JP5284788B2 - Heteroaryl ring-substituted pyridine derivatives and antifungal agents containing them - Google Patents

Description

  The present invention relates to novel heteroaryl ring-substituted pyridine derivatives and antifungal agents containing them.

  In recent years, as the number of patients and elderly people whose immune functions have been reduced by advanced chemotherapy or the like has increased, countermeasures against opportunistic infections have become increasingly important. As the fact that opportunistic infections with different attenuated bacteria occur one after another, as long as there are underlying diseases that reduce the patient's resistance, the problem of infectious diseases is constant. Therefore, in the aging society that will surely come in the near future, new countermeasures against infectious diseases including the problem of resistant bacteria are expected to be one of the important issues.

  In the field of antifungal agents, for example, polyene-based amphotericin B, azole-based fluconazole, itraconazole, voriconazole, and the like have been developed for the treatment of deep mycosis. Many existing drugs already on the market have similar mechanisms, and the emergence of azole-resistant bacteria has become a problem at present.

  In recent years, cyclic hexapeptide caspofandine and micafungin derived from natural products have been developed as 1,3-β-glucan synthase inhibitors with a novel mechanism. However, it is still not enough as an antifungal agent.

Thus, it cannot be said that the existing antifungal agent is sufficient, and development of a highly safe drug based on a novel mechanism is eagerly desired.
Patent Documents 1 and 2 are prior arts related to antifungal agents based on such a novel mechanism. Patent Documents 1 and 2 describe that GPI (glycosylphosphatidyl-inositol) anchor protein transport process to the cell wall is inhibited to inhibit cell wall surface protein expression, cell wall assembly is inhibited, and fungi adhere to cells. Pyridine derivatives have been described that have an effect on the onset, progression and persistence of infectious diseases by inhibiting and preventing pathogens from exhibiting pathogenicity.

  However, the compound group disclosed in Patent Document 1 has 2-benzylpyridine as a common structure and is clearly different in structure from the compound according to the present invention. Furthermore, although the compound group currently disclosed by patent document 1 shows activity in vitro, it has problems, such as being easily metabolized in the body. In addition, the compound group disclosed in Patent Document 2 exhibits excellent antifungal activity,

Even if the compound group has a structure represented by the formula (1) and has a pyridine ring skeleton, the compound group is commonly bonded to a single ring at the 3-position of the pyridine ring using an amidomethylene group as a linker. The structure is clearly different from the compound according to the present invention in terms of structure.

  Further, there are Patent Documents 3 to 5 as prior arts that approximate the structure of the compound according to the present invention. Patent Document 3 describes a pyridine derivative substituted with a tetrazole ring used as an anticancer agent based on the inhibitory action of a lyase enzyme, and Patent Document 4 describes a triazole ring used as an NK-1 receptor antagonist. Patent Document 5 describes a pyridine derivative substituted with a tetrazole ring, which is used as a therapeutic agent for osteoarthritis or rheumatoid arthritis based on matrix metalloproteinase inhibitory action. Yes.

  However, Patent Documents 3 to 5 do not describe the compounds according to the present invention, and the compounds disclosed in Patent Documents 3 to 5 are Candida and Aspergillus, which are common bacterial species in human mycosis. No antifungal action against Cryptococcus is disclosed.

International Publication No. 02/04626 Pamphlet International Publication No. 05/033079 Pamphlet International Publication No. 03/027095 Pamphlet International Publication No. 03/091226 Pamphlet International Publication No. 04/014366 Pamphlet

  An object of the present invention is to provide an antifungal agent which has an excellent antifungal action not found in conventional antifungal agents, and which is also excellent in terms of physical properties, safety and metabolic stability.

  As a result of intensive studies in view of the above circumstances, the present inventors have found that the following formula (I)

A novel pyridine derivative (hereinafter referred to as “the present invention”) characterized by a chemical structure in which a pyridine ring and a 5- or 6-membered heteroaryl ring or a benzene ring are bonded using a 5-membered heteroaryl ring as a linker. The present invention was completed by discovering that these compounds have excellent antifungal activity.

That is, the present invention
[1]: A compound represented by the following formula (I) or a salt thereof;

In the formula, R ¹ represents a hydrogen atom, a halogen atom, an amino group, a C _1-6 alkyl group, a C _1-6 alkoxy group, or a C _1-6 alkoxy C _1-6 alkyl group;
R ² represents a hydrogen atom or an amino group;
X, Y, Z, and W each independently represent a nitrogen atom, an oxygen atom, a sulfur atom, or —CH—, but at least two of X, Y, and W represent a nitrogen atom. ;
Ring A means a 5 or 6 membered heteroaryl ring or a benzene ring;
Q represents a methylene group, an oxygen atom, —CH ₂ O—, —OCH ₂ —, —NH—, —NHCH ₂ —, or —CH ₂ NH—;
R ³ may have one or two substituents each selected from substituent group α, C _1-6 alkyl group, C _3-8 cycloalkyl group, C _6-10 aryl group, or Means a 5- or 6-membered heteroaryl group.
However, among 5-membered heteroaryl rings containing X, Y, Z, and W, the pyrazole ring is excluded.
[Substituent group α]
A halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, and a C _2-6 alkynyl group;
[2]: The following formula (I)

The following formula (II)

The compound or salt thereof according to [1], wherein the partial structure represented by the formula is a partial structure selected from the following group;

[3]: The following formula (I)

The following formula (II)

The partial structure represented by the formula (V)

Or a salt thereof according to [1], which is a partial structure represented by:
[4]: The following formula (I)

The following formula (II)

The partial structure represented by formula (v)

Or a salt thereof according to [3], which is a partial structure represented by:
[5]: The following formula (I)

The following formula (II)

The partial structure represented by the following formula (III)

Or a partial structure represented by the following formula (IV)

Or a salt thereof according to [1], which is a partial structure represented by:
[6]: The following formula (I)

The following formula (II)

The compound or a salt thereof according to [5], wherein the partial structure represented by is a partial structure selected from the following group;

[7]: The following formula (I)

The following formula (II)

The compound or salt thereof according to [1], wherein the partial structure represented by the formula is a partial structure selected from the following group;

[8]: The following formula (I)

The following formula (II)

The compound or a salt thereof according to [7], wherein the partial structure represented by is a partial structure selected from the following group;

[9]: The compound or a salt thereof according to any one of [1] to [8], wherein R ² is an amino group;
[10]: The compound or salt thereof according to [9], wherein R ¹ is a hydrogen atom, an amino group, or a C _1-6 alkoxy C _1-6 alkyl group;
[11]: The compound or salt thereof according to any one of [1] to [8], wherein R ¹ is an amino group and R ² is a hydrogen atom;
[12]: The compound or salt thereof according to any one of [1] to [11], wherein Ring A is a pyridine ring, a benzene ring, a furan ring, a thiophene ring, or a pyrrole ring;
[13]: The compound or salt thereof according to [12], wherein ring A is a pyridine ring or a benzene ring;
[14]: The compound or salt thereof according to any one of [1] to [13], wherein Q is an oxygen atom, —CH ₂ O—, or —OCH ₂ —;
[15]: A pharmaceutical composition comprising the compound according to any one of [1] to [14] or a salt thereof;
[16]: A medicament containing the compound or salt thereof according to any one of [1] to [14];
[17]: An antifungal agent comprising the compound or a salt thereof according to any one of [1] to [14] as an active ingredient;
[18]: A method for preventing and / or treating a fungal infection by administering a pharmacologically effective amount of the compound or salt thereof according to any one of [1] to [14];
[19]: Use of the compound or a salt thereof according to any one of [1] to [14] for the manufacture of an antifungal agent;
Is to provide.

  The compound (I) or a salt thereof of the present invention 1) inhibits fungal GPI biosynthesis, inhibits expression of cell wall surface protein, inhibits cell wall assembly and inhibits fungi from attaching to cells, Inhibiting the pathogenicity of the virus, it has an effect on the onset, progress, and persistence of infectious diseases. 2) Excellent in physical properties, safety and metabolic stability. It is extremely useful as a preventive or therapeutic agent.

Hereinafter, the present invention will be described in detail with reference to definitions of symbols, terms, and the like described in the present specification, embodiments of the present invention, and the like.
In the present specification, the structural formula of a compound may represent a certain isomer for convenience, but the present invention includes all geometrical isomers that can occur in the structure of the compound, optical isomers based on asymmetric carbon, stereo It includes isomers such as isomers, rotational isomers, tautomers, and isomer mixtures, and is not limited to the description of formulas for convenience, and may be either one isomer or a mixture. Therefore, the compound of the present invention may have an asymmetric carbon atom in the molecule, and an optically active substance and a racemate may exist. However, the present invention is not limited and includes both. In addition, there may be a crystal polymorph, but it is not limited in the same manner, and any single crystal form or a mixture of two or more crystal forms may be used. The compounds of the present invention include anhydrides and solvates such as hydrates.

  In addition, the compound of the present invention undergoes metabolism such as oxidation, reduction, hydrolysis, and conjugation in vivo (so-called metabolite) and metabolizes such as oxidation, reduction, hydrolysis, and conjugation in vivo. Compounds that produce inventive compounds (so-called prodrugs) are also encompassed within the scope of the present invention.

The “C _1-6 alkyl group” used in the present specification is a monovalent group derived by removing one arbitrary hydrogen atom from an aliphatic hydrocarbon having 1 to 6 carbon atoms. 1-6 linear or branched alkyl groups are meant. Specifically, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, sec-pentyl group , Neopentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, n-hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3- Dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1- And til-1-methylpropyl group, 1-ethyl-2-methylpropyl group and the like, preferably methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group Tert-butyl group and the like.

As used herein, “C _2-6 alkenyl group” means a linear or branched alkenyl group having 2 to 6 carbon atoms which may contain 1 to 2 double bonds. To do. Specifically, for example, ethenyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, pentenyl group, 3-methyl- 2-butenyl group, hexenyl group, hexanedienyl group and the like can be mentioned, preferably ethenyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl -1-propenyl group, 3-methyl-2-butenyl group and the like.

As used herein, “C _2-6 alkynyl group” means a linear or branched alkynyl group having 2 to 6 carbon atoms which may contain 1 to 2 triple bonds. . Specific examples include ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, pentynyl group, hexynyl group, hexanediynyl group, and the like. Is an ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group and the like.

The “C _3-8 cycloalkyl group” used in the present specification means a cyclic aliphatic hydrocarbon group having 3 to 8 carbon atoms. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like, and a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like are preferable.

The “C _1-6 alkoxy group” used in the present specification means a group in which an oxygen atom is bonded to the terminal of the above-defined “C _1-6 alkyl group”. Specifically, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, isopentyloxy group, sec-pentyloxy group, neopentyloxy group, 1-methylbutoxy group, 2-methylbutoxy group, 1,1-dimethylpropoxy group, 1,2-dimethylpropoxy group, n-hexyloxy group, isohexyloxy group, 1-methylpentyloxy group, 2-methylpentyloxy group, 3-methylpentyloxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2,2-dimethylbutoxy group, 1,3-dimethyl Butoxy group, 2,3-dimethylbutoxy group, 3,3-dimethylbutoxy group, 1-ethylbutoxy group, -Ethylbutoxy group, 1,1,2-trimethylpropoxy group, 1,2,2-trimethylpropoxy group, 1-ethyl-1-methylpropoxy group, 1-ethyl-2-methylpropoxy group and the like are preferable, Are a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, and the like.

As used herein, “C _6-10 aryl group” means an aromatic hydrocarbon cyclic group having 6 to 10 carbon atoms. Specific examples include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, an indenyl group, an azulenyl group, a heptalenyl group, and the like, and a phenyl group, a 1-naphthyl group, a 2-naphthyl group, and the like are preferable.

The _{"C 1-6} alkoxy _{C 1-6} alkyl group" as used herein, any hydrogen atom in the definition _{"C 1-6} alkyl group", the definition _{"C 1-6} alkoxy group Means a group substituted by Specific examples include methoxymethyl group, ethoxymethyl group, n-propoxymethyl, methoxyethyl group, ethoxyethyl group and the like.

  As used herein, “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

  As used herein, “heteroatom” means a nitrogen atom, a sulfur atom or an oxygen atom.

  As used herein, the term “5- or 6-membered heteroaryl ring” means that the number of atoms constituting the ring is 5 or 6, and one to a plurality of heteroatoms are contained in the atoms constituting the ring. An aromatic ring is meant. Specifically, for example, furan ring, thiophene ring, pyrrole ring, pyridine ring, pyrazine ring, pyridazine ring, pyrimidine ring, triazole ring (1,2,3-triazole ring, 1,2,4-triazole ring, etc.), Examples include a tetrazole ring (for example, 1H-tetrazole ring, 2H-tetrazole ring, etc.), thiazole ring, pyrazole ring, oxazole ring, isoxazole ring, isothiazole ring, oxadiazole ring, thiadiazole ring, and the like.

  As used herein, the term “5- or 6-membered heteroaryl group” refers to an aromatic group in which the number of atoms constituting a ring is 5 or 6, and one to a plurality of heteroatoms are contained in the atoms constituting the ring. It means a monovalent group derived by removing one hydrogen atom at an arbitrary position from a group ring. Specifically, for example, furyl group (for example, 2-furyl group, 3-furyl group, etc.), thienyl group (for example, 2-thienyl group, 3-thienyl group, etc.), pyrrolyl group (for example, 1-pyrrolyl group, 2-pyrrolyl group, etc.) Group, 3-pyrrolyl group, etc.), pyridyl group (eg 2-pyridyl group, 3-pyridyl group, 4-pyridyl group etc.), pyrazinyl group, pyridazinyl group (eg 3-pyridazinyl group, 4-pyridazinyl group etc.), pyrimidinyl Group (for example, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group, etc.), triazolyl group (for example, 1,2,3-triazolyl group, 1,2,4-triazolyl group, etc.), tetrazolyl group (for example, 1H- Tetrazolyl group, 2H-tetrazolyl group, etc.), thiazolyl group (for example, 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, etc.), pyrazolyl (Eg, 3-pyrazolyl group, 4-pyrazolyl group, etc.), oxazolyl group (eg, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, etc.), isoxazolyl group (eg, 3-isoxazolyl group, 4-isoxazolyl group, 5 -Isoxazolyl group), isothiazolyl group (for example, 3-isothiazolyl group, 4-isothiazolyl group, 5-isothiazolyl group, etc.), oxadiazolyl group, thiadiazolyl group and the like.

  As used herein, “may have one or two substituents” means that one or two substituents may be arbitrarily combined at substitutable sites. means.

Next, the variable group in the compound according to the present invention represented by the formula (I) will be described. R ¹ represents a hydrogen atom, a halogen atom, an amino group, a C _1-6 alkyl group, a C _1-6 alkoxy group, or a C _1-6 alkoxy C _1-6 alkyl group, and in particular, a hydrogen atom, C _{1 A -6} alkyl group, an amino group, or a C _1-6 alkoxy C _1-6 alkyl group is preferable, and the C _1-6 alkyl group is preferably a methyl group, and the C _1-6 alkoxy C _1-6 alkyl group Is preferably a methoxymethyl group.

R ² means a hydrogen atom or an amino group.

  X, Y, Z, and W each independently represent a nitrogen atom, an oxygen atom, a sulfur atom, or —CH—, but at least two of X, Y, and W represent a nitrogen atom. The ring comprising X, Y, Z, and W is a 5-membered heteroaryl ring.

  However, the pyrazole ring is excluded from the 5-membered heteroaryl ring composed of X, Y, Z, and W from the present invention.

  Formula (II) including X, Y, Z, and W

Specifically, the partial structure represented by is preferably any of the structural structures represented below,

Furthermore, any of the partial structures represented below is more preferable.

Note that the formula (iv-b)

It is known that the partial structure represented by the following equilibrium state:

In this specification, the partial structure represented by the formula (iv-b) includes the equilibrium state of the above formula (iv-b ′).

Formula (II) including X, Y, Z, and W

Can be classified into the following three groups based on the types and numbers of X, Y, Z, and W.

  The first group is a case where X, Y, Z and W are all nitrogen atoms, and the following formula (II)

The partial structure represented by formula (V)

In particular, the formula (v)

The partial structure represented by is preferable.

  The second group is a case where three of X, Y, Z and W are nitrogen atoms and the remaining one is -CH-, and the following formula (II)

The partial structure represented by the following formula (III)

Or a partial structure represented by the following formula (IV)

Is a partial structure represented by
Among these, a partial structure selected from the following group is more preferable,

In particular, the formula (iii-a)

The partial structure represented by is preferable.

  The third group is a case where, among X, Y, Z and W, two are nitrogen atoms, one is an oxygen atom or sulfur atom, and the other is —CH—. Of these, the following formula (II)

The partial structure represented by is preferably a partial structure selected from the following group,

Furthermore, a partial structure selected from the following group is more preferable,

In particular, the formula (vi)

And a partial structure represented by formula (viii)

The partial structure represented by is preferable.

The 5-membered heteroaryl ring composed of X, Y, Z, and W each has a left end bonded to the 3-position of the pyridine ring through a single bond, and a right end connected to the A ring through a methylene group. Is preferable.
For example, a 5-membered heteroaryl ring composed of X, Y, Z, and W is a tetrazole ring and has the following formula (II)

The partial structure represented by the following formula (v)

The structure of the compound of the present invention is represented by the following formula.

  Ring A means a 5- or 6-membered heteroaryl ring or a benzene ring, and is preferably a pyridine ring, a benzene ring, a furan ring, a thiophene ring, or a pyrrole ring, and the pyridine ring, benzene ring, or thiophene ring is More preferred is a pyridine ring or a benzene ring.

Q represents a methylene group, an oxygen atom, —CH ₂ O—, —OCH ₂ —, —NH—, —NHCH ₂ —, or —CH ₂ NH—, of which a methylene group, an oxygen atom, —CH ₂ O-, or -OCH ₂ - are preferred, oxygen atom, _-CH 2 O-, or -OCH ₂ - is more preferable.

R ³ may have 1 or 2 substituents each selected from substituent group α, C _1-6 alkyl group, C _3-8 cycloalkyl group, C _6-10 aryl group, or Means a 5- or 6-membered heteroaryl group.
[Substituent group α]
Halogen atom, C _1-6 alkyl group, C _1-6 alkoxy group, C _3-8 cycloalkyl group, C _2-6 alkenyl group, and C _2-6 alkynyl group

Examples of preferred groups as R ³ include ethyl group, n-butyl group, cyclopropyl group, phenyl group, fluorophenyl group, furyl group, chlorofuryl group, methylfuryl group, thienyl group, bromothienyl group, methylthienyl group, A pyridyl group or a methylpyridyl group is mentioned. R ³ may have, and the substituent selected from the substituent group α preferably includes a fluoro, chloro, bromo, or methyl group.
R ³ is more preferably an ethyl group, n-butyl group, phenyl group, fluorophenyl group, furyl group, chlorofuryl group, bromothienyl group, methylthienyl group, or pyridyl group.

Q and R ³ can form a substituent of ring A by any combination. Preferable examples of R ³ -Q- as the substituent of ring A thus configured include benzyl group, phenoxy group, phenoxymethyl group, benzyloxy group, 2-fluoro-benzyloxy group, 3-fluoro -Benzyloxy group, 4-fluoro-benzyloxy group, 4-fluoro-phenoxy group, 5-chloro-furan-2-ylmethyl group, 5-methyl-furan-2-ylmethyl group, 5-bromo-thiophen-2-yl Ylmethyl group, 5-methyl-thiophen-2-ylmethyl group, pyridin-2-yloxymethyl group, 6-methyl-pyridin-2-yloxymethyl group, pyridin-2-ylmethoxy group, 6-methyl-pyridine-2 -Ylmethoxy, 4-methyl-pyridin-2-ylmethoxy, ethoxy, butoxy, butoxymethyl, or Chloropropylmethoxy group, and among these, benzyl group, phenoxy group, phenoxymethyl group, benzyloxy group, 4-fluoro-phenoxy group, 5-chloro-furan-2-ylmethyl group, 5-methyl-furan 2-ylmethyl group, 5-bromo-thiophen-2-ylmethyl group, 5-methyl-thiophen-2-ylmethyl group, pyridin-2-yloxymethyl group, pyridin-2-ylmethoxy group, ethoxy group, butoxy group, Or a butoxymethyl group is preferable.

  Examples of the “salt” used in the present specification include a salt with an inorganic acid, a salt with an organic acid, a salt with an acidic amino acid, and the like, and among them, a pharmacologically acceptable salt is preferable. The salt of the compound according to the present invention includes an anhydride of the salt and a solvate of the salt such as a hydrate.

  Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and preferable examples of the salt with organic acid include, for example, acetic acid and succinic acid. And salts with fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like.

  Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like, and preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like. It is done.

  As used herein, “antifungal agent” means a prophylactic and / or therapeutic agent for fungal infections.

  The compound according to the present invention or a salt thereof or a hydrate thereof can be converted into tablets, powders, fine granules, granules, coated tablets, capsules, syrups, troches, inhalants, suppositories by conventional methods. , Injections, ointments, eye ointments, tapes, eye drops, nasal drops, ear drops, poultices, lotions and the like.

  Excipients, binders, lubricants, coloring agents, flavoring agents, and if necessary stabilizers, emulsifiers, absorption promoters, surfactants, pH adjusters, preservatives, Antioxidants and the like can be used, and they are generally formulated by blending ingredients used as raw materials for pharmaceutical preparations. For example, in order to produce an oral preparation, the compound according to the present invention or a pharmacologically acceptable salt and excipient thereof, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent, and a flavoring agent. Etc. are added to powders, fine granules, granules, tablets, coated tablets, capsules and the like by conventional methods.

  Examples of these components include animal and vegetable oils such as soybean oil, beef tallow and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane and solid paraffin; for example, ester oils such as octyldodecyl myristate and isopropyl myristate; , Cetostearyl alcohol, higher alcohol such as behenyl alcohol; silicone resin; silicone oil; for example, polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene poly Surfactants such as oxypropylene block copolymers; for example, hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylidene Water-soluble polymers such as pyrrolidone and methylcellulose; for example, lower alcohols such as ethanol and isopropanol; for example, polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol and sorbitol; for example, sugars such as glucose and sucrose; Examples thereof include inorganic powders such as anhydrous silicic acid, magnesium aluminum silicate and aluminum silicate, and purified water.

  Examples of excipients include lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, and silicon dioxide.Examples of binders include polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, Gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polypropylene glycol / polyoxyethylene block polymer, meglumine, etc. are disintegrants such as starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, carbonic acid Sodium hydride, calcium citrate, dextrin, pectin, carboxymethylcellulose calcium, etc. Nesium, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc. are permitted to be added to pharmaceuticals as coloring agents, and as flavoring agents, for example, cocoa powder, mint brain, aroma powder, mint oil Borneolum, cinnamon powder, etc. are used. Of course, these tablets and granules may be appropriately coated with sugar coating, etc. if necessary.

  Further, when producing a liquid preparation such as a syrup or an injectable preparation, the compound according to the present invention or a pharmacologically acceptable salt thereof, a pH adjuster, a solubilizer, an isotonic agent, etc. Add solubilizers, stabilizers, etc. as appropriate, and formulate in a conventional manner. The method for producing the external preparation is not limited and can be produced by a conventional method. That is, as a base material used for formulation, various raw materials usually used for pharmaceuticals, quasi drugs, cosmetics, and the like can be used. Specific examples of base materials to be used include animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, and polyhydric alcohols. , Raw materials such as water-soluble polymers, clay minerals, purified water and the like, and if necessary, for example, pH adjusters, antioxidants, chelating agents, antiseptic / antifungal agents, coloring agents, fragrances, etc. However, the base material of the external preparation according to the present invention is not limited thereto. Moreover, components having differentiation-inducing action, blood flow promoters, bactericides, anti-inflammatory agents, cell activators, vitamins, amino acids, humectants, keratolytic agents, and the like can be blended as necessary. In addition, the addition amount of the said base raw material is an amount used as the density | concentration normally set in manufacture of an external preparation.

  When the compound of the present invention or a salt thereof is administered, its form is not particularly limited, and it may be administered orally or parenterally by a commonly used method. For example, tablets, powders, granules, capsules, syrups, troches, inhalants, suppositories, injections, ointments, eye ointments, tapes, eye drops, nasal drops, ear drops, poultices It can be formulated and administered as an agent such as a lotion.

  The dosage of the medicament according to the present invention can be appropriately selected according to the degree of symptoms, age, sex, body weight, dosage form / salt type, specific type of disease, and the like.

  The dose varies significantly depending on the patient's disease type, symptom level, patient age, sex difference, sensitivity to drugs, etc. In the case of oral preparations, it is usually 1 to 10,000 mg, preferably 10 -2000 mg is administered in 1 to several times a day. In the case of an injection, it is usually 0.1 mg to 10000 mg, preferably 1 mg to 2000 mg per day as an adult.

[General synthesis method]
A method for producing a compound represented by formula (I) (hereinafter referred to as compound (I)) according to the present invention will be described. The compound according to the present invention can be synthesized using ordinary organic synthesis means. For example, among the compounds (I), the following formula (1a), formula (2a), formula (3a), formula (4a) ), Formula (5a), formula (6a), formula (7a), compounds represented by formula (8a) and formula (9a) (hereinafter, compound (1a), compound (2a), compound (3a), compound ( 4a), the compound (5a), the compound (6a), the compound (7a), the compound (8a) and the compound (9a)) are prepared by the following [Production Method 1], [Production Method 2], and [Production Method 3]. ], [Production Method 4], [Production Method 5], [Production Method 6], [Production Method 7], [Production Method 8], and [Production Method 9].

