyanuric acid, bromine and the like. The reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 1 hour to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
Compound (20) can be produced according to a method described in the literature or a method analogous thereto, in addition to using a commercially available product.

Process 4-2
Compound (23) can be produced by reacting compound (21) with compound (22) in a solvent. Examples of the solvent used include N, N-dimethylformamide, ethanol, dichloromethane, toluene, benzene and the like. The reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 1 hour to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
Compound (22) can be produced according to a method described in the literature or a method analogous thereto, in addition to using a commercially available product.

Process 4-3 (process4-3)
Compound (24) can be produced by reacting compound (23) with carbon monoxide in a solvent in the presence of RaOH, a base, and a palladium catalyst. Examples of the solvent used include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. Examples of RaOH include n-propanol and n-butanol. Examples of the base include triethylamine, N, N-diisopropylethylamine and the like. Examples of the palladium catalyst include palladium acetate, bis (triphenylphosphine) palladium (II) dichloride, 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) dichloride, tetrakis (triphenylphosphine) palladium (0). Etc. If necessary, a ligand such as 1,3-bis (diphenylphosphino) propane, 1,1′-bis (diphenylphosphino) ferrocene, bis (adamantan-1-yl) (butyl) phosphine may be added. It can be performed by adding. The reaction temperature is from room temperature to the solvent reflux temperature, and the reaction time is usually from 2 hours to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.

Process 4-4 (process4-4)
Compound (25) can be produced from compound (24) by the same method as in Step 1-4.

The optically active compound (31) can be produced, for example, by the method shown in Scheme 5 (Scheme 5).

(Wherein R ^4a , R ^4b , R ^7a and R ^7b are as defined above; ring C1 is C _6-10 aryl or a heterocycle containing no NH; R ^6z is hydroxy, hydroxy C _{1- 6} alkyl, R ⁶ excluding amino (R ⁶ is as defined above); the atom marked with * is a chiral atom)

Process 5-1 (process5-1)
Compound (28) can be produced by reacting compound (26) with compound (27) in the presence of a Lewis acid in a solvent. Examples of the solvent used include tetrahydrofuran, cyclopentyl methyl ether, 1,4-dioxane, toluene and the like. Examples of the Lewis acid include tetraethyl orthotitanate and tetraisopropyl orthotitanate. The reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 1 hour to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
Compound (26) and compound (27) can be produced in accordance with methods described in the literature or methods analogous thereto, in addition to using commercially available products.

Process 5-2 (process5-2)
Compound (30) can be produced by reacting compound (28) with compound (29) in the presence of a base in a solvent. Such a method for synthesizing an optically active amine using Ellman's imine is well known to those skilled in the art, and can be synthesized, for example, using the method described in Chemical Reviews 2010, 110, 3600-3740. Examples of the solvent used include tetrahydrofuran, 1,4-dioxane, toluene and the like. Examples of the base include n-butyllithium, lithium diisopropylamide, bis (trifluoromethanesulfonyl) imide lithium and the like. The reaction temperature is −78 ° C. to room temperature, and the reaction time is usually 1 hour to 12 hours, although it varies depending on the raw material used, the solvent, the reaction temperature, and the like.
Compound (29) can be produced according to a method described in the literature or a method analogous thereto, in addition to using a commercially available product.

Process 5-3 (process5-3)
Compound (31) can be produced by using compound (30) in a solvent with an acid. Examples of the solvent to be used include tetrahydrofuran, 1,4-dioxane, methanol, ethanol, acetonitrile, water, a mixed solvent thereof and the like. Examples of the acid include hydrogen chloride, trifluoroacetic acid, acetic acid, sulfuric acid and the like. The reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 10 minutes to 1 day, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.

Compound (31b) can be produced, for example, by the method shown in Scheme 6 (Scheme 6).

(Wherein, ring C, R ^4a , R ^4b , R ⁶ , R ^7a , R ^7b , R ⁸ and U are as defined above; Q is a protecting group)

Process 6-1
Compound (33) can be produced by reacting compound (32) with an organic phosphorus compound and an iodinating agent in a solvent in the presence of a base. Substitution of hydroxy to iodine atoms using such organophosphorus compounds and iodinating agents is well known to those skilled in the art, for example, the method described in Angelwandte Chemie International Edition in England 1975, 14, 801-811 Or it can synthesize | combine using the method according to it. Examples of the solvent to be used include tetrahydrofuran, acetonitrile, dichloromethane, acetone, N, N-dimethylformamide, N, N-dimethylacetamide and the like. Examples of the base include imidazole and pyridine. Examples of the iodinating agent include iodine and sodium iodide. Examples of the organic phosphorus compound include triphenylphosphine and tri (n-butyl) phosphine. The reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 30 minutes to 1 day, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
Compound (32) can be produced according to a method described in the literature or a method analogous thereto, in addition to using a commercially available product.

Process 6-2 (process6-2)
Compound (31a) can be produced by reacting compound (33) with zinc in a solvent and then reacting with compound (34) in the presence of a palladium catalyst. Examples of the solvent used include N, N-dimethylformamide, N, N-dimethylacetamide, toluene, acetonitrile, tetrahydrofuran and the like. Examples of the palladium catalyst include bis (triphenylphosphine) palladium (II) dichloride, 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) dichloride, tetrakis (triphenylphosphine) palladium (0), bis ( Examples thereof include dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0), dichlorobis [di-tert-butyl (4-dimethylaminophenyl) phosphino] palladium (II), and the like. The reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 30 minutes to 1 day, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
Compound (34) can be produced according to a method described in the literature or a method analogous thereto, in addition to using a commercially available product.

Deprotection
Compound (31b) can be produced by deprotecting compound (31a) according to a conventional method.

Compound (31d) can be produced, for example, by the method shown in Scheme 7 (Scheme 7).

(Wherein R ^4a , R ^4b , R ^7a , R ^7b , R ⁶ and Q are as defined above; ring C2 is a heterocycle containing NH; ring C3 is a nitrogen-containing heterocycle; Y is a leaving group such as methanesulfonyloxy, p-toluenesulfonyloxy, iodine atom)

Process 7-1 (process7-1)
Compound (35) (Y is methanesulfonyloxy, p-toluenesulfonyloxy) can be produced by reacting compound (32) with a sulfonyl halide or sulfonic anhydride in the presence of a base in a solvent. it can. Examples of the solvent used include dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile and the like. Examples of the base include pyridine, triethylamine, N, N-diisopropylethylamine and the like. Examples of the sulfonyl halide include p-toluenesulfonyl chloride and methanesulfonyl chloride. Examples of the sulfonic acid anhydride include trifluoromethanesulfonic acid anhydride. The reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 30 minutes to 1 day, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
In addition, compound (35) (Y is an iodine atom) can also be produced from compound (32) by the same method as in Step 6-1.

Process 7-2 (process7-2)
Compound (31c) can be produced by reacting compound (35) with compound (36) in the presence of a base in a solvent. Alternatively, compound (35) can be reacted in the presence of a base in a solvent to produce compound (37), and then reacted with compound (36) to produce compound (31c). Examples of the solvent used include N, N-dimethylformamide, N, N-dimethylacetamide, toluene, acetonitrile, tetrahydrofuran, N-methylpyrrolidone and the like. Examples of the base include cesium carbonate, potassium carbonate, pyridine, triethylamine, N, N-diisopropylethylamine, tert-butoxypotassium, sodium hydride and the like. The reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 30 minutes to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
Compound (36) can be produced according to a method described in the literature or a method analogous thereto, in addition to using a commercially available product.

Deprotection
Compound (31d) can be produced by deprotecting compound (31c) according to a conventional method.

Compound (31d) can also be produced, for example, by the method shown in Scheme 8 (Scheme 8).

(Wherein, ring C2, ring C3, R ^4a , R ^4b , R ^7a , R ^7b and R ⁶ are as defined above; W is a leaving group such as methanesulfonyloxy, p-toluenesulfonyloxy, etc. )

Process 8-1 (process8-1)
Compound (39) can be produced by reacting compound (38) with an organic phosphorus compound in a solvent in the presence of an azo reagent. Examples of the solvent used include tetrahydrofuran, acetonitrile, 1,4-dioxane, toluene and the like. Examples of the organic phosphorus compound include triphenylphosphine and tri (n-butyl) phosphine. Examples of the azo reagent include azodicarboxylic acid diisopropyl ester, azodicarboxylic acid diethyl ester, azodicarbonyldipiperazine, and the like. The reaction temperature is from room temperature to solvent reflux temperature, and the reaction time is usually from 30 minutes to 2 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.
Compound (38) can be produced according to a method described in the literature or a method analogous thereto, in addition to using a commercially available product.

Process 8-2 (process8-2)
Compound (40) can be produced by reacting compound (39) with compound (36) in a solvent in the presence or absence of a base. Examples of the solvent used include N, N-dimethylformamide, N, N-dimethylacetamide, toluene, acetonitrile, tetrahydrofuran and the like. Examples of the base include cesium carbonate, potassium carbonate, pyridine, triethylamine, N, N-diisopropylethylamine, tert-butoxypotassium, sodium hydride and the like. The reaction temperature is from 0 ° C. to the solvent reflux temperature, and the reaction time is usually from 30 minutes to 2 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.

Process 8-3 (process8-3)
Compound (41) can be produced from compound (40) by the same method as in Step 7-1.

Process 8-4 (process8-4)
Compound (42) can be produced by reacting compound (41) with an azide reagent in a solvent. Examples of the solvent used include N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, acetonitrile, 1,4-dioxane, toluene and the like. Examples of the azide reagent include sodium azide. The reaction temperature is from room temperature to solvent reflux temperature, and the reaction time is usually from 30 minutes to 2 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.

Process 8-5 (process8-5)
Compound (31d) can be produced by reacting compound (42) with hydrogen in a solvent in the presence of a catalyst. Examples of the solvent used include methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid and the like. Examples of the catalyst include palladium carbon and platinum carbon. The reaction temperature is from room temperature to the solvent reflux temperature, and the reaction time is usually from 30 minutes to 1 day, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
In addition, compound (31d) can be produced by reacting compound (42) in a solvent with an organic phosphorus compound and water. Examples of the solvent used include tetrahydrofuran and 1,4-dioxane. Examples of the organic phosphorus compound include triphenylphosphine and tri (n-butyl) phosphine. The reaction temperature is from room temperature to the solvent reflux temperature, and the reaction time is usually from 1 hour to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.

The compound represented by the formula (I) of the present invention can be produced, for example, by the method shown in Scheme 9 (Scheme 9).

(Wherein, ring A, ring B, ring C, R ^2a , R ^2b , R ³ , R ^4a , R ^4b , R ⁵ , R ⁶ , R ^7a , R ^7b and n are as defined above)

Process 9-1 (process9-1)
The compound represented by formula (I) can be produced by reacting compound (43) with a condensing agent and compound (44) in a solvent in the presence or absence of a base. Examples of the solvent used include N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide, tetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, methanol, water and the like. Examples of the base include triethylamine, N, N-diisopropylethylamine, pyridine and the like. Examples of the condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, N, N′-carbonyldiimidazole, 1H-benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride, propylphosphonic anhydride and the like. If necessary, an activator such as 1-hydroxybenzotriazole or 1-hydroxyazabenzotriazole may be added. The reaction temperature is from room temperature to solvent reflux temperature, and the reaction time is usually from 30 minutes to 5 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.
Compound (43) and compound (44) may each be a commercially available product, or can be produced according to methods described in the literature or methods analogous thereto.

The scheme shown above is an example of a method for producing a compound represented by the formula (I) of the present invention or a production intermediate thereof. The above scheme can be modified in various ways as can be easily understood by those skilled in the art.

In addition, when a protective group is required depending on the type of functional group, the protection and deprotection operations can be appropriately combined according to a conventional method. For the type of protecting group, protection, and deprotection, see, eg, Theodora W. Green & Peter G. M. Edited by Wuts, “Green's Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience, 2006 or Peter G. M. For example, the method described in Wuts, “Green's Protective Groups in Organic Synthesis”, fifth edition, Wiley-Interscience, 2014.

The intermediates used to produce the compounds of formula (I) of the present invention, or pharmacologically acceptable salts thereof, are optionally isolated as is well known to those skilled in the art. -It can be isolated and purified by means of purification such as solvent extraction, crystallization / recrystallization, chromatography, preparative high performance liquid chromatography and the like.

The pharmaceutical composition containing the compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient may be used in various dosage forms depending on the usage. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches, sublinguals, etc. It is administered orally or parenterally.

These pharmaceutical compositions are prepared according to known methods depending on the dosage form, using appropriate excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents. It can be prepared by appropriately mixing or diluting / dissolving with pharmaceutical additives such as emulsifiers, dispersants, stabilizers, and solubilizing agents. In addition, when the compound represented by the formula (I) of the present invention, or a pharmacologically acceptable salt thereof, and a drug other than a TRPM8 inhibitor are used in combination, each active ingredient can be used simultaneously or separately. It can be produced by formulating in the same manner as described above.

The compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof exhibits a strong inhibitory action based on TRPM8 inhibition in an Icilin-induced wet-dog shake inhibitory action confirmation test. Therefore, a medicament containing the compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient has a disease or symptom caused by TRPM8 activation due to TRPM8 inhibitory action. It can be used as a therapeutic or prophylactic agent.

“Disease or symptom resulting from activation of TRPM8” means a disease or symptom resulting from hyperexcitation or disorder of afferent nerves.
“Diseases or symptoms resulting from afferent nerve overexcitation or disorder” include anxiety, depression, lower urinary tract symptoms (LUTS), pain, circulatory disturbance, itching, numbness, urticaria and the like.

In one embodiment, the compound represented by the formula (I) of the present invention, or a pharmacologically acceptable salt thereof, is a lower urine among diseases or symptoms caused by hyperexcitability or disorder of afferent nerves. It is particularly useful as a therapeutic or prophylactic agent for tract symptoms (LUTS) or pain.

“Lower urinary tract symptoms (LUTS)” refers to symptoms caused by lower urinary tract dysfunction, etc., and “lower urinary tract dysfunction” includes overactive bladder, detrusor overactivity, nocturia, stroma Cystitis such as cystitis, prostatitis such as chronic prostatitis, bladder pain syndrome, hypersensitive bladder syndrome, urinary incontinence, prostatic hypertrophy, urethral stricture and the like. Preferred examples include overactive bladder, detrusor overactivity, interstitial cystitis, and bladder pain syndrome.

“Circulating disorders” include cold rhinitis, Raynaud's disease, and the like.

“Pain” includes toothache, oxaliplatin-induced peripheral neuropathy, migraine, postoperative pain, cold allodynia, anticancer drug-induced peripheral neuralgia, diabetic peripheral neuropathy. Preferred examples include toothache, oxaliplatin-induced peripheral neuropathy, migraine, postoperative pain, and cold allodynia.

The compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof can be used in appropriate combination with at least one drug other than the TRPM8 inhibitor.

Examples of the drug that can be used in combination with the compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof include opioid analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), and barbiturates. Benzodiazepines with sedation, H1 blockers with sedation, sedatives, skeletal muscle relaxants, NMDA receptor antagonists, α-adrenergic agents, tricyclic antidepressants, anticonvulsants, tachykinin antagonists ( NK antagonist), muscarinic receptor antagonist, COX-2 selective inhibitor, coal tar analgesic, neuroleptic, TRPV1 agonist, TRPV1 inhibitor, beta blocker, local anesthetic, corticosteroid, 5-HT Receptor agonist, 5-HT2A receptor antagonist, cholinergic analgesic, PDE5 inhibitor, PDE9 inhibitor, α2δ ligand, cannabi Id, metabotropic glutamate receptor 1 antagonist (mGluR1 antagonist), metabotropic glutamate receptor 5 antagonist (mGluR5 antagonist), serotonin reuptake inhibitor, noradrenaline reuptake inhibitor, serotonin / noradrenaline reuptake inhibitor, Inducible nitric oxide synthase inhibitor (iNOS inhibitor), acetylcholinesterase inhibitor (AChE inhibitor), EP4 antagonist, leukotriene B4 antagonist, 5-lipoxygenase inhibitor, sodium channel blocker, 5-HT3 antagonist, Drug for chemotherapy, EP1 antagonist, β3 adrenergic agent, TRPA1 inhibitor, TRPV3 inhibitor, TRPV4 inhibitor, T-type calcium channel inhibitor, ASIC inhibitor, P2X inhibitor, Trk inhibitor, FAAH inhibitor Botulinum toxin, α-reductase inhibitor, anti-NGF antibody, NGF modulator, IgE production inhibitor, histamine H2 inhibitor, bladder mucosa protective agent, NOS activity modulator, bladder muscle relaxant, GABA reuptake inhibitor, GABA receptor modulator , GABA aminotransferase inhibitor, etc.

Moreover, although the chemical | medical agent used in combination is specifically illustrated as follows, the content of this invention is not limited to these. In addition, specific compounds include free forms thereof and other pharmacologically acceptable salts.

Examples of the “α-adrenergic drug” include doxazosin, tamsulosin, silodosin, clonidine, guanfacine, dexmedetomidine, modafinil, tizanidine, moxonidine and the like.

Examples of the “muscarinic receptor antagonist” include oxybutynin, tolterodine, propiverine, darifenacin, solifenacin, temiverine, ipratropium bromide, trospium, propantheline, temiverine, imidafenacin, fesoterodine and the like.

Examples of the “EP1 antagonist” include GSK-269984A, ONO-8539 and the like.

Examples of the “β3 adrenergic agonist” include mirabegron, sorabegron, TRK-380 and the like.

Examples of the “bladder mucosa protective agent” include polysulfate pentosan, hyaluronic acid, chondroitin sulfate and the like.

When the compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof and one or more of the above drugs are administered in combination, the present invention includes the following 1) to 5) ):
1) Simultaneous administration with combination drug,
2) As separate formulations, co-administration by the same route of administration,
3) As separate formulations, co-administration by different routes of administration,
Any method of administration, including 4) administration at different times by the same route of administration as separate formulations, and 5) administration at different times by different routes of administration as separate formulations is included. Also, when administered at different times as separate preparations such as 4) or 5), it is administered in combination with the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof. The order of administration with the above-mentioned drugs is not particularly limited.

In addition, the compound of the present invention, or a pharmacologically acceptable salt thereof, is advantageously combined with one or more kinds of the above-mentioned drugs in an appropriate combination, and thus has an advantageous effect on the prevention or treatment of the above diseases. An effect can be obtained. Or, similarly, reduce the amount used compared to when administered alone, reduce the side effects of drugs other than the combined TRPM8 inhibitor, or avoid the side effects of drugs other than the combined TRPM8 inhibitor Or it can be reduced.

The pharmaceutical composition of the present invention can be administered systemically or locally, orally or parenterally (nasal, pulmonary, intravenous, rectal, subcutaneous, intramuscular, transdermal, etc.).

When the pharmaceutical composition of the present invention is used for actual treatment, the dose of the compound represented by the formula (I) of the present invention, which is the active ingredient, or a pharmacologically acceptable salt thereof is determined by the age of the patient. It is appropriately determined depending on sex, body weight, disease, degree of treatment, and the like. For example, in the case of oral administration, an adult (with a body weight of 60 kg) can be appropriately administered in one or several divided doses within a range of about 1 to 3000 mg per day. The daily dose as an oral preparation is preferably 10 to 1000 mg, more preferably 20 to 400 mg. In the case of parenteral administration, it can be appropriately administered in one or several divided doses in the range of about 0.6 to 300 mg per day for an adult. The daily dose as a parenteral preparation is preferably 1 to 100 mg, more preferably 6 to 60 mg. The dose of the compound represented by formula (I), which is an active ingredient of the TRPM8 inhibitor of the present invention, or a pharmacologically acceptable salt thereof depends on the dose of the drug other than the TRPM8 inhibitor. You can lose weight.

Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples and Test Examples, but the scope of the present invention is not limited thereto.

Of the symbols used in each reference example, each example, and each table, Ref. Ex. Are reference example numbers, Ex. No. Is an example number, Str. Means chemical structural formula, PD means spectral data, and PC means purification conditions. An atom marked with * means a chiral atom. Rel. Means relative configuration. ¹ H-NMR means hydrogen nuclear magnetic resonance spectrum, CDCl ₃ means chloroform-d, DMSO-d ₆ means dimethyl sulfoxide-d ₆ , and CD ₃ OD means methanol-d ₄ . MS means mass spectrometry and ESI-MS means electrospray ionization mass spectrometry. RT means retention time of high performance liquid column chromatography. SiO2 means silica gel column chromatography, and APS means aminopropyl silica gel column chromatography. Low polarity or LP means a compound that elutes first when a mixture of stereoisomers is separated and purified using normal phase column chromatography. High polarity or HP means a compound that elutes later. . N. D. Means unmeasured. T3P is propylphosphonic anhydride (cyclic trimer), TBS is tert-butyldimethylsilyl, TBDPS is tert-butyldiphenylsilyl, Bn is benzyl, MOM is methoxymethyl, Cbz is benzyloxycarbonyl, Boc is tert-butoxycarbonyl, Bu means n-butyl.

In each reference example, the microwave irradiation was performed using Biotage Initiator + or Biotage Initiator.

In each example, high performance liquid column chromatography and ESI-MS were performed under the following conditions.
Instrument: 6520 Accurate-Mass Q-TOF instrument (Agilent)
Column: Inertsil ODS-4 (GL-science) 2.1 x 50mm 3μm
Flow rate: 0.75mL / min.
Gradient:

Reference Example 1-1-1
3-Fluoro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] benzoic acid To a solution of 2-bromothiazole (300 mg) in 1,2-dimethoxyethane (8 mL), Reference Example 1-6-1 (615 mg), dichlorobis [di-tert-butyl (4-dimethylaminophenyl) phosphino] palladium (II) (130 mg) and aqueous sodium carbonate (2 mol / L, 1.8 mL) were added at room temperature, The mixture was stirred at 120 ° C. for 30 minutes under microwave irradiation. The reaction mixture was poured into water and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to give 3-fluoro-2- (1,3-thiazol-2-yl) benzoic acid methyl ester (103 mg). . To a solution of the product (410 mg) in N, N-dimethylformamide (5 mL), N-bromosuccinimide (923 mg) was added at room temperature, and the mixture was stirred at the same temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to give 2- (5-bromo-1,3-thiazol-2-yl) -3-fluorobenzoic acid methyl ester (450 mg ) To a solution of the product (450 mg) in 1,2-dimethoxyethane (9 mL), (4-fluorophenyl) boronic acid (199 mg), tetrakis (triphenylphosphine) palladium (0) (165 mg) and aqueous sodium carbonate (2 mol / L, 1.4 mL) was added at room temperature and the mixture was stirred at 120 ° C. for 30 minutes under microwave irradiation. The reaction mixture was poured into water and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 3-fluoro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] benzoate. Acid methyl ester (340 mg) was obtained. To a solution of the product (340 mg) in methanol (3 mL) was added aqueous sodium hydroxide (2 mol / L, 2.1 mL) at room temperature, and the mixture was stirred at 60 ° C. for 1 hour. After the reaction mixture was cooled to room temperature, hydrochloric acid (2 mol / L, 2.2 mL) and water were added to the mixture. The precipitate was collected by filtration to give the title compound (290 mg).

Reference Examples 1-1-2 to 1-1-29
Reference Examples 1-1-2 to 1-1-29 were synthesized in the same manner as Reference Example 1-1-1 using the corresponding starting materials.

Reference Example 1-2-1
3-Fluoro-2- [2- (4-fluorophenyl) -1,3-thiazol-5-yl] benzoic acid To a solution of 2-bromothiazole (300 mg) in 1,2-dimethoxyethane (3.5 mL), Water (1 mL), (4-fluorophenyl) boronic acid (307 mg), tetrakis (triphenylphosphine) palladium (0) (106 mg) and potassium carbonate (758 mg) were added at room temperature, and the mixture was heated at 120 ° C. under microwave irradiation. For 30 minutes. The reaction mixture was poured into water and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to give 2- (4-fluorophenyl) -1,3-thiazole (270 mg). To a solution of the product (270 mg) in N, N-dimethylformamide (3 mL) was added N-bromosuccinimide (402 mg) at room temperature and the mixture was stirred at the same temperature overnight. Water was added to the reaction mixture, and the insoluble material was collected by filtration to obtain 5-bromo-2- (4-fluorophenyl) -1,3-thiazole (350 mg). To a solution of this product (100 mg) in 1,2-dimethoxyethane (3 mL), Reference Example 1-6-1 (108 mg), dichlorobis [di-tert-butyl (4-dimethylaminophenyl) phosphino] palladium (II) (27 mg) and aqueous sodium carbonate (2 mol / L, 0.4 mL) were added at room temperature, and the mixture was stirred at 120 ° C. for 30 minutes under microwave irradiation. The reaction mixture was poured into water and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 3-fluoro-2- [2- (4-fluorophenyl) -1,3-thiazol-5-yl. ] Methyl benzoate (80 mg) was obtained. To a solution of the product (80 mg) in methanol (1 mL) was added aqueous sodium hydroxide solution (2 mol / L, 0.5 mL) at room temperature, and the mixture was stirred at 60 ° C. for 1 hour. After the reaction mixture was cooled to room temperature, hydrochloric acid (2 mol / L, 0.55 mL) and water were added to the mixture. The precipitate was collected by filtration to give the title compound (60 mg).

Reference Examples 1-2-2 to 1-2-6
Reference Examples 1-2-2 to 1-2-6 were synthesized in the same manner as Reference Example 1-2-1 using the corresponding starting materials.

Reference Example 1-3-1
2- {4-[(tert-butoxycarbonyl) amino] -5- (4-fluorophenyl) -1,3-thiazol-2-yl} benzoic acid 2-bromo-5- (4-fluorophenyl) -1 Triethylamine (88 mg) and diphenylphosphoryl azide (238 mg) were added to a solution of, 3-thiazole-4-carboxylic acid (218 mg) in tert-butyl alcohol (3 mL) at room temperature, and the mixture was stirred at 90 ° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give N- [2-bromo-5- (4-fluorophenyl) -1,3-thiazol-4-yl] carbamine. Acid tert-butyl ester (90 mg) was obtained. To a solution of the product (150 mg) in 1,2-dimethoxyethane (9 mL), 2- (tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid methyl ester (105 mg), tetrakis (triphenylphosphine) Palladium (0) (47 mg) and aqueous sodium carbonate (2 mol / L, 0.4 mL) were added at room temperature, and the mixture was stirred at 120 ° C. for 30 minutes under microwave irradiation. The reaction mixture was poured into water and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 2- {4-[(tert-butoxycarbonyl) amino] -5- (4-fluorophenyl) -1,3. -Thiazol-2-yl} benzoic acid methyl ester (34 mg) was obtained. To a solution of the product (34 mg) in methanol (3 mL) was added aqueous sodium hydroxide (2 mol / L, 0.4 mL) at room temperature, and the mixture was stirred at 60 ° C. for 1 hour. After the reaction mixture was cooled to room temperature, hydrochloric acid (2 mol / L, 0.41 mL) and water were added to the mixture. The precipitate was collected by filtration to give the title compound (30 mg).

Reference Examples 1-3-2 to 1-3-3
Reference Examples 1-3-2 to 1-3-3 were synthesized in the same manner as Reference Example 1-3-1 using the corresponding starting materials.