[Production Method 1] Representative production method of compound (1a) which is compound (I)

[Production Method 1-1] Method for producing Compound (1a) which is Compound (I)

[In the formula, Hal means a halogen atom, and A, R ¹ , R ² , Q and R ³ have the same meaning as defined above. ]

  As compound (1b) and compound (1c), commercially available products can be used as they are, and they can also be produced from commercially available products by known methods.

[Step 1-1]
In this step, compound (1a) is obtained by reacting compound (1b) with compound (1c). Compound (1a) can be obtained in one pot by irradiating the reaction mixture of compound (1b) and compound (1c) with microwaves in the presence of a copper catalyst and an azidating agent. Examples of the copper catalyst used in this reaction include copper (0) such as copper powder, copper (I) chloride, copper (I), copper (I) such as copper (I), copper (II) chloride, Copper (II) such as copper (II) bromide, copper (II) iodide, copper sulfate, copper trifluoromethanesulfonate, copper carbonate, and copper nitrate can be used. In order to perform the reaction safely and obtain good results, copper (0) such as copper powder and copper (II) such as copper sulfate may be mixed and used to produce copper (I) in the system. it can. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials and reagents to some extent and does not inhibit the reaction. For example, alcohols such as tert-butyl alcohol, ethanol, methanol, etc. Solvents such as solvents, ether solvents such as tetrahydrofuran and 1,4-dioxane, amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone, dimethyl sulfoxide, water or a mixed solvent thereof can be used. As the azidating agent used in this reaction, sodium azide, trimethylsilyl azide and the like can be used. Compound (1c) is used in the amount of 1 to 3 equivalents based on compound (1b). The copper catalyst is used in the amount of 0.01 to 1 equivalent based on compound (1b). The azidating agent is used in the amount of 1 to 5 equivalents based on compound (1c). The irradiation power is from 10 watts to 200 watts, the reaction temperature is from room temperature to 200 ° C., and the reaction time is from 10 seconds to 30 minutes.

[Production Method 1-2] Method for producing Compound (1a) which is Compound (I)

[In the formula, Hal means a halogen atom, and A, R ¹ , R ² , Q and R ³ have the same meaning as defined above. ]

[Step 1-2]
This step is a step of obtaining a compound (1d) by reacting the compound (1b) with an azidating agent. Compound (1d) can be obtained by reacting compound (1b) with an azide in the presence of a copper catalyst. Examples of the copper catalyst used in this reaction include copper (0) such as copper powder, copper (I) chloride, copper (I), copper (I) such as copper (I), copper (II) chloride, Copper (II) such as copper (II) bromide and copper (II) iodide can be used. As the azidating agent used in this reaction, sodium azide, trimethylsilyl azide and the like can be used. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials and reagents to some extent and does not inhibit the reaction. For example, alcohols such as tert-butyl alcohol, ethanol, methanol, etc. Solvents such as solvents, ether solvents such as tetrahydrofuran and 1,4-dioxane, amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone, dimethyl sulfoxide, water or a mixed solvent thereof can be used. The azidating agent is used in the amount of 1 to 5 equivalents based on compound (1b). The copper catalyst is used in the amount of 0.01 to 0.5 equivalents based on compound (1b). The reaction temperature is from room temperature to reflux temperature, and the reaction time is from 30 minutes to 24 hours.

[Step 1-3]
This step is a step of obtaining compound (1a) by reacting compound (1d) with compound (1c). Compound (1a) can be obtained by reacting compound (1d) with compound (1c) in the presence of a base. Examples of the base used in this reaction include sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, lithium methoxide, sodium acetate, potassium acetate, triethylamine, etc. Can be used. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran and 1,4-dioxane, An amide solvent such as N, N-dimethylformamide and N-methylpyrrolidinone, an alcohol solvent such as methanol and ethanol, acetone, acetonitrile, dimethyl sulfoxide, water, or a mixed solvent thereof can be used. Compound (1c) is used in the amount of 1 to 5 equivalents based on compound (1d). The base can be used in the amount of 1 to 5 equivalents based on compound (1d). The reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 1 minute to 24 hours.

[Production method 1-3] Method for producing compound (1b)

[Wherein, R ¹ and R ² have the same meanings as defined above, Hal represents a halogen atom, and R ⁹ and R ¹⁰ each independently represent a C _1-6 alkyl group. ]

  As the compound (1b-1), a commercially available product can be used as it is, and it can also be produced from a commercially available product by a known method.

[Step 1-4]
This step is a step of obtaining a compound (1b-2) by reacting the compound (1b-1) with an ethynylsilane derivative. Compound (1b-2) can be obtained by reacting compound (1b-1) with an ethynylsilane derivative in the presence of a palladium catalyst, a base, and copper (I) iodide. To obtain good results, a phosphine ligand may be added. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran and 1,4-dioxane, Amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone, acetonitrile, dimethyl sulfoxide, or a mixed solvent thereof can be used. As the ethynylsilane derivative, for example, trimethylsilylacetylene, triethylsilylacetylene, triisopropylsilylacetylene, t-butyldimethylsilylacetylene, or the like can be used. Examples of the palladium catalyst include palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (tri-o-tolylphosphine) palladium (II), bis (Tri-t-butylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), or the like can be used. As the base, for example, triethylamine, N, N-diisopropylethylamine, pyridine, or the like can be used. As the phosphine ligand, triphenylphosphine, tri-o-tolylphosphine, tri-t-butylphosphine, and the like can be used. The ethynylsilane derivative is used in the amount of 1 to 5 equivalents based on compound (1b-1). The palladium catalyst is used in the amount of 0.01 to 0.3 equivalents based on compound (1b-1). The base is used in the amount of 2 to 5 equivalents based on compound (1b-1). The phosphine ligand is used in the amount of 0.01 to 0.6 equivalents based on compound (1b-1). Copper (I) iodide is used in an amount of 0.001 equivalents to 0.1 equivalents with respect to compound (1b-1). The reaction temperature is from room temperature to reflux temperature, and the reaction time is from 30 minutes to 24 hours.

[Step 1-5]
This step is a step of obtaining compound (1b) by reacting compound (1b-2) with a base. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran and diethyl ether, methanol, ethanol An alcohol solvent such as N, N-dimethylformamide, an amide solvent such as N-methylpyrrolidinone, acetonitrile, dimethyl sulfoxide, water, or a mixed solvent thereof can be used. As the base, for example, potassium carbonate, sodium hydroxide, tetrabutylammonium fluoride, potassium fluoride, cesium fluoride and the like can be used. The base is used in the amount of 0.05 to 10 equivalents based on compound (1b-2). The reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 5 minutes to 24 hours.

[Production Method 1-4] Production Method of Compound (1b)

[Wherein, R ¹ and R ² are as defined above, and R ⁴ is a C _1-6 alkyl group. ]

Commercially available products can be used as they are for the respective compounds in the above process diagrams, and they can also be produced from commercially available products by known methods.

[Step 1-6]
This step is a step in which compound (1b-4) is obtained by esterification of compound (1b-3) in the presence of an acid. As the solvent used in this reaction, alcohol solvents such as methanol and ethanol are preferable. As the acid, sulfuric acid, hydrochloric acid, bromic acid or the like can be used. The reaction temperature is from room temperature to reflux temperature, and the reaction time is from 1 hour to 72 hours.
In addition, compound (1b-4) can be obtained from compound (1b-3) by the method described in the following alternative method (1), (2), or (3).

  Alternative Method (1): Compound (1b-3) can be converted to a methyl ester using diazomethane or trimethylsilyldiazomethane. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, but ether solvents such as tetrahydrofuran and diethyl ether, benzene, toluene and the like. Aromatic hydrocarbon solvents, alcohol solvents such as methanol and ethanol, methylene chloride, hexane, or a mixed solvent thereof can be used. Diazomethane or trimethylsilyldiazomethane is used in the amount of 1 to 2 equivalents based on compound (1b-3). The reaction temperature is from 0 ° C. to room temperature, and the reaction time is from 10 minutes to 24 hours.

  Alternative method (2): Compound (1b-3) can be converted to compound (1b-4) using an alkylating agent in the presence of a base. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran and diethyl ether, benzene, toluene Aromatic hydrocarbon solvents such as N, N-dimethylformamide, amide solvents such as N-methylpyrrolidinone, alcohol solvents such as methanol and ethanol, water, acetone, acetonitrile, dimethyl sulfoxide, or mixed solvents thereof Can be used. A phase transfer catalyst such as tetrabutylammonium bromide can be added to the reaction. As the base used in this reaction, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, cesium fluoride and the like can be used. As the alkylating agent, iodomethane, iodoethane, dimethyl sulfate, or the like can be used. The base is used in the amount of 1 to 1.5 equivalents based on compound (1b-3). The alkylating agent is used in the amount of 1 to 2 equivalents based on compound (1b-3). The reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 1 hour to 72 hours.

  Alternative method (3): Compound (1b-3) can be converted into an acid chloride using a halogenating agent, and then converted into compound (1b-4) by adding an alcohol. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, aromatic hydrocarbon solvents such as benzene and toluene, N Amide solvents such as N, dimethylformamide, N-methylpyrrolidinone, acetonitrile, methylene chloride, 1,2-dichloroethane, or a mixed solvent thereof can be used. A halogenating agent can also be used as a solvent. A catalytic amount of a phase transfer catalyst such as benzyltriethylammonium chloride or pyridine can be added to the reaction. As the halogenating agent, thionyl chloride, phosphorus pentachloride and the like can be used. As the alcohol, methanol, ethanol or the like can be used. The halogenating agent is used in the amount of 1 to 20 equivalents based on compound (1b-3). The alcohol is used in the amount of 1 to 20 equivalents based on compound (1b-3). The reaction temperature during conversion to the acid chloride is from 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 48 hours. The reaction temperature when the alcohol is reacted is from 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 48 hours. In this reaction, alcohol can also be used as a solvent. In this case, compound (1b-4) can be obtained by adding a halogenating agent to the mixture of the solvent and compound (1b-3). The reaction temperature is from 0 ° C. to room temperature, and the reaction time is from 10 minutes to 24 hours.

[Step 1-7]
This step is a step of obtaining compound (1b-5) by reducing compound (1b-4). The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, but tetrahydrofuran is preferably used. Examples of the reducing agent used in this reaction include lithium aluminum hydride, lithium aluminum hydride-aluminum chloride (1 to 1.5 equivalents of aluminum chloride is used relative to lithium aluminum hydride), lithium borohydride, sodium borohydride, and the like. Can be used. The reducing agent is used in the amount of 0.5 to 4 equivalents based on compound (1b-4). The reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 48 hours.

[Step 1-8]
This step is a step of obtaining compound (1b-6) by oxidizing compound (1b-5). The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, but ether solvents such as tetrahydrofuran and diethyl ether, benzene, toluene and the like. Aromatic hydrocarbon solvents, alcohol solvents such as methanol and ethanol, methylene chloride, acetone, hexane, or mixed solvents thereof can be used. Examples of the oxidizing agent used in this reaction include manganese dioxide, pyridinium chlorochromate, pyridinium dichromate, dimethyl sulfoxide-activator, tetrapropylammonium perthenate, dichlorotris (triphenylphosphine) ruthenium (II), 1,1, 1-tris (acetyloxy) -1,1-dihydro-1,2-benziodoxol-3- (1H) -one (Dess-Martin periodinane) and the like can be used. The oxidizing agent is used in an amount of 10 equivalents to the amount of the catalyst (1b-5). In the case of oxidation with a dimethyl sulfoxide-activating agent, the activating agent may be an acid anhydride such as acetic anhydride or trifluoroacetic anhydride, an acid chloride such as oxalyl chloride, thionyl chloride, chlorine, N-chlorosuccini A mid or the like can be used. Dimethyl sulfoxide is used in an amount of 1 to 20 equivalents based on the activator. When tetrapropylammonium pearlate or dichlorotris (triphenylphosphine) ruthenium (II) is used in a catalytic amount, an oxidizing agent such as N-methylmorpholine-N-oxide or bis (trimethylsilyl) peroxide can be used at the same time. The reaction temperature is from -78 ° C to reflux temperature, and the reaction time is from 10 minutes to 72 hours.

[Step 1-9]
In this step, compound (1b-6) is obtained in the presence of a base using a diazo compound. As the diazo compound used in this reaction, trimethylsilyldiazomethane, (1-diazo-2-oxopropyl) -phosphoric acid dimethyl ester, diazomethyl phosphoric acid dimethyl ester, and the like can be used. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran and diethyl ether, benzene, toluene Aromatic hydrocarbon solvents such as methanol, alcohol solvents such as methanol and ethanol, methylene chloride, hexane, or a mixed solvent thereof can be used. When trimethylsilyldiazomethane is used as the diazo compound, n-butyllithium or lithium diisopropylamide can be used as the base. When a phosphate ester derivative such as (1-diazo-2-oxopropyl) -phosphoric acid dimethyl ester or diazomethyl phosphoric acid dimethyl ester is used as the diazo compound, potassium carbonate or potassium t-butoxide is used as the base. be able to. The diazo compound is used in the amount of 1 to 1.5 equivalents based on compound (1b-6). The base is used in the amount of 1 to 2 equivalents based on compound (1b-6). The reaction temperature is from -78 ° C to room temperature, and the reaction time is from 10 minutes to 24 hours.
In addition, compound (1b) can be obtained from compound (1b-6) by the method described in the following alternative method (1) or (2).

Alternative method (1): Compound (1b-6) can be obtained by converting compound (1b-6) to a dihaloalkene in the presence of a base and then reacting with a base.
Synthesis of dihaloalkene: The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran and diethyl ether, Aromatic hydrocarbon solvents such as benzene and toluene, hexane, or a mixed solvent thereof can be used. Examples of the reagent for converting the compound (1b-6) into a dihaloalkene include (dichloromethyl) -phosphoric acid dimethyl ester, dibromomethyltriphenylphosphonium bromide (Tetrahedron Letters, Vol. 40, No. 49, 8575-8578.), And the like. Can be used. As the base used in this reaction, lithium diisopropylamide or potassium t-butoxide can be used. The reagent for converting to dihaloalkene is used in the amount of 1 to 1.5 equivalents based on compound (1b-6). The base is used in the amount of 1 to 2 equivalents based on compound (1b-6). The reaction temperature is from -78 ° C to room temperature, and the reaction time is from 10 minutes to 24 hours.

  As another method for synthesizing dihaloalkenes, there is the following alternative method using carbon tetrabromide. Compound (1b-6) can be converted to a dihaloalkene using carbon tetrabromide and triphenylphosphine, and then compound (1b) can be obtained using a base. Zinc can also be added to this reaction. The solvent used in this reaction is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction, but tetrahydrofuran or methylene chloride is preferably used. Carbon tetrabromide can be used in the amount of 1 to 2 equivalents based on compound (1b-6). Triphenylphosphine can be used in the amount of 2 to 4 equivalents based on compound (1b-6). One equivalent of zinc can be used with respect to carbon tetrabromide. The reaction temperature is from 0 ° C. to room temperature, and the reaction time is from 10 minutes to 12 hours.

  Synthesis of compound (1b) from dihaloalkene: The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, such as tetrahydrofuran and diethyl ether. An ether solvent, an aromatic hydrocarbon solvent such as benzene or toluene, hexane, or a mixed solvent thereof can be used. As the base used in this reaction, n-butyllithium, t-butyllithium, potassium t-butoxide and the like can be used. The base is used in the amount of 2 to 3 equivalents based on the dihaloalkene. The reaction temperature is from -78 ° C to room temperature, and the reaction time is from 10 minutes to 24 hours.

[Production Method 1-5] Production Method of Compound (1b-8) which is Compound (1b-3)

[Wherein, Hal and R ² are as defined above, and R ⁵ is a C _1-6 alkyl group. ]

As compound (1b-7), a commercially available product can be used as is, or it can also be produced from a commercially available product by a known method.

[Step 1-10]
This step is a step wherein compound (1b-8) is obtained by reacting compound (1b-7) with an alcohol in the presence of a base. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran and diethyl ether, benzene, toluene An aromatic hydrocarbon solvent such as N, N-dimethylformamide, an amide solvent such as N-methylpyrrolidinone, an alcohol solvent such as methanol or ethanol, dimethyl sulfoxide, or a mixed solvent thereof can be used. As the base, sodium hydride, potassium t-butoxide, potassium hexamethyldisilazide and the like can be used. This reaction can also be performed by adding a copper catalyst. As the copper catalyst, copper, copper (I) iodide, copper (I) bromide, copper (I) chloride, or the like can be used. The base can be used in the amount of 1 to 20 equivalents based on compound (1b-7). The alcohol can be used in the amount of 1 to 20 equivalents based on compound (1b-7). The copper catalyst can be used in the amount of 0.01 to 0.3 equivalents based on compound (1b-7). The reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 30 minutes to 48 hours.

[Production method 1-6] Method for producing compound (1b-10) which is compound (1b-4)

[Wherein, Hal, R ² and R ⁴ are as defined above, and R ⁶ is a C _1-6 alkyl group. ]

  Compound (1b-9) can be a commercially available product, or can be produced from a commercially available product by a known method. As the compound (1b-9-1), a commercially available product can be used as it is, and it can be produced from a commercially available product by a known method (for example, WO2005 / 033079 A1, pages 82-84 and the like).

[Step 1-11]
This step is a step of obtaining compound (1b-10) by reacting compound (1b-9) with compound (1b-9-1) in the presence of a palladium catalyst. A phosphine ligand can also be added to obtain good results. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as 1,4-dioxane and tetrahydrofuran, Aromatic hydrocarbon solvents such as toluene and xylene, amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone, dimethyl sulfoxide, or a mixed solvent thereof can be used. Examples of the palladium catalyst include palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (tri-o-tolylphosphine) palladium (II), bis ( Tri-t-butylphosphine) palladium (0), tetrakis (triphenylphosphine) palladium (0), 1,1′-bis (diphenylphosphinoferrocene) dichloropalladium (II), or the like can be used. As the phosphine ligand, triphenylphosphine, tri-o-tolylphosphine, tri-t-butylphosphine, diphenylphosphinoferrocene, or the like can be used. Compound (1b-9-1) is used in the amount of 1 to 3 equivalents based on compound (1b-9). The palladium catalyst is used in the amount of 0.01 to 0.3 equivalents based on compound (1b-9). The phosphine ligand is used in the amount of 0.01 to 1.2 equivalents based on compound (1b-9). The reaction temperature is from room temperature to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Production Method 1-7] Production Method of Compound (1c-3)

[Wherein, ring A, R ³ , Q and Hal are as defined above, and R ⁷ and R ⁸ are C _1-6 alkyl groups or bridged to represent — (CH ₂ ) _n —. n means 2 or 3. ]

  Commercially available products can be used as they are for the respective compounds in the above process diagrams, and they can also be produced from commercially available products by known methods. In addition, the method described in the production examples in the examples, [Production method 1-8], [Production method 1-9], [Production method 1-10], [Production method 1-12], and [Production method 1- 13], [Manufacturing method 1-14], [Manufacturing method 1-15], [Manufacturing method 1-16], [Manufacturing method 1-17], [Manufacturing method 2-4], [Manufacturing method 2-5] [Manufacturing method 2-6], [Manufacturing method 2-7], [Manufacturing method 2-8] and the like.

[Step 1-12]
In this step, the halogen atom of compound (1c-1) is substituted with a metal atom to form an organometallic compound, and then a formylation reagent is allowed to act to obtain compound (1c-6). The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, but ether solvents such as tetrahydrofuran and diethyl ether are preferable. Examples of organometallic compounds include organolithium compounds obtained by the action of bases such as n-butyllithium, s-butyllithium, t-butyllithium, and lithium diisopropylamide, metal magnesium, ethylmagnesium bromide, isopropylmagnesium chloride, and the like. There are Grignard reagents obtained by the action. When preparing a Grignard reagent using metallic magnesium, a catalytic amount of iodine, dibromoethane or the like may be added. The temperature for preparing the organolithium compound is from -78 ° C to room temperature, preferably from -78 ° C to -40 ° C. The base is used in the amount of 1 to 1.5 equivalents based on compound (1c-1), and the reaction time is 30 minutes to 24 hours. The temperature for preparing the Grignard reagent using magnesium metal is from room temperature to the reflux temperature of the solvent. Metal magnesium is used in the amount of 1 to 2 equivalents based on compound (1c-1), and the reaction time is from 30 minutes to 12 hours. The temperature for preparing the Grignard reagent using ethylmagnesium bromide or isopropylmagnesium bromide is from −60 ° C. to reflux temperature, and ethylmagnesium bromide or isopropylmagnesium chloride is 1 equivalent to 1.6 equivalents relative to compound (1c-1). And the reaction time is from 5 minutes to 12 hours. As the formylation reagent, dimethylformamide, N-formylpiperidine, N-formylmorpholine, N-methylformanilide and the like can be used. The formylating reagent may be used in an amount of 1 to 20 equivalents, preferably 1 to 2 equivalents, based on the metal compound. The reaction temperature of the metal compound and the formylation reagent is from −78 ° C. to room temperature in the case of the organolithium compound, and the reaction time is from 5 minutes to 6 hours. In the case of the Grignard reagent, the reaction temperature is from 0 ° C. to the reflux temperature of the solvent. Yes, the reaction time is from 5 minutes to 24 hours.

[Step 1-13]
In this step, an acetal of compound (1c-2) is reacted with an acid to deprotect it to obtain compound (1c-6). The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran and diethyl ether, benzene, toluene An aromatic hydrocarbon solvent such as N, N-dimethylformamide, an amide solvent such as N-methylpyrrolidinone, an alcohol solvent such as methanol or ethanol, dimethyl sulfoxide, or a mixed solvent thereof can be used. As the acid to be used, inorganic acids such as hydrochloric acid, sulfuric acid and bromic acid, and organic acids such as citric acid, trifluoroacetic acid and p-toluenesulfonic acid can be used. The reaction temperature is from 0 ° C. to the reflux temperature of the solvent, and the reaction time is from 5 minutes to 24 hours.

[Step 1-14]
This step is a step of obtaining compound (1c-3) by reducing compound (1c-6). Compound (1c-3) can be manufactured according to the methods similar to those of [Step 1-7].

[Step 1-15]
This step is a step of obtaining compound (1c-6) by reducing compound (1c-4).
The compound (1c-6) can be obtained by carrying out a reduction reaction using a reducing agent such as diisobutylaluminum hydride, sodium triethoxyaluminum hydride, lithium triethoxyaluminum hydride and the like. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, aromatic hydrocarbon solvents such as toluene, tetrahydrofuran and the like An ether solvent can be used. The reducing agent is used in the amount of 1 to 2 equivalents based on compound (1c-4). The reaction temperature is from -78 ° C to room temperature, and the reaction time is from 10 minutes to 24 hours.

[Step 1-16]
This step is a step of obtaining compound (1c-5) by reducing compound (1c-4).
A compound (1c-5) can be obtained by carrying out a reduction reaction using a reducing agent such as lithium aluminum hydride or diisobutylaluminum hydride. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran and diethyl ether, toluene and the like Aromatic hydrocarbon solvents can be used. The reducing agent is used in the amount of 1 to 10 equivalents based on compound (1c-4). The reaction temperature is from room temperature to 80 ° C., and the reaction time is from 10 minutes to 24 hours.
In addition, compound (1c-5) can be obtained from compound (1c-4) by the method described in the following alternative method (1).

  Alternative Method (1): Compound (1c-5) can be obtained by performing catalytic hydrogenation of compound (1c-4) using a catalyst such as Raney nickel or palladium-carbon in a hydrogen atmosphere. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, an alcohol solvent such as methanol, ethanol, propanol or the like is used. Can do. The reaction pressure is 1 to 4 atmospheres. The catalyst is used in an excess amount from a catalyst amount.

[Step 1-17]
In this step, the amino group of compound (1c-5) is converted to an acetoxy group by the action of sodium nitrite and acetic acid, and then hydrolyzed with a base to obtain compound (1c-3). is there.
Acetoxylation reaction: The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, a mixed solvent of acetic acid and water is preferable. More preferably, the ratio of acetic acid to water is 1 to 5 to 5 to 1. Sodium nitrite is used in the amount of 1 to 20 equivalents based on compound (1c-5). The reaction temperature is from 0 ° C. to room temperature, and the reaction time is from 1 minute to 12 hours.

Hydrolysis reaction: The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, alcohol solvents such as methanol and ethanol, tetrahydrofuran An ether solvent such as N, N-dimethylformamide, an amide solvent such as N-methylpyrrolidinone, water, dimethyl sulfoxide, or a mixed solvent thereof can be used. As the base, sodium hydroxide, potassium hydroxide, potassium carbonate and the like can be used. The reaction temperature is 0 ° C. to 60 ° C., more preferably 20 ° C. to 40 ° C., and the reaction time is 5 minutes to 12 hours.
In addition, compound (1c-3) can be obtained from compound (1c-5) by the method described in the following alternative method (1).

  Alternative method (1): Compound (1c-3) can be obtained by heating compound (1c-5) under strong basicity. The solvent is preferably diethylene glycol, and the base is preferably potassium hydroxide. Potassium hydroxide is used in the amount of 5 to 30 equivalents based on compound (1c-5), the reaction temperature is 150 ° C. to 230 ° C., and the reaction time is 1 hour to 12 hours. During the reaction, the inside of the reaction vessel is preferably replaced with an inert gas.