Reference Example 1-4-1
3-Fluoro-2- [2- (4-fluoro-2-hydroxyphenyl) -1,3-thiazol-5-yl] benzoic acid 2-bromothiazole (300 mg) of 1,2-dimethoxyethane (3.5 mL) ) Solution (1 mL), [2- (benzyloxy) -4-fluorophenyl] boronic acid (539 mg), tetrakis (triphenylphosphine) palladium (0) (106 mg) and potassium carbonate (758 mg) at room temperature. In addition, the mixture was stirred at 120 ° C. for 30 minutes under microwave irradiation. The reaction mixture was poured into water and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to give 2- [2- (benzyloxy) -4-fluorophenyl] -1,3-thiazole (310 mg). . To a solution of this product (310 mg) in N, N-dimethylformamide (3 mL) was added N-bromosuccinimide (290 mg) at room temperature, and the mixture was stirred at the same temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 2- [2- (benzyloxy) -4-fluorophenyl] -5-bromo-1,3-thiazole (370 mg). ) To a solution of this product (200 mg) in 1,2-dimethoxyethane (3.5 mL), Reference Example 1-6-1 (200 mg), dichlorobis [di-tert-butyl (4-dimethylaminophenyl) phosphino] palladium ( II) (39 mg) and aqueous sodium carbonate (2 mol / L, 0.7 mL) were added at room temperature, and the mixture was stirred at 120 ° C. for 30 minutes under microwave irradiation. The reaction mixture was poured into water and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. This residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 2- {2- [2- (benzyloxy) -4-fluorophenyl] -1,3-thiazole-5- IL} -3-fluorobenzoic acid methyl ester (210 mg) was obtained. Ethanol (3 mL) and 10% palladium carbon (50% wet, 100 mg) were added to this product (210 mg) at room temperature, and the mixture was stirred at 60 ° C. for 1 hour in a hydrogen atmosphere. The reaction mixture was passed through a celite pad and the filtrate was concentrated under reduced pressure. To a methanol (3 mL) solution of this residue, an aqueous sodium hydroxide solution (2 mol / L, 0.85 mL) was added at room temperature, and the mixture was stirred at 60 ° C. for 1 hour. After the reaction mixture was cooled to room temperature, hydrochloric acid (2 mol / L, 0.95 mL) and water were added to the mixture. The precipitate was collected by filtration and dried under reduced pressure to give the title compound (110 mg).

Reference Example 1-5-1
4-fluoro-2- [5- (4-fluorophenyl) -4-methyl-1,3-thiazol-2-yl] benzoic acid 1- (4-fluorophenyl) propan-2-one (612 mg) To a carbon chloride (13 mL) solution, N-bromosuccinimide (787 mg) and 2,2′-azodiisobutyronitrile (66 mg) were added at room temperature, and the mixture was stirred at 80 ° C. for 4 hours. After the reaction mixture was cooled to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to give 1-bromo-1- (4-fluorophenyl) propan-2-one (668 mg). To a solution of this product (22 mg) in N, N-dimethylformamide (1 mL) was added 2-bromo-6-fluorobenzene-1-carbothioamide (22 mg) at room temperature and the mixture was stirred at 80 ° C. overnight. After the reaction mixture was cooled to room temperature, the mixture was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 2- (2-bromo-6-fluorophenyl) -5- (4- Fluorophenyl) -4-methyl-1,3-thiazole (30 mg) was obtained. This product (21 mg), n-propanol (1.2 mL), N-methylpyrrolidone (0.4 mL), 1,1′-bis (diphenylphosphino) ferrocene (5 mg), 1,1′-bis A mixture of (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (7 mg) and triethylamine (26 mg) was stirred at 100 ° C. for 13 hours under a carbon monoxide atmosphere. After the reaction mixture was cooled to room temperature, the mixture was poured into hydrochloric acid (1 mol / L), and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 3-fluoro-2- [5- (4-fluorophenyl) -4-methyl-1,3-thiazole-2. -Il] benzoic acid propyl ester (14 mg) was obtained. To a solution of this product (14 mg) in methanol (0.5 mL) was added aqueous sodium hydroxide solution (2 mol / L, 0.5 mL) at room temperature, and the mixture was stirred at 60 ° C. for 1 hour. After the reaction mixture was cooled to 0 ° C., hydrochloric acid (2 mol / L, 0.5 mL) was added to the mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (6 mg).

Reference Example 1-5-2
Reference Example 1-5-2 was synthesized in the same manner as Reference Example 1-5-1 using the corresponding starting materials.

Reference Example 1-6-1
3-Fluoro-2- (tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid methyl ester 2-bromo-3-fluorobenzoic acid methyl ester (1.17 g) of 1,4-dioxane (30 mL) ) To the solution were added bis (pinacolato) diboron (1.40 g), 1,1′-bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane adduct (0.205 g) and potassium acetate (1.87 g). The mixture was stirred overnight under heating to reflux. After the reaction mixture was cooled to room temperature, the mixture was passed through a celite pad. Water was added to the filtrate and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to give the title compound (1.1 g).

Reference Example 1-7-1
3-chloro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] benzoic acid 2-bromo-3-chlorobenzoic acid methyl ester (325 mg) to bromo (1,3-thiazole -2-yl) zinc tetrahydrofuran solution (0.5 mol / L, 8 mL) and dichlorobis [di-tert-butyl (4-dimethylaminophenyl) phosphino] palladium (II) (185 mg) were added at room temperature and the mixture was The mixture was stirred at 120 ° C. for 90 minutes under wave irradiation. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to give 3-chloro-2- (1,3-thiazol-2-yl) benzoic acid methyl ester (91 mg). . To a solution of the product (91 mg) in N, N-dimethylformamide (2 mL) was added N-bromosuccinimide (160 mg) at room temperature, and the mixture was stirred at the same temperature overnight. To this mixture, N, N-dimethylformamide (1 mL) and N-bromosuccinimide (255 mg) were added at room temperature, and the mixture was stirred at the same temperature for 4.5 hours. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to give 2- (5-bromo-1,3-thiazol-2-yl) -3-chlorobenzoic acid methyl ester (50 mg ) To a solution of the product (48 mg) in 1,2-dimethoxyethane (2.3 mL), (4-fluorophenyl) boronic acid (22 mg), tetrakis (triphenylphosphine) palladium (0) (34 mg) and aqueous sodium carbonate solution ( 2 mol / L, 0.22 mL) was added at room temperature and the mixture was stirred at 120 ° C. for 90 minutes under microwave irradiation. The reaction mixture was poured into water and the crude product was extracted with ethyl acetate. The organic layer was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 3-chloro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] benzoate. Acid methyl ester (40 mg) was obtained. Methanol (0.3 mL), tetrahydrofuran (0.3 mL) and aqueous sodium hydroxide (2 mol / L, 0.16 mL) were added to the product (36 mg) at room temperature, and the mixture was stirred at the same temperature for 1 hour. After the reaction mixture was cooled to room temperature, hydrochloric acid (2 mol / L, 0.21 mL) and water were added to the mixture, and the crude product was extracted with dichloromethane. The organic layer was concentrated under reduced pressure to obtain the title compound (20 mg).

Reference Examples 1-7-2 to 1-7-4
Reference Examples 1-7-2 to 1-7-4 were synthesized in the same manner as Reference Example 1-7-1 using the corresponding starting materials.

Reference Example 1-8-1
2- [5- (4-Fluorophenyl) -4- (hydroxymethyl) -1,3-thiazol-2-yl] benzoic acid 5-Bromo-2-[(tert-butoxycarbonyl) amino] -1,3 To a solution of -thiazole-4-carboxylic acid ethyl ester (1.31 g) in 1,2-dimethoxyethane (14.4 mL) was added (4-fluorophenyl) boronic acid (574 mg), tetrakis (triphenylphosphine) palladium (0 ) (429 mg) and potassium carbonate (1.55 g) and water (3.6 mL) were added at room temperature and the mixture was stirred at 120 ° C. for 1 hour under microwave irradiation. The reaction mixture was poured into water and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 2-[(tert-butoxycarbonyl) amino] -5- (4-fluorophenyl) -1,3-thiazole- 4-Carboxylic acid ethyl ester (867 mg) was obtained. To a solution of this product (702 mg) in tetrahydrofuran (4 mL) was added methanol (116 μL) and lithium borohydride (63 mg) at 0 ° C., and the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to give N- [5- (4-fluorophenyl) -4- (hydroxymethyl) -1,3-thiazol-2-yl]. Carbamic acid tert-butyl ester (385 mg) was obtained. To a solution of this product (194 mg) in dichloromethane (6 mL) was added trifluoroacetic acid (3 mL) at room temperature, and the mixture was stirred at the same temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. To a solution of this residue (265 mg) in acetonitrile (5 mL) was added copper (II) bromide (292 mg) and 3-methylbutyl nitrite (209 mg) at room temperature, and the mixture was stirred at 70 ° C. for 1 hour. After the reaction mixture was cooled to room temperature, hydrochloric acid (1 mol / L) was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give [2-bromo-5- (4-fluorophenyl) -1,3-thiazol-4-yl] methanol (205 mg ) To a solution of the product (76 mg) in 1,2-dimethoxyethane (3.2 mL), water (0.8 mL), 2- (tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid methyl ester ( 251 mg), tetrakis (triphenylphosphine) palladium (0) (100 mg) and potassium carbonate (360 mg) were added at room temperature, and the mixture was stirred at 120 ° C. for 1 hour under microwave irradiation. The reaction mixture was poured into water and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 2- [5- (4-fluorophenyl) -4- (hydroxymethyl) -1,3-thiazole-2- Il] benzoic acid methyl ester (276 mg) was obtained. To a solution of the product (276 mg) in methanol (2 mL) was added aqueous sodium hydroxide (2 mol / L, 2 mL) at room temperature, and the mixture was stirred at 60 ° C. for 1 hour. After the reaction mixture was cooled to 0 ° C., hydrochloric acid (1 mol / L) was added to the mixture. The precipitate was collected by filtration to give the title compound (175 mg).

Reference Example 1-9-1
2- [2- (2-{[2- (Pyridin-2-yl) ethyl] carbamoyl} phenyl) -1,3-thiazol-5-yl] benzoic acid 2- (5-bromo-1,3-thiazole -2-yl) benzoic acid methyl ester (75 mg) in methanol (2 mL) was added aqueous sodium hydroxide (2 mol / L, 0.4 mL) at room temperature, and the mixture was stirred at 55 ° C. for 2 hours. After the reaction mixture was cooled to room temperature, hydrochloric acid (2 mol / L, 0.45 mL) was added to the mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. To this residue was added dichloromethane (2 mL), 2- (pyridin-2-yl) ethan-1-amine (36 mg), N, N-diisopropylethylamine (121 mg) and T3P® ethyl acetate solution (1.7 mol / L, 0.32 mL) was added at room temperature and the mixture was stirred at the same temperature for 1.5 hours. Water was added to the reaction mixture and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 2- (5-bromo-1,3-thiazol-2-yl) -N- [2- (pyridine -2-yl) ethyl] benzamide (80 mg) was obtained. To a solution of this product (80 mg) in 1,2-dimethoxyethane (2 mL) was added [2- (methoxycarbonyl) phenyl] boronic acid (41 mg), tetrakis (triphenylphosphine) palladium (0) (24 mg) and potassium carbonate. (85 mg) was added at room temperature and the mixture was stirred at 90 ° C. overnight. After the reaction mixture was cooled to room temperature, the mixture was poured into water and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to give 2- [2- (2-{[2- (pyridin-2-yl) ethyl] carbamoyl} phenyl) -1,3 -Thiazol-5-yl] benzoic acid methyl ester (50 mg) was obtained. To this product (50 mg) was added methanol (1 mL) and aqueous sodium hydroxide (2 mol / L, 0.3 mL) at room temperature, and the mixture was stirred at 60 ° C. for 4 hours. After the reaction mixture was cooled to room temperature, hydrochloric acid (2 mol / L, 0.35 mL) and water were added to the mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound (31 mg).

Reference Example 1-10-1
3-Fluoro-2- [5- (4-fluorophenyl) -4-hydroxy-1,3-thiazol-2-yl] benzoic acid 2-bromo-2- (4-fluorophenyl) acetic acid methyl ester (300 mg) To a solution of N, N-dimethylformamide (5 mL) was added 2-bromo-6-fluorobenzene-1-carbothioamide (284 mg) at room temperature and the mixture was stirred at 80 ° C. overnight. After the reaction mixture was cooled to room temperature, water was added to the mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 2- (2-bromo-6-fluorophenyl) -5- (4-fluorophenyl) -1,3-thiazole. -4-ol (346 mg) was obtained. This product (167 mg), n-propanol (1.2 mL), N-methylpyrrolidone (0.4 mL), 1,1′-bis (diphenylphosphino) ferrocene (25 mg), 1,1′-bis A mixture of (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane adduct (37 mg) and triethylamine (138 mg) was stirred at 100 ° C. for 13 hours under a carbon monoxide atmosphere. After the reaction mixture was cooled to room temperature, the mixture was poured into hydrochloric acid (1 mol / L), and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 3-fluoro-2- [5- (4-fluorophenyl) -4-hydroxy-1,3-thiazole-2. -Il] benzoic acid propyl ester (70 mg) was obtained. To a solution of this product (70 mg) in methanol (1 mL) was added aqueous sodium hydroxide solution (2 mol / L, 1 mL) at room temperature, and the mixture was stirred at 60 ° C. for 1 hour. The reaction mixture was cooled to 0 ° C., hydrochloric acid (1 mol / L) was added to the mixture, and the precipitate was collected by filtration to give the title compound (51 mg).

Reference Example 1-1-1
2- (4-Phenyl-1,3-thiazol-2-yl) benzoic acid To a solution of 2,4-dibromothiazole (200 mg) in 1,2-dimethoxyethane (3 mL), [2- (methoxycarbonyl) phenyl] Boronic acid (148 mg), tetrakis (triphenylphosphine) palladium (0) (95 mg) and potassium carbonate (341 mg) were added at room temperature and the mixture was stirred at 90 ° C. for 1 day. The reaction mixture was poured into water and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to obtain 2- (4-bromo-1,3-thiazol-2-yl) benzoic acid methyl ester (183 mg). . To a solution of the product (183 mg) in 1,2-dimethoxyethane (3 mL), water (1 mL), phenylboronic acid (82 mg), tetrakis (triphenylphosphine) palladium (0) (71 mg) and potassium carbonate (255 mg). At room temperature, the mixture was stirred at 90 ° C. for 8 hours. The reaction mixture was poured into water and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to obtain 2- (4-phenyl-1,3-thiazol-2-yl) benzoic acid methyl ester (184 mg). . To a solution of the product (75 mg) in methanol (1 mL) was added aqueous sodium hydroxide solution (2 mol / L, 0.5 mL) at room temperature, and the mixture was stirred at 60 ° C. for 1 hour. After the reaction mixture was cooled to room temperature, hydrochloric acid (2 mol / L, 0.55 mL) and water were added to the mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (71 mg).

Reference Examples 1-11-2 to 1-11-3
Reference Examples 1-11-2 to 1-11-3 were synthesized in the same manner as in Reference Example 1-11-1 using the corresponding starting materials.

Reference Example 1-12-1
2- {2- [2- (methoxymethoxy) phenyl] -1,3-thiazol-4-yl} benzoic acid To a solution of 2,4-dibromothiazole (300 mg) in 1,2-dimethoxyethane (3 mL), water (1 mL), [2- (methoxymethoxy) phenyl] boronic acid (225 mg), tetrakis (triphenylphosphine) palladium (0) (143 mg) and potassium carbonate (512 mg) were added at room temperature and the mixture was added at 65 ° C. at 2 ° C. Stir for days. The reaction mixture was poured into water and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 4-bromo-2- [2- (methoxymethoxy) phenyl] -1,3-thiazole (230 mg). Obtained. To a solution of the product (230 mg) in 1,2-dimethoxyethane (5 mL), [2- (methoxycarbonyl) phenyl] boronic acid (166 mg), tetrakis (triphenylphosphine) palladium (0) (89 mg) and potassium carbonate ( 317 mg) was added at room temperature and the mixture was stirred at 90 ° C. for 1 day. The reaction mixture was poured into water and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 2- {2- [2- (methoxymethoxy) phenyl] -1,3-thiazol-4-yl} benzoic acid. The methyl ester (170 mg) was obtained. To a solution of the product (170 mg) in methanol (2 mL) was added aqueous sodium hydroxide (2 mol / L, 0.72 mL) at room temperature, and the mixture was stirred at 50 ° C. overnight. After the reaction mixture was cooled to room temperature, hydrochloric acid (2 mol / L, 0.80 mL) and water were added to the mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (120 mg).

Reference examples represented by the following formula (A) are shown in Table 3. In the table, Wa, Ya and Za represent a group of the formula (A).

Table 4 shows a reference example represented by the following formula (B). In the table, Wb, Yb and Zb represent a group of the formula (B).

Reference Example 2-1-1
N-((2R) -2-Amino-3-phenylpropyl) phthalimide hydrochloride N-[(2R) -1-hydroxy-3-phenylpropan-2-yl] carbamic acid tert-butyl ester (0.50 g) Solution of phthalimide (0.32 g), triphenylphosphine (0.78 g) and azodicarboxylic acid diethyl ester in toluene (2.2 mol / L, 1.36 mL) at room temperature. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give N-[(2R) -1- (1,3-dioxo-2,3-dihydro-1H-isoindole- 2-yl) -3-phenylpropan-2-yl] carbamic acid tert-butyl ester (0.63 g) was obtained. To a solution of this product (0.63 g) in tetrahydrofuran (2 mL) was added hydrogen chloride 1,4-dioxane solution (4 mol / L, 2 mL) at room temperature, and the mixture was stirred at the same temperature overnight. Diethyl ether was added to the reaction mixture, and the insoluble material was collected by filtration to give the title compound (0.40 g).

Reference Examples 2-1-2 to 2-1-3
Reference Examples 2-1-2 to 2-1-3 were synthesized in the same manner as Reference Example 2-1-1 using the corresponding starting materials.

Reference Example 2-2-1
[(3,4-trans) -4- (pyridin-2-yl) pyrrolidin-3-yl] methanol (3,4-trans) -1-benzyl-4- (pyridin-2-yl) pyrrolidine To a solution of 3-carboxylic acid ethyl ester (0.30 g) in tetrahydrofuran (3 mL) was added lithium aluminum hydride (37 mg) at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture and passed through a celite pad. The filtrate was concentrated under reduced pressure to obtain [(3,4-trans) -1-benzyl-4- (pyridin-2-yl) pyrrolidin-3-yl] methanol (0.26 g). To this product (0.10 g) was added ethanol (3 mL) and 10% palladium on carbon (50% wet, 0.02 g) at room temperature, and the mixture was stirred at the same temperature under a hydrogen atmosphere overnight. The reaction mixture was passed through a celite pad and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound (0.05 g).

Reference Example 2-3-1
(3R) -3-Amino-4- (pyridin-2-yl) butan-1-ol hydrochloride To a solution of 3- (tert-butyldimethylsilyloxy) propanal (0.40 g) in tetrahydrofuran (4 mL) (R) -2-Methylpropane-2-sulfinamide (0.258 g) and tetraethyl orthotitanate (0.63 g) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added saturated brine and passed through a celite pad. The filtrate was concentrated under reduced pressure. This residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) and (R) -N-[(1E) -3- (tert-butyldimethylsilyloxy) propylidene] -2-methylpropane. -2-Sulfinamide (0.33 g) was obtained. To a solution of 2-methylpyridine (0.14 g) in tetrahydrofuran (2 mL) was added n-butyllithium n-hexane solution (1.6 mol / L, 0.96 mL) at −78 ° C., and the mixture was stirred at the same temperature for 10 Stir for minutes. To this mixture was added a solution of (R) -N-[(1E) -3- (tert-butyldimethylsilyloxy) propylidene] -2-methylpropane-2-sulfinamide (0.30 g) in tetrahydrofuran (2 mL). The solution was added dropwise at 78 ° C. and stirred at the same temperature for 0.5 hour. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. This residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol). The crude product was purified by reverse phase preparative column chromatography (CapcellPakC18 UG80, elution solvent: acetonitrile / water), and (R) -N-[(2R) -4- (tert-butyldimethylsilyl) as a highly polar product. Oxy) -1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide (0.174 g) and (R) -N-[(2S)-as the low polarity product 4- (tert-Butyldimethylsilyloxy) -1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide (0.060 g) was obtained. (R) -N-[(2R) -4- (tert-butyldimethylsilyloxy) -1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide (0. To a solution of 90 g) in methanol (2 mL) was added hydrogen chloride 1,4-dioxane solution (4 mol / L, 2 mL) at room temperature, and the mixture was stirred at the same temperature for 2 hours. The precipitate was collected by filtration to give the title compound (0.50 g).

Reference Examples 2-3-2 to 2-3-3
Reference Examples 2-3-2 to 2-3-3 were synthesized in the same manner as Reference Example 2-3-1 using the corresponding starting materials.

Reference Example 2-4-1
(2R) -2-Amino-3- (3-methoxypyridin-2-yl) propan-1-ol hydrochloride (2S) -2-[(tert-butoxycarbonyl) amino] -3-iodopropionic acid methyl ester (1.45 g) and a suspension of zinc (634 mg) in N, N-dimethylformamide (5 mL) were stirred at room temperature for 2 hours under an argon atmosphere. To this mixture, 2-bromo-3-methoxypyridine (1.08 g), bis (triphenylphosphine) palladium (II) dichloride (64 mg) were added at room temperature, and the mixture was stirred at the same temperature for 13 hours. To this mixture was added saturated aqueous ammonium chloride solution and passed through a celite pad. The crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (2R) -2-[(tert-butoxycarbonyl) amino] -3- (3-methoxypyrimidine-2. -Yl) propionic acid methyl ester (1.4 g) was obtained. To a mixture of product (1.4 g), ethanol (10 mL), water (10 mL) was added sodium borohydride (427 mg) at 0 ° C. and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. A hydrogen chloride 1,4-dioxane solution (4 mol / L, 3 mL) was added to a methanol (3 mL) solution of the residue at room temperature, and the mixture was stirred at the same temperature for 2 hours. The solvent was distilled off under reduced pressure to obtain the title compound (762 mg).

Reference Examples 2-4-2 to 2-4-3
Reference Examples 2-4-2 to 2-4-3 were synthesized in the same manner as Reference Example 2-4-1 using the corresponding starting materials.

Reference Example 2-5-1
(2S, 3R) -3-Amino-4- (pyrimidin-2-yl) butane-1,2-diol hydrochloride N-[(1R) -1-((4S) -2,2-dimethyl-1, To a mixture of 3-dioxolan-4-yl) -2-hydroxyethyl} carbamic acid tert-butyl ester (1.25 g), imidazole (521 mg), triphenylphosphine (2.01 g), tetrahydrofuran (10 mL), iodine ( 1.7 g) was added at 0 ° C. and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and N-{(1S) -1-[(4S) -2,2-dimethyl-1,3-dioxolane-4 -Il] -2-iodoethyl} carbamic acid tert-butyl ester (1.45 g) was obtained. A mixture of the product (1.45 g), zinc (562 mg) and N, N-dimethylformamide (5 mL) was stirred at room temperature for 2 hours under an argon atmosphere. To this mixture, 2-bromopyrimidine (621 mg), bis (triphenylphosphine) palladium (II) dichloride (274 mg) were added at room temperature, and the mixture was stirred at the same temperature for 4 hours. To this mixture was added saturated aqueous ammonium chloride solution and passed through a celite pad. The crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give N-{(1R) -1-[(4S) -2,2-dimethyl-1,3-dioxolane. -4-yl] -2- (pyrimidin-2-yl) ethyl} carbamic acid tert-butyl ester (928 mg) was obtained. A mixture of the product (150 mg), 1,4-dioxane (1 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (119 mg).

Reference Example 2-6-1
(2R) -2-Amino-3- (1H-pyrazol-1-yl) propan-1-ol hydrochloride (2S) -2-[(tert-butoxycarbonyl) amino] -3-iodopropion A mixture of acid methyl ester (1.45 g), pyrazole (100 mg), cesium carbonate (957 mg) and N, N-dimethylformamide (5 mL) was stirred at 80 ° C. for 5 hours. After the reaction mixture was cooled to room temperature, water was added to the mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) and (2R) -2-[(tert-butoxycarbonyl) amino] -3- (1H-pyrazol-1-yl). ) Propionic acid methyl ester (103 mg) was obtained. To a mixture of product (103 mg), ethanol (1 mL), water (1 mL) was added sodium borohydride (35 mg) at 0 ° C. and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. A mixture of this residue, methanol (1 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (64 mg).

Reference Examples 2-7-1, 2-7-2
(R) -N-[(2S) -1,4-di (tert-butyldimethylsilyloxy) -1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide (2-7-1: HP)
(R) -N-[(2R) -1,4-di (tert-butyldimethylsilyloxy) -1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide (2-7-2: LP)
To a solution of 2- (tert-butyldimethylsilyloxymethyl) pyridine (0.268 g) in tetrahydrofuran (2 mL) was added n-butyllithium n-hexane solution (2.6 mol / L, 0.4 mL) at −78 ° C. The mixture was stirred at 0 ° C. for 10 minutes. To this mixture was added a solution of (R) -N-[(1E) -3- (tert-butyldimethylsilyloxy) propylidene] -2-methylpropane-2-sulfinamide (0.250 g) in tetrahydrofuran (2 mL) at -78. The mixture was stirred at 30 ° C. for 30 minutes at the same temperature. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to obtain the title compound (0.141 g: HP, 0.036 g: LP).

Reference Example 2-8-1
(2R, 3S) -4- (Benzyloxy) -3-methoxy-1- (pyridin-2-yl) butan-2-amine 3- (Benzyloxy) -2-methoxypropanal (1.90 g) in tetrahydrofuran To the (20 mL) solution, (R) -2-methylpropane-2-sulfinamide (1.53 g) and tetraethyl orthotitanate (3.53 g) were added at room temperature, and the mixture was stirred at the same temperature overnight. To the reaction mixture was added saturated brine and passed through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (R) -N-[(1E, 2S) -3- (benzyloxy) -2-methoxy as a highly polar product. Propyridene] -2-methylpropane-2-sulfinamide (0.57 g) and (R) -N-[(1E, 2R) -3- (benzyloxy) -2-methoxypropylidene] as the low polarity product -2-Methylpropane-2-sulfinamide (0.70 g) was obtained. N-Butyllithium n-hexane solution (2.6 mol / L, 1.0 mL) was added to a solution of 2-methylpyridine (0.27 g) in tetrahydrofuran (5 mL) at −78 ° C., and the mixture was added at the same temperature to 10 ° C. Stir for minutes. To this mixture was added (R) -N-[(1E, 2S) -3- (benzyloxy) -2-methoxypropylidene] -2-methylpropane-2-sulfinamide (0.57 g) in tetrahydrofuran (4 mL). The solution was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 1.5 hours. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. This residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol). The crude product was purified by reverse phase preparative column chromatography (CapcellPakC18 UG80, elution solvent: acetonitrile / water), and (R) -N-[(2R, 3S) -4- (benzyloxy) as a highly polar product. -3-Methoxy-1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide (0.20 g) was obtained. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 2 mL) was added to a solution of the product (0.20 g) in methanol (2 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound (0.15 g).

Reference Example 2-9-1
To a solution of (2R, 3R) -4- (benzyloxy) -3-methoxy-1- (pyridin-2-yl) butan-2-amine 2-methylpyridine (0.19 g) in tetrahydrofuran (3 mL) was added n- A butyllithium n-hexane solution (2.6 mol / L, 1.0 mL) was added at −78 ° C., and the mixture was stirred at the same temperature for 10 minutes. To this mixture was added (R) -N-[(1E, 2R) -3- (benzyloxy) -2-methoxypropylidene] -2-methylpropane-2-sulfinamide (0.40 g) in tetrahydrofuran (2 mL). The solution was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 1.5 hours. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol), and (R) -N-[(2R, 3R) -4- (benzyloxy) -3-methoxy-1- (pyridine-2) -Yl) butan-2-yl] -2-methylpropane-2-sulfinamide and (R) -N-[(2S, 3R) -4- (benzyloxy) -3-methoxy-1- (pyridine-2) A mixture (0.47 g) of -yl) butan-2-yl] -2-methylpropane-2-sulfinamide was obtained. To the product (0.42 g) was added tetrahydrofuran (4 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound (0.15 g) as a low polarity product.