[Production Method 1-8] Production Method of Compound (1c-9) which is Compound (1c-1)

[Wherein, R ³ has the same meaning as defined above, and L represents a leaving group such as a halogen atom, a p-toluenesulfonyl group, and a trifluoromethanesulfonyl group. ]

  As compound (1c-7), compound (1c-8), compound (1c-7-1) and compound (1c-8-1), commercially available products can be used as they are, and they are produced from commercially available products by known methods. You can also

[Step 1-18]
This step is a step of obtaining compound (1c-9) by reacting compound (1c-7) and compound (1c-7-1) in the presence of a base. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran and diethyl ether, benzene, toluene An aromatic hydrocarbon solvent such as N, N-dimethylformamide, an amide solvent such as N-methylpyrrolidinone, an alcohol solvent such as methanol or ethanol, dimethyl sulfoxide, or a mixed solvent thereof can be used. As the base, sodium hydride, potassium t-butoxide, sodium ethoxide, sodium methoxide, N, N-diisopropylethylamine, triethylamine, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate and the like can be used. The base is used in the amount of 1 to 5 equivalents based on compound (1c-7-1). Compound (1c-7-1) is used in the amount of 1 to 20 equivalents based on compound (1c-7). The reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 5 minutes to 6 hours.

[Step 1-19]
This step is a step wherein compound (1c-9) is obtained by reacting compound (1c-8) with an organophosphorus compound, an azo reagent, and compound (1c-7-1). The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran and diethyl ether, benzene, toluene An aromatic hydrocarbon solvent such as N, N-dimethylformamide, an amide solvent such as N-methylpyrrolidinone, ethyl acetate, acetonitrile, methylene chloride, or a mixed solvent thereof can be used. As the organic phosphorus compound, triphenylphosphine, tri-n-butylphosphine, or the like can be used. As the azo reagent, an ester derivative such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, or an amide derivative such as 1,1 ′-(azodicarbonyl) dipiperidine can be used. Compound (1c-7-1) is used in the amount of 1 to 1.5 equivalents based on compound (1c-8). The organic phosphorus compound is used in the amount of 1 to 3 equivalents based on compound (1c-8). The azo reagent is used in the amounts of 1 equivalent to 3 equivalents based on compound (1c-8). The reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 5 minutes to 24 hours.

[Step 1-20]
In this step, compound (1c-9) is obtained by reacting compound (1c-8) with compound (1c-8-1) in the presence of a base. To obtain good results, a catalytic amount of sodium iodide or potassium iodide, or tetrabutylammonium iodide may be added, or a copper catalyst may be added. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, but ether solvents such as tetrahydrofuran and diethyl ether, benzene, toluene and the like. An aromatic hydrocarbon solvent, an amide solvent such as N, N-dimethylformamide and N-methylpyrrolidinone, an alcohol solvent such as methanol and ethanol, dimethyl sulfoxide, or a mixed solvent thereof can be used. As the base, sodium hydride, potassium t-butoxide, sodium ethoxide, sodium methoxide, N, N-diisopropylethylamine, triethylamine, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate and the like can be used. As the copper catalyst, copper (0), copper (I) iodide, copper (I) bromide, copper (I) chloride, or the like can be used. Compound (1c-8-1) is used in the amount of 1 to 5 equivalents based on compound (1c-8). The base is used in the amount of 1 to 5 equivalents based on compound (1c-8). The copper catalyst can be used in the amount of 0.01 to 0.3 equivalents based on compound (1c-8). The reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 5 minutes to 48 hours.

[Production Method 1-9] Production Method of Compound (1c-11) which is Compound (1c-3)

[Wherein, L and R ³ have the same meaning as defined above. ]

  A commercial item can be used for compound (1c-10). As compound (1c-8-1), a commercially available product can be used, and it can also be produced from a commercially available product by a known method.

[Step 1-21]
This step is a step of obtaining compound (1c-11) by reacting compound (1c-10) with compound (1c-8-1). Compound (1c-11) is produced in the same manner as in [Step 1-20], using 0.2 to 1.0 equivalent of compound (1c-8-1) relative to compound (1c-10). Can do.

[Production method 1-10] Method for producing compound (1c-15) which is compound (1c-3)

[Wherein R ³ _, R ⁷ , R ⁸ and Hal are as defined above. ]

  As the compounds (1c-12) and (1c-12-1), commercially available products can be used as they are, and they can also be produced from commercially available products by known methods.

[Step 1-22]
In this step, the halogen atom of compound (1c-12) is substituted with a metal atom to form an organometallic compound, and then compound (1c-12-1) is reacted to obtain compound (1c-13). The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran and diethyl ether, benzene, toluene An aromatic hydrocarbon solvent such as, or a mixed solvent thereof can be used. As a reagent for converting the compound (1c-12) into an organometallic compound, n-butyllithium, s-butyllithium, ethylmagnesium bromide, ethylmagnesium chloride, isopropylmagnesium chloride, magnesium, zinc, and the like can be used. The reagent for converting compound (1c-12) to an organometallic compound is used in the amount of 1 to 3 equivalents based on compound (1c-12). Compound (1c-12-1) is used in the amounts of 1 equivalent to 2 equivalents based on compound (1c-12). The reaction temperature in the reaction for converting the compound (1c-12) to an organometallic compound is from −78 ° C. to reflux temperature, and the reaction time is from 10 minutes to 12 hours. The reaction temperature in the reaction for adding the compound (1c-12-1) is from -78 ° C to room temperature, and the reaction time is from 10 minutes to 6 hours.

[Step 1-23]
This step is a step of obtaining compound (1c-14) by deprotecting the acetal of compound (1c-13). Compound (1c-14) can be manufactured according to the methods similar to those of [Step 1-13].

[Step 1-24]
This step is a step of obtaining compound (1c-14) by reacting compound (1c-12) with compound (1c-12-1). In this step, compound (1c-13) can be produced by the same method as in [Step 1-22], and then acid can be added in the reaction system or at the post-treatment stage to obtain compound (1c-14). . As the acid used in this reaction, inorganic acids such as hydrochloric acid, sulfuric acid and bromic acid, organic acids such as citric acid, trifluoroacetic acid and p-toluenesulfonic acid, acidic silica gel and the like can be used. The reaction temperature is from 0 ° C. to the reflux temperature of the solvent, and the reaction time is from 5 minutes to 24 hours.

[Step 1-25]
This step is a step wherein compound (1c-15) is obtained by reducing compound (1c-14). The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran and diethyl ether, benzene, toluene Aromatic hydrocarbon solvents such as can be used. As the reducing agent, lithium aluminum hydride-aluminum chloride can be used. Lithium aluminum hydride is used in the amounts of 2 equivalents to 6 equivalents based on compound (1c-14). Aluminum chloride is used in the amount of 2 to 9 equivalents based on compound (1c-14). The reaction temperature is from 0 ° C. to room temperature, and the reaction time is from 10 minutes to 10 hours.

[Production Method 1-11] Production Method of Compound (1c)

[Wherein, ring A, R ³ , Hal and Q are as defined above. ]

  As compound (1c-3), a commercially available product can be used as is, or it can also be produced from a commercially available product by a known method. Furthermore, it can also manufacture by the method as described in the manufacture example in an Example, or [manufacturing method 1-3].

[Step 1-26]
This step is a step of obtaining compound (1c) by converting the hydroxyl group of compound (1c-3) to a halogen atom.

When Hal is a chlorine atom or a bromine atom: Compound (1c-3) can be obtained by halogenating compound (1c-3) with tetrachloromethane or tetrabromomethane in the presence of triphenylphosphine. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran, N, N-dimethylformamide, etc. An amide solvent such as N-methylpyrrolidinone, methylene chloride, or a mixed solvent thereof can be used, and tetrachloromethane or tetrabromomethane can also be used as a solvent. Triphenylphosphine is used in the amounts of 1 equivalent to 2 equivalents based on compound (1c-3). Tetrachloromethane or tetrabromomethane is used in the amount of 1 equivalent to a solvent amount relative to compound (1c-3). The reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 12 hours.
In addition, compound (1c) can be obtained from compound (1c-3) by the method described in the following alternative methods (1), (2) and (3).

  Alternative method (1): Compound (1c-3) can be converted to compound (1c) under acidic conditions. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as diethyl ether, water, ethyl acetate, Alternatively, a mixed solvent thereof or the like can be used. In this reaction, a phase transfer catalyst such as tetrabutylammonium bromide may be added in an amount of 0.01 to 2 equivalents relative to compound (1c-3). As the acid, hydrochloric acid, bromic acid or the like can be used. To obtain a good yield, sulfuric acid can also be added. The reaction temperature is from 0 ° C. to room temperature, and the reaction time is from 10 minutes to 12 hours.

  Alternative Method (2): Compound (1c) can be obtained by reacting compound (1c-3) with thionyl chloride. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, aromatic hydrocarbon solvents such as benzene and toluene, acetonitrile , Chloroform, methylene chloride, and the like, and thionyl chloride can also be used as a solvent. To obtain a good yield, a catalytic amount of pyridine can be added to the reaction. Thionyl chloride is used in the amount of 1 equivalent to a solvent amount based on compound (1c-3). The reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 12 hours.

  Alternative Method (3): Compound (1c) can be obtained by reacting compound (1c-3) with phosphorus halide. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, an ether solvent such as diethyl ether, N, N-dimethyl, etc. Formamide, acetonitrile, chloroform and the like can be used. As the phosphorus halide, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, or the like can be used. The phosphorus halide is used in the amount of 0.33 to 3 equivalents based on compound (1c-3). The reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 12 hours.

[Production Method 1-12] Production Method-1 of Compound (1c-4)

[Wherein R ³ and Hal have the same meaning as defined above. ]

  Compound (1c-16), Compound (1c-18), Compound (1c-20), Compound (1c-22), Compound (1c-24), Compound (1c-7-1), Compound (1c-16-16) As for 1) and compound (1c-12-1), commercially available products can be used as they are, and they can also be produced from commercially available products by known methods.

[Step 1-27]
This step is a step of obtaining compound (1c-17) by reacting compound (1c-16) with compound (1c-7-1) in the presence of a base. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran, N, N-dimethylformamide, etc. An amide solvent such as N-methylpyrrolidinone, an alcohol solvent such as methanol or ethanol, dimethyl sulfoxide, or a mixed solvent thereof can be used. As the base, sodium hydride, potassium t-butoxide, sodium ethoxide, sodium methoxide, N, N-diisopropylethylamine, triethylamine, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate and the like can be used. The base is used in the amount of 1 to 5 equivalents based on compound (1c-7-1). Compound (1c-7-1) is used in the amount of 1 equivalent to a solvent amount based on compound (1c-16). The reaction temperature is from room temperature to reflux temperature, and the reaction time is from 30 minutes to 48 hours.

[Step 1-28]
In this step, compound (1c-19) is obtained by reacting compound (1c-18) with compound (1c-7-1). Compound (1c-19) can be manufactured according to the methods similar to those of [Step 1-19].

[Step 1-29]
This step is a step of obtaining compound (1c-19) by reacting compound (1c-20) with compound (1c-7-1). Compound (1c-19) can be manufactured according to the methods similar to those of [Step 1-18].

[Step 1-30]
This step is a step of obtaining compound (1c-21) by reacting compound (1c-16) and compound (1c-16-1) in the presence of a palladium catalyst. To obtain good results, phosphine ligands can also be added to the reaction system. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as 1,4-dioxane and tetrahydrofuran, Alcohol solvents such as methanol and ethanol, aromatic hydrocarbon solvents such as toluene and xylene, amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone, or a mixed solvent thereof can be used. Examples of the palladium catalyst include palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (tri-o-tolylphosphine) palladium (II), bis ( Tri-t-butylphosphine) palladium (0), tetrakis (triphenylphosphine) palladium (0), palladium (0) pentadienone, and the like can be used. Examples of the phosphine ligand include triphenylphosphine, tri-o-tolylphosphine, tri-t-butylphosphine, diphenylphosphinoferrocene, 2-dicyclohexylphosphinobiphenyl, 2-di-t-butylphosphinobiphenyl, 2, 2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), and the like can be used. As the base, sodium t-butoxide, cesium carbonate, potassium carbonate, potassium phosphate and the like can be used. Compound (1c-16-1) is used in the amount of 1 equivalent to excess with respect to compound (1c-16). The palladium catalyst is used in the amount of 0.01 to 0.3 equivalents based on compound (1c-16). The phosphine ligand is used in the amount of 0.01 to 1.2 equivalents based on compound (1c-16). The base is used in the amounts of 1 equivalent to 4 equivalents based on compound (1c-16). The reaction temperature is from room temperature to reflux temperature, and the reaction time is from 30 minutes to 72 hours.

[Step 1-31]
In this step, compound (1c-22) and compound (1c-16-1) are reacted to perform reductive amination to obtain compound (1c-23). Acetic acid may be added to accelerate the reaction. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as 1,4-dioxane and tetrahydrofuran, Alcohol solvents such as methanol and ethanol, methylene chloride, or a mixed solvent thereof can be used. As the reducing agent, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, 2-picoline-borane and the like can be used. Compound (1c-16-1) is used in the amounts of 1 equivalent to 2 equivalents based on compound (1c-22). The reducing agent is used in the amounts of 1 equivalent to 2 equivalents based on compound (1c-22). The reaction temperature is from room temperature to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Step 1-32]
In this step, compound (1c-24) and compound (1c-12-1) are reacted to perform reductive amination to obtain compound (1c-25). Compound (1c-25) can be manufactured according to the methods similar to those of [Step 1-31].

[Production Method 1-13] Production Method-2 for Compound (1c-4)

[Wherein R ³ and Hal have the same meaning as defined above. ]

  Compound (1c-16) can be a commercially available product, or can be produced from a commercially available product by a known method. As the compound (1c-12-1), a commercially available product can be used as it is, and it can also be produced from a commercially available product by a known method.

[Step 1-33]
This step is a step wherein compound (1c-26) is obtained by reacting compound (1c-16) with compound (1c-12-1). Compound (1c-26) can be manufactured according to the methods similar to those of [Step 1-22].

[Step 1-34]
This step is a step of obtaining compound (1c-27) by reducing compound (1c-26) with iodotrimethylsilane. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran, acetonitrile, methylene chloride and the like are used. More preferably, methylene chloride or acetonitrile can be used. The compound (1c-26) is used in an amount of 2 to 10 equivalents of iodotrimethylsilane, the reaction temperature is 0 ° C. to 60 ° C., and the reaction time is 5 minutes to 6 hours. The iodotrimethyl orchid used in the reaction may be a commercially available product, or may be prepared and used by reacting sodium iodide and chlorotrimethylsilane in acetonitrile at room temperature.

[Production method 1-14] Method for producing compound (1c-28) which is compound (1c-5)

[Wherein R ³ has the same meaning as defined above. ]

  As compound (1c-26), a commercially available product can be used as is, or it can also be produced from a commercially available product by a known method.

[Step 1-35]
This step is a step of obtaining compound (1c-28) by reducing compound (1c-26). The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran and diethyl ether, benzene, toluene Aromatic hydrocarbon solvents such as can be used. As the reducing agent, lithium aluminum hydride-aluminum chloride can be used. The lithium aluminum hydride is used in the amount of 3 to 8 equivalents based on compound (1c-26). Aluminum chloride is used in the amount of 3 to 10 equivalents based on compound (1c-26). The reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 48 hours.

[Production method 1-15] Method for producing compound (1c-29) which is compound (1c-6)

[Wherein R ³ , R ⁷ and R ⁸ have the same meaning as defined above. ]

  Compound (1c-13) can be a commercially available product, or can be produced from a commercially available product by a known method.

[Step 1-36]
In this step, iodotrimethylsilane is allowed to act on compound (1c-13) to simultaneously perform reduction and acetal deprotection to obtain compound (1c-29). The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran, acetonitrile, methylene chloride, etc. More preferably, methylene chloride and acetonitrile can be used. Iodotrimethylsilane is used in the amount of 2 to 10 equivalents based on compound (1c-13). The reaction temperature is from 0 ° C. to 60 ° C., and the reaction time is from 5 minutes to 6 hours. The iodotrimethylsilane used in the reaction may be a commercially available product, or may be prepared at the time of use by reacting sodium iodide and chlorotrimethylsilane in acetonitrile at room temperature.

[Production method 1-16] Method for producing compound (1c-34) which is compound (1c-3)

[Wherein R ³ and L have the same meanings as defined above. In the formula, R ¹³ represents a C _1-6 alkyl group which may be substituted with halogen or the like. ]

  As compound (1c-30), compound (1c-30-1) and compound (1c-30-2), commercially available products can be used as they are, and they can also be produced from commercially available products by known methods.

[Step 1-37]
This step is a step of obtaining compound (1c-31) by reacting compound (1c-30) with an organophosphorus compound, an azo reagent, and compound (1c-30-1). Compound (1c-31) can be obtained in the same manner as in [Step 1-19].

[Step 1-38]
This step is a step of obtaining compound (1c-31) by reacting compound (1c-30) and compound (1c-30-2) in the presence of a base. Compound (1c-31) can be obtained in the same manner as in [Step 1-18].

[Step 1-39]
This step is a step of obtaining compound (1c-32) by reacting compound (1c-31) and peroxide. As the peroxide used in this reaction, m-chloroperbenzoic acid, hydrogen peroxide solution, dimethyldioxirane, benzoyl peroxide, peracetic acid and the like can be used. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, but it may be a halogen solvent such as chloroform or methylene chloride, methanol, ethanol or the like. Alcohol solvents, amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone, aromatic hydrocarbon solvents such as benzene and toluene, diethyl ether, acetone, acetonitrile, acetic acid and water can be used. The peroxide is used in the amount of 1 to 5 equivalents based on compound (1c-31). The reaction temperature is from −40 ° C. to reflux temperature, and the reaction time is from 1 minute to 48 hours.

[Step 1-40]
This step is a step of obtaining compound (1c-33) by reacting compound (1c-32) with an acid anhydride. As the acid anhydride used in this reaction, acetic anhydride, trifluoroacetic anhydride, or the like can be used. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, and a halogen-based solvent such as chloroform or methylene chloride, or an aromatic such as benzene or toluene. A group hydrocarbon solvent, acetic acid, trifluoroacetic acid and the like can be used. An acid anhydride can also be used as a solvent. The acid anhydride is used in the amount of 1 equivalent to excess with respect to compound (1c-32). The reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Step 1-41]
This step is a step of hydrolyzing the compound (1c-33) to obtain the compound (1c-34). For example, the compound (1c-33) is hydrolyzed in the presence of an acid such as hydrochloric acid or sulfuric acid, or in the presence of an alkali such as sodium hydroxide, potassium hydroxide, sodium methoxide, potassium carbonate, sodium carbonate or the like. (1c-34) can be obtained. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, but ether solvents such as 1,4-dioxane and tetrahydrofuran, methanol, Alcohol solvents such as ethanol, halogen solvents such as methylene chloride and chloroform, aromatic hydrocarbon solvents such as benzene and toluene, amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone, dimethyl sulfoxide, acetonitrile , Water, or a mixed solvent thereof can be used. The acid or base is used in the amount of 1 equivalent to excess based on compound (1c-33). The reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Production method 1-17] Method for producing compound (1c-41) which is compound (1c-3)

[Wherein R ³ and Hal are as defined above. In the formula, R ¹³ represents a C _1-6 alkyl group which may be substituted with halogen or the like. ]

  As compound (1c-35) and compound (1c-7-1), commercially available products can be used as they are, and they can also be produced from commercially available products by known methods.

[Step 1-42]
This step is a step of obtaining compound (1c-36) by reducing compound (1c-35). It can be obtained by the same method as in [Step 1-7].

[Step 1-43]
This step is a step of obtaining a compound (1c-38) by reacting the compound (1c-36) with an organic phosphorus compound, an azo reagent and a compound (1c-7-1). Compound (1c-38) can be obtained in the same manner as in [Step 1-19].

[Step 1-44]
This step is a step of obtaining compound (1c-37) by converting the hydroxyl group of compound (1c-36) to a leaving group. Compound (1c-37) can be obtained in the same manner as in [Step 1-26].

[Step 1-45]
This step is a step of obtaining compound (1c-38) by reacting compound (1c-37) with compound (1c-7-1) in the presence of a base. Compound (1c-38) can be obtained in the same manner as in [Step 1-18].

[Step 1-46]
This step is a step wherein compound (1c-39) is obtained by reacting compound (1c-38) with a peroxide. Compound (1c-39) can be obtained in the same manner as in [Step 1-39].

[Step 1-47]
This step is a step wherein compound (1c-40) is obtained by reacting compound (1c-39) with an acid anhydride. Compound (1c-40) can be obtained in the same manner as in [Step 1-40].

[Step 1-48]
This step is a step of hydrolyzing the compound (1c-40) to obtain the compound (1c-41). Compound (1c-41) can be obtained in the same manner as in [Step 1-41].

[Production Method 2] Representative production method of compound (2a) which is compound (I)

[Wherein, A, R ¹ , R ² , Q and R ³ have the same meaning as defined above. ]

[Production Method 2-1] A production method of (2a) which is compound (I)

[Wherein, A, Hal, R ¹ , R ² , Q and R ³ have the same meaning as defined above. ]

  As compound (1c) and compound (1c-3), commercially available products can be used as they are, and they can be produced from commercially available products by a known method or the method described in this patent.

[Step 2-1]
This step is a step of obtaining a compound (2a) by reacting the compounds (2b) and (1c) in the presence of a base. As the base used in this reaction, triethylamine, N, N-diisopropylethylamine, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and the like can be used. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials and reagents to some extent and does not inhibit the reaction. For example, ethers such as tetrahydrofuran and 1,4-dioxane A solvent, an amide solvent such as N, N-dimethylformamide, N-methylpyrrolidinone, dimethyl sulfoxide, or a mixed solvent thereof can be used. Compound (1c) and the base are used in the amounts of 1 equivalent to 2 equivalents based on compound (2b). The reaction temperature is from room temperature to reflux temperature, and the reaction time is from 10 minutes to 48 hours.

[Step 2-2]
This step is a step of obtaining a compound (2a) by reacting the compounds (2b) and (1c-3) with an azo reagent and an organophosphorus compound. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials and reagents to some extent and does not inhibit the reaction. For example, aromatic hydrocarbon solvents such as toluene and xylene Ether solvents such as tetrahydrofuran and 1,4-dioxane, halogen solvents such as dichloromethane and chloroform, amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone, dimethyl sulfoxide, or a mixed solvent thereof. Can be used. As the organic phosphorus compound, triphenylphosphine, tri-2-furylphosphine, diphenyl-2-pyridylphosphine and the like can be used. As the azo reagent, diethyl azodicarboxylate, diisopropyl azodicarboxylate, dimethyl azodicarboxylate and the like can be used. Compound (1c-3), organophosphorus compound, and azo reagent are used in the amounts of 1 equivalent to 3 equivalents based on compound (2b). The reaction temperature is −20 ° C. to 80 ° C., and the reaction time is 5 minutes to 48 hours.

[Manufacturing method 2-2] (2b) manufacturing method

[Wherein R ¹ and R ² have the same meanings as defined above. ]

  As the compound (2b-1), a commercially available product can be used as it is, and it can be synthesized from a commercially available product by a known method or the method described in this patent.

[Step 2-3]
This step is a step of obtaining compound (2b) by reacting compound (2b-1) with sodium azide in the presence of a salt. As a salt used in this reaction, triethylamine hydrochloride, ammonium chloride and the like can be used. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials and reagents to some extent and does not inhibit the reaction. For example, N, N-dimethylformamide, N-methylpyrrolidinone An amide solvent such as dimethyl sulfoxide or a mixed solvent thereof can be used. Sodium azide is used in the amount of 1 to 10 equivalents based on compound (2b-1). The salt is used in the amount of 1 to 5 equivalents based on sodium azide. The reaction temperature is from 60 ° C. to reflux temperature, and the reaction time is from 1 hour to 48 hours.
In addition, compound (2b) can be obtained from compound (2b-1) by the method described in the following alternative method (1).

  Alternative Method (1): Compound (2b-1) is reacted with an azating agent such as trimethyltin azide or tributyltin azide and then reacted with an acid to deprotect the trialkyltin group to give compound (2b). Can be obtained. The azidating agent is used in the amount of 1 to 10 equivalents based on compound (2b-1). The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials and reagents to some extent and does not inhibit the reaction. For example, aromatic hydrocarbon solvents such as toluene and xylene An ether solvent such as 1,4-dioxane, an amide solvent such as N, N-dimethylformamide and N-methylpyrrolidinone, dimethyl sulfoxide, or a mixed solvent thereof can be used. The reaction temperature is from 60 ° C. to reflux temperature, and the reaction time is from 30 minutes to 48 hours. Although there is no restriction | limiting in particular as an acid used for the deprotection of a trialkyltin group, Strong acids, such as hydrochloric acid, are preferable. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials and reagents to some extent and does not inhibit the reaction. For example, aromatic hydrocarbon solvents such as toluene and xylene , Tetrahydrofuran, 1,4-dioxane and other ether solvents, N, N-dimethylformamide, amide solvents such as N-methylpyrrolidinone, dimethyl sulfoxide, or a mixed solvent thereof can be used. The reaction temperature is from 0 ° C. to the reflux temperature of the solvent, the acid is used in an amount of 2 equivalents to an excess amount relative to compound (1b), and the reaction time is from 10 minutes to 24 hours.

[Production method 2-3] Method for producing compound (2b-1)

[In the formula, Hal means halogen, and R ¹ and R ² have the same meaning as defined above. ]

  Commercially available products can be used as they are for the respective compounds in the above process diagrams, and they can also be produced from commercially available products by known methods.

[Step 2-4]
This step is a step of obtaining compound (2b-1) by cyanating compound (1b-1) with zinc cyanide in the presence of a catalyst. To obtain good results, a phosphine ligand may be added. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran and 1,4-dioxane, Amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone, acetonitrile, dimethyl sulfoxide, or a mixed solvent thereof can be used. Examples of the palladium catalyst include palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (tri-o-tolylphosphine) palladium (II), bis (Tri-t-butylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), or the like can be used. As the phosphine ligand, triphenylphosphine, tri-o-tolylphosphine, tri-t-butylphosphine, or the like can be used. Zinc cyanide is used in the amount of 0.5 to 5 equivalents based on compound (1b-1). The palladium catalyst is used in the amount of 0.01 to 0.3 equivalents based on compound (1b-1). The phosphine ligand is used in the amount of 0.01 to 1.2 equivalents based on compound (1b-1). The reaction temperature is from 60 ° C. to reflux temperature, and the reaction time is from 30 minutes to 24 hours.