Reference Example 2-10-1
(3R) -3-Amino-4- (pyrimidin-2-yl) butan-1-ol hydrochloride (2S) -2-[(tert-butoxycarbonyl) amino] -4-methoxy-4-oxobutanoic acid (2 g ) In tetrahydrofuran (10 mL) was added N-methylmorpholine (981 mg) and chloroformic acid isobutyl ester (1.22 g) at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was passed through a celite pad and the filtrate was concentrated under reduced pressure. To a solution of this residue in methanol (10 mL), sodium borohydride (337 mg) was added at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (3S) -3-[(tert-butoxycarbonyl) amino] -4-hydroxybutanoic acid methyl ester (1.18 g). Got. To a mixture of product (1.18 g), imidazole (551 mg), triphenylphosphine (2.12 g), tetrahydrofuran (40 mL) was added iodine (1.8 g) at 0 ° C., and the mixture was stirred at room temperature for 2 hours. . Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (3S) -3-[(tert-butoxycarbonyl) amino] -4-iodobutanoic acid methyl ester (1.5 g). ) A mixture of the product (1.5 g), zinc (629 mg) and N, N-dimethylformamide (10 mL) was stirred at room temperature for 2 hours under an argon atmosphere. To this mixture, 2-bromopyrimidine (695 mg), bis (triphenylphosphine) palladium (II) dichloride (307 mg) were added at room temperature, and the mixture was stirred at the same temperature for 12 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture and passed through a celite pad. The crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel (elution solvent: ethyl acetate / n-hexane) to give (3R) -3-[(tert-butoxycarbonyl) amino] -4- (pyrimidin-2-yl) butane. Acid methyl ester (746 mg) was obtained. To a mixture of product (746 mg), ethanol (3 mL), water (3 mL) was added sodium borohydride (239 mg) at 0 ° C. and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel (elution solvent: ethyl acetate / n-hexane), and N-[(2R) -4-hydroxy-1- (pyrimidin-2-yl) butan-2-yl] Carbamic acid tert-butyl ester was obtained. Methanol (3 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 3 mL) were added to the product at room temperature, and the mixture was stirred at the same temperature for 13 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (50 mg).

Reference Example 2-11-1
(2S, 3R) -3-Amino-1-ethoxy-4- (pyridin-2-yl) butan-2-ol (2R) -2-[(benzyloxy) methyl] oxirane (1.00 g) To a solution of ethanol (10 mL) was added potassium hydroxide (1.03 g) at 0 ° C. and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. This residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to obtain (2R) -1- (benzyloxy) -3-ethoxypropan-2-ol (1.25 g). To a solution of the product (1.25 g) in dichloromethane (20 mL) were added imidazole (1.01 g) and tert-butyldimethylchlorosilane (0.99 g) at room temperature, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to obtain [(2R) -1- (benzyloxy) -3-ethoxypropan-2-yl] (tert-butyldimethylsilyl). Ether (2.00 g) was obtained. To a solution of the product (2.00 g) in ethanol (20 mL) was added 10% palladium carbon (50% wet, 0.2 g) at room temperature, and the mixture was stirred at the same temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was passed through a celite pad and the filtrate was concentrated under reduced pressure. This residue was dissolved in dichloromethane (10 mL), iodobenzene diacetate (2.87 g) and AZADOL (registered trademark) (0.046 g) were added under ice cooling, and the mixture was stirred at room temperature for 2 hours. A sodium thiosulfate aqueous solution (1 mol / L) and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture, and the crude product was extracted with dichloromethane. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. To this residue, tetrahydrofuran (20 mL), (R) -tert-butylsulfinamide (793 mg) and tetraethyl orthotitanate (1.85 mL) were added at room temperature. The mixture was stirred at room temperature overnight. To the reaction mixture was added saturated brine and passed through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (R) -N-[(1E, 2S) -2- (tert-butyldimethylsilyloxy) -3-ethoxypropiate. Redene] -2-methylpropane-2-sulfinamide (0.85 g) was obtained. To a solution of 2-methylpyridine (0.35 g) in tetrahydrofuran (6 mL) was added n-butyllithium n-hexane solution (1.6 mol / L, 2.2 mL) at −78 ° C., and the mixture was stirred at Stir for minutes. To this mixture was added (R) -N-[(1E, 2S) -2- (tert-butyldimethylsilyloxy) -3-ethoxypropylidene] -2-methylpropane-2-sulfinamide (0.85 g). A tetrahydrofuran (3 mL) solution was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 1.5 hours. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. This residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol). The crude product was purified by reverse phase preparative column chromatography (CapcellPakC18 UG80, elution solvent: acetonitrile / water), and (R) -N-[(2R, 3S) -3- (tert-butyl) as a highly polar product. Dimethylsilyloxy) -4-ethoxy-1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide (0.36 g) was obtained. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 2 mL) was added to a solution of the product (0.36 g) in methanol (2 mL) at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound (0.16 g).

Reference Example 2-11-2
Reference Example 2-11-2 was synthesized in the same manner as Reference Example 2-11-1 using the corresponding starting materials.

Reference Example 2-12-1
(1R) -1-((4R) -2,2-dimethyl-1,3-dioxolan-4-yl) -2- (pyrimidin-2-yl) ethan-1-amine N-[(1R) -1 -((4R) -2,2-dimethyl-1,3-dioxolan-4-yl) -2-hydroxyethyl] carbamic acid benzyl ester (1.78 g), imidazole (656 mg), triphenylphosphine (2.53 g ), Tetrahydrofuran (20 mL), iodine (2.14 g) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and N-[(1S) -1-((4R) -2,2-dimethyl-1,3-dioxolane-4- Yl) -2-iodoethyl] carbamic acid benzyl ester (1.9 g). A mixture of the product (1.0 g), zinc (355 mg) and N, N-dimethylformamide (10 mL) was stirred at room temperature for 2 hours under an argon atmosphere. To this mixture, 2-bromopyrimidine (392 mg), bis (triphenylphosphine) palladium (II) dichloride (173 mg) were added at room temperature, and the mixture was stirred at the same temperature for 13 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and passed through a celite pad. The crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: ethyl acetate / n-hexane) to give N-[(1R) -1-((4R) -2,2-dimethyl-1,3-dioxolane. -4-yl) -2- (pyrimidin-2-yl) ethyl] carbamic acid benzyl ester (614 mg) was obtained. A mixture of product (400 mg), 10% palladium on carbon (50% wet, 10 mg), ethyl acetate (5 mL) was stirred at room temperature for 5 hours under hydrogen atmosphere. The reaction mixture was passed through a celite pad. The filtrate was concentrated under reduced pressure to give the title compound (140 mg).

Reference Example 2-13-1
(2S) -3- (Benzyloxy) -1-methoxy-1- (pyridin-2-yl) propan-2-amine hydrochloride 2- (tert-butyldimethylsilyloxymethyl) pyridine (1.032 g) in tetrahydrofuran N-Butyllithium n-hexane solution (2.6 mol / L, 1.5 mL) was added to the (5 mL) solution at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. A solution of (R) -N-[(1E) -2- (tert-butyldimethylsilyloxy) ethylidene] -2-methylpropane-2-sulfinamide (0.836 g) in tetrahydrofuran (5 mL) was added at -78 ° C. The mixture was stirred at the same temperature for 30 minutes. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) and (R) -N-[(2S) -3- (benzyloxy) -1- (tert-butyldimethylsilyloxy) -1- (pyridin-2-yl) propan-2-yl] -2-methylpropane-2-sulfinamide (HP, 0.345 g), and (R) -N-[(2S) -3- (benzyl Oxy) -1- (tert-butyldimethylsilyloxy) -1- (pyridin-2-yl) propan-2-yl] -2-methylpropane-2-sulfinamide (LP, 0.354 g) was obtained. (R) -N-[(2S) -3- (benzyloxy) -1- (tert-butyldimethylsilyloxy) -1- (pyridin-2-yl) propan-2-yl] -2-methylpropane- To a solution of 2-sulfinamide (HP, 0.345 g) in tetrahydrofuran (4 mL) was added tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 1 mL) at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. did. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: methanol / ethyl acetate) and (R) -N-[(2S) -3- (benzyloxy) -1-hydroxy-1- (pyridin-2-yl). ) Propan-2-yl] -2-methylpropane-2-sulfinamide (0.185 g). Sodium hydride (60% oil dispersion, 0.006 g) was added to a solution of the product (0.093 g) in tetrahydrofuran (1 mL) at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. To this mixture was added iodomethane (0.145 g) at room temperature and the mixture was stirred at the same temperature overnight. Ice was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (R) -N-[(2S) -3- (benzyloxy) -1-methoxy-1- (pyridine-2) -Yl) propan-2-yl] -2-methylpropane-2-sulfinamide (0.042 g) was obtained. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) was added to a solution of the product (0.024 g) in 1,4-dioxane (1 mL) at room temperature, and the mixture was stirred at the same temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. This residue was washed with n-hexane to obtain the title compound (0.015 g).

Reference Example 2-14-1
(2R, 3S) -4- (tert-Butyldiphenylsilyloxy) -3-methoxy-1- (1H-pyrazol-1-yl) butan-2-amine N-[(1R) -1-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) -2-hydroxyethyl] carbamic acid tert-butyl ester (12.6 g) in dichloromethane (70 mL) in triethylamine (9.76 g), methanesulfonyl Chloride (7.18 g) was added at 0 ° C. and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. To a solution of this residue in N, N-dimethylformamide (100 mL), cesium carbonate (47.13 g) and pyrazole (6.57 g) were added at room temperature, and the mixture was stirred at 80 ° C. for 4 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. This residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and N-[(1R) -1-((4S) -2,2-dimethyl-1,3-dioxolane-4- Yl) -2- (1H-pyrazol-1-yl) ethyl] carbamic acid tert-butyl ester (6.5 g) was obtained. Trifluoroacetic acid (1.6 mL) was added to a mixture of the product (6.5 g) in methanol (21 mL) and water (7 mL) at room temperature, and the mixture was stirred at the same temperature for 2 days. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol), and N-[(2R, 3S) -3,4-dihydroxy-1- (1H-pyrazol-1-yl) butane-2- [Il] carbamic acid tert-butyl ester (5.0 g) was obtained. To a solution of the product (5.0 g) in N, N-dimethylformamide (20 mL), imidazole (1.71 g) and tert-butyldiphenylchlorosilane (6.31 g) were added at 0 ° C., and the mixture was stirred at the same temperature for 3 hours. Stir for hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -3-hydroxy-1- ( 1H-pyrazol-1-yl) butan-2-yl] carbamic acid tert-butyl ester (7.8 g) was obtained. To a mixture of the product (7.8 g), iodomethane (2.61 g), tetrahydrofuran (30 mL) and N, N-dimethylformamide (3 mL), a small amount of sodium hydride (60% oil dispersion, 642 mg) at 0 ° C. The mixture was added in portions and the mixture was stirred at the same temperature for 4 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -3-methoxy-1- (1H -Pyrazol-1-yl) butan-2-yl] carbamic acid tert-butyl ester (6.8 g) was obtained. To a solution of the product (6.8 g) in dichloromethane (20 mL) was added trifluoroacetic acid (10 mL) at room temperature, and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. To this residue was added aqueous sodium hydroxide solution (2 mol / L), and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: ethyl acetate / n-hexane) to give the title compound (4.5 g).

Reference Examples 2-14-2 to 2-14-3
Reference Examples 2-14-2 to 2-14-3 were synthesized in the same manner as in Reference Example 2-14-1, using the corresponding starting materials.

Reference Example 2-15-1
N-[(2S, 3S) -4- (tert-Butyldiphenylsilyloxy) -1-iodo-3-methoxybutan-2-yl] carbamic acid tert-butyl ester (4S) -4-[(1R)- To a solution of 1-azido-2- (benzyloxy) ethyl] -2,2-dimethyl-1,3-dioxolane (2.3 g) in methanol (5 mL), a hydrogen chloride 1,4-dioxane solution (4 mol / L, 10 mL) was added at room temperature and the mixture was stirred at the same temperature for 4 hours. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 10 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at 60 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. To a solution of this residue in N, N-dimethylformamide (25 mL), imidazole (678 mg) and tert-butyldiphenylchlorosilane (2.51 g) were added at 0 ° C., and the mixture was stirred at the same temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (2S, 3R) -3-azido-4- (benzyloxy) -1- (tert-butyldiphenylsilyloxy) butane. -2-ol (4.58 g) was obtained. To a mixture of product (4.58 g), N, N-dimethylformamide (10 mL), iodomethane (2.05 g), sodium hydride (60% oil dispersion, 425 mg) was added at 0 ° C. Stir at temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and [(2S, 3R) -3-azido-4- (benzyloxy) -2-methoxybutyl] (tert-butyldiphenyl). Silyl) ether (4.3 g) was obtained. A mixture of the product (4.3 g), di-tert-butyl dicarbonate (2.3 g), 20% palladium hydroxide on carbon (50% wet, 2 g), ethanol (30 mL) at 60 ° C. under hydrogen atmosphere for 13 hours. Stir. The reaction mixture was passed through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -1-hydroxy-3-methoxybutane. -2-yl] carbamic acid tert-butyl ester (2.88 g) was obtained. To a mixture of product (2.88 g), imidazole (662 mg), triphenylphosphine (2.55 g), tetrahydrofuran (10 mL) was added iodine (2.16 g) at 0 ° C. and the mixture was stirred at room temperature for 1 hour. . Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to give the title compound (3.08 g).

Reference Example 2-15-2
Reference Example 2-15-2 was synthesized in the same manner as in Reference Example 2-15-1, using the corresponding starting materials.

Reference Example 2-16-1
(2S, 3R) -3-Amino-2-methoxy-4- (pyrimidin-2-yl) butan-1-ol Reference Example 2-15-1 (1.09 g), zinc (268 mg), N, N— A mixture of dimethylformamide (10 mL) was stirred at room temperature for 2 hours under an argon atmosphere. To this mixture, 2-bromopyrimidine (296 mg) and bis (triphenylphosphine) palladium (II) dichloride (131 mg) were added at room temperature, and the mixture was stirred at the same temperature for 4 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture and passed through a celite pad. The crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -3-methoxy-1 -(Pyrimidin-2-yl) butan-2-yl] carbamic acid tert-butyl ester (455 mg) was obtained. A mixture of the product (455 mg) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 5 mL) was stirred at 50 ° C. for 3 days. The reaction mixture was concentrated under reduced pressure. To a solution of this residue in tetrahydrofuran (1 mL) was added tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 1 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound (150 mg).

Reference Example 2-17-1
(2R, 3S) -4- (benzyloxy) -3-fluoro-1- (1H-pyrazol-1-yl) butan-2-amine (1S) -2- (benzyloxy) -1-[(4S) -2,2-Dimethyl-1,3-dioxolan-4-yl] ethane-1-ol (1.4 g) in dichloromethane (10 mL) was added (diethylamino) sulfur trifluoride (1.34 g) at -78 ° C. And the mixture was stirred at the same temperature for 1 hour and further at room temperature for 2 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (4S) -4-[(1R) -2- (benzyloxy) -1-fluoroethyl] -2,2- Dimethyl-1,3-dioxolane (0.52 g) was obtained. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 3 mL) was added to a solution of the product (0.52 g) in methanol (3 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (2S, 3R) -4- (benzyloxy) -3-fluorobutane-1,2-diol (0.21 g). Got. Triphenylphosphine (67 mg) and azodicarboxylic acid diethyl ester toluene solution (2.2 mol / L, 116 μL) were added to a solution of the product (50 mg) in toluene (1 mL) at room temperature, and the mixture was stirred at 80 ° C. overnight. After the reaction mixture was cooled to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (2R) -2-[(1R) -2- (benzyloxy) -1-fluoroethyl] oxirane (40 mg). Obtained. To a solution of the product (40 mg) in N, N-dimethylformamide (1 mL), cesium carbonate (133 mg) and pyrazole (15 mg) were added at room temperature, and the mixture was stirred at 100 ° C. for 1 hour. After the reaction mixture was cooled to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (2S, 3R) -4- (benzyloxy) -3-fluoro-1- (1H-pyrazol-1- Yl) butan-2-ol (32 mg) was obtained. To a solution of the product (32 mg) in dichloromethane (2 mL) was added N, N-diisopropylethylamine (39 mg), 4-dimethylaminopyridine (2 mg) and methanesulfonyl chloride (18 mg) at room temperature, and the mixture was added at 0 ° C at the same temperature. Stir for 5 hours. Water was added to the reaction mixture and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. To this residue was added N, N-dimethylformamide (2 mL) and sodium azide (24 mg) at room temperature, and the mixture was stirred at 100 ° C. for 2 days. After the reaction mixture was cooled to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 1-[(2R, 3S) -2-azido-4- (benzyloxy) -3-fluorobutyl] -1H- Pyrazole (33 mg) was obtained. To a solution of the product (33 mg) in ethanol (3 mL) was added 10% palladium on carbon (50% wet, 10 mg) at room temperature, and the mixture was stirred at the same temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was passed through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound (21 mg).

Reference Examples 2-17-2 to 2-17-3
Reference Examples 2-17-2 to 2-17-3 were synthesized in the same manner as in Reference Example 2-17-1, using the corresponding starting materials.

Reference Example 2-18-1
(2R) -4- (Benzyloxy) -3,3-difluoro-1- (2H-1,2,3-triazol-2-yl) butan-2-amine hydrochloride [(2R) -2-azido- To a solution of 4-benzyloxy-3,3-difluorobutan-1-yl] (tert-butyldiphenylsilyl) ether (3.5 g) in ethanol (20 mL), di-tert-butyl dicarbonate (1.7 g), 10% palladium on carbon (50% wet, 500 mg) was added at room temperature, and the mixture was stirred at the same temperature under a hydrogen atmosphere for 5 hours. The reaction mixture was passed through a celite pad. The filtrate was concentrated under reduced pressure. To this residue were added tetrahydrofuran (10 mL) and tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 8.5 mL) at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and N-[(2R) -4- (benzyloxy) -3,3-difluoro-1-hydroxybutan-2-yl Carbamic acid tert-butyl ester (1.5 g) was obtained. Triethylamine (611 mg) and methanesulfonyl chloride (450 mg) were added to a solution of the product (1.0 g) in dichloromethane (5 mL) at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. To a solution of this residue in N, N-dimethylformamide (5 mL), cesium carbonate (2.95 g) and 1,2,3-triazole (417 mg) were added at room temperature, and the mixture was stirred at 60 ° C. for 3 hours. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added to the mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate) to give N-[(2R) -4- (benzyloxy) -3,3-difluoro-1- (2H-1, 2,3-Triazol-2-yl) butan-2-yl] carbamic acid tert-butyl ester (590 mg) was obtained. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) was added to a solution of the product (590 mg) in methanol (1 mL) at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (480 mg).

Reference Examples 2-18-2 to 2-18-3
Reference Examples 2-18-2 to 2-18-3 were synthesized in the same manner as in Reference Example 2-18-1, using the corresponding starting materials.

Reference Example 2-19-1
(R) -N-[(1R) -1-((4R) -2,2-dimethyl-1,3-dioxolan-4-yl) -2- (pyridin-2-yl) ethyl] -2-methyl Propane-2-sulfinamide (4S) -2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (0.50 g) in tetrahydrofuran (11.5 mL) in a solution of (R) -2-methylpropane-2 Sulphinamide (0.61 g) and tetraethyl orthotitanate (1.40 g) were added at room temperature and the mixture was stirred at the same temperature overnight. To the reaction mixture was added saturated brine and passed through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (R) -N-[(1E)-((4R) -2,2-dimethyl-1,3-dioxolane- 4-yl) methylidene] -2-methylpropane-2-sulfinamide (0.48 g) was obtained. To a solution of 2-methylpyridine (60 mg) in tetrahydrofuran (1 mL) was added n-butyllithium n-hexane solution (2.6 mol / L, 0.22 mL) at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. . (R) -N-[(1E)-((4R) -2,2-dimethyl-1,3-dioxolan-4-yl) methylidene] -2-methylpropane-2-sulfinamide (100 mg) was added to this mixture. Of tetrahydrofuran (1 mL) was added at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / ethyl acetate) to give the title compound (70 mg).

Reference Example 2-19-2
Reference Example 2-19-2 was synthesized in the same manner as Reference Example 2-19-1 using the corresponding starting materials.

Reference Example 2-20-1
(R) -N-[(1S) -1-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) -2- (pyridin-2-yl) ethyl] -2-methyl Propane-2-sulfinamide (4R) -2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (2.50 g) in a solution of (R) -2-methylpropane-2-sulfine in tetrahydrofuran (30 mL) Amide (3.03 g) and tetraethyl orthotitanate (7.01 g) were added at room temperature and the mixture was stirred at the same temperature overnight. To the reaction mixture was added saturated brine and passed through a celite pad. Water was added to the filtrate and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (R) -N-[(1E)-((4S) -2,2-dimethyl-1,3-dioxolane- 4-yl) methylidene] -2-methylpropane-2-sulfinamide (3.10 g) was obtained. To a solution of 2-methylpyridine (0.96 g) in tetrahydrofuran (15 mL) was added n-butyllithium n-hexane solution (2.6 mol / L, 3.6 mL) at −78 ° C., and this mixture was kept at the same temperature for 10 minutes. Stir. To this mixture was added (R) -N-[(1E)-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) methylidene] -2-methylpropane-2-sulfinamide (1 .60 g) in tetrahydrofuran (6 mL) was added at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / ethyl acetate) to give the title compound (0.610 g) as a low polarity product.

Reference Example 2-21-1
(R) -N-[(1R) -1-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) -2- (pyridin-2-yl) propyl] -2-methyl Propane-2-sulfinamide 2-ethylpyridine (0.17 g) in tetrahydrofuran (2.5 mL) was added n-butyllithium n-hexane solution (2.6 mol / L, 0.57 mL) at −78 ° C. The mixture was stirred at the same temperature for 10 minutes. To this mixture was added (R) -N-[(1E)-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) methylidene] -2-methylpropane-2-sulfinamide (0 .25 g) in tetrahydrofuran (2.5 mL) was added at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / ethyl acetate) to give the title compound (0.089 g) as a highly polar product.

Reference Example 2-22-1
(R) -N-[(1R) -1-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) -2-hydroxy-2- (pyridin-2-yl) ethyl] -2-Methylpropane-2-sulfinamide 2- (tert-butyldimethylsilyloxymethyl) pyridine (1.21 g) in tetrahydrofuran (6 mL) was added to n-butyllithium n-hexane solution (2.6 mol / L, 1 .82 mL) was added at −78 ° C. and the mixture was stirred at the same temperature for 10 minutes. To this mixture was added (R) -N-[(1E)-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) methylidene] -2-methylpropane-2-sulfinamide (0 .788 g) in tetrahydrofuran (4 mL) was added at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane). The crude product was purified by reverse phase preparative liquid chromatography (CapcellPak C18 UG80, elution solvent: acetonitrile / water), and a diastereomeric mixture (0.429 g) as a low polarity product and (R)-as a high polarity product. N-[(1S) -2- (tert-butyldimethylsilyloxy) -1-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) -2- (pyridin-2-yl) ) Ethyl] -2-methylpropane-2-sulfinamide (0.375 g) was obtained. The low polarity product (0.429 g) was dissolved in tetrahydrofuran (9 mL). To this mixture was added tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 1.0 mL) at 0 ° C., and the mixture was stirred at the same temperature for 3 hours. After adding saturated aqueous ammonium chloride solution to the reaction mixture, the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / ethyl acetate) to give the title compound (0.185 g) as a highly polar product.

Reference Example 2-23-1
(2R) -2-Amino-3- [3- (hydroxymethyl) pyridin-2-yl] propan-1-ol hydrochloride (2S) -2-[(tert-butoxycarbonyl) amino] -3-iodopropane A mixture of acid methyl ester (0.91 g), zinc (396 mg) and N, N-dimethylformamide (5 mL) was stirred at room temperature for 2 hours under an argon atmosphere. To this mixture, 2-bromopyridine-3-carboxylic acid methyl ester (595 mg) and bis (triphenylphosphine) palladium (II) dichloride (193 mg) were added at room temperature, and the mixture was stirred at the same temperature for 24 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture and passed through a celite pad. The crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel (elution solvent: ethyl acetate / n-hexane) to give 2-[(2R) -2-[(tert-butoxycarbonyl) amino] -3-methoxy-3-oxo. Propyl] pyridine-3-carboxylic acid methyl ester (890 mg) was obtained. To a mixture of product (890 mg), ethanol (3 mL) and water (3 mL) was added sodium borohydride (249 mg) at 0 ° C. and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. To this residue, methanol (3 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 3 mL) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound.

Reference Example 2-4-1
(R) -N-[(1R) -1-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) -2-hydroxy-2- (pyridin-2-yl) ethyl] -2-Methylpropane-2-sulfinamide (R) -N-[(1S) -2- (tert-butyldimethylsilyloxy) -1-((4S) -2,2-dimethyl-1,3-dioxolane -4-yl) -2- (pyridin-2-yl) ethyl] -2-methylpropane-2-sulfinamide (0.375 g) was dissolved in tetrahydrofuran (8 mL). To this mixture was added tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 0.82 mL) at 0 ° C., and the mixture was stirred at the same temperature for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / ethyl acetate) to give the title compound (0.209 g).

Reference Example 2-25-1
(R) -N-[(1R) -1-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) -2-methoxy-2- (pyridin-2-yl) ethyl] -2-Methylpropane-2-sulfinamide Reference Example 2-24-1 (0.209 g) in tetrahydrofuran (3 mL) was added to sodium hydride (60% oil dispersion, 0.025 g) and iodine methane (0. 346 g) was added at 0 ° C. and the mixture was stirred at room temperature overnight. Ice was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: ethyl acetate / n-hexane) to give the title compound (0.175 g).

Reference Example 2-26-1
(R) -N-[(2S) -1,4-di (tert-butyldimethylsilyloxy) -1- (pyridin-2-yl) pentan-2-yl] -2-methylpropane-2-sulfinamide To a solution of (3S) -3- (tert-butyldimethylsilyloxy) butanal (2.06 g) in tetrahydrofuran (30 mL) was added (R)-(+)-2-methylpropane-2-sulfinamide (1.65 g). Tetraethyl orthotitanate (3.81 g) was added at room temperature and the mixture was stirred at the same temperature overnight. To the reaction mixture were added saturated brine and ethyl acetate, and passed through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) and (R) -N-[(1E) -3- (tert-butyldimethylsilyloxy) butylidene] -2-methylpropane. -2-Sulfinamide (2.66 g) was obtained. To a solution of 2- (tert-butyldimethylsilyloxymethyl) pyridine (1.11 g) in tetrahydrofuran (5 mL) was added n-butyllithium n-hexane solution (2.6 mol / L, 1.67 mL) at −78 ° C. The mixture was stirred at the same temperature for 10 minutes. To this mixture was added a solution of (R) -N-[(1E) -3- (tert-butyldimethylsilyloxy) butylidene] -2-methylpropane-2-sulfinamide (1.00 g) in tetrahydrofuran (5 mL). The mixture was added at 78 ° C., and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane). The crude product was purified by reverse phase preparative liquid chromatography (CapcellPak C18 UG80, elution solvent: acetonitrile / water) to obtain the title compound (0.37 g).

Reference Example 2-27-1
(3R) -3-Amino-2,2-difluoro-4- (2H-1,2,3-triazol-2-yl) butan-1-ol hydrochloride N-[(2R) -4- (benzyloxy ) -3,3-difluoro-1- (2H-1,2,3-triazol-2-yl) butan-2-yl] carbamic acid tert-butyl ester (50 mg) in a solution of methanol (1 mL) with hydrogen chloride 1,4-Dioxane solution (4 mol / L, 0.2 mL) and 10% palladium on carbon (50% wet, 10 mg) were added at room temperature, and the mixture was stirred at the same temperature for 4 hours under a hydrogen atmosphere. To this mixture was added hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was passed through a celite pad. The filtrate was concentrated under reduced pressure to give the title compound (30 mg).

Reference Examples 2-27-2 to 2-27-4
Reference Examples 2-27-2 to 2-27-4 were synthesized in the same manner as in Reference Example 2-27-1 using the corresponding starting materials.