[Step 2-5]
This step is a step of obtaining compound (1b-11) by amidating compound (1b-3). Compound (1b-11) can be obtained by allowing ammonium chloride to act on compound (1b-3) together with a condensing agent in the presence of a base. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran and 1,4-dioxane, Amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone, acetonitrile, dimethyl sulfoxide, or a mixed solvent thereof can be used. As the base, for example, triethylamine, diisopropylethylamine, potassium carbonate, sodium hydroxide and the like can be used. Examples of the condensing agent include (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (hereinafter referred to as “WSC”), N, N-dicyclohexylcarbodiimide (hereinafter referred to as “DCC”), and the like. Ammonium chloride is used in an amount of 1 to 10 equivalents based on compound (1b-3), a base is used in an amount of 1 to 5 equivalents based on ammonium chloride, and the reaction temperature is from room temperature to reflux temperature. The reaction time is 1 hour to 72 hours.

[Step 2-6]
This step is a step of obtaining compound (2b-1) by allowing a dehydrating agent to act on compound (1b-11). The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran and 1,4-dioxane, An amide solvent such as N, N-dimethylformamide and N-methylpyrrolidinone, an aromatic hydrocarbon solvent such as toluene and xylene, pyridine, acetonitrile, dimethyl sulfoxide, or a mixed solvent thereof can be used. It is also effective to use a dehydrating agent as a solvent. As the dehydrating agent, phosphorus pentoxide, thionyl chloride, dicyclohexylcarbodiimide, phosphorus oxychloride and the like can be used. The dehydrating agent is used in an amount from 1 equivalent to an excess amount relative to compound (1b-11). The reaction temperature is from room temperature to the reflux temperature of the solvent.

[Production Method 2-4] Method for producing Compound (1c-44) which is Compound (1c-3)

[Wherein, R ¹¹ represents a C _1-6 alkyl group, and R ³ has the same meaning as defined above. ]

  Compound (1c-42) and compound (1c-30-1) may be commercially available products, and can be produced from commercially available products by known methods.

[Step 2-7]
This step is a step of condensing the compounds (1c-42) and (1c-30-1) in the presence of an organic phosphorus compound and an azo reagent to obtain the compound (1c-43). Compound (1c-43) can be obtained in the same manner as in [Step 2-2].

[Step 2-8]
This step is a step of obtaining compound (1c-44) by reducing compound (1c-43). Compound (1c-44) can be obtained in the same manner as described in [Step 1-7].

[Production method 2-5] Method for producing compound (1c-47), which is compound (1c-3)

[Wherein R ³ represents the above definition. ]

  As the compounds (1c-45) and (1c-45-1), commercially available products can be used as they are, or they can be produced from commercially available products by known methods.

[Step 2-9]
This step is a step of obtaining compound (1c-46) by reacting compound (1c-45) with compound (1c-45-1). The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials and reagents to some extent and does not inhibit the reaction. For example, acetic acid or the like can be used. Compound (1c-45-1) is used in the amount of 1 equivalent based on compound (1c-45). The reaction temperature is 50 ° C. to 110 ° C., and the reaction time is 5 minutes to 1 hour.

[Step 2-10]
This step is a step of obtaining compound (1c-47) by reducing compound (1c-46). Compound (1c-47) can be obtained in the same manner as in the method described in [Step 1-7].

[Production Method 2-6] Method for producing Compound (1c-49) which is Compound (1c-6)

[Wherein, E represents an oxygen atom or a sulfur atom; Ar represents a C _6-10 aryl group, each of which may have one or two substituents selected from substituent group α, or Means a 5- or 6-membered heteroaryl group. ]
[Substituent group α]
Halogen atom, C _1-6 alkyl group, C _1-6 alkoxy group, C _3-8 cycloalkyl group, C _2-6 alkenyl group, and C _2-6 alkynyl group

  As the compound (1c-48), a commercially available product can be used as it is. Compound (1c-48-1) may be a commercially available product, or can be produced from a commercially available product by a known method.

[Step 2-11]
This step is a step of obtaining compound (1c-49) by reacting compound (1c-48) with compound (1c-48-1) in the presence of a base. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran and 1,4-dioxane, Amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone, acetonitrile, dimethyl sulfoxide, or a mixed solvent thereof can be used. As the base, for example, sodium hydride, potassium carbonate, sodium hydroxide and the like can be used. Compound (1c-48-1) is used in the amounts of 1 equivalent to 2 equivalents based on compound (1c-48). The base is used in the amounts of 1 equivalent to 2 equivalents based on compound (1c-48). The reaction temperature is from 0 ° C. to the reflux temperature of the solvent, and the reaction time is from 5 minutes to 24 hours.

[Production Example 2-7] Method for producing compound (1c-52) which is compound (1c-6)

[Wherein R ³ has the same meaning as defined above. ]

  As the compound (1c-50), a commercially available product can be used as it is.

[Step 2-12]
In this step, compound (1c-50) and compound (1c-30-1) are reacted in the presence of 1,10-phenanthroline, a base and a catalyst to obtain compound (1c-51). The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, aromatic hydrocarbon solvents such as toluene and xylene, tetrahydrofuran An ether solvent such as 1,4-dioxane, an amide solvent such as N, N-dimethylformamide and N-methylpyrrolidinone, acetonitrile, dimethyl sulfoxide, or a mixed solvent thereof can be used. As the base, for example, potassium carbonate, cesium carbonate, potassium phosphate and the like can be used. As the catalyst, copper (I) iodide, copper (I) chloride, copper (I) bromide, or the like can be used. The base is used in an amount of 1 to 5 equivalents relative to (1c-50), the catalyst is used in an amount of 0.05 to 0.5 equivalents relative to (1c-50), and 1,10-phenanthroline is relative to (1c-50). 0.05 to 1 equivalent is used. Compound (1c-30-1) is used in the amount of 1 to 3 equivalents based on compound (1c-50). The reaction temperature is from 80 ° C. to the reflux temperature of the solvent, and the reaction time is from 30 minutes to 24 hours.

[Step 2-13]
In this step, the hydrogen atom of compound (1c-51) is substituted with a metal atom using a strong base to form an organometallic compound, and then a formylation reagent is allowed to act to obtain compound (1c-52). is there. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, but ether solvents such as tetrahydrofuran and diethyl ether are preferable. As the strong base, n-butyllithium, s-butyllithium, t-butyllithium, lithium diisopropylamide and the like can be used. The temperature for preparing the organometallic compound is -78 ° C to room temperature, preferably -78 ° C to -40 ° C. The base is used in the amount of 1 to 1.5 equivalents based on compound (1c-51), and the reaction time is 30 minutes to 24 hours. As the formylation reagent, dimethylformamide, N-formylpiperidine, N-formylmorpholine, N-methylformanilide and the like can be used. The formylating reagent may be used in an amount of 1 to 20 equivalents, preferably 1 to 2 equivalents, based on the metal compound. The temperature for reacting the metal compound with the formylation reagent is from -78 ° C to room temperature, and the reaction time is from 5 minutes to 6 hours.

[Production Method 3] Representative Production Method of Compound (3a) which is Compound (I)

[Wherein, A, R ¹ , R ² , Q and R ³ have the same meaning as defined above. ]

[Production Method 3-1] Method for producing Compound (3a) which is Compound (I)

[Wherein, A, R ¹ , R ² , Q and R ³ have the same meaning as defined above. ]

Compound (2b-1) may be a commercially available product, or can be produced from a commercially available product by a known method. Furthermore, it can also manufacture using the method as described in the manufacture example in an Example, or [manufacturing method 2-3].
Compound (3b) can also be produced from a commercially available product by a known method. Furthermore, it can also manufacture using the manufacturing method in an Example, or the method as described in [manufacturing method 3-2], [manufacturing method 3-3], etc.

[Step 3-1]
This step is a step of obtaining compound (3a) by reacting compound (2b-1) with compound (3b) in the presence of an acid or base, or heating under neutral conditions. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, alcohol solvents such as methanol and ethanol, tetrahydrofuran, diethyl ether and the like Ether solvents, aromatic hydrocarbon solvents such as benzene and toluene, amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone, water, methylene chloride, chloroform, ethyl acetate, dimethyl sulfoxide, or these A mixed solvent or the like can be used. As the acid used in this reaction, hydrochloric acid, sulfuric acid and the like can be used, and as the base, sodium methoxide, sodium ethoxide and the like can be used. The acid and base are used in the amounts of 0.1 equivalent to 1 equivalent based on compound (2b-1). Compound (3b) is used in the amount of 1.0 to 1.5 equivalents based on compound (2b-1). The reaction temperature is from room temperature to reflux temperature, and the reaction time is from 1 hour to 60 hours.

[Production Method 3-2] Production Method of Compound (3b)

[Wherein, R ¹² represents a C _1-6 alkyl group, and A, Q, and R ³ have the same meaning as defined above. ]

  Commercially available products can be used as they are for the respective compounds in the above process diagrams, and they can also be produced from commercially available products by known methods.

[Step 3-2]
This step is a step of obtaining compound (3b-2) by esterifying compound (3b-1) in the presence of an acid. Compound (3b-2) can be obtained in the same manner as in [Step 1-6].

[Step 3-3]
This step is a step of obtaining a compound (3b-3) by reacting the compound (3b-1) with a halogenating agent. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, aromatic hydrocarbon solvents such as benzene and toluene, N Amide solvents such as N, dimethylformamide, N-methylpyrrolidinone, acetonitrile, methylene chloride, 1,2-dichloroethane, or a mixed solvent thereof can be used. A halogenating agent can also be used as a solvent. A catalytic amount of a phase transfer catalyst such as benzyltriethylammonium chloride or pyridine can be added to the reaction. As the halogenating agent, thionyl chloride, phosphorus pentachloride and the like can be used. The halogenating agent is used in the amount of 1 to 20 equivalents based on compound (3b-1). The reaction time is 10 minutes to 5 hours. The reaction temperature is from 0 ° C. to room temperature.

[Step 3-4]
This step is a step of obtaining compound (3b) by reacting compound (3b-2) with hydrazine. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, but alcohol solvents such as ethanol and propanol are preferred. The reaction proceeds even without solvent. Hydrazine is used in the amount of 1 to 20 equivalents based on compound (3b-2). The reaction temperature is from room temperature to reflux temperature, and the reaction time is from 1 hour to 72 hours.

[Step 3-5]
This step is a step of obtaining compound (3b) by reacting compound (3b-3) with hydrazine in the presence of a base. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, but alcohol solvents such as ethanol and propanol are preferred. The reaction proceeds even without solvent. Hydrazine is used in the amounts of 1 equivalent to 20 equivalents based on compound (3b-3). As the base, triethylamine, sodium hydroxide, potassium hydroxide and the like can be used, and the base is used in the amount of 1 to 1.5 equivalents based on compound (3b-3). The reaction temperature is from room temperature to reflux temperature, and the reaction time is from 1 hour to 72 hours.

[Production Method 3-3] Production Method of (3b-4) which is Compound (3b)

[Wherein, R ¹² represents a C _1-6 alkyl group. A, R ³ and L have the same meaning as defined above. ]

  Commercially available products can be used as they are for the respective compounds in the above process diagrams, and they can also be produced from commercially available products by known methods.

[Step 3-6]
This step is a step in which compound (3b-6) is obtained by esterification by reacting compound (3b-5) with diazomethane or trimethylsilyldiazomethane. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran and diethyl ether, benzene, toluene Aromatic hydrocarbon solvents such as methanol, alcohol solvents such as methanol and ethanol, methylene chloride, hexane, or a mixed solvent thereof can be used. Diazomethane or trimethylsilyldiazomethane is used in the amounts of 1 equivalent to 2 equivalents based on compound (3b-5). The reaction temperature is from 0 ° C. to room temperature, and the reaction time is from 10 minutes to 24 hours.

[Step 3-7]
This step is a step wherein compound (3b-8) is obtained by reacting compound (3b-6) with compound (3b-7) in the presence of a base. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran and diethyl ether, benzene, toluene An aromatic hydrocarbon solvent such as N, N-dimethylformamide, an amide solvent such as N-methylpyrrolidinone, an alcohol solvent such as methanol or ethanol, dimethyl sulfoxide, or a mixed solvent thereof can be used. As the base, sodium hydride, potassium t-butoxide, sodium ethoxide, sodium methoxide, N, N-diisopropylethylamine, triethylamine, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate and the like can be used. The base is used in the amount of 1 to 5 equivalents based on compound (3b-6). Compound (3b-7) is used in the amount of 1 to 20 equivalents based on compound (3b-6). The reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 5 minutes to 6 hours.

[Step 3-8]
This step is a step of obtaining compound (3b-4) by reacting compound (3b-8) with hydrazine. Compound (3b-4) can be manufactured according to the methods similar to those of [Step 3-4].

[Production Method 4] Representative Production Method of Compound (4a) which is Compound (I)

[Wherein, A, R ¹ , R ² , Q and R ³ have the same meaning as defined above. ]

[Production Method 4-1] Production Method of Compound (4a) which is Compound (I)

[Wherein, Hal, A, R ¹ , R ² , Q and R ³ have the same meaning as defined above. ]

Compound (1b-1) can be a commercially available product, or can be produced from a commercially available product by a known method.
Compound (4b) can also be produced from a commercially available product by a known method. Furthermore, it can also manufacture using the method as described in the manufacture example in an Example, or [manufacturing method 4-2].

[Step 4-1]
This step is a step of obtaining the compound (4a) by reacting the compound (1b-1), the compound (4b), and a catalytic amount of copper in the presence of an azidating agent. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, but a mixed solvent such as dimethyl sulfoxide-water or t-butanol-water may be used. preferable. As the azidating agent, sodium azide, trimethylsilyl azide and the like can be used. The azidating agent is used in the amount of 1 to 1.5 equivalents based on compound (1b-1). As the copper, monovalent copper such as copper (I) iodide, copper (I) bromide, copper (I) chloride can be used. Moreover, what produces | generates monovalent | monohydric copper in reaction systems, such as copper sulfate (II) -copper (0), may be used. Copper is used in the amount of 0.1 to 1.0 equivalents based on compound (1b-1). In order to increase the reaction rate, a catalytic amount of an amine-based ligand such as (1S, 2S) -N, N′-dimethylcyclohexane-1,2-diamine may be added. Moreover, it can also react by irradiating a microwave. The reaction temperature is from room temperature to reflux temperature, and the reaction time is from 5 minutes to 48 hours.

[Production Method 4-2] Production Method of Compound (4b)

[Wherein, Hal, A, R ³ , R ⁹ , R ¹⁰ and Q have the same meanings as defined above. ]

  Compound (1c) can be a commercially available product, or can be produced from a commercially available product by a known method. Furthermore, it can also manufacture using the method as described in the manufacture example in an Example, or [manufacturing method 1-11].

[Step 4-2]
This step is a step of obtaining a compound (4b-1) by reacting the compound (1c) with an ethynylsilane derivative. A compound (4b-1) can be obtained by reacting an ethynyl-Grignard reagent obtained by reacting an ethynylsilane derivative and a Grignard reagent with the compound (1c). In order to obtain good results, a copper compound such as copper (I) bromide or copper (I) iodide may be added. As the ethynylsilane derivative, for example, trimethylsilylacetylene, triethylsilylacetylene, triisopropylsilylacetylene, t-butyldimethylsilylacetylene, or the like can be used. As the Grignard reagent, alkyl magnesium halides such as ethyl magnesium bromide and isopropyl magnesium chloride can be used. The ethynylsilane derivative can be used in the amount of 1 to 3 equivalents based on compound (1c). The Grignard reagent can be used in the amount of 1 to 3 equivalents based on compound (1c). The copper compound can be used in the amount of 0.1 to 3 equivalents based on compound (1c). The reaction temperature is from room temperature to reflux temperature, and the reaction time is from 1 hour to 72 hours.

[Step 4-3]
This step is a step of obtaining compound (4b) by deprotecting the trialkylsilyl group of compound (4b-1). The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as tetrahydrofuran and diethyl ether, methanol, ethanol An alcohol solvent such as N, N-dimethylformamide, an amide solvent such as N-methylpyrrolidinone, acetonitrile, dimethyl sulfoxide, water, or a mixed solvent thereof can be used. As the base, for example, potassium carbonate, sodium hydroxide, tetrabutylammonium fluoride, potassium fluoride, cesium fluoride and the like can be used. The base is used in the amount of 0.05 to 10 equivalents based on compound (4b-1). The reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 5 minutes to 24 hours.

[Production Method 5] Representative Production Method of Compound (5a) which is Compound (I)

[Wherein, A, R ¹ , R ² , Q and R ³ have the same meaning as defined above. ]

[Production Method 5-1] Method for producing Compound (5a) which is Compound (I)

[Wherein, A, R ¹ , R ² , Q and R ³ have the same meaning as defined above. ]

[Step 5-1]
This step is a step of obtaining compound (5a) by reacting compound (5b) with phosphorus halide. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as diethyl ether, benzene, toluene and the like Aromatic hydrocarbon solvents, N, N-dimethylformamide, acetonitrile, chloroform, and the like can be used, and phosphorus halides can also be used as the solvent. As the phosphorus halide, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, or the like can be used. The phosphorus halide is used in the amount of 1 equivalent to a solvent amount based on compound (5b). The reaction temperature is from room temperature to reflux temperature, and the reaction time is from 10 minutes to 12 hours.
In addition, compound (5a) can be obtained from compound (5b) by the method described in the following alternative methods (1) and (2).

  Alternative method (1): Compound (5a) can be obtained by reacting compound (5b) with diphosphorus pentoxide. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, an aromatic hydrocarbon solvent such as toluene or xylene is used. Can be used. The diphosphorus pentoxide is used in the amount of 1 to 20 equivalents based on compound (5b). The reaction temperature is from room temperature to reflux temperature, and the reaction time is from 10 minutes to 12 hours.

  Alternative Method (2): Compound (5a) can be obtained by reacting compound (5b) with thionyl chloride. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, aromatic hydrocarbon solvents such as benzene and toluene, acetonitrile , Chloroform, methylene chloride, and the like, and thionyl chloride can also be used as a solvent. To obtain a good yield, a catalytic amount of pyridine can be added to the reaction. Thionyl chloride is used in the amount of 1 equivalent to a solvent amount based on compound (5b). The reaction temperature is from room temperature to reflux temperature, and the reaction time is from 10 minutes to 12 hours.

[Production Method 5-2] Production Method of Compound (5b)

[Wherein, A, R ¹ , R ² , R ³ , R ⁴ , and Q have the same meaning as defined above. ]

  As the compound (3b), the compound (1b-3) and the compound (1b-4), commercially available products can be used as they are, and they can be synthesized from commercially available products by a known method or the method described in this patent.

[Step 5-2]
This step is a step of obtaining compound (5b) by condensing compound (3b) and compound (1b-3) using a condensing agent. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, halogenated hydrocarbons such as dichloromethane and chloroform, dimethyl sulfoxide, and the like. Etc., esters such as ethyl acetate, ethers such as tetrahydrofuran and 1,4-dioxane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and the like can be used. As the condensing agent, (1H-1,2,3-benzotriazol-1-yloxy (tri (dimethylamino)) phosphonium hexafluorophosphate) (hereinafter referred to as “Bop”), WSC, DCC, carbonyldiimidazole ( Hereinafter, it is referred to as “CDI”), diethylphosphoryl cyanide, and the like. Compound (1b-3) is used in the amount of 0.8 to 1.2 equivalents based on compound (3b). The condensing agent is used in the amount of 0.8 to 1.2 equivalents based on compound (3b). In this step, 1 to 5 equivalents of an organic base such as triethylamine can be added. The reaction temperature is from room temperature to reflux temperature, and the reaction time is from 10 minutes to 30 hours.

[Step 5-3]
This step is a step of obtaining compound (5b) by reacting compound (3b) with compound (1b-4). The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, alcohol solvents such as ethanol and propanol, tetrahydrofuran, 1, Ether solvents such as 4-dioxane, amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone, dimethyl sulfoxide, or a mixed solvent thereof can be used. Compound (3b) can also be used as a solvent. Compound (3b) is used in the amount of 1 equivalent to a solvent amount relative to compound (1b-4). The reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Production Method 6] Representative Production Method of Compound (6a) which is Compound (I)

[Wherein, A, R ¹ , R ² , Q and R ³ have the same meaning as defined above. ]

[Production Method 6-1] Method for producing Compound (6a) which is Compound (I)

[Wherein, A, R ¹ , R ² , Q and R ³ have the same meaning as defined above. ]

  Compound (5b) can be synthesized by the method described in [Production Method 5-2].

[Step 6-1]
In this step, the compound (5b) is reacted with 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetan-2,4-disulfide (Lawson reagent) or diphosphorus pentasulfide. In this step, compound (6a) is obtained. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, an aromatic hydrocarbon solvent such as benzene or toluene is used. be able to. Lawesson's reagent or diphosphorus pentasulfide is used in the amount of 1 to 20 equivalents based on compound (5b). The reaction temperature is from room temperature to reflux temperature, and the reaction time is from 10 minutes to 12 hours.

[Production Method 7] Representative production method of compound (7a) which is compound (I)

[Wherein, A, R ¹ , R ² , Q and R ³ have the same meaning as defined above. ]

[Production Method 7-1] Method for producing Compound (7a) which is Compound (I)

[Wherein, A, R ¹ , R ² , Q and R ³ have the same meaning as defined above. ]

  As compound (7b) and compound (7c), commercially available products can be used as they are, and they can also be produced from commercially available products by known methods.

[Step 7-1]
In this step, compound (7a) is obtained by reacting compound (7c) with acid anhydride, acid chloride or active ester and then reacting with compound (7b). The step of converting the compound (7c) into an acid anhydride is a step of obtaining an acid anhydride of the compound (7c) by dehydrating in a solvent using a condensing agent. The solvent used is not particularly limited, but halogenated hydrocarbons such as dichloromethane and chloroform, sulfoxides such as dimethyl sulfoxide, esters such as ethyl acetate, ethers such as tetrahydrofuran and 1,4-dioxane, N, N Amides such as dimethylformamide and N, N-dimethylacetamide are used. As the condensing agent, WSC, DCC or the like can be used. The condensing agent is used in the amount of 1 to 1.5 equivalents based on compound (7c). If necessary, 1 equivalent to an excess amount of an organic base such as triethylamine may be added. The reaction temperature is 0 ° C. to 80 ° C., and the reaction time is 10 minutes to 30 hours.

  The step of converting the compound (7c) into an acid chloride comprises reacting the compound (7c) with 1 equivalent to an excess of an acid chloride synthesis reagent in the absence of a solvent or in the presence of a solvent such as dichloromethane, benzene, or toluene. Done. A catalytic amount of N, N-dimethylformamide may be added to the reaction system. As the acid chloride synthesis reagent, thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride and the like can be used. The reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

  The step of using compound (7c) as an active ester is carried out by reacting compound (7c) with an active ester synthesis reagent in the presence of a condensing agent such as DCC in a solvent such as 1,4-dioxane or tetrahydrofuran. N-hydroxysuccinimide etc. can be used as an active ester synthesis reagent. The active ester synthesis reagent and the condensing agent are used in the amount of 1 to 1.5 equivalents based on compound (7c). The reaction temperature is from 0 ° C. to room temperature. The reaction time is 2 to 24 hours.

  The step of reacting the acid anhydride, acid chloride or active ester with the compound (7b) is a step of obtaining the compound (7a) by reacting in the presence of a base. As the base, pyridine, triethylamine, sodium hydride, sodium methoxide, sodium ethoxide and the like can be used. The solvent to be used is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, but halogenated hydrocarbons such as dichloromethane and chloroform, sulfoxides such as dimethyl sulfoxide, ethyl acetate Esters such as tetrahydrofuran, ethers such as 1,4-dioxane, alcohols such as methanol and ethanol, 1-methyl-2-pyrrolidinone (hereinafter referred to as “NMP”), N, N-dimethylformamide, N Amides such as N-dimethylacetamide are used. The base is used in the amount of 1 to 10 equivalents based on compound (7b). The reaction temperature is from room temperature to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Production Method 7-2] Production Method of Compound (7b)

[Wherein R ¹ and R ² have the same meanings as defined above. ]

  As the compound (2b-1), a commercially available product can be used as it is, and it can also be produced from a commercially available product by a known method. Furthermore, it can also manufacture using the method as described in the manufacture example in an Example, or [manufacturing method 2-3].

[Step 7-2]
This step is a step of obtaining compound (7b) by reacting compound (2b-1) with hydroxylammonium chloride. As the base used in this reaction, pyridine, sodium acetate, potassium acetate, sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide and the like can be used. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. , Ethers such as tetrahydrofuran and 1,4-dioxane, alcohols such as methanol and ethanol, amides such as NMP, N, N-dimethylformamide and N, N-dimethylacetamide, pyridine, water or a mixed solvent thereof Can be used. Hydroxylammonium chloride is used in the amount of 1 to 5 equivalents based on compound (2b-1). The base is used in the amount of 1 equivalent to an excess with respect to compound (2b-1). The reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 48 hours.

[Production Method 8] Representative production method of compound (8a) which is compound (I)

[Wherein, A, R ¹ , R ² , Q and R ³ have the same meaning as defined above. ]

[Production Method 8-1] Production Method of Compound (8a) which is Compound (1)

[Wherein, A, R ¹ , R ² , Q, Hal and R ³ have the same meaning as defined above. ]

  Compound (8b) and compound (1c) can be synthesized from commercially available products by a known method or the method described in this patent.

[Step 8-1]
This step is a step of obtaining a compound (8a) by reacting the compounds (8b) and (1c) in the presence of a base. Compound (8a) can be obtained in the same manner as described in [Step 2-1].

[Production method 8-2] Method for producing compound (8b)

[Wherein, R ¹ and R ² have the same meaning as defined above. ]

  Compound (1b-11) can be synthesized from a commercially available product by a known method or the method described in this patent.

[Step 8-2]
This step is a step in which compound (1b-12) is obtained by converting compound (1b-11) to thioamide. Compound (1b-11) is reacted with 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawson reagent) to give compound (1b-12) ) Can be obtained. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials and reagents to some extent and does not inhibit the reaction. For example, ethers such as tetrahydrofuran and 1,4-dioxane A solvent, an aromatic hydrocarbon solvent such as toluene or xylene, a halogen solvent such as dichloroethane, or a mixed solvent thereof can be used. The Lawesson's reagent is used in the amount of 0.5 to 5 equivalents based on compound (1b-11). The reaction temperature is from room temperature to the reflux temperature of the solvent, and the reaction time is from 10 minutes to 48 hours.
In addition, compound (1b-12) can be obtained from compound (1b-11) by the method described in the following alternative methods (1) and (2).

  Alternative method (1): Compound (1b-12) can be obtained by reacting compound (1b-11) with phosphorus pentasulfide. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials and reagents to some extent and does not inhibit the reaction. For example, ethers such as tetrahydrofuran and 1,4-dioxane A solvent, an aromatic hydrocarbon solvent such as benzene, toluene, xylene, a halogen solvent such as dichloroethane, or a mixed solvent thereof can be used. The phosphorous pentasulfide is used in the amount of 0.5 to 5 equivalents based on compound (1b-11). The reaction temperature is from room temperature to the reflux temperature of the solvent, and the reaction time is from 10 minutes to 48 hours.

  Alternative Method (2): Compound (1b-12) can be obtained by reacting compound (1b-11) with phosphorous pentasulfide or hexamethyldisiloxane. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials and reagents to some extent and does not inhibit the reaction. For example, ethers such as tetrahydrofuran and 1,4-dioxane Solvents, aromatic hydrocarbon solvents such as benzene, toluene and xylene, halogen solvents such as dichloroethane, hexamethylphosphorylamide (HMPA), or a mixed solvent thereof can be used. Hexamethyldisiloxane is used in an amount of 0.5 to 3 equivalents relative to compound (1b-11), and phosphorous pentasulfide is used in an amount of 1 to 6 equivalents relative to compound (1b-11). The reaction temperature is from room temperature to the reflux temperature of the solvent, and the reaction time is from 10 minutes to 48 hours.

[Step 8-3]
This step is a step wherein compound (8b) is obtained by allowing formic hydrazide to act on compound (1b-12). The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials and reagents to some extent and does not inhibit the reaction. For example, ethers such as tetrahydrofuran and 1,4-dioxane A solvent, an aromatic hydrocarbon solvent such as benzene, toluene, xylene, a halogen solvent such as dichloroethane, or a mixed solvent thereof can be used. Formic hydrazide can also be used as a solvent. Formic hydrazide is used in the amount of 3 equivalents to a solvent amount based on compound (1b-12). The reaction temperature is 60 ° C to 140 ° C.

[Production Method 9] Representative production method of compound (9a) which is compound (I)

[Wherein R ¹ , R ² , R ³ , W, X, Y and Z have the same meaning as defined above. ]

[Production Method 9-1] Production Method of Compound (9a) which is Compound (1)

[Wherein R ¹ , R ² , R ³ , L, W, X, Y and Z have the same meanings as defined above. ]

  Compound (9b) can be produced by the method described in the production examples in the examples. As compound (9b-1) and compound (9b-2), commercially available products can be used as they are, and they can also be produced from commercially available products by known methods.

[Step 9-1]
This step is a step of obtaining compound (9a) by adding 1 equivalent of a base to compound (9b) to form a phenoxide ion and then reacting compound (9b-1).
Generation of phenoxide ion: A phenoxide ion can be obtained by adding 1 equivalent of a base to compound (9b) in a solvent such as tetrahydrofuran or methanol. As the base, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium t-butoxide and the like can be used, and potassium hydroxide is more preferably used. Preferably, the solvent used is concentrated and used in the next reaction. The reaction temperature is room temperature and the reaction time is from 1 minute to 1 hour.

Reaction of phenoxide ion with compound (9b-1): Compound (9a) can be obtained by reacting phenoxide ion with compound (9b-1) in a solvent. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, but N, N-dimethylformamide, 1-methyl-2-pyrrolidinone, An amide solvent such as hexamethylphosphoric acid amide, dimethyl sulfoxide, or a mixed solvent thereof can be used. Compound (9b-1) is used in the amount of 1 to 3 equivalents based on compound (9b). The reaction temperature is from room temperature to reflux temperature, and the reaction time is from 10 minutes to 48 hours.
In addition, compound (9a) can be obtained from compound (9b) by the method described in the following alternative method (1).

  Alternative method (1): Compound (9a) can be obtained by reacting compound (9b) with compound (9b-1) in the presence of a base. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, but ether solvents such as tetrahydrofuran and diethyl ether, benzene, toluene and the like. An aromatic hydrocarbon solvent, an amide solvent such as N, N-dimethylformamide, 1-methyl-2-pyrrolidinone, dimethyl sulfoxide, or a mixed solvent thereof can be used. As the base, sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide and the like can be used. To obtain good results, a catalytic amount of sodium or potassium iodide, or tetrabutylammonium iodide may be added. The base is used in the amount of 1 to 1.5 equivalents based on compound (9b). The reaction temperature is from room temperature to reflux temperature, and the reaction time is from 10 minutes to 48 hours.

[Step 9-2]
This step is a step of obtaining a compound (9a) by reacting the compound (9b) with the compound (9b-2). Compound (9a) can be manufactured according to the methods similar to those of [Step 1-19].

[Production Method 9-2] Production Method of Compound (9b)

[Wherein R ¹ , R ² , W, X, Y and Z have the same meaning as defined above. ]

  Compound (9c) can be prepared according to the production examples in Examples or [Production Method 1], [Production Method 2], [Production Method 3], [Production Method 4], [Production Method 5], [Production Method 6], [ It can be manufactured by the method described in [Manufacturing method 7] and [Manufacturing method 8].

[Step 9-3]
This step is a step of obtaining compound (9b) by allowing an acid to act on compound (9c). In order to obtain better results, an additive such as thioanisole may be added to the reaction system. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, but is preferably an ether solvent such as diethyl ether or tetrahydrofuran, methylene chloride, , Trifluoroacetic acid and the like can be used. As the acid, organic acids such as trifluoroacetic acid and methanesulfonic acid, inorganic acids such as sulfuric acid, and Lewis acids such as boron trifluoride diethyl etherate can be used. As an additive, thioanisole, ethanethiol, dl-methionine, or the like can be used. The acid is used in the amount of 1 equivalent to a solvent amount based on compound (9c). The additive is used in the amount of 1 to 5 equivalents based on compound (9c). The reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 72 hours.
In addition, compound (9b) can be obtained from compound (9c) by the method described in the following alternative method (1).

  Alternative method (1): Compound (9b) can be obtained by reacting compound (9c) with boron tribromide or boron trichloride. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, but preferably methylene chloride is used. Boron tribromide and boron trichloride are used in the amount of 1 to 10 equivalents based on compound (9c). The reaction temperature is from -78 ° C to room temperature, and the reaction time is from 30 minutes to 24 hours.

[Example]
Hereinafter, the present invention will be described in more detail with reference to examples and pharmacological test examples according to the present invention. However, these examples are illustrative, and the present invention is not limited to the following examples. . Those skilled in the art can implement the present invention by making various modifications to the embodiments shown below, and such modifications are included in the scope of the claims of the present application.

The meanings of the abbreviations used below are as follows:
NMP: 1-methyl-2-pyrrolidinone;
THF: tetrahydrofuran;
DMSO: dimethyl sulfoxide;
DMF: N, N-dimethylformamide;
NaH: sodium hydride;
WSC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride);
HOBt: 1-hydroxybenzotriazole;
LAH: lithium aluminum hydride;
TFA: trifluoroacetic acid.

Example 1 3- (1- (4-Benzyloxy-benzyl) -1H- [1,2,3] triazol-4-yl) -pyridin-2-ylamine

To a solution of 3-ethynyl-pyridin-2-ylamine (30 mg) described in Preparation Example 1-2 in tert-butyl alcohol (500 μL) and water (600 μL) at room temperature, 1-benzyloxy-4-chloromethyl-benzene ( 59 mg), sodium azide (17 mg), copper sulfate (8 mg), copper (13 mg) were added, and 100 W microwave was irradiated at an upper limit of 125 ° C. for 10 minutes. Water was added to the reaction mixture, and filtration was performed using Celite. The obtained filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% TFA)), and further purified by silica gel column chromatography (ethyl acetate: methanol = 15: 1). Purification gave the title compound (7 mg).
MS m / e (ESI) (MH ⁺ ) 358.22 (MH ⁺ )
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.08 (2H, s), 5.56 (2H, s), 6.60 (1H, dd, J = 4.8Hz, 7.5Hz), 6.87 (2H, s ), 7.01 (2H, d, J = 8.8Hz), 7.30-7.42 (7H, m), 7.81 (1H, dd, J = 1.8Hz, 7.5Hz), 7.93 (1H, dd, J = 1.8Hz, 4.8 Hz), 8.65 (1H, s).

The starting material 3-ethynyl-pyridin-2-ylamine was synthesized by the following method.

[Production Example 1-1] 3-Trimethylsilanylethynyl-pyridin-2-ylamine

To a solution of 2-amino-3-bromopyridine (5.72 g, 33.1 mmol) in NMP (120 mL), trimethylsilylacetylene (9.36 mL, 66.2 mmol), tetrakis (triphenylphosphine) palladium (0) at room temperature. (1.91 g, 1.66 mmol), copper (I) iodide (630 mg, 3.31 mmol), N, N-diisopropylethylamine (11.5 mL, 66.2 mmol) were added, and the mixture was added at 70 ° C. under a nitrogen atmosphere. Stir for hours. Water was added to the reaction solution at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (5.9 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 0.225 (9H, s), 6.07 (2H, brs), 6.51 (1H, dd, J = 4.9 Hz, 7.5 Hz), 7.49 (1H, dd , J = 1.8Hz, 7.5Hz), 7.94 (1H, dd, J = 1.8Hz, 4.9Hz).

[Production Example 1-2] 3-ethynyl-pyridin-2-ylamine

To a solution of 3-trimethylsilanylethynyl-pyridin-2-ylamine (5.9 g) described in Production Example 1-1 in THF (120 mL) was added tetrabutylammonium fluoride (34 mL, 1 M THF solution) at 0 ° C. Stir at room temperature for 25 minutes. Water was added to the reaction solution at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (2.3 g).
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 3.42 (1H, s), 5.12 (2H, brs), 6.62 (1H, dd, J = 4.9 Hz, 7.5 Hz), 7.58 (1H, dd, J = 1.8Hz, 7.5Hz), 8.05 (1H, dd, J = 1.7Hz, 4.9Hz).

Alternative: Synthesis method of 3-trimethylsilanylethynyl-pyridin-2-ylamine [Production Example 1-2-1] 2,2-dimethyl-N-pyridin-2-yl-propionamide

Triethylamine (81 mL) and pivaloyl chloride (72 mL) were added to a solution of 2-aminopyridine (50 g) in methylene chloride (500 mL) at 0 ° C., and the mixture was stirred at room temperature for 4 hours 30 minutes. Water was added to the reaction solution and extracted with methylene chloride. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. To a solution of the obtained residue in methanol (300 mL), potassium carbonate (73 g) was added at 0 ° C., and the mixture was stirred at room temperature for 90 minutes. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Heptane (300 mL) was added to the residue, and the precipitated solid was collected by filtration to obtain the title compound (80 g). Further, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (12 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 1.22 (9H, s), 7.06-7.09 (1H, m), 7.72-7.77 (1H, m), 8.01-8.03 (1H, m), 8.29-8.31 (1H, m), 9.71 (1H, s).

[Production Example 1-2-2] N- (3-iodo-pyridin-2-yl) -2,2-dimethyl-propionamide

2,2-dimethyl-N-pyridin-2-yl-propionamide (3.0 g, 17 mmol), N, N, N ′, N′-tetramethylethylenediamine (6.3 mL) described in Preparation Example 1-2-1 , 42 mmol), and THF (60 mL) were added dropwise n-butyllithium (1.6 M n-hexane solution, 30 mL) at −78 ° C., and the mixture was stirred at 0 ° C. overnight. Iodine (6.8 g) was added to the reaction mixture at −78 ° C., and the mixture was stirred at 0 ° C. for 1.5 hours. Water and saturated aqueous sodium thiosulfate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 2: 1) to obtain the title compound (2.9 g).
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 1.38 (9H, s), 6.85 (1H, dd, J = 4.8, 7.9Hz), 7.94 (1H, brs), 8.11 (1H, dd, J = 1.7Hz, 7.9Hz), 8.46 (1H, dd, J = 1.7Hz, 4.6Hz).

[Production Example 1-2-3] 3-Iodo-pyridin-2-ylamine

N- (3-iodo-pyridin-2-yl) -2, 2-dimethyl-propionamide (66.2 g, 218 mmol) described in Preparation Example 1-2-2, 5N aqueous sodium hydroxide solution (200 mL), methanol ( 200 mL) was stirred at reflux for 1 hour and 20 minutes. The reaction solution was returned to room temperature, water was added, and the mixture was extracted 3 times with ethyl acetate. The ethyl acetate layers were combined, washed once with brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the solvent was concentrated under reduced pressure to obtain the title compound (41 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 6.00 (2H, brs), 6.32 (1H, dd, J = 4.8Hz, 7.2Hz), 7.87 (1H, d, J = 7.2Hz), 7.92 (1H, d, J = 4.8Hz).

[Production Example 1-2-4] 3-Trimethylsilanylethynyl-pyridin-2-ylamine

3-Iodo-pyridin-2-ylamine (40 g), trimethylsilylacetylene (52 mL), copper (I) iodide (3.5 g), N, N-diisopropylethylamine (64 mL) described in Preparation Example 1-2-3 Tetrakis (triphenylphosphine) palladium (0) (10 g) was added to a mixture of NMP (200 mL), and the mixture was stirred at room temperature for 3 hours and 10 minutes under a nitrogen stream. Water was added to the reaction solution, and extracted four times with ethyl acetate. The solvent was concentrated under reduced pressure and purified by NH-silica gel chromatography (heptane: ethyl acetate = 4: 1). The resulting solution was concentrated under reduced pressure and purified by silica gel chromatography (heptane: ethyl acetate = 2: 1 then 1: 1) to obtain the title compound (28 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 0.25 (9H, s), 6.09 (2H, brs), 6.51-6.57 (1H, m), 7.50-7.55 (1H, m), 7.95- 7.99 (1H, m).

Example 2 5- (1- (4-Benzyloxy-benzyl) -1H- [1,2,3] triazol-4-yl) -2-methyl-pyridine

In the same manner as in Example 1, from the 5-ethynyl-2-methyl-pyridine (16 mg) and 1-benzyloxy-4-chloromethyl-benzene (35 mg) described in Preparation Example 2-1, the title compound (3 0.5 mg) was obtained.
MS m / e (ESI) (MH ⁺ ) 357.26 (MH ⁺ )

The starting material 5-ethynyl-2-methyl-pyridine was synthesized by the following method.
[Production Example 2-1] 5-ethynyl-2-methyl-pyridine

To a solution of 5-bromo-2-methyl-pyridine (1.0 g) in NMP (20 mL) at room temperature, trimethylsilylacetylene (1.2 mL), tetrakis (triphenylphosphine) palladium (0) (130 mg), copper iodide (I) (44 mg) and N, N-diisopropylethylamine (2.0 mL) were added, and the mixture was stirred at 65 ° C. for 2 hours under a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 5: 1) to obtain a mixture (810 mg) of 2-methyl-5-trimethylsilanylethynyl-pyridine and 5-bromo-2-methyl-pyridine. It was. Subsequently, a mixture of 2-methyl-5-trimethylsilanylethynyl-pyridine and 5-bromo-2-methyl-pyridine (810 mg) in THF (10 mL) and ethanol (5 mL) was added at room temperature with potassium carbonate (1. 2 g) was added and stirred at room temperature for 2 hours 30 minutes. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 5: 1) to obtain the title compound (55 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 2.26 (3H, s), 4.13 (1H, s), 7.06 (1H, d, J = 8.1 Hz), 7.56 (1H, dd, J = 2.2Hz, 8.1Hz), 8.32 (1H, d, J = 1.7Hz).

Example 3 5- (1- (4-Benzyloxy-benzyl) -1H- [1,2,3] triazol-4-yl) -pyridin-2-ylamine

In the same manner as in Example 1, from the 5-ethynyl-pyridin-2-ylamine (10 mg) described in Preparation Example 3-3 and 1-benzyloxy-4-chloromethyl-benzene (22 mg), the title compound (1 .8 mg) was obtained.
MS m / e (ESI) (MH ⁺ ) 358.21 (MH ⁺ )

The starting material 5-ethynyl-pyridin-2-ylamine was synthesized by the following method.
[Production Example 3-1] 2-nitro-5-trimethylsilanylethynyl-pyridine

To a solution of 5-bromo-2-nitropyridine (1.00 g, 4.93 mmol) in NMP (20 mL) at room temperature, trimethylsilylacetylene (1.4 mL), tetrakis (triphenylphosphine) palladium (0) (110 mg), Copper (I) iodide (38 mg) and N, N-diisopropylethylamine (1.7 mL) were added, and the mixture was stirred at 65 ° C. for 4 hours under a nitrogen atmosphere. Water was added to the reaction solution at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 6: 1) to obtain the title compound (490 mg).
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 0.30 (9H, s), 8.03-8.05 (1H, m), 8.22 (1H, J = 8.4Hz), 8.66 (1H, d, J = 2.0Hz ).

[Production Example 3-2] 5-Trimethylsilanylethynyl-pyridin-2-ylamine

Iron (510 mg) and ammonium chloride (200 mg) were added to a solution of 2-nitro-5-trimethylsilanylethynyl-pyridine (410 mg) described in Preparation Example 3-1 in THF (10 mL) and water (5 mL) at room temperature. , And stirred at 70 ° C. for 75 minutes. The reaction solution was cooled to room temperature and then filtered through celite, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (320 mg).
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 0.237 (9H, s), 4.73 (2H, brs), 6.44 (1H, d, J = 8.6Hz), 7.51 (1H, dd, J = 2.2Hz , 8.4Hz), 8.19 (1H, d, J = 2.2Hz).

[Production Example 3-3] 5-Ethynyl-pyridin-2-ylamine

To a solution of 5-trimethylsilanylethynyl-pyridin-2-ylamine (26 mg) described in Preparation Example 3-2 in THF (1 mL) and methanol (1 mL), potassium carbonate (38 mg) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. Stir. Water was added to the reaction solution at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (16 mg).
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 3.07 (1H, s), 4.73 (2H, brs), 6.46 (1H, d, J = 8.6Hz), 7.53 (1H, dd, J = 2.2Hz , 8.6Hz), 8.21 (1H, s).

Example 4 3- (1- (4-Benzyloxy-benzyl) -1H- [1,2,3] triazol-4-yl) -pyridine-2,6-diamine

To a solution of 3-ethynyl-pyridine-2,6-diamine (20 mg) described in Preparation Example 4-3 in NMP (200 μL) and water (200 μL) at room temperature, 1-benzyloxy-4-chloromethyl-benzene (37 mg) was added. ), Sodium azide (15 mg), copper sulfate (4.8 mg), copper (7.4 mg) were added, and 100 W microwave was irradiated at an upper limit of 125 ° C. for 30 seconds. To the reaction mixture was added aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography (heptane: ethyl acetate = 1: 3, then ethyl acetate) to obtain the title compound (1.2 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.09 (2H, s), 5.51 (2H, s), 5.66 (2H, s), 5.75 (1H, d, J = 8.0 Hz), 6.47 (2H, s), 7.00-7.05 (2H, m), 7.30-7.48 (8H, m), 8.30 (1H, s).

[Production Example 4-1] 3-iodo-pyridine-2,6-diamine

2,6-diaminopyridine (100 g) was dissolved in DMSO (400 mL), and N-iodosuccinimide (100 g) was added all at once with stirring at room temperature. The reaction solution was stirred at room temperature for 10 minutes, water (3.5 L) was added, and the precipitated solid was removed by filtration. The resulting aqueous layer was extracted with ethyl acetate (1.3 L) three times. The ethyl acetate layers were combined and concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (heptane: ethyl acetate = 2: 3) to obtain the title compound (24 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.41 (2H, brs), 5.57 (1H, d, J = 8.0Hz), 5.64 (2H, brs), 7.37 (1H, d, J = 8.0Hz).

[Production Example 4-2] 3-Trimethylsilanylethynyl-pyridine-2,6-diamine

3-Iodo-pyridine-2,6-diamine (20 g), trimethylsilylacetylene (24 mL), copper (I) iodide (3.3 g), N, N-diisopropylethylamine (19 g) described in Preparation Example 4-1. Tetrakis (triphenylphosphine) palladium (0) (9.8 g) was added to a mixture of NMP (290 mL), and the mixture was stirred at room temperature for 30 minutes under an argon stream. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed 4 times with water and dried over sodium sulfate. Sodium sulfate was removed by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by NH-silica gel chromatography (heptane: ethyl acetate = 4: 1 then 1: 1). The solid obtained by concentrating the eluate under reduced pressure was washed with heptane containing a small amount of ethyl acetate to obtain the title compound (11 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 0.20 (9H, s), 5.53 (2H, brs), 5.66 (1H, d, J = 8.0 Hz), 5.95 (2H, brs), 7.11 (1H, d, J = 8.0Hz).

[Production Example 4-3] 3-ethynyl-pyridine-2,6-diamine

To a solution of 3-trimethylsilanylethynyl-pyridine-2,6-diamine (7.0 g) described in Production Example 4-2 in THF (100 mL), tetrabutylammonium fluoride (1M THF solution, 17 mL) was cooled with ice. And then stirred at room temperature for 10 minutes. Water was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (3.4 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.08 (1H, s), 5.57 (2H, brs), 5.68 (1H, d, J = 8.0Hz), 5.89 (2H, brs), 7.14 (1H, d, J = 8.0Hz).

Example 5 3- (2- (4-Benzyloxy-benzyl) -2H-tetrazol-5-yl) -pyridin-2-ylamine

3- (2H-tetrazol-5-yl) -pyridin-2-ylamine (100 mg), 4-benzyloxybenzyl chloride (172 mg), sodium iodide (111 mg), DMF (3 mL) described in Preparation Example 5-1. To the solution, NaH (18 mg) was added and stirred at 60 ° C. for 40 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and purified by NH-silica gel chromatography (hexane: ethyl acetate = 4: 1, then 2: 1, then 1: 1). Ethyl acetate was added to the resulting residue and the solid was collected by filtration to obtain the title compound (38 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.11 (2H, s), 5.94 (2H, s), 6.71-6.76 (1H, m), 6.90 (2H, s), 7.04 (2H, d, J = 8.8Hz), 7.30-7.46 (7H, m), 8.13-8.16 (1H, m), 8.22-8.8.25 (1H, m).

The starting material 3- (2H-tetrazol-5-yl) -pyridin-2-ylamine was synthesized by the following method.

[Production Example 5-1] 3- (2H-tetrazol-5-yl) -pyridin-2-ylamine

2-Amino-3-cyanopyridine (1.0 g), sodium azide (1.1 g), ammonium chloride (0.89 g), and DMF (15 mL) were stirred at 100 ° C. for 1.5 hours. The reaction solution was directly purified by silica gel chromatography (ethyl acetate, then ethyl acetate: methanol: concentrated aqueous ammonia = 6: 2: 0.5) to obtain the title compound (0.66 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 6.70-6.77 (1H, m), 7.50 (2H, brs), 8.01-8.07 (1H, m), 8.20-8.26 (1H, m).

Example 6 3- (2- (4-Benzyloxy-benzyl) -2H-tetrazol-5-yl) -6-methoxymethyl-pyridin-2-ylamine

6-methoxymethyl-3- (2H-tetrazol-5-yl) pyridin-2-ylamine (50 mg), 4-benzyloxybenzyl chloride (57 mg), sodium iodide (36 mg) described in Preparation Example 6-3, NaH (9.7 mg / 60% in oil) and DMF (3 mL) were stirred at 60 ° C. for 15 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and purified by NH-silica gel column chromatography (hexane: ethyl acetate = 2: 1). The obtained residue was solidified with ethyl acetate-hexane to obtain the title compound (12 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.36 (3H, s), 4.35 (2H, s), 5.10 (2H, s), 5.92 (2H, s), 6.76 (1H, d, J = 8.0Hz), 6.93 (2H, brs), 7.04 (2H, d, J = 8.8Hz), 7.30-7.45 (7H, m), 8.24 (1H, d, J = 8.0Hz).

The starting material 6-methoxymethyl-3- (2H-tetrazol-5-yl) pyridin-2-ylamine was synthesized by the following method.

[Production Example 6-1] 2-Amino-6-methoxymethyl-nicotinamide

2-amino-6-methoxymethyl-nicotinic acid (0.50 g), WSC (1.1 g), HOBt (0.74 g), and ammonium chloride (0.44 g), diisopropylethylamine (2.6 g), DMSO (10 mL) was stirred at room temperature for 29 hours. Water was added and extracted with ethyl acetate. The organic layer was concentrated and purified by NH-silica gel chromatography (ethyl acetate). Ethyl acetate was added to the resulting residue and the solid was collected by filtration to obtain the title compound (290 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.34 (3H, s), 4.28 (2H, s), 6.57 (1H, d, J = 8.0 Hz), 7.22 (2H, brs), 7.25 (1H, brs), 7.89 (1H, brs), 7.94 (1H, d, J = 8.0Hz).

[Production Example 6-2] 2-Amino-6-methoxymethyl-nicotinonitrile

2-Amino-6-methoxymethyl-nicotinamide (90 mg) and phosphorus oxychloride (3.0 g) described in Production Example 6-1 were stirred at 100 ° C. for 0.5 hour. The reaction solution was added to dilute aqueous sodium hydroxide at 0 ° C. and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (40 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.34 (3H, s), 4.31 (2H, s), 6.65 (1H, d, J = 8.0 Hz), 6.89 (2H, brs), 7.86 (1H, d, J = 8.0Hz).

[Production Example 6-3] 6-methoxymethyl-3- (2H-tetrazol-5-yl) pyridin-2-ylamine

160 of 2-amino-6-methoxymethyl-nicotinonitrile (0.20 g), sodium azide (0.40 g), triethylamine hydrochloride (1.7 g) and NMP (25 mL) described in Preparation Example 6-2 Stir at 0 ° C. for 2 hours. The reaction solution was directly purified by silica gel chromatography (ethyl acetate, then ethyl acetate: methanol: concentrated aqueous ammonia = 6: 2: 1). The obtained organic layer was concentrated and purified by silica gel chromatography (ethyl acetate: methanol = 4: 1) to obtain the title compound (170 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.38 (3H, s), 4.38 (2H, s), 6.80 (1H, d, J = 8.0 Hz), 7.38 (2H, brs), 8.17 (1H, d, J = 8.0Hz).

Example 7 3- (2- (4-Benzyloxy-benzyl) -2H-tetrazol-5-yl) -pyridine-2,6-diamine

3- (2H-tetrazol-5-yl) -pyridine-2,6-diamine (60 mg), 4-benzyloxybenzyl chloride (79 mg), sodium iodide (51 mg), NaH (described in Production Example 7-3) 14 mg, 60% in oil) and DMF (0.69 mL) were stirred at 60 ° C. for 10 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and purified by NH-silica gel column chromatography (hexane: ethyl acetate = 2: 1, then ethyl acetate). Ethyl acetate-hexane was added to the obtained residue, and the solid was collected by filtration to obtain the title compound (26 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.10 (2H, s), 5.83 (2H, s), 5.85 (1H, d, J = 8.0 Hz), 6.07 (2H, brs), 6.47 (2H, brs), 7.02 (2H, d, J = 8.4Hz), 7.30-7.46 (7H, m), 7.84 (1H, d, J = 8.0Hz).

The starting material 3- (2H-tetrazol-5-yl) -pyridine-2,6-diamine was synthesized by the following method.

[Production Example 7-1] 2,6-diamino-nicotinamide

2,6-diaminonicotinic acid (1.5 g), WSC (2.8 g), HOBt (2.0 g), ammonium chloride (1.6 g), diisopropylethylamine (7.6 g), DMSO (45 mL) at room temperature For 15 hours. Water was added and extracted with ethyl acetate. The organic layer was concentrated and purified by silica gel chromatography (ethyl acetate followed by ethyl acetate: methanol = 4: 1). The obtained organic layer was concentrated and purified by NH-silica gel chromatography (ethyl acetate). Ethyl acetate and hexane were added to the resulting residue, and the solid was collected by filtration to obtain the title compound (1.1 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.64 (1H, d, J = 8.0 Hz), 6.06 (2H, brs), 7.01 (2H, brs), 7.60 (1H, d, J = 8.0Hz).

[Production Example 7-2] 2,6-diamino-nicotinonitrile

2,6-Diamino-nicotinamide (520 mg) and phosphorus oxychloride (5.0 g) described in Production Example 7-1 were stirred at 100 ° C. for 0.5 hour. The reaction solution was added to dilute aqueous sodium hydroxide at 0 ° C. and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by NH-silica gel chromatography (ethyl acetate) to obtain the title compound (340 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.73 (1H, d, J = 8.0 Hz), 6.20 (2H, brs), 6.48 (2H, brs), 7.32 (1H, d, J = 8.0Hz).

[Production Example 7-3] 3- (2H-tetrazol-5-yl) -pyridine-2,6-diamine

2,6-diamino-nicotinonitrile (0.50 g), sodium azide (1.2 g), triethylamine hydrochloride (5.1 g) and NMP (45 mL) described in Production Example 7-2 were added at 160 ° C. Stir for hours. The reaction solution was directly purified by silica gel chromatography (ethyl acetate, then ethyl acetate: methanol: concentrated aqueous ammonia = 6: 2: 1). The obtained organic layer was concentrated and purified by silica gel chromatography (ethyl acetate, then ethyl acetate: methanol = 4: 1, then ethyl acetate: methanol: concentrated aqueous ammonia = 6: 2: 1) to obtain the title compound (270 mg). It was.
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.87 (1H, d, J = 8.0 Hz), 6.28 (2H, brs), 6.94 (2H, brs), 7.75 (1H, d, J = 8.0Hz).

Example 8 3- (5- (4-Benzyloxy-benzyl)-[1,3,4] thiadiazol-2-yl))-pyridin-2-ylamine

To a mixture of 2-amino-nicotinic acid N ′-(2- (4-benzyloxy-phenyl) -acetyl) -hydrazide (30 mg) and toluene (2 mL) described in Preparation Example 8-2, Lawson's reagent ( 65 mg) was added, and the mixture was stirred at 110 ° C. for 90 minutes. The reaction mixture was brought to room temperature, and the solvent was distilled off under reduced pressure. The residue was purified by NH-silica gel column chromatography (heptane: ethyl acetate = 1: 2) to obtain the title compound (19 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.40 (2H, s), 5.07 (2H, s), 6.62-6.65 (1H, m), 6.99 (2H, d, J = 8.2Hz) , 7.27-7.43 (7H, m), 7.52 (2H, brs), 7.82 (1H, dd, J = 1.1Hz, 7.7Hz), 8.09-8.11 (1H, m).

The starting material 2-amino-nicotinic acid N ′-(2- (4-benzyloxy-phenyl) -acetyl) -hydrazide was synthesized by the following method.

[Production Example 8-1] (4-Benzyloxy-phenyl) -acetic acid hydrazide

To a mixture of 4-benzyloxyphenylacetyl chloride (1.1 g) and THF (10 mL) were added triethylamine (1.8 mL) and hydrazine hydrate (0.20 mL) at room temperature, and the mixture was stirred at the same temperature for 7.5 hours. . Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with saturated brine. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (methanol: ethyl acetate = 1: 30) to obtain the title compound (0.23 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.24 (2H, s), 4.15 (2H, s), 5.05 (2H, s), 6.90 (2H, d, J = 8.2 Hz), 7.14 (2H, d, J = 8.2Hz), 7.28-7.31 (1H, m), 7.34-7.42 (4H, m), 9.12 (1H, brs).

[Production Example 8-2] 2-Amino-nicotinic acid N ′-(2- (4-benzyloxy-phenyl) -acetyl) -hydrazide

To a solution of (4-benzyloxy-phenyl) -acetic acid hydrazide (130 mg) described in Preparation Example 8-1 in DMSO (3 mL) at room temperature, triethylamine (0.21 mL), 2-aminonicotinic acid (70 mg) And BOP reagent (benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate) (250 mg) were added, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction solution, and the precipitated solid was collected by filtration to obtain the title compound (170 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.43 (2H, s), 5.07 (2H, s), 6.56 (1H, dd, J = 4.9, 7.6 Hz), 6.94 (2H, d, J = 8.6Hz), 7.00 (2H, s), 7.22 (2H, d, J = 8.2Hz), 7.28-7.43 (5H, m), 7.88 (1H, d, J = 7.7Hz), 8.08 (1H, d, J = 4.6Hz), 10.04 (1H, s), 10.21 (1H, brs).

Example 9 3- (5- (4-Benzyloxy-benzyl)-[1,3,4] oxadiazol-2-yl))-pyridin-2-ylamine

A mixture of 2-amino-nicotinic acid N ′-(2- (4-benzyloxy-phenyl) -acetyl) -hydrazide (30 mg), phosphorous pentoxide (68 mg), and toluene (1 mL) described in Preparation Example 8-2. Was heated to reflux for 1 hour. The reaction mixture was brought to 0 ° C., water was added at the same temperature, and the reaction mixture was neutralized by dropwise addition of 1N aqueous sodium hydroxide solution at the same temperature. Dichloromethane was added to the reaction mixture for extraction, and the organic layer was washed with saturated brine. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 1: 2) to obtain the title compound (2.5 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.21 (2H, s), 5.06 (2H, s), 6.57 (2H, brs), 6.69 (1H, dd, J = 4.9, 7.7 Hz) , 6.96 (2H, d, J = 8.6Hz), 7.27 (2H, d, J = 8.6Hz), 7.30-7.43 (5H, m), 7.94 (1H, dd, J = 1.7Hz, 7.8Hz), 8.19 −8.20 (1H, m).

Example 10 3- (5- (4-Benzyloxy-benzyl)-[1,3,4] thiadiazol-2-yl))-pyridine-2,6-diamine

To a mixture of 2,6-diamino-nicotinic acid N ′-(2- (4-benzyloxy-phenyl) -acetyl) -hydrazide (21 mg) and toluene (1.6 mL) described in Preparation Example 10-1 at room temperature Then, Lawesson's reagent (2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide) (43 mg) was added and stirred at 110 ° C. for 2 hours. The reaction mixture was brought to 0 ° C., water was added at the same temperature, and the precipitated solid was collected by filtration. The solid was purified by reversed-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% TFA)) and then filtered through an NH-silica gel column to give the title compound (1.2 mg). Obtained.
MS m / e (ESI) (MH ⁺ ) 390.35 (MH ⁺ )

The starting material 2,6-diamino-nicotinic acid N ′-(2- (4-benzyloxy-phenyl) -acetyl) -hydrazide was synthesized by the following method.

[Production Example 10-1] 2,6-diamino-nicotinic acid N '-(2- (4-benzyloxy-phenyl) -acetyl) -hydrazide

To a solution of (4-benzyloxy-phenyl) -acetic acid hydrazide (46 mg) described in Preparation Example 8-1 in DMF (1 mL) at room temperature, triethylamine (0.10 ml), described in Preparation Example 10-2-4 Of 2,6-diaminonicotinic acid (30 mg), HOBt (27 mg), and WSC (41 mg) were added and stirred at the same temperature overnight. Water was added to the reaction solution, and the precipitated solid was collected by filtration to obtain the title compound (47 mg) as a crude product. This compound was used in the next reaction as a crude product.

The starting material 2,6-diamino-nicotinic acid was synthesized by the following method.

[Production Example 10-2-1] 4-Cyano-2-diaminomethylene-butyric acid ethyl ester

(1-Ethoxyformimidoyl) 1-acetic acid ethyl ester hydrochloride (50 g) is suspended in an ammonia-ethanol solution (300 mL; prepared by saturating ammonia gas with ethanol at room temperature) and at room temperature. Stir for 4 hours. The precipitated solid was filtered, and the filtrate was concentrated under reduced pressure until the volume became about 1/3. Hydrochloric acid-methanol (130 mL; hydrochloric acid content 7.5%) was added to the reaction mixture, and the solvent was distilled off under reduced pressure to obtain 3,3-diamino-acrylic acid ethyl ester hydrochloride (40 g).
To a mixture of the obtained 3,3-diamino-acrylic acid ethyl ester hydrochloride (2.2 g) and THF (40 mL), triethylamine (2.0 mL) and acrylonitrile (1.2 mL) were added at room temperature and heated for 6 hours. Refluxed. The reaction mixture was brought to room temperature, the resulting triethylamine hydrochloride was filtered, and the filtrate was evaporated under reduced pressure to give the title compound (0.60 g).
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 1.26 (3H, t, J = 7.2 Hz), 2.42-2.49 (2H, m), 2.50-2.57 (2H, m), 4.12 (2H, q, J = 7.2Hz), 4.22 (2H, brs), 6.45 (2H, brs).

[Production Example 10-2-2] 2,6-diamino-4,5-dihydro-pyridine-3-carboxylic acid ethyl ester

A solution of 4-cyano-2-diaminomethylene-butyric acid ethyl ester (0.55 g) described in Preparation Example 10-2-1 in THF (7 mL) was added NaH (210 mg / 60% in oil) in THF (7 mL). The solution was added dropwise to the suspension and heated to reflux for 19 hours and 20 minutes. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product of the title compound (0.19 g).
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 1.27 (3H, t, J = 7.2Hz), 2.28-2.34 (2H, m), 2.46-2.52 (2H, m), 4.14 (2H, q, J = 7.2Hz).

[Production Example 10-2-3] 2,6-diamino-nicotinic acid ethyl ester

To a solution of 2,6-diamino-4,5-dihydro-pyridine-3-carboxylic acid ethyl ester (4.5 g) described in Preparation Example 10-2-2 in THF (300 mL), 2,3-dichloro-5 , 6-dicyano-1,4-benzoquinone (5.6 g) was added and stirred at room temperature for 40 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by NH-silica gel column chromatography (ethyl acetate) and then washed with hexane to obtain the title compound (3.1 g).
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 1.35 (3H, t, J = 7.2Hz), 4.27 (2H, q, J = 7.2Hz), 4.60 (2H, brs), 5.82 (1H, d , J = 8.4Hz), 7.90 (1H, d, J = 8.4Hz).

[Production Example 10-2-4] 2,6-diamino-nicotinic acid

2,6-Diamino-nicotinic acid ethyl ester (2.0 g) described in Production Example 10-2-3 was dissolved in ethanol (15 mL), 1N aqueous sodium hydroxide solution (15 mL) was added, and the mixture was heated to reflux for 2 hours. . The reaction mixture was brought to room temperature, and ethanol was evaporated under reduced pressure. The reaction mixture was neutralized with 1N hydrochloric acid at 0 ° C. The precipitated solid was collected by filtration to obtain the title compound (1.7 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.70 (1H, d, J = 8.4Hz), 6.31 (2H, brs), 6.58-7.12 (1H, brs), 7.62 (1H, d, J = 8.4Hz).

Example 11 3- (5- (4-Benzyloxy-benzyl)-[1,3,4] oxadiazol-2-yl))-6-methoxymethyl-pyridin-2-ylamine

2-amino-6-methoxymethyl-nicotinic acid N ′-(2- (4-benzyloxy-phenyl) -acetyl) -hydrazide (30 mg), phosphorous pentoxide (68 mg), and toluene described in Preparation Example 11-5 (1 mL) was stirred at 90 ° C. for 1 hour and then at 100 ° C. for 3 hours. The reaction mixture was brought to 0 ° C., water, ethyl acetate and THF were added at the same temperature, followed by filtration. The organic layer of the filtrate was washed with saturated brine. After evaporating the solvent under reduced pressure, the residue was purified by reverse phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% TFA)) to obtain the TFA salt (0.57 mg) of the title compound. Obtained.
MS m / e (ESI) (MH ⁺ ) 403.29 (MH ⁺ )

The starting material 2-amino-6-methoxymethyl-nicotinic acid N '-(2- (4-benzyloxy-phenyl) -acetyl) -hydrazide was synthesized by the following method.

[Production Example 11-1] 2-amino-6-chloro-nicotinic acid

To a mixture of 2,6-dichloronicotinic acid (36 g), acetamide (80 g), potassium carbonate (78 g), copper (I) chloride (0.93 g) and xylene (80 mL) was added tris (2- (2-methoxy Ethoxy) ethyl) amine (3.0 mL) was added and stirred at 145 ° C. overnight. The reaction mixture was brought to room temperature, copper (I) chloride (0.46 g) was added to the reaction mixture at the same temperature, and the mixture was stirred at 145 ° C. overnight. The reaction mixture was cooled to 105 ° C., water (100 mL) was added at the same temperature, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was brought to room temperature, 5N hydrochloric acid (150 mL) was added at the same temperature, and then the reaction mixture was neutralized with an aqueous citric acid solution. Ethyl acetate was added to the reaction mixture, and the mixture was filtered through celite. The organic layer was washed with saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from an ethyl acetate-hexane system to obtain the title compound (1.4 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 6.61 (1H, d, J = 8.1Hz), 7.53 (2H, brs), 8.01 (1H, d, J = 8.1Hz).

[Production Example 11-2] 2-Amino-6-chloro-nicotinic acid methyl ester

Concentrated sulfuric acid (25 mL) and 2-amino-6-chloro-nicotinic acid (4.3 g) described in Production Example 11-1 were added to methanol (50 mL) under ice-cooling, and the mixture was stirred at 70 ° C. for 5 hours. The reaction mixture was brought to room temperature, and neutralized by adding an aqueous solution of sodium hydrogen carbonate (90 g) at the same temperature. The produced solid was collected by filtration to obtain the title compound (3.2 g).
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 3.88 (3H, s), 6.62 (1H, d, J = 8.2Hz), 8.05 (1H, d, J = 8.1Hz).

[Production Example 11-3] 2-Amino-6-methoxymethyl-nicotinic acid methyl ester

2-amino-6-chloro-nicotinic acid methyl ester (1.4 g) described in Preparation Example 11-2, tributyl-methoxymethyl-tin (3.1 g) described in Preparation Example 11-3-1, tetrakis ( A mixture of triphenylphosphine) palladium (0) (440 mg) and NMP (20 mL) was stirred at 130 ° C. for 3.5 hours. The reaction mixture was allowed to cool, an aqueous potassium fluoride solution and ethyl acetate were added under ice cooling, and the mixture was filtered through celite. The organic layer was washed with saturated brine and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (0.93 g).
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 3.47 (3H, s), 3.88 (3H, s), 4.41 (2H, s), 6.74 (1H, d, J = 7.9Hz), 8.14 (1H , d, J = 7.9Hz).

[Production Example 11-3-1] Tributyl-methoxymethyl-tin

To a mixture of diisopropylamine (9.4 ml) and THF (150 mL), n-butyllithium (2.4 M n-hexane solution, 25 mL) was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. Tributyltin hydride (16 mL) was added dropwise to the reaction mixture at the same temperature, followed by stirring for 30 minutes under ice cooling. The reaction solution was -78 ° C, chloromethyl methyl ether (4.6 mL) was added dropwise, and the temperature was gradually raised to room temperature. Water (100 mL) and diethyl ether (300 mL) were added to the reaction solution, and the organic layer was washed with saturated brine, and the solvent was distilled off under reduced pressure. The residue was purified by neutral silica gel column chromatography (heptane: ethyl acetate = 30: 1) to obtain the title compound (18 g).
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 0.88-0.93 (15H, m), 1.26-1.35 (6H, m), 1.47-1.55 (6H, m), 3.30 (3H, s), 3.71 ( (2H, t, J = 6.8Hz).

[Production Example 11-4] 2-Amino-6-methoxymethyl-nicotinic acid

To a mixture of 2-amino-6-methoxymethyl-nicotinic acid methyl ester (2.9 g), THF (30 mL), methanol (7.5 mL), water (7.5 mL) described in Preparation Example 11-3, Lithium oxide monohydrate (1.2 g) was added, and the mixture was stirred overnight at room temperature. Acetic acid (1.7 mL) was added to the reaction mixture at the same temperature, and the solvent was distilled off under reduced pressure. The mixture was filtered using silica gel (methanol: ethyl acetate = 1: 3), the solvent was distilled off under reduced pressure, and the residue was washed with water to obtain the title compound (2.1 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.32 (3H, s), 4.29 (2H, s), 6.61 (1H, d, J = 7.9 Hz), 7.16 (2H, brs), 8.02 (1H, d, J = 7.9Hz).

[Production Example 11-5] 2-amino-6-methoxymethyl-nicotinic acid N '-(2- (4-benzyloxy-phenyl) -acetyl) -hydrazide

In the same manner as in Production Example 8-2, 2-amino-6-methoxymethyl-nicotinic acid (33 mg) described in Production Example 11-4 and (4-benzyloxy-phenyl) described in Production Example 8-1 -Acetic acid The title compound (57 mg) was obtained from hydrazide (46 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.32 (3H, s), 3.43 (2H, s), 4.28 (2H, s), 5.07 (2H, s), 6.59 (1H, d, J = 7.9Hz), 6.94 (2H, d, J = 8.6Hz), 7.06 (2H, brs), 7.22 (2H, d, J = 8.4Hz), 7.28-7.32 (1H, m), 7.35-7.43 ( 4H, m), 7.92 (1H, d, J = 7.9Hz), 10.03 (1H, brs), 10.19 (1H, brs).

Example 12 3- (4- (4-Benzyloxy-benzyl)-[1,2,3] triazol-1-yl) -pyridin-2-ylamine

Sodium azide (16 mg) at room temperature in a solution of 1-benzyloxy-4-prop-2-ynyl-benzene (50 mg) described in Preparation Example 12-2 in DMSO (5.0 mL) and water (1.0 mL) 3-iodo-pyridin-2-ylamine (50 mg), copper (I) iodide (4.3 mg), (1S, 2S) -N, N′-dimethylcyclohexane-1, described in Preparation Example 1-2 2-diamine (CAS No.87583-89-9; 4.8 mg) and sodium ascorbate (4.5 mg) were added, and the mixture was stirred at 60 ° C. for 3 hours, and then stirred at room temperature for 2 days. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography (ethyl acetate: heptane = 2: 1) to obtain the title compound (6.7 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.01 (2H, s), 5.08 (2H, s), 6.30 (2H, s), 6.70-6.74 (1H, m), 6.94-6.96 ( 2H, m), 7.23-7.25 (2H, m), 7.32-7.45 (5H, m), 7.64-7.66 (1H, m), 8.09-8.10 (1H, m), 8.23 (1H, s).

The starting material 1-benzyloxy-4-prop-2-ynyl-benzene was synthesized by the following method.

[Production Example 12-1] (3- (4-Benzyloxy-phenyl) -prop-1-ynyl) -trimethyl-silane

Under a nitrogen atmosphere, ethylmagnesium bromide (3M diethyl ether solution, 1.9 mL) was added to a THF (20 mL) solution of trimethylsilylacetylene (850 μL) at room temperature, and the mixture was stirred at 65 ° C. for 40 minutes. After cooling the reaction solution to room temperature, copper (I) bromide (310 mg) and 4-benzyloxybenzyl chloride (1.0 g) were added to the reaction solution, and the mixture was stirred at 65 ° C. for 8 hours and 45 minutes. Saturated aqueous ammonia chloride solution was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 30: 1) to obtain the title compound (910 mg).
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 0.18 (9H, s), 3.59 (2H, s), 5.06 (2H, s), 6.92-6.95 (2H, m), 7.23-7.26 (2H, m), 7.30-7.34 (1H, m), 7.36-7.40 (2H, m), 7.42-7.44 (2H, m).

[Production Example 12-2] 1-benzyloxy-4-prop-2-ynyl-benzene

To a solution of (3- (4-benzyloxy-phenyl) -prop-1-ynyl) -trimethyl-silane (910 mg) described in Production Example 12-1 in methanol (20 mL), potassium carbonate (850 mg) was added at room temperature. The mixture was stirred at room temperature for 4 hours and 10 minutes. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 20: 1) to obtain the title compound (620 mg).
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 2.16 (1H, t, J = 2.4Hz), 3.54 (2H, d, J = 2.4Hz), 5.05 (2H, s), 6.91-6.94 (2H m), 7.24-7.26 (2H, m), 7.29-7.43 (5H, m).

Example 13 3- (5- (4-Benzyloxy-benzyl)-[1,2,4] oxadiazol-3-yl) -pyridin-2-ylamine

To a solution of (4-benzyloxy-phenyl) -acetic acid (220 mg) in dichloromethane (5 mL) was added N, N′-dicyclohexylcarbodiimide (95 mg) at 0 ° C., and the mixture was stirred at 0 ° C. for 2 hours and 20 minutes. The reaction mixture was filtered using celite, and the filtrate was evaporated under reduced pressure. Pyridine (5 mL) and 2-amino-N-hydroxy-nicotinamidine (70 mg) described in Production Example 13-1 were added to the residue, and the mixture was stirred for 4 hours and 10 minutes with heating under reflux. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. Water was added to the residue, extraction was performed with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (85 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.35 (2H, s), 5.08 (2H, s), 6.70-6.73 (1H, m), 6.84 (2H, s), 6.99 (2H, d, J = 8.1Hz), 7.29-7.31 (3H, m), 7.35-7.39 (2H, m), 7.41-7.43 (2H, m), 8.14-8.16 (2H, m).

The starting material 2-amino-N-hydroxy-nicotineamidine was synthesized by the following method.
[Production Example 13-1] 2-Amino-N-hydroxy-nicotineamidine

Hydroxylamine hydrochloride (510 mg) and potassium carbonate (1.4 g) were added to a solution of 2-amino-nicotinonitrile (590 mg) in ethanol (10 mL) at room temperature, and the mixture was stirred for 7 hours 30 minutes with heating under reflux. After stirring for 13 hours and 30 minutes at room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to obtain the title compound (520 mg) as a cis / trans mixture. The title compound was used in the next reaction without further purification.

Example 14 3- (1- (4-Benzyloxy-benzyl) -1H- [1,2,4] triazol-3-yl) -pyridin-2-ylamine

3- (1H- [1,2,4] triazol-3-yl) -pyridin-2-ylamine (20 mg), 4-benzyloxybenzyl chloride (32 mg), potassium carbonate (86 mg) described in Preparation Example 14-3 ), DMF (3.0 mL) was stirred at 60 ° C. for 0.5 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and purified by NH-silica gel column chromatography (heptane: ethyl acetate = 2: 1, then 1: 1) to obtain the title compound (27 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.09 (2H, s), 5.40 (2H, s), 6.64 (1H, dd, J = 4.8 Hz, 8.0 Hz), 6.99 (2H, brs ), 7.01 (2H, dd, J = 2.0Hz, 6.4Hz), 7.30-7.46 (7H, m), 8.01 (1H, dd, J = 2.0Hz, 4.8Hz), 8.18 (1H, dd, J = 2.0 Hz, 8.0Hz), 8.75 (1H, s).

The starting material 3- (1H- [1,2,4] triazol-3-yl) -pyridin-2-ylamine was synthesized by the following method.

[Production Example 14-1] 2-Amino-nicotinamide

2-aminonicotinic acid (5.0 g), WSC (10 g), HOBt (7.3 g), ammonium chloride (5.8 g), diisopropylethylamine (28 g), and DMSO (100 mL) were stirred at room temperature for 16 hours. Water was added and extracted with ethyl acetate and THF. The organic layer was concentrated and purified by silica gel chromatography (ethyl acetate) to obtain the title compound (2.6 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 6.53-6.58 (1H, m), 7.17 (2H, brs), 7.29 (1, brs), 7.92 (1H, brs), 7,92 ( 1H, dd, J = 2.0Hz, 8.0Hz), 8.06 (1H, dd, J = 2.0Hz, 4.8Hz).

[Production Example 14-2] 2-Amino-thionicotinamide

2-amino-nicotinamide (1.6 g), hexamethyldisiloxane (3.2 g), phosphorous pentasulfide (950 mg) and hexamethylphosphoramide (13 mL) described in Production Example 14-1 at 18 ° C. Stir for hours. The reaction solution was passed through a glass filter (eluted with ethyl acetate) in which NH-silica gel and silica gel were spread 1: 1. The eluate was purified by NH-silica gel chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (290 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 6.62-6.66 (1H, m), 6.86 (2H, brs), 7.85 (1H, dd, J = 2.0 Hz, 8.0 Hz), 8.20 (1H , dd, J = 2.0Hz, 4.8Hz).

[Production Example 14-3] 3- (1H- [1,2,4] triazol-3-yl) -pyridin-2-ylamine

2-amino-thionicotinamide (240 mg) and formic acid hydrazide (2.0 g) described in Production Example 14-2 were stirred at 150 ° C. for 3 hours. Water was added and extracted with ethyl acetate. The organic layer was concentrated and purified by silica gel chromatography (ethyl acetate and then ethyl acetate: methanol = 20: 1) to obtain the title compound (100 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 6.68 (1H, dd, J = 4.8 Hz, 8.0 Hz), 8.05 (1H, dd, J = 2.0 Hz, 4.8 Hz), 8.20 (1H, d, J = 8.0Hz), 8.56 (2H, brs).

Example 15 3- (5- (4-Benzyloxy-benzyl) -4H- [1,2,4] triazol-3-yl) -pyridin-2-ylamine

To a solution of 4-benzyloxy-phenylacetic acid hydrazide (200 mg) described in Preparation Example 15-1 in methanol (10 mL) at room temperature, 2-amino-3-cyanopyridine (92 mg) and 28% sodium methoxide- A methanol solution (30 mg) was added, and the mixture was stirred with heating under reflux for 14 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 5) to obtain the title compound (3 mg).
MS m / e (ESI) (MH ⁺ ) 358.22 (MH ⁺ )
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.05 (2H, s), 5.07 (2H, s), 6.15-6.65 (1H, m), 6.96 (2H, d, J = 8.4 Hz) , 7.11 (2H, brs), 7.23 (2H, d, J = 8.4Hz), 7.31-7.44 (5H, m), 8.00-8.01 (1H, m), 8.13-8.15 (1H, m).

The starting material 4-benzyloxy-phenylacetic acid hydrazide was synthesized by the following method.

[Production Example 15-1] 4-Benzyloxy-phenylacetic acid hydrazide

To a solution of 4-benzyloxy-phenylacetic acid (7.0 g) in THF (50 mL), hydrazine monohydrate (4.3 g), WSC (6.7 g), HOBt (4.7 g), triethylamine (3 0.5 g) and stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the precipitated solid was collected by filtration to obtain the title compound (1.2 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.26 (2H, s), 4.20 (2H, s), 5.06 (2H, s), 6.91-6.94 (2H, m), 7.12-7.20 ( 2H, m), 7.30-7.42 (5H, m), 9.15 (1H, s).

Example 16 3- (1- (4- (5-Chloro-furan-2-ylmethyl) -benzene) -1H- [1,2,3] triazol-4-yl) -pyridin-2-ylamine

In the same manner as in Example 1, 3-ethynyl-pyridin-2-ylamine (30 mg) described in Preparation Example 1-2 and 2-chloro-5- (4-chloromethyl-) described in Preparation Example 16-4 were used. The title compound (30 mg) was obtained from (benzyl) -furan (67 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.95 (2H, s), 5.64 (2H, s), 6.24 (1H, d, J = 3.2 Hz), 6.34 (1H, d, J = 3.2Hz), 6.62 (1H, dd, J = 4.8Hz, 7.5Hz), 6.88 (2H, s), 7.25 (2H, d, J = 8.1Hz), 7.32 (2H, d, J = 8.1Hz), 7.83 (1H, dd, J = 1.8Hz, 7.5Hz), 7.95 (1H, dd, J = 1.8Hz, 4.8Hz), 8.70 (1H, s).

The starting material 2-chloro-5- (4-chloromethyl-benzyl) -furan was synthesized by the following method.

[Production Example 16-1] 4-((5-Chloro-furan-2-yl) -hydroxy-methyl) -benzonitrile

To a solution of 4-iodobenzonitrile (2.0 g) in THF (40 mL) was added dropwise isopropylmagnesium chloride (2M, 6.1 mL) at −78 ° C. in a nitrogen atmosphere, and the mixture was stirred at 0 ° C. for 1 hour and 10 minutes. After cooling to −78 ° C., 5-chloro-2-furaldehyde (1.4 g) was added dropwise and stirred at room temperature for 15 minutes. Saturated aqueous ammonium chloride solution was added at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (2.4 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.78 (1H, d, J = 4.9 Hz), 6.28 (1H, d, J = 3.3 Hz), 6.37 (1H, d, J = 4.9 Hz) ), 6.39 (1H, d, J = 3.3Hz), 7.59 (2H, d, J = 8.4Hz), 7.84 (2H, d, J = 8.4Hz).

[Production Example 16-2] 4- (5-Chloro-furan-2-ylmethyl) -benzylamine

Aluminum chloride (9.7 g) was added to a suspension of LAH (2.4 g) in THF (40 mL) at 0 ° C. and stirred until the aluminum chloride was dissolved. Subsequently, 4-((5-chloro-furan-2-yl) -hydroxy-methyl) -benzonitrile (2.4 g) described in Production Example 16-1 was added at 0 ° C., and the mixture was stirred at room temperature for 4 hours 30 minutes. Stir. An aqueous ammonia solution was added to the reaction suspension at 0 ° C., and filtration was performed using Celite. The filtrate was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography (heptane: ethyl acetate = 1: 2) to obtain the title compound (1.6 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 1.80 (2H, brs), 3.66 (2H, s), 3.90 (2H, s), 6.20 (1H, d, J = 3.2 Hz), 6.33 (1H, d, J = 3.2Hz), 7.14 (2H, d, J = 7.6Hz), 7.25 (2H, d, J = 8.0Hz).

[Production Example 16-3] 4- (5-Chloro-furan-2-ylmethyl) -phenyl) -methanol

To a solution of 4- (5-chloro-furan-2-ylmethyl) -benzylamine (1.5 g) described in Preparation Example 16-2 in acetic acid (10 mL) and water (10 mL) at 0 ° C., sodium nitrite (4 .6 g) was added and stirred at room temperature for 35 minutes. To the reaction mixture was added 5N aqueous sodium hydroxide solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure. Subsequently, 5N aqueous sodium hydroxide solution (5 mL) was added to a solution of the residue in ethanol (10 mL) and THF (10 mL) at 0 ° C., and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (1.2 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.91 (2H, s), 4.44 (2H, d, J = 5.7 Hz), 5.11 (1H, t, J = 5.7 Hz), 6.20 (1H , d, J = 3.3Hz), 6.33 (1H, d, J = 3.1Hz), 7.16 (2H, d, J = 8.1Hz), 7.24 (2H, d, J = 7.9Hz).

[Production Example 16-4] 2-chloro-5- (4-chloromethyl-benzyl) -furan

To a carbon tetrachloride (10 mL) solution of 4- (5-chloro-furan-2-ylmethyl) -phenyl) -methanol (500 mg) described in Preparation Example 16-3, triphenylphosphine (767 mg) was added at room temperature. The mixture was stirred for 19 hours and 25 minutes under reflux. The reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 5: 1) to obtain the title compound (396 mg).
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 3.92 (2H, s), 4.58 (2H, s), 5.99 (1H, dt, J = 0.92Hz, 3.3Hz), 6.05 (1H, d, J = 3.3Hz), 7.22 (2H, d, J = 8.2Hz), 7.34 (2H, d, J = 8.2Hz).

Example 17 5- (1- (4- (5-Chloro-furan-2-ylmethyl) -benzyl) -1H- [1,2,3] triazol-4-yl) -2-methyl-pyridine

In the same manner as in Example 1, 5-ethynyl-2-methyl-pyridine (10 mg) described in Preparation Example 2-1 and 2-chloro-5- (4-chloromethyl-) described in Preparation Example 16-4 were used. The title compound (17 mg) was obtained from (benzyl) -furan (21 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 2.47 (3H, s), 3.93 (2H, s), 5.61 (2H, s), 6.22 (1H, d, J = 3.1 Hz), 6.32 (1H, d, J = 3.3Hz), 7.24 (2H, d, J = 8.2Hz), 7.29-7.31 (3H, m), 8.07 (1H, dd, J = 2.4Hz, 8.1Hz), 8.67 (1H , s), 8.88 (1H, d, J = 2.2Hz).

Example 18 5- (1- (4- (5-Chloro-furan-2-ylmethyl) -benzyl) -1H- [1,2,3] triazol-4-yl) -pyridin-2-ylamine

In the same manner as in Example 1, 5-ethynyl-pyridin-2-ylamine (10 mg) described in Preparation Example 3-3 and 2-chloro-5- (4-chloromethyl- The title compound (11 mg) was obtained from (benzyl) -furan (23 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.94 (2H, s), 5.57 (2H, s), 6.08 (2H, s), 6.23 (1H, d, J = 3.3 Hz), 6.34 (1H, d, J = 3.1Hz), 6.48 (1H, d, J = 8.6Hz), 7.24 (2H, d, J = 8.1Hz), 7.29 (2H, d, J = 8.1Hz), 7.78 (1H , dd, J = 2.4Hz, 8.6Hz), 8.36 (1H, d, J = 2.2Hz), 8.40 (1H, s).

Example 19 3- (1- (4- (5-Chloro-furan-2-ylmethyl) -benzyl) -1H- [1,2,3] triazol-4-yl) -6-methoxymethyl-pyridine -2-ylamine

In the same manner as in Example 1, 3-ethynyl-6-methoxymethyl-pyridin-2-ylamine (15 mg) described in Preparation Example 19-3 and 2-chloro-5- ( From 4-chloromethyl-benzyl) -furan (25 mg), the TFA salt of the title compound (3.7 mg) was obtained.
MS m / e (ESI) (MH ⁺ ) 410.10 (MH ⁺ )

The starting material 3-ethynyl-6-methoxymethyl-pyridin-2-ylamine was synthesized by the following method.

[Production Example 19-1] (2-Amino-6-methoxymethyl-pyridin-3-yl) methanol

To a mixture of LAH (80%, 220 mg) and THF (5 mL) was added 2-amino-6-methoxymethyl-nicotinic acid methyl ester (300 mg) described in Preparation Example 11-3 at 0 ° C. Stir for minutes. To the reaction mixture, 28% aqueous ammonia solution was added dropwise at the same temperature until LAH was inactivated. The reaction mixture was brought to room temperature and filtered. The filtrate was evaporated under reduced pressure to give the title compound (260 mg).
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 3.45 (3H, s), 4.39 (2H, s), 4.62 (2H, s), 5.03 (2H, brs), 6.70 (1H, d, J = 7.3Hz), 7.31 (1H, d, J = 7.5Hz).

[Production Example 19-2] 2-Amino-6-methoxymethyl-pyridine-3-carbaldehyde

Manganese dioxide (1.3 g) was added to a mixture of (2-amino-6-methoxymethyl-pyridin-3-yl) methanol (260 mg) and methylene chloride (15 mL) described in Preparation Example 19-1 at room temperature. Stir overnight. The reaction mixture was filtered using celite, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 3: 2) to obtain the title compound (210 mg).
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 3.48 (3H, s), 4.44 (2H, s), 6.87 (1H, d, J = 7.9Hz), 7.82 (1H, d, J = 7.7Hz) ), 9.84 (1H, s).

[Production Example 19-3] 3-ethynyl-6-methoxymethyl-pyridin-2-ylamine

To a mixture of diisopropylamine (0.15 mL) and THF (2 mL), n-butyllithium (1.6 M n-hexane solution, 0.68 mL) was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. Trimethylsilyldiazomethane (2M n-hexane solution, 0.50 mL) was added to the reaction mixture at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, a mixture of 2-amino-6-methoxymethyl-pyridine-3-carbaldehyde (150 mg) and THF (1.5 mL) described in Preparation Example 19-2 was added dropwise at −78 ° C. Stir for 30 minutes. After the reaction mixture was cooled to −78 ° C., a mixture of acetic acid (0.10 mL) and THF (1 mL) was added dropwise. The reaction mixture was gradually warmed to 0 ° C. and extracted with water and ethyl acetate. The organic layer was washed with saturated brine, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 2: 3) to obtain the title compound (73 mg).
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 3.40 (1H, s), 3.45 (3H, s), 4.39 (2H, s), 5.07 (2H, brs), 6.72 (1H, d, J = 7.7Hz), 7.58 (1H, d, J = 7.5Hz).

Example 20 3- (1- (4- (5-Chloro-furan-2-ylmethyl) benzyl) -1H- [1,2,3] triazol-4-yl) -pyridine-2,6-diamine

In the same manner as in Example 1, 3-ethynyl-pyridine-2,6-diamine (50 mg) described in Preparation Example 4-3 and 2-chloro-5- (4-chloro described in Preparation Example 16-4 were used. The title compound (3.6 mg) was obtained from methyl-benzyl) -furan (100 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.94 (2H, s), 5.57 (2H, s), 5.66 (2H, s), 5.76 (1H, d, J = 8.4 Hz), 6.23 (1H, d, J = 3.2Hz), 6.34 (1H, d, J = 3.2Hz), 6.48 (2H, s), 7.24 (2H, d, J = 8.4Hz), 7.29 (2H, d, J = 8.4Hz), 7.46 (1H, d, J = 8.4Hz), 8.34 (1H, s).

Example 21 3- (2- (4- (5-Chloro-furan-2-ylmethyl) -benzyl) -2H-tetrazol-5-yl) -pyridin-2-ylamine

2-Chloro-5- (4-chloromethyl-benzyl) -furan described in Preparation Example 16-4 and 3- (2H-tetrazol-5-yl) -pyridin-2-ylamine described in Preparation Example 5-1. Was used in the same manner as in Example 5 to obtain the title compound (16 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.96 (2H, s), 6.00 (2H, s), 6.24 (1H, d, J = 3.2 Hz), 6.34 (1H, d, J = 3.2Hz), 6.72 (1H, dd, J = 4.8Hz, 8.0Hz), 6.89 (2H, brs), 7.27 (2H, d, J = 8.0Hz), 7.39 (2H, d, J = 8.0Hz), 8.14 (1H, dd, J = 2.0Hz, 4.8Hz), 8.23 (1H, dd, J = 2.0Hz, 8.0Hz).

Example 22 3- (2- (4- (5-Chloro-furan-2-ylmethyl) -benzyl) -2H-tetrazol-5-yl) -pyridine-2,6-diamine

2-Chloro-5- (4-chloromethyl-benzyl) -furan described in Preparation Example 16-4 and 3- (2H-tetrazol-5-yl) -pyridine-2,6 described in Preparation Example 7-3 Using the diamine, the title compound (3.9 mg) was obtained in the same manner as in Example 5.
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.96 (2H, s), 5.95 (2H, s), 6.13 (1H, d, J = 8.8 Hz), 6.24 (1H, d, J = 3.2Hz), 6.35 (1H, d, J = 3.2Hz), 7.26 (2H, d, J = 8.0Hz), 7.37 (2H, d, J = 8.0Hz), 8.19 (1H, d, J = 8.8Hz) ).

Example 23 3- (5- (4- (Pyridin-2-ylmethoxy) -benzyl)-[1,2,4] oxadiazol-3-yl) -pyridin-2-ylamine

4- (3- (2-amino-pyridin-3-yl)-[1,2,4] oxadiazol-5-ylmethyl) -phenol (22 mg) described in Preparation Example 23-1 in THF (2 mL) To the solution was added 5N aqueous sodium hydroxide solution (16 μL) at room temperature, and the mixture was stirred for several minutes, and then the solvent was distilled off under reduced pressure. To a solution of the residue in DMSO (3.3 mL), a separately prepared THF solution of 2-chloromethyl-pyridine (2-chloromethyl-pyridine hydrochloride (40 mg) in THF (2 mL) and water (2 mL)) was added 5N water. An aqueous sodium oxide solution (45 μL) was added and stirred for several seconds, and then the organic layer was separated) at room temperature, and stirred at room temperature for 14 hours and 30 minutes. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography (heptane: ethyl acetate = 1: 1) and then reverse-phase high performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% TFA)). To give the title compound (4.2 mg).
MS m / e (ESI) (MH ⁺ ) 360.02 (MH ⁺ )
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 4.24 (2H, s), 5.20 (2H, s), 6.28 (2H, s), 6.75 (1H, dd, J = 4.9Hz, 7.7Hz), 6.97−7.00 (2H, m), 7.21−7.24 (1H, m), 7.27−7.30 (2H, m), 7.50 (1H, d, J = 7.9Hz), 7.69−7.73 (1H, m), 8.18 ( 1H, dd, J = 1.8Hz, 4.9Hz), 8.33 (1H, dd, J = 1.8Hz, 7.7Hz), 8.59-8.61 (1H, m).

The starting material 4- (3- (2-amino-pyridin-3-yl)-[1,2,4] oxadiazol-5-ylmethyl) -phenol was synthesized by the following method.

[Production Example 23-1] 4- (3- (2-Amino-pyridin-3-yl)-[1,2,4] oxadiazol-5-ylmethyl) -phenol

A solution of 3- (5- (4-benzyloxy-benzyl)-[1,2,4] oxadiazol-3-yl) -pyridin-2-ylamine (52 mg) described in Example 13 in TFA (2 mL). To the solution, thioanisole (68 μL) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hours and 40 minutes. Sodium hydrogen carbonate and water were added to the reaction mixture at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 20: 1) to obtain the title compound (40 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.30 (2H, s), 6.73 (2H, d, J = 8.4 Hz), 6.77-6.80 (1H, m), 7.10 (2H, s) , 7.17 (2H, d, J = 8.2Hz), 8.17-8.18 (1H, m), 8.24-8.26 (1H, m), 9.42 (1H, s).

Example 24 3- (5- (4- (Pyridin-2-ylmethoxy) -benzyl)-[1,3,4] oxadiazol-2-yl) -pyridin-2-ylamine

In the same manner as in Example 23, 4- (5- (2-amino-pyridin-3-yl)-[1,3,4] oxadiazol-2-ylmethyl)-described in Preparation Example 24-1 was used. From the phenol (11 mg) and 2-picolyl chloride hydrochloride (13 mg), the TFA salt (3.7 mg) of the title compound was obtained.
MS m / e (ESI) (MH ⁺ ) 360.14 (MH ⁺ )

The starting material 4- (5- (2-amino-pyridin-3-yl)-[1,3,4] oxadiazol-2-ylmethyl) -phenol was synthesized by the following method.

[Production Example 24-1] 4- (5- (2-Amino-pyridin-3-yl)-[1,3,4] oxadiazol-2-ylmethyl) -phenol

3- (5- (4-Benzyloxy-benzyl)-[1,3,4] oxadiazol-2-yl))-pyridine- described in Preparation Example 9 by a method similar to that in Example 23-1. The title compound (31 mg) was obtained from 2-ylamine (93 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.20 (2H, s), 6.70-6.74 (2H, m), 6.76 (1H, dd, J = 5.0, 7.8Hz), 7.13-7.16 ( 2H, m), 7.45 (2H, brs), 8.02 (1H, dd, J = 1.7,7.7Hz), 8.18 (1H, dd, J = 1.8,4.9Hz), 9.39 (1H, brs).

Example 25 3- (2- (4- (Pyridin-2-ylmethoxy) -benzyl) -2H-tetrazol-5-yl) -pyridin-2-ylamine

(4- (Pyridin-2-ylmethoxy) -phenyl) -methanol (130 mg) described in Preparation Example 25-2 and 3- (2H-tetrazol-5-yl) -pyridine-2 described in Preparation Example 5-1. -To a solution of ylamine (100 mg) and triphenylphosphine (210 mg) in THF (10 mL) was added diisopropyl azodicarboxylate (160 mg) at 0 ° C. After stirring at room temperature for 10 minutes, the organic layer was concentrated and purified by NH-silica gel chromatography (heptane: ethyl acetate = 2: 1 then 1: 1). The obtained organic layer was concentrated and purified by silica gel chromatography (ethyl acetate and then ethyl acetate: methanol = 10: 1) to obtain the title compound (72 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.18 (2H, s), 5.94 (2H, s), 6.73 (1H, dd, J = 4.8 Hz, 8.0 Hz), 6.90 (2H, brs ), 7.06 (2H, d, J = 8.8Hz), 7.32-7.36 (1H, m), 7.41 (2H, d, J = 8.8Hz), 7.49 (1H, d, J = 8.0Hz), 7.82 (1H , ddd, J = 2.0Hz, 8.0Hz, 8.0Hz), 8.14 (1H, dd, J = 2.0Hz, 4.8Hz), 8.23 (1H, dd, J = 2.0Hz, 8.0Hz), 8.55-8.59 (1H , m).

The starting material (4- (pyridin-2-ylmethoxy) -phenyl) -methanol was synthesized by the following method.

[Production Example 25-1] 4- (Pyridin-2-ylmethoxy) -benzoic acid methyl ester

Diisopropyl azodicarboxylate (3) was added to a solution of 2- (hydroxymethyl) pyridine (1.5 g), methyl p-hydroxybenzoate (2.1 g), triphenylphosphine (5.0 g) in THF (50 mL) at 0 ° C. 0.9 g) and stirred at room temperature for 20 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was evaporated under reduced pressure, the residue was purified by NH-silica gel chromatography (heptane: ethyl acetate = 2: 1), and further purified by silica gel chromatography (heptane: ethyl acetate = 1: 1). The title compound (4.9 g) was obtained.
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.79 (3H, s), 5.25 (2H, s), 7.12 (2H, d, J = 8.8 Hz), 7.32-7.36 (1H, m) , 7.50 (1H, d, J = 8.0Hz), 7.82 (1H, ddd, J = 2.0Hz, 8.0Hz, 8.0Hz), 7.90 (2H, d, J = 8.8Hz), 8.56-8.59 (1H, m ).

[Production Example 25-2] (4- (Pyridin-2-ylmethoxy) -phenyl) -methanol

LAH (1.0 g) was added at 0 ° C. to a solution of (4- (pyridin-2-ylmethoxy) -benzoic acid methyl ester (4.9 g) described in Preparation Example 25-1 in THF (50 mL) at room temperature. The reaction solution was added with water and extracted with ethyl acetate, and the organic layer was concentrated and purified by silica gel chromatography (heptane: ethyl acetate = 1: 1 and then ethyl acetate) to give the title compound (1.6 g). Obtained.
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.41 (2H, d, J = 6.0 Hz), 5.05 (1H, d, J = 6.0 Hz), 5.16 (2H, s), 6.98 (2H , d, J = 8.8Hz), 7.23 (2H, d, J = 8.8Hz), 7.32-7.37 (1H, m), 7.50 (1H, d, J = 8.0Hz), 7.82 (1H, ddd, J = 2.0Hz, 8.0Hz, 8.0Hz), 8.56-8.59 (1H, m).

Example 26 3- (1- (4- (Pyridin-2-yloxymethyl) -benzyl) -1H- [1,2,3] triazol-4-yl) -pyridin-2-ylamine

In the same manner as in Example 1, 3-ethynyl-pyridin-2-ylamine (28 mg) described in Preparation Example 1-2 and 2- (4-chloromethyl-benzyloxy)-described in Preparation Example 26-2 were used. The title compound (38 mg) was obtained from pyridine (55 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.32 (2H, s), 5.65 (2H, s), 6.60 (1H, dd, J = 4.9 Hz, 7.7 Hz), 6.84 (1H, d , J = 8.2Hz), 6.86 (2H, s), 6.95-6.98 (1H, m), 7.35 (2H, d, J = 8.1Hz), 7.44 (2H, d, J = 8.1Hz), 7.67-7.71 (1H, m), 7.81 (1H, dd, J = 1.7Hz, 7.5Hz), 7.93 (1H, dd, J = 1.7Hz, 4.8Hz), 8.14 (1H, dd, J = 1.7Hz, 5.5Hz) , 8.69 (1H, s).

The starting material 2- (4-chloromethyl-benzyloxy) -pyridine was synthesized by the following method.

[Production Example 26-1] (4- (Pyridin-2-yloxymethyl) -phenyl) -methanol

To a solution of 1,4-benzenedimethanol (5.5 g) and 2-fluoropyridine (1.3 g) in DMF (15 mL) was added NaH (1.4 g / 66% in oil) at 0 ° C, and at 70 ° C. Stir for 1 hour. The reaction mixture was brought to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was distilled off under reduced pressure. The residue was purified by NH-silica gel column chromatography (ethyl acetate: heptane = 1: 1) to obtain the title compound (1.9 g).
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 4.71 (2H, s), 5.38 (2H, s), 6.81 (1H, td, J = 0.9, 8.4Hz), 6.89 (1H, ddd, J = 0.9Hz, 5.1Hz, 7.1Hz), 7.37-7.47 (4H, m), 7.59 (1H, ddd, J = 2.0Hz, 7.1Hz, 8.3Hz), 8.17 (1H, ddd, J = 0.7Hz, 2.0Hz , 5.1Hz).

[Production Example 26-2] 2- (4-Chloromethyl-benzyloxy) -pyridine

(4- (Pyridin-2-yloxymethyl) -phenyl) -methanol (540 mg, 2.51 mmol), triphenylphosphine (856 mg, 3.27 mmol), carbon tetrachloride (10. 8 g, 10.2 mmol) was stirred with heating under reflux for 2 hours and 10 minutes. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 8: 1) to obtain the title compound (300 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.76 (2H, s), 5.35 (2H, s), 6.86-6.90 (1H, m), 6.97-7.20 (1H, m), 7.44 ( 4H, s), 7.70-7.76 (1H, m), 8.15-8.18 (1H, m).

Example 27 3- (2- (4- (Pyridin-2-ylmethoxy) -benzyl) -2H-tetrazol-5-yl) -pyridine-2,6-diamine

2- (4-Chloromethyl-benzyloxy) -pyridine (120 mg) described in Preparation Example 26-2 and 3- (2H-tetrazol-5-yl) -pyridine-2,6 described in Preparation Example 7-3 -The title compound (85 mg) was obtained in the same manner as in Example 5 using diamine (80 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.34 (2H, s), 5.85 (1H, d, J = 8.0 Hz), 5.93 (2H, s), 6.08 (2H, brs), 6.47 (2H, brs), 6.85-6.89 (1H, m), 6.98 (1H, ddd, J = 2.0Hz, 8.0Hz, 8.0Hz), 7.39 (2H, d, J = 8.0Hz), 7.46 (2H, d , J = 8.0Hz), 7.70-7.76 (1H, m), 7.85 (1H, d, J = 8.0Hz), 8.14-8.18 (1H, m).

Example 28 3- (1- (3-Phenoxy-benzyl) -1H- [1,2,3] triazol-4-yl) -pyridin-2-ylamine

In the same manner as in Example 1, 3-ethynyl-pyridin-2-ylamine (10 mg) described in Preparation Example 1-2 and 1-chloromethyl-3-phenoxy-benzene (20 mg described in Preparation Example 28-1) were obtained. ) Gave the title compound (8.4 mg).
MS m / e (ESI) (MH ⁺ ) 344.30 (MH ⁺ )
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.67 (2H, s), 6.63 (1H, dd, J = 4.8Hz, 7.5Hz), 6.88 (2H, s), 6.96 (1H, dd , J = 2.0Hz, 7.9Hz), 7.01−7.05 (3H, m), 7.10 (1H, d, J = 8.1Hz), 7.15 (1H, t, J = 7.5Hz), 7.37−7.42 (3H, m ), 7.83 (1H, dd, J = 1.8Hz, 7.5Hz), 7.96 (1H, dd, J = 1.8Hz, 4.8Hz), 8.71 (1H, s).

The starting material 1-chloromethyl-3-phenoxy-benzene was synthesized by the following method.

[Production Example 28-1] 1-chloromethyl-3-phenoxy-benzene

To a solution of (3-phenoxy-phenyl) -methanol (2.0 g) in carbon tetrachloride (40 mL) was added triphenylphosphine (3.2 g) at room temperature, and the mixture was heated to reflux for 5 hours and 40 minutes in a nitrogen atmosphere. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 10: 1) to obtain the title compound (2.1 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.37 (2H, s), 6.94-6.97 (1H, m), 7.00-7.03 (2H, m), 7.05-7.06 (1H, m), 7.13-7.20 (3H, m), 7.37-7.41 (2H, m).

Example 29 5- (1- (3-phenoxy-benzyl) -1H- [1,2,3] triazol-4-yl) -pyridin-2-ylamine

In the same manner as in Example 1, 5-ethynyl-pyridin-2-ylamine (10 mg) described in Preparation Example 3-3 and 1-chloromethyl-3-phenoxy-benzene (20 mg described in Preparation Example 28-1) were prepared. ) Gave the title compound (11 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.60 (2H, s), 6.09 (2H, s), 6.49 (1H, d, J = 8.8Hz), 6.93-6.96 (1H, m) , 7.01−7.03 (3H, m), 7.07 (1H, d, J = 8.1Hz), 7.15 (1H, t, J = 7.5Hz), 7.37−7.41 (3H, m), 7.78 (1H, dd, J = 2.4Hz, 8.8Hz), 8.37 (1H, d, J = 2.4Hz), 8.43 (1H, s).

Example 30 3- (1- (3-Phenoxy-benzyl) -1H- [1,2,3] triazol-4-yl) -pyridine-2,6-diamine

In the same manner as in Example 1, 3-ethynyl-pyridine-2,6-diamine (70 mg) described in Preparation Example 4-3 and 1-chloromethyl-3-phenoxy-benzene described in Preparation Example 28-1 were used. (140 mg) gave the title compound (6.7 mg).
MS m / e (ESI) (MH ⁺ ) 359.32 (MH ⁺ )

Example 31 3- (2- (3-Phenoxy-benzyl) -2H-tetrazol-5-yl) -pyridin-2-ylamine

The title compound (37 mg) was prepared in the same manner as in Example 25 from 3-phenoxybenzyl alcohol (61 mg) and 3- (2H-tetrazol-5-yl) -pyridin-2-ylamine (150 mg) described in Preparation Example 5-1. )
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 6.03 (2H, s), 6.74 (1H, dd, J = 4.8 Hz, 8.0 Hz), 6.89 (2H, brs), 6.98-7.06 (3H , m), 7.09 (1H, s), 7.14-7.19 (2H, m), 7.37-7.45 (3H, m), 8.16 (1H, dd, J = 2.0Hz, 4.8Hz), 8.22 (1H, dd, J = 2.0Hz, 8.0Hz).

Example 32 3- (1- (4-Phenoxy-benzyl) -1H- [1,2,3] triazol-4-yl) -pyridin-2-ylamine

In the same manner as in Example 1, 3-ethynyl-pyridin-2-ylamine (10 mg) described in Preparation Example 1-2 and 1-chloromethyl-4-phenoxy-benzene (20 mg described in Preparation Example 32-1) were obtained. ) Gave the title compound (7.3 mg).
MS m / e (ESI) (MH ⁺ ) 344.30 (MH ⁺ )
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.65 (2H, s), 6.62 (1H, dd, J = 4.9Hz, 7.5Hz), 6.90 (2H, s), 7.00-7.04 (4H , m), 7.15 (1H, t, J = 7.3Hz), 7.37-7.42 (4H, m), 7.84 (1H, dd, J = 1.8Hz, 7.5Hz), 7.96 (1H, dd, J = 1.8Hz) , 4.9Hz), 8.71 (1H, s).

The starting material 1-chloromethyl-4-phenoxy-benzene was synthesized by the following method.

[Production Example 32-1] 1-chloromethyl-4-phenoxy-benzene

To a solution of (4-phenoxy-phenyl) -methanol (410 mg) in carbon tetrachloride (8.2 mL) was added triphenylphosphine (640 mg) at room temperature, and the mixture was heated to reflux for 7 hours and 40 minutes in a nitrogen atmosphere. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 10: 1) to obtain the title compound (410 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.76 (2H, s), 6.98-7.05 (4H, m), 7.15-7.19 (1H, m), 7.39-7.46 (4H, m).

Example 33 5- (1- (4-Phenoxy-benzyl) -1H- [1,2,3] triazol-4-yl) -pyridin-2-ylamine

In the same manner as in Example 1, 5-ethynyl-pyridin-2-ylamine (10 mg) described in Preparation Example 3-3 and 1-chloromethyl-4-phenoxy-benzene (20 mg described in Preparation Example 32-1) were obtained. ) Gave the title compound (9.0 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.58 (2H, s), 6.09 (2H, s), 6.49 (1H, dd, J = 0.73Hz, 8.6Hz), 7.00-7.03 (4H , m), 7.15 (1H, t, J = 7.5Hz), 7.36-7.41 (4H, m), 7.79 (1H, dd, J = 2.4Hz, 8.6Hz), 8.37 (1H, d, J = 2.4Hz) ), 8.42 (1H, s).

Example 34 3- (1- (4-Phenoxy-benzyl) -1H- [1,2,3] triazol-4-yl) -pyridine-2,6-diamine

In the same manner as in Example 1, 3-ethynyl-pyridine-2,6-diamine (70 mg) described in Preparation Example 4-3 and 1-chloromethyl-3-phenoxy-benzene described in Preparation Example 32-1 were used. (130 mg) gave the title compound (1.5 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.57 (2H, s), 5.67 (2H, s), 5.67 (1H, d, J = 8.4 Hz), 6.48 (2H, s), 7.00 −7.02 (4H, m), 7.13−7.17 (1H, m), 7.37−7.41 (4H, m), 7.47 (1H, d, J = 8.4Hz), 8.36 (1H, s).

Example 35 3- (2- (4-Phenoxy-benzyl) -2H-tetrazol-5-yl) -pyridin-2-ylamine

In the same manner as in Example 25, the title compound was obtained from 4-phenoxybenzyl alcohol (93 mg) and 3- (2H-tetrazol-5-yl) -pyridin-2-ylamine (50 mg) described in Preparation Example 5-1. (20 mg) was obtained.
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 6.00 (2H, s), 6.73 (1H, dd, J = 4.8 Hz, 8.0 Hz), 6.90 (2H, brs), 7.00-7.06 (4H , m), 7.14-7.20 (1H, m), 7.37-7.44 (2H, m), 7.48 (2H, d, J = 8.0Hz), 8.14-8.17 (1H, m), 8.22-8.26 (1H, m ).

Example 36 3- (1- (5-Phenoxymethyl-pyridin-2-ylmethyl) -1H- [1,2,3] triazol-4-yl) -pyridine-2,6-diamine

In the same manner as in Example 1, 3-ethynyl-pyridine-2,6-diamine (70 mg) described in Preparation Example 4-3 and 1-chloromethyl-5-phenoxymethyl- described in Preparation Example 37-1 were used. The title compound (1.8 mg) was obtained from pyridine (140 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.15 (2H, s), 5.68 (2H, s), 5.73 (2H, s), 5.77 (1H, d, J = 8.0 Hz), 6.49 (2H, s), 6.93-6.97 (1H, m), 7.00-7.03 (2H, m), 7.28-7.35 (3H, m), 7.49 (1H, d, J = 8.0Hz), 7.90-7.92 (1H , m), 8.38 (1H, s), 8.64 (1H, m).

Example 37 3- (1- (5-phenoxymethyl-pyridin-2-ylmethyl) -1H- [1,2,3] triazol-4-yl) -pyridin-2-ylamine

In the same manner as in Example 1, 3-ethynyl-pyridin-2-ylamine (10 mg) described in Preparation Example 1-2 and 2-chloromethyl-5-phenoxymethyl-pyridine described in Preparation Example 37-1 ( 22 mg) gave the title compound (13 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.93 (2H, s), 5.59 (2H, s), 6.41 (1H, dd, J = 2.7Hz, 7.5Hz), 6.68 (2H, s ), 6.73 (1H, t, J = 7.3Hz), 6.79 (2H, d, J = 7.9Hz), 7.08 (2H, dd, J = 7.3Hz, 8.8Hz), 7.18 (1H, d, J = 7.7 Hz), 7.64 (1H, dd, J = 1.8Hz, 7.5Hz), 7.70 (1H, dd, J = 2.0Hz, 7.9Hz), 7.74 (1H, dd, J = 1.8Hz, 4.8Hz), 8.42 ( 1H, d, J = 2.0Hz), 8.52 (1H, s).

The starting material 2-chloromethyl-5-phenoxymethyl-pyridine was synthesized by the following method.

[Production Example 37-1] 2-chloromethyl-5-phenoxymethyl-pyridine

To a carbon tetrachloride (20 mL) solution of a known compound (5-phenoxymethyl-pyridin-2-yl) -methanol (1.4 g), triphenylphosphine (2.1 g) was added at room temperature, The mixture was heated to reflux for 15 minutes. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (1.3 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.79 (2H, s), 5.17 (2H, s), 6.96 (1H, t, J = 7.3Hz), 7.03 (2H, d, J = 8.1Hz), 7.29-7.33 (2H, m), 7.58 (1H, d, J = 8.1Hz), 7.92 (1H, dd, J = 2.0Hz, 8.1Hz), 8.65 (1H, d, J = 2.0Hz) ).

Example 38 3- (1- (5-Benzyloxy-pyridin-2-ylmethyl) -1H- [1,2,3] triazol-4-yl) -pyridin-2-ylamine

In the same manner as in Example 1, 3-ethynyl-pyridin-2-ylamine (30 mg) described in Preparation Example 1-2 and 5-benzyloxy-2-chloromethyl-pyridine described in Preparation Example 38-1 ( The title compound (38 mg) was obtained from 65 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.19 (2H, s), 5.70 (2H, s), 6.62 (1H, dd, J = 4.8Hz, 7.5Hz), 6.89 (2H, s ), 7.34−7.46 (6H, m), 7.51 (1H, dd, J = 2.9Hz, 8.6Hz), 7.85 (1H, dd, J = 1.8Hz, 7.5Hz), 7.95 (1H, dd, J = 1.8 Hz, 4.8Hz), 8.33 (1H, d, J = 2.9Hz), 8.68 (1H, s).

The starting material 5-benzyloxy-2-chloromethyl-pyridine was synthesized by the following method.

[Production Example 38-1] 5-Benzyloxy-2-chloromethyl-pyridine

To a carbon tetrachloride (10 mL) solution of a known compound (5-benzyloxy-pyridin-2-yl) -methanol (500 mg), triphenylphosphine (791 mg) is added at room temperature, and heated under a nitrogen atmosphere for 19 hours and 35 minutes. Refluxed. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 3: 1) to obtain the title compound (386 mg).
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 4.64 (2H, s), 5.12 (2H, s), 7.25-7.28 (1H, m), 7.35-7.44 (6H, m), 8.34 (1H, d , J = 2.7Hz).

Example 39 3- (2- (5-Benzyloxy-pyridin-2-ylmethyl) -2H-tetrazol-5-yl) -pyridin-2-ylamine

In the same manner as in Example 25, the known compound (5-benzyloxy-pyridin-2-yl) -methanol (130 mg) and 3- (2H-tetrazol-5-yl) -pyridine described in Preparation Example 5-1 were used. The title compound (7.0 mg) was obtained from -2-ylamine (100 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.19 (2H, s), 6.05 (2H, s), 6.73 (1H, dd, J = 4.8 Hz, 8.0 Hz), 6.88 (2H, brs ), 7.30-7.55 (7H, m), 8.14 (1H, dd, J = 2.0Hz, 4.8Hz), 8.22 (1H, dd, J = 2.0Hz, 8.0Hz), 8.30 (1H, d, J = 2.0 Hz).

Example 40 3- (2- (5-Benzyloxy-pyridin-2-ylmethyl) -2H-tetrazol-5-yl) -pyridin-2,6-diamine

In the same manner as in Example 25, the known compound (5-benzyloxy-pyridin-2-yl) -methanol (73 mg) and 3- (2H-tetrazol-5-yl) -pyridine described in Preparation Example 7-3 were prepared. The title compound (44 mg) was obtained from -2,6-diamine (100 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.18 (2H, s), 5.85 (1H, d, J = 8.0 Hz), 5.94 (2H, s), 6.07 (2H, brs), 6.46 (2H, brs), 7.30-7.48 (6H, m), 7.52 (1H, dd, J = 2.0Hz, 8.0Hz), 7.84 (1H, d, J = 8.0Hz), 8.30 (1H, d, J = 2.0Hz).

Example 41 3- [1- (4-Butoxymethyl-benzyl) -1H- [1,2,3] triazol-4-yl] -6-methoxymethyl-pyridin-2-ylamine

In the same manner as in Example 1, 3-ethynyl-6-methoxymethyl-pyridin-2-ylamine (15 mg) described in Preparation Example 19-3 and 1-butoxymethyl-4-described in Preparation Example 43-4 were prepared. From chloromethyl-benzene (22 mg), the TFA salt (1.4 mg) of the title compound was obtained.
MS m / e (ESI) (MH ⁺ ) 382.10 (MH ⁺ )

Example 42 3- (1- (4-Butoxymethyl-benzyl) -1H- [1,2,3] triazol-4-yl) -pyridine-2,6-diamine

In the same manner as in Example 1, 3-ethynyl-pyridine-2,6-diamine (100 mg) described in Preparation Example 4-3 and 1-butoxymethyl-4-chloromethyl- described in Preparation Example 43-4 were used. The title compound (6.2 mg) was obtained from benzene (190 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 0.86 (3H, t, J = 7.6 Hz), 1.29-1.35 (2H, m), 1.47-1.52 (2H, m), 3.40 (2H, t, J = 6.4Hz), 4.43 (2H, s), 5.59 (2H, s), 5.67 (2H, m), 5.76 (1H, d, J = 8.4Hz), 6.48 (2H, s), 7.32 ( 4H, s), 7.46 (1H, d, J = 8.4Hz), 8.34 (1H, s).

Example 43 3- (1- (4-Butoxymethyl-benzyl) -1H- [1,2,3] triazol-4-yl) -pyridin-2-ylamine

In the same manner as in Example 1, 3-ethynyl-pyridin-2-ylamine (20 mg) described in Preparation Example 1-2 and 1-butoxymethyl-4-chloromethyl-benzene described in Preparation Example 43-4 ( 40 mg) and purified by silica gel chromatography (heptane: ethyl acetate = 2: 1), and further by reverse phase high performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% TFA)). Purification gave the title compound (15 mg).
MS m / e (ESI) (MH ⁺ ) 338.30 (MH ⁺ )

The starting material 1-butoxymethyl-4-chloromethyl-benzene was synthesized by the following method.

[Production Example 43-1] 4-Butoxymethyl-benzonitrile

To a mixture of NaH (270 mg / 66% in oil) and THF (20 mL), n-butanol (1.1 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was cooled to 0 ° C., and a mixture of 4-cyanobenzyl bromide (1.5 g) and THF (10 mL) was added dropwise at the same temperature. The reaction mixture was stirred at room temperature for 3 hours, DMF (10 mL) was added to the reaction mixture, and the mixture was stirred at the same temperature for 4.5 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, and the organic layer was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography (ethyl acetate: heptane = 1: 6) to obtain the title compound (1.2 g).
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 0.93 (3H, t, J = 7.3Hz), 1.37-1.46 (2H, m), 1.59-1.66 (2H, m), 3.50 (2H, t, J = 6.6Hz), 4.55 (2H, s), 7.43-7.46 (2H, m), 7.62-7.65 (2H, m).

[Production Example 43-2] 4-Butoxymethyl-benzylamine

To a mixture of LAH (80%, 600 mg) and THF (10 mL) was added a mixture of 4-butoxymethyl-benzonitrile (600 mg) and THF (10 mL) described in Preparation Example 43-1 at 0 ° C. at room temperature. Stir for hours. To the reaction mixture, 28% aqueous ammonia solution was added dropwise at 0 ° C. to quench excess LAH. The mixture was heated to room temperature and filtered. The filtrate was evaporated under reduced pressure to give the title compound (620 mg).
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 0.92 (3H, t, J = 7.3Hz), 1.37-1.44 (2H, m), 1.56-1.63 (2H, m), 3.47 (2H, t, J = 6.6Hz), 3.86 (2H, s), 4.49 (2H, s), 7.27-7.32 (4H, m).

[Production Example 43-3] (4-Butoxymethyl-phenyl) -methanol

Sodium nitrite (1.1 g) was added at 0 ° C. to a mixture of 4-butoxymethyl-benzylamine (250 mg), acetic acid (2 mL) and water (2 mL) described in Preparation Example 43-2, and the mixture was stirred at room temperature for 40 minutes. Stir. The reaction mixture was added to a mixture of ethyl acetate and water and extracted. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated saline solution. The organic layer was evaporated under reduced pressure. Methanol (2 mL) and potassium carbonate (360 mg) were added to the residue, and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was evaporated under reduced pressure. The residue was purified by neutral silica gel column chromatography (ethyl acetate: heptane = 1: 1) to obtain the title compound (200 mg).
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 0.92 (3H, t, J = 7.3Hz), 1.35-1.44 (2H, m), 1.57-1.64 (2H, m), 3.47 (2H, t, J = 6.6Hz), 4.50 (2H, s), 4.69 (2H, s), 7.34 (4H, s).

[Production Example 43-4] 1-butoxymethyl-4-chloromethyl-benzene

A mixture of (4-butoxymethyl-phenyl) -methanol (190 mg), triphenylphosphine (310 mg) and carbon tetrachloride (3 mL) described in Production Example 43-3 was heated to reflux for 7 hours. The reaction mixture was allowed to cool to room temperature, and the solvent was distilled off under reduced pressure. The residue was purified by neutral silica gel column chromatography (ethyl acetate: heptane = 1: 15) to obtain the title compound (180 mg).
¹ H-NMR Spectrum (CDCl ₃ ) δ (ppm): 0.92 (3H, t, J = 7.3Hz), 1.35-1.45 (2H, m), 1.57-1.64 (2H, m), 3.47 (2H, t, J = 6.6Hz), 4.50 (2H, s), 4.59 (2H, s), 7.32-7.38 (4H, m).

Example 44 5- (1- (4-Butoxymethyl-benzyl) -1H- [1,2,3] triazol-4-yl) -pyridin-2-ylamine

In the same manner as in Example 1, 3-ethynyl-pyridin-2-ylamine (20 mg) described in Preparation Example 3-3 and 1-butoxymethyl-4-chloromethyl-benzene described in Preparation Example 43-4 ( 40 mg), purified by silica gel chromatography (ethyl acetate), and further purified by reverse phase high performance liquid chromatography (using acetonitrile-water mobile phase (containing 0.1% TFA)) to give the title compound ( 11 mg) was obtained.
MS m / e (ESI) (MH ⁺ ) 338.11 (MH ⁺ )

Example 45 3- (5- (4-Butoxy-benzyl)-[1,3,4] oxadiazol-2-yl) -pyridin-2-ylamine

In the same manner as in Example 23, 4- (5- (2-amino-pyridin-3-yl)-[1,3,4] oxadiazol-2-ylmethyl)-described in Preparation Example 24-1 was used. From the phenol (7.0 mg) and 1-iodobutane (8.9 mg), the TFA salt (3.1 mg) of the title compound was obtained.
MS m / e (ESI) (MH ⁺ ) 325.27 (MH ⁺ )

Example 46 3- (2- (5-Phenoxy-thiophen-2-ylmethyl) -2H-tetrazol-5-yl) -pyridin-2-ylamine

(5-phenoxy-thiophen-2-yl) -methanol (100 mg) described in Preparation Example 46-1 and 3- (2H-tetrazol-5-yl) -pyridin-2-ylamine described in Preparation Example 5-1. (79 mg) and triphenylphosphine (250 mg) in THF (5 mL) were added diethyl azodicarboxylate (170 mg, 40% toluene solution) at room temperature and stirred for 20 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was evaporated under reduced pressure, purified by silica gel chromatography (hexane: ethyl acetate = 2: 1, then 1: 1), and further purified by NH-silica gel chromatography (heptane: ethyl acetate = 2: 1). And purified. The obtained organic layer was evaporated under reduced pressure, methanol and 2N aqueous sodium hydroxide were added to the residue, and the mixture was stirred at 80 ° C. for 20 min. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed 3 times with water. The organic layer was evaporated under reduced pressure and purified by NH-silica gel chromatography (ethyl acetate) to obtain the title compound (20 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 6.17 (2H, s), 6.59 (1H, d, J = 4.0 Hz), 6.73-6.77 (1H, m), 6.91 (2H, brs) , 7.10-7.21 (4H, m), 7.41 (2H, dd, J = 8.0Hz, 8.0Hz), 8.14-8.18 (1H, m), 8.23-8.28 (1H, m).

The starting material (5-phenoxy-thiophen-2-yl) -methanol was synthesized by the following method.

[Production Example 46-1] (5-phenoxy-thiophen-2-yl) -methanol

LAH (390 mg) was added to a THF (60 mL) solution of 5-phenoxy-thiophene-2-carbaldehyde (2.8 g) at 0 ° C., and the mixture was stirred at room temperature for 10 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was evaporated under reduced pressure, purified by NH-silica gel chromatography (ethyl acetate), and further purified by silica gel chromatography (hexane: ethyl acetate 4: 1 then 2: 1) to give the title compound (2 0.0 g) was obtained.
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.52 (2H, d, J = 6.0 Hz), 5.43 (1H, t, J = 6.0 Hz), 6.52 (1H, d, J = 4.0 Hz) ), 6.71-6.75 (1H, m), 7.07-7.18 (3H, m), 7.36-7.42 (2H, m).

Example 47 5- (2- (5-phenoxy-thiophen-2-ylmethyl) -2H-tetrazol-5-yl) -pyridin-2-ylamine

In the same manner as in Example 46, 5- (2H-tetrazol-5-yl) -pyridin-2-ylamine (79 mg) described in Preparation Example 47-1 and (5-phenoxy described in Preparation Example 46-1) were prepared. The title compound (14 mg) was obtained from -thiophen-2-yl) -