Reference Example 2-28-1
(2S, 3R) -3-Amino-4- (pyridin-2-yl) butane-1,2-diol hydrochloride To a solution of 2-methylpyridine (0.35 g) in tetrahydrofuran (4 mL) was added n-butyllithium n A -hexane solution (2.6 mol / L, 1.35 mL) was added at -78 ° C., and the mixture was stirred at the same temperature for 10 minutes. To this mixture was added (R) -N-[(1E)-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methylidene] -2-methylpropane-2-sulfinamide (0 .59 g) in tetrahydrofuran (4 mL) was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 0.5 hour. The mixture was warmed to room temperature and stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol), and (R) -N-[(1R) -1-[(4S) -2,2-dimethyl-1 was obtained as a highly polar product. , 3-Dioxolan-4-yl] -2- (pyridin-2-yl) ethyl] -2-methylpropane-2-sulfinamide (0.26 g). To a solution of this product (0.26 g) in methanol (1 mL) was added hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) at room temperature, and the mixture was stirred at the same temperature for 2 hours. The precipitate was collected by filtration to give the title compound (0.16 g).

Reference Example 2-29-1
(R) -N-[(1R) -1-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) -2-methoxy-2- (pyridin-2-yl) ethyl] -2-Methylpropane-2-sulfinamide Reference Example 2-22-1 (0.185 g) in tetrahydrofuran (2 mL) was mixed with sodium hydride (60% oil dispersion, 0.022 g) and iodine methane (0. 306 g) was added at 0 ° C. and the mixture was stirred at room temperature overnight. Ice was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: ethyl acetate / n-hexane) to give the title compound (0.162 g).

Example 1-1
2- [5- (2-Hydroxyphenyl) -1,3-thiazol-2-yl] -N- [2- (pyridin-2-yl) ethyl] benzamide Reference Example 1-1-3 (19 mg) in dichloromethane To the suspension (1 mL), 2- (pyridin-2-yl) ethan-1-amine (6 mg), N, N-diisopropylethylamine (23 mg) and T3P® N, N-dimethylformamide solution (1 .6 mol / L, 65 μL) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to give 2- {5- [2- (benzyloxy) phenyl] -1,3-thiazol-2-yl} -N- [ 2- (Pyridin-2-yl) ethyl] benzamide (20 mg) was obtained. To a suspension of this product (20 mg) in ethanol (1 mL) was added 10% palladium on carbon (50% wet, 20 mg) at room temperature, and the mixture was stirred at the same temperature under a hydrogen atmosphere for 12 hours. The reaction mixture was passed through a celite pad and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound (10 mg).

Examples 1-2 to 1-8
Examples 1-2 to 1-8 were synthesized in the same manner as in Example 1-1 using the corresponding starting materials.

Example 2-1
N-[(2R, 3S) -3,4-dihydroxy-1- (pyridin-2-yl) butan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1,3 -Thiazol-2-yl] benzamide To a suspension of Reference Example 1-1-1 (40 mg) in N, N-dimethylformamide (1 mL) was added 1-hydroxybenzotriazole monohydrate (19 mg), Reference Example 2- 28-1 (32 mg), triethylamine (51 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (24 mg) were added at room temperature and the mixture was stirred at the same temperature overnight. Water was added to the reaction mixture, and the precipitate was collected by filtration to give the title compound (45 mg).

Examples 2-2 to 2-64
Examples 2-2 to 2-64 were synthesized in the same manner as in Example 2-1, using the corresponding starting materials.

Example 3-1
2- [5- (3,4-Difluorophenyl) -1,3-thiazol-2-yl] -3-fluoro-N-[(2R) -4-hydroxy-3- (hydroxymethyl) -1- ( Pyridin-2-yl) butan-2-yl] benzamide To a suspension of Reference Example 1-1-9 (35 mg) in N, N-dimethylformamide (1 mL) was added 1-hydroxybenzotriazole monohydrate (19 mg). Reference Example 2-3-3 (48 mg), triethylamine (42 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (24 mg) were added at room temperature, and the mixture was stirred at the same temperature for 20 hours. did. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. Ethyl acetate was added to the aqueous layer, and the organic layer was partitioned. The combined organic layers were washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to give 2- [5- (3,4-difluorophenyl) -1,3-thiazol-2-yl] -3-fluoro- N-[(1R) -2- (pyridin-2-yl) -1-((2R, 5R) -2-phenyl-1,3-dioxane-5-yl) ethyl] benzamide (29 mg) was obtained. To this product (29 mg) was added acetic acid (0.8 mL) and water (0.2 mL) at room temperature and the mixture was stirred at 40 ° C. for 23 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound (12 mg).

Examples 3-2 to 3-4
Examples 3-2 to 3-4 were synthesized in the same manner as in Example 3-1, using the corresponding starting materials.

Example 4-1
2- {5- [2- (hydroxymethyl) phenyl] -1,3-thiazol-2-yl} -N- [2- (pyridin-2-yl) ethyl] benzamide Reference Example 1-9-1 (20 mg ) In tetrahydrofuran (1 mL) was added triethylamine (14 mg) and chloroformic acid isobutyl ester (10 mg) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. To this mixture was added sodium borohydride (4 mg) and methanol (0.1 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound (12 mg).

Example 5-1
2- [4-Amino-5- (4-fluorophenyl) -1,3-thiazol-2-yl] -N-[(2R, 3S) -3,4-dihydroxy-1- (pyridin-2-yl) ) Butan-2-yl] benzamide hydrochloride Reference Example 1-3-1 (30 mg) in N, N-dimethylformamide (1 mL) suspension, 1-hydroxybenzotriazole monohydrate (12 mg), Reference Example 2-28-1 (19 mg), triethylamine (29 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (15 mg) were added at room temperature and the mixture was stirred at the same temperature overnight. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Tetrahydrofuran (2 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) were added to the residue at room temperature, and the mixture was stirred at the same temperature for 1 hour. The insoluble material was collected by filtration and washed with diethyl ether to give the title compound (28 mg).

Examples 5-2 to 5-6
Examples 5-2 to 5-6 were synthesized in the same manner as in Example 5-1, using the corresponding starting materials.

Example 6-1
N-[(2R) -1-amino-3-phenylpropan-2-yl] -2- (5-phenyl-1,3-thiazol-2-yl) benzamide Reference Example 1-1-2 (48 mg) To a dichloromethane (1 mL) suspension, Reference Example 2-1-1 (59 mg), N, N-diisopropylethylamine (77 mg) and T3P® ethyl acetate solution (1.7 mol / L, 185 μL) were added at room temperature. In addition, the mixture was stirred at the same temperature for 2.5 hours. Water was added to the reaction mixture and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give N-[(2R) -1- (1,3-dioxo-2,3-dihydro-1H-iso Indol-2-yl) -3-phenylpropan-2-yl] -2- (5-phenyl-1,3-thiazol-2-yl) benzamide (80 mg) was obtained. To a solution of this product (80 mg) in methanol (1 mL) was added hydrazine monohydrate (42 mg) at room temperature, and the mixture was stirred with heating under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound (37 mg).

Examples 6-2 to 6-3
Examples 6-2 to 6-3 were synthesized in the same manner as in Example 6-1 using the corresponding starting materials.

Example 7-1
2- [5- (3,4-Difluorophenyl) -1,3-thiazol-2-yl] -N-[(2S, 3R) -1,2-dihydroxy-4- (pyridin-2-yl) pentane -3-yl] -3-fluorobenzamide Reference Example 22-1 (79 mg) in 1,4-dioxane (1.5 mL) solution in 1,4-dioxane hydrogen chloride solution (4 mol / L, 1.5 mL) Was added at room temperature and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. N-Hexane was added to the residue, and the solvent was removed by decantation. To a solution of this residue in N, N-dimethylformamide (1 mL), Reference Example 1-1-9 (28 mg), 1-hydroxybenzotriazole monohydrate (15 mg), 1-ethyl-3- (3-dimethylamino) Propyl) carbodiimide hydrochloride (19 mg) and triethylamine (33 mg) were added at room temperature and the mixture was stirred at the same temperature for 17 hours. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. Ethyl acetate was added to the aqueous layer, and the crude product was extracted with ethyl acetate. The combined organic layers were washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound (19 mg).

Examples 7-2 to 7-8
Examples 7-2 to 7-8 were synthesized in the same manner as in Example 7-1 using the corresponding starting materials.

Example 8-1
3-Fluoro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] -N-[(2R) -1-hydroxy-3- (2-hydroxyphenyl) propane-2- [Il] benzamide To a solution of Example 2-23 (65 mg) in dichloromethane (3 mL) was added boron tribromide dichloromethane solution (1 mol / L, 1 mL) at −78 ° C., and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the precipitate was collected by filtration to give the title compound (38 mg).

Example 9-1
3-Fluoro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] -N-[(2R, 3S) -4-hydroxy-3-methoxy-1- (1H-pyrazole -1-yl) butan-2-yl] benzamide To a suspension of Reference Example 1-1-1 (40 mg) in N, N-dimethylformamide (1 mL), 1-hydroxybenzotriazole monohydrate (21 mg), Reference Example 2-14-1 (54 mg), diisopropylethylamine (33 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (27 mg) were added at room temperature, and the mixture was stirred at 55 ° C. for 2 hours. did. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane). To a solution of the purified product in tetrahydrofuran (1 mL) was added tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 150 μL) at 0 ° C., and the mixture was stirred at the same temperature for 30 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. This residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol). Acetone was added to the crude product to dissolve it. N-Hexane was added to this solution to suspend it, and this suspension was heated to dissolve insoluble matters. The mixture was cooled to room temperature, and the precipitate was collected by filtration to give the title compound (17 mg).

Example 10-1
3-Fluoro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] -N-[(2R, 3S) -4-hydroxy-3-methoxy-1- (pyridine-2 -Il) butan-2-yl] benzamide To a suspension of Reference Example 1-1-1 (40 mg) in N, N-dimethylformamide (1 mL) was added Reference Example 2-8-1 (36 mg), 1-hydroxybenzo Triazole monohydrate (21 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (27 mg) and triethylamine (51 mg) were added at room temperature and the mixture was stirred at the same temperature overnight. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol), and N-[(2R, 3S) -4- (benzyloxy) -3-methoxy-1- (pyridin-2-yl) butane. -2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] benzamide (67 mg) was obtained. To a solution of this product (67 mg) in trifluoroacetic acid (0.95 mL) was added water (0.1 mL) and dimethyl sulfide (0.2 mL) at room temperature, and the mixture was stirred at 60 ° C. for 1 day. The reaction mixture was cooled to room temperature, poured into a saturated aqueous sodium hydrogen carbonate solution, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound (45 mg).

Examples 10-2 to 10-5
Examples 10-2 to 10-5 were synthesized in the same manner as in Example 10-1, using the corresponding starting materials.

Example 11-1
N-[(2R) -3,3-difluoro-4-hydroxy-1- (2H-1,2,3-triazol-2-yl) butan-2-yl] -3-fluoro-2- [5- (4-Fluorophenyl) -1,3-thiazol-2-yl] benzamide To a suspension of Reference Example 1-1-1 (35 mg) in N, N-dimethylformamide (1 mL), Reference Example 2-27-1 (30 mg), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (34 mg) and N, N-diisopropylethylamine (71 mg) were added at room temperature. The mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed successively with hydrochloric acid (1 mol / L), water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Diethyl ether was added to the residue, and the insoluble material was collected by filtration to give the title compound (30 mg).

Examples 11-2 to 11-4
Examples 11-2 to 11-4 were synthesized in the same manner as in Example 11-1, using the corresponding starting materials.

Example 12-1
N-[(2R) -3,3-difluoro-4-hydroxy-1- (1H-pyrazol-1-yl) butan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] benzamide To a suspension of Reference Example 1-1-1 (51 mg) in N, N-dimethylformamide (1 mL), Reference Example 2-18-3 (50 mg) and 4- (4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (49 mg) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed successively with hydrochloric acid (1 mol / L), water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. To the residue were added trifluoroacetic acid (2 mL), water (0.2 mL) and dimethyl sulfide (0.4 mL), and the mixture was stirred at 50 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / methanol). Diethyl ether was added to the crude product, and the insoluble material was collected by filtration to give the title compound (42 mg).

Example 13-1
3-Fluoro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] -N-[(2R, 3S) -4-hydroxy-3-methoxy-1- (2H-1 , 2,3-Triazol-2-yl) butan-2-yl] benzamide To a suspension of Reference Example 1-1-1 (30 mg) in N, N-dimethylformamide (1 mL) was added Reference Example 2-14-3. (44 mg) and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (29 mg) were added at room temperature and the mixture was stirred at the same temperature for 2 hours. did. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Tetrahydrofuran (1 mL) and tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 0.11 mL) were added to the residue at 0 ° C., and the mixture was stirred at the same temperature for 30 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Diethyl ether was added to the residue, and the insoluble material was collected by filtration to give the title compound (21 mg).

Example 14-1
N-[(2R) -1-amino-3- (pyridin-2-yl) propan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1,3-thiazole-2 -Il] benzamide To a suspension of Reference Example 1-1-1 (35 mg) in N, N-dimethylformamide (1 mL), Reference Example 2-1-3 (39 mg), 1-hydroxybenzotriazole monohydrate ( 25 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (32 mg) and triethylamine (45 mg) were added at room temperature, and the mixture was stirred at the same temperature for 2 days. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol), and N-[(2R) -1- (1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl ) -3- (Pyridin-2-yl) propan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] benzamide (70 mg) It was. To a solution of this product (70 mg) in methanol (2 mL) was added hydrazine monohydrate (28 mg) at room temperature, and the mixture was stirred with heating under reflux for 2 hours. The reaction mixture was purified by aminopropyl silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound (29 mg).

Example 15-1
N-[(2R, 3S) -3,4-dihydroxy-1- (pyridin-2-yl) butan-2-yl] -3-fluoro-2- [5- (2-amino-4-fluorophenyl) -1,3-thiazol-2-yl] benzamide To a suspension of Reference Example 1-1-28 (41 mg) in N, N-dimethylformamide (0.4 mL) was added 1-hydroxybenzotriazole monohydrate (19 mg). ), Reference Example 2-28-1 (25 mg), triethylamine (48 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (36 mg) were added at room temperature, and the mixture was stirred at the same temperature overnight. did. Water was added to the reaction mixture, and the precipitate was collected by filtration. Tetrahydrofuran (1 mL), hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) and trifluoroacetic acid (1 mL) were added to the crude product at room temperature, and the mixture was stirred at the same temperature overnight. Water and sodium carbonate (2 g) were added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (32 mg).

Example 16-1
2- (4-Amino-5-phenyl-1,3-thiazol-2-yl) -N- [2- (pyridin-2-yl) ethyl] benzamide Reference Example 1-3-3 (6 mg) in dichloromethane ( 1 mL) to a suspension, 2- (pyridin-2-yl) ethan-1-amine (4 mg), N, N-diisopropylethylamine (7 mg) and T3P® ethyl acetate solution (1.7 mol / L, 20 μL) was added at room temperature and the mixture was stirred at the same temperature for 0.5 h. Water was added to the reaction mixture and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / n-hexane). Dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) were added to the crude product at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound (3 mg).

Example 16-2
Example 16-2 was synthesized in the same manner as in Example 16-1, using the corresponding starting materials.

Example 17-1
3-Fluoro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] -N-[(2R, 3S) -1,3,4-trihydroxy-1- (pyridine- 2-yl) butan-2-yl] benzamide A solution of 1,4-dioxane hydrogen chloride (4 mol / L, 1 mL) in a solution of Reference Example 22-2 (45 mg) in 1,4-dioxane (1 mL) at room temperature In addition, the mixture was stirred at 50 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure. N-Hexane was added to the residue, and the solvent was removed by decantation. To a solution of this residue in N, N-dimethylformamide (2 mL), Reference Example 1-1-1 (41 mg), 1-hydroxybenzotriazole monohydrate (24 mg), 1-ethyl-3- (3-dimethylamino) Propyl) carbodiimide hydrochloride (30 mg) and triethylamine (52 mg) were added at room temperature, and the mixture was stirred at the same temperature for 17 hours. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. Ethyl acetate was added to the aqueous layer, and the crude product was extracted with ethyl acetate. The combined organic layers were washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound (29 mg).

Example 17-2
Example 17-2 was synthesized in the same manner as Example 17-1 using the corresponding starting materials.

Example 18-1
N-[(2S, 3S) -3,4-Dihydroxy-1-methoxy-1- (pyridin-2-yl) butan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] benzamide Reference Example 2-29-1 (162 mg) in 1,4-dioxane (2 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 2 mL) at room temperature And the mixture was stirred at 50 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure. N-Hexane was added to the residue, and the solvent was removed by decantation. To a solution of this residue (29 mg) in N, N-dimethylformamide (1 mL), Reference Example 1-1-1 (32 mg), 1-hydroxybenzotriazole monohydrate (19 mg), 1-ethyl-3- (3 -Dimethylaminopropyl) carbodiimide hydrochloride (23 mg) and triethylamine (40 mg) were added at room temperature and the mixture was stirred at the same temperature for 17 hours. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. Ethyl acetate was added to the aqueous layer, and the crude product was extracted with ethyl acetate. The combined organic layers were washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound (37 mg).

Example 18-2
Example 18-2 was synthesized in the same manner as in Example 18-1, using the corresponding starting material.

Example 19-1
N-[(2S, 3S) -3,4-Dihydroxy-1-methoxy-1- (pyridin-2-yl) butan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] benzamide Reference Example 2-25-1 (175 mg) in 1,4-dioxane (2 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 2 mL) at room temperature And the mixture was stirred at 50 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure. N-Hexane was added to the residue, and the solvent was removed by decantation. To a solution of this residue (29 mg) in N, N-dimethylformamide (1 mL), Reference Example 1-1-1 (32 mg), 1-hydroxybenzotriazole monohydrate (16 mg), 1-ethyl-3- (3 -Dimethylaminopropyl) carbodiimide hydrochloride (23 mg) and triethylamine (40 mg) were added at room temperature and the mixture was stirred at the same temperature for 17 hours. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. Ethyl acetate was added to the aqueous layer, and the crude product was extracted with ethyl acetate. The combined organic layers were washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound (35 mg).

Example 19-2
Example 19-2 was synthesized in the same manner as in Example 19-1, using the corresponding starting material.

Example 20-1
3-Fluoro-2- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] -N-[(2R, 3S) -1,3,4-trihydroxy-1- (pyridine- 2-yl) butan-2-yl] benzamide A solution of 1,4-dioxane hydrogen chloride (4 mol / L, 2 mL) at room temperature was added to a solution of Reference Example 2-4-1 (208 mg) in 1,4-dioxane (2 mL). In addition, the mixture was stirred at the same temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. N-Hexane was added to the residue, and the solvent was removed by decantation. To a solution of this residue (55 mg) in N, N-dimethylformamide (2 mL), Reference Example 1-1-1 (63 mg), 1-hydroxybenzotriazole monohydrate (37 mg), 1-ethyl-3- (3 -Dimethylaminopropyl) carbodiimide hydrochloride (46 mg) and triethylamine (80 mg) were added at room temperature and the mixture was stirred at the same temperature for 17 hours. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. Ethyl acetate was added to the aqueous layer, and the crude product was extracted with ethyl acetate. The combined organic layers were washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound (29 mg).

Example 21-1
N-[(2S, 4S) -1,4-dihydroxy-1- (pyridin-2-yl) pentan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1,3 -Thiazol-2-yl] benzamide To a solution of Reference Example 2-26-1 (370 mg) in 1,4-dioxane (2 mL) was added 1,4-dioxane hydrogen chloride solution (4 mol / L, 2 mL) at room temperature. The mixture was stirred at 50 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure. N-Hexane was added to the residue, and the solvent was removed by decantation. To a solution of this residue (62 mg) in N, N-dimethylformamide (2 mL), Reference Example 1-1-1 (64 mg), 1-hydroxybenzotriazole monohydrate (37 mg), 1-ethyl-3- (3 -Dimethylaminopropyl) carbodiimide hydrochloride (46 mg) and triethylamine (80 mg) were added at room temperature and the mixture was stirred at the same temperature for 17 hours. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. Ethyl acetate was added to the aqueous layer, and the crude product was extracted with ethyl acetate. The combined organic layers were washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. This residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol). To a solution of the purified product in tetrahydrofuran (1 mL) was added tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 200 μL) at 0 ° C., and the mixture was stirred at room temperature for 17 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound (56 mg).

Example 21-2
Example 21-2 was synthesized in the same manner as in Example 21-1, using the corresponding starting material.

Test example 1
Icilin-induced wet-dog shake inhibitory action test

Dissolve the test compound in dimethylacetamide (Wako Pure Chemical Industries), add 0.5% methylcellulose solution (Wako Pure Chemical Industries) so that the content of dimethylacetamide is 5%, prepare a solution or suspension, It was orally administered to SD rats at 0.3 to 10 mg / kg / 5 mL. One hour later, Icilin (1 mg / kg) dissolved in polyethylene glycol 400 (Wako Pure Chemical Industries, Ltd.) was intraperitoneally administered to induce wet-dog shake. From 5 minutes after the administration of Icilin, 5 minutes of wet-dog shake were counted. As a comparative test, a medium (dimethylacetamide (Wako Pure Chemical Industries): 0.5% methylcellulose solution (Wako Pure Chemical Industries) = 5:95 mixed solution) was similarly administered, and the number of wet-dog shakes at this time was the same. Counted. The wet-dog shake inhibition rate of the test compound was calculated from the following formula: [1- (wet-dog shake count for test compound administration / wet-dog shake count for vehicle administration)] × 100. The results are shown in Table 33.

Test example 2
A test to confirm the prolongation of acetic acid-induced detrusor overactive bladder urination interval

Urethane (Sigma) was dissolved in pure water to 25% w / v and anesthetized by subcutaneous administration to female SD rats at 1.25 g / kg. A catheter was inserted into the rat's bladder and femoral vein, and the bladder catheter was connected to a syringe pump and a pressure transducer. Intravesical pressure was monitored using a pressure transducer, and at the same time, 0.25% acetic acid / saline solution was continuously infused into the bladder at 3.6 ml / hour to induce detrusor overactivity. Immediately after administration, a solution obtained by dissolving a test compound in a mixed solution of dimethylacetamide and physiological saline (20:80) is administered from an intravenous catheter, and the average value of three intervals of urination immediately before administration is defined as 100%. The average value of the interval was calculated as the urination interval extension rate (Elongation of micturition interval (%)). The doses and results are shown in Table 34.

As shown in Table 33, the compound of the present invention exhibited a strong TRPM8 inhibitory action. Furthermore, as shown in Table 34, it was found that the compound of the present invention has a prolonging effect on the micturition interval and is effective in suppressing detrusor overactivity.

Since the compound of the present invention has a potent TRPM8 inhibitory action, it treats or prevents a disease or symptom caused by the activation of TRPM8, particularly lower urinary tract symptom (LUTS), particularly, overactive bladder (OAB). Useful as a therapeutic or prophylactic agent.

Claims

Compound represented by formula (I):

[Where,
Ring A is a group selected from the group consisting of the following (a) to (d):

((**) represents the bonding position with the benzene ring, and (***) represents the bonding position with the ring B);
R 1 is a hydrogen atom, hydroxy, amino, C 1-6 alkyl or hydroxy C 1-6 alkyl;
Ring B is C 6-10 aryl or heterocycle;
R 2a and R 2b each independently represent a hydrogen atom, a halogen atom, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl, haloC 1-6 alkyl or haloC 1-6 alkoxy;
R 3 is a hydrogen atom, a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl or C 1-6 alkoxy;
R 4a is a hydrogen atom or CR 8 R 9 R 10 ;
R 4b is a hydrogen atom or C 1-6 alkyl;
R 5 is a hydrogen atom or C 1-6 alkyl;
Ring C is a group selected from C 6-10 aryl or the group consisting of: pyridyl, pyrimidyl, thiazolyl, pyrazinyl, pyrazolyl, imidazolyl, pyridazinyl, triazolyl, indolyl, isoquinolyl and tetrazolyl;
R 6 represents a hydrogen atom, a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, cyano, hydroxy C 1-6 alkyl, hydroxy C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1 -6 alkoxy, amino, C 1-6 alkoxy C 1-6 alkoxy, carbamoyl or C 1-6 alkoxy C 1-6 alkyl;
R 7a is a hydrogen atom, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl, hydroxy C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, fluorine atom or amino C 1-6 alkyl;
R 7b is a hydrogen atom, a fluorine atom or C 1-6 alkyl;
However, R 5 and R 7b together are the following groups:

May be formed;
R 8 , R 9 and R 10 are each independently a hydrogen atom, hydroxy, C 1-6 alkyl, amino, NR 11 R 12 C 1-6 alkyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl C 1-6 alkoxy C 1-6 alkyl, fluorine atom, carbamoyl, fluoro C 1-6 alkyl or dihydroxy C 1-6 alkyl;
R 11 and R 12 are each independently a hydrogen atom, C 1-6 alkyl or (C 1-6 alkyl) carbonyl;
R 13 is hydroxy C 1-6 alkyl;
n is 0 or 1] or a pharmacologically acceptable salt thereof.
A compound according to claim 1, wherein:
Ring A is a group represented by the following formula:

((**), (***) and R 1 have the same meaning as in claim 1);
Or a pharmacologically acceptable salt thereof.
A compound according to claim 2 comprising:
Ring B is C 6-10 aryl;
R 2a and R 2b are each independently a hydrogen atom, a halogen atom, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy or hydroxy C 1-6 alkyl;
R 3 is a hydrogen atom or a halogen atom;
R 4b is a hydrogen atom;
Ring C is C 6-10 aryl or a group selected from: pyridyl, pyrimidyl, pyrazolyl and triazolyl;
R 6 is a hydrogen atom, a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, cyano, hydroxy C 1-6 alkyl or hydroxy C 1-6 alkoxy;
R 7a is a hydrogen atom, hydroxy, C 1-6 alkyl, C 1-6 alkoxy or hydroxy C 1-6 alkyl;
R 8 , R 9 and R 10 are each independently a hydrogen atom, hydroxy, C 1-6 alkyl, amino, C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 A compound or a pharmaceutically acceptable salt thereof, which is an alkyl or fluorine atom.
A compound according to claim 3 comprising:
Ring B is phenyl;
A compound or a pharmaceutically acceptable salt thereof, wherein n is 1.
5. A compound according to claim 4, wherein:
R 5 is a hydrogen atom;
R 7a is a hydrogen atom, hydroxy, C 1-6 alkyl or C 1-6 alkoxy;
A compound or a pharmaceutically acceptable salt thereof, wherein R 7b is a hydrogen atom.
6. A compound according to claim 5, wherein:
R 4a is CR 8 R 9 R 10 (R 8 , R 9 and R 10 have the same meaning as in claim 3);
Or a pharmacologically acceptable salt thereof.
7. A compound according to claim 6 comprising:
Ring A is a group represented by the following formula:

((**), (***), and R 1 have the same meaning as in claim 1);
Or a pharmacologically acceptable salt thereof.
8. A compound according to claim 7, wherein:
R 1 is a hydrogen atom, hydroxy or amino;
Ring C is a group selected from the group consisting of: pyridyl, pyrimidyl, pyrazolyl and triazolyl;
A compound or a pharmaceutically acceptable salt thereof, wherein R 6 is a hydrogen atom, hydroxy or halogen atom.
The compound according to claim 1, which is represented by formula (II):

[Where
R 2c and R 2d are each independently a hydrogen atom, a halogen atom or C 1-6 alkoxy (however, they are not simultaneously a hydrogen atom);
Ring C ′ is a group selected from C 6-10 aryl or the group consisting of: pyridyl, pyrimidyl, pyrazolyl and triazolyl;
R 3a is a hydrogen atom, a halogen atom, C 1-6 alkyl or C 1-6 alkoxy;
R 4c is a group represented by the following formula:

R 6a is a hydrogen atom or a halogen atom;
R 7c is a hydrogen atom, hydroxy, C 1-6 alkyl or C 1-6 alkoxy;
R 9a and R 10a are each independently a hydrogen atom, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl or a fluorine atom] or a pharmaceutically acceptable salt thereof salt.
10. A compound according to claim 9, wherein:
R 3a is a hydrogen atom or a halogen atom;
R 4c is a group represented by the following formula:

(Wherein R 9a and R 10a have the same meaning as in claim 9);
Or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, or a pharmacologically acceptable salt thereof, and a pharmaceutical additive.
12. The pharmaceutical composition according to claim 11, which is a pharmaceutical composition for treating or preventing a disease or symptom caused by hyperexcitability or disorder of afferent nerve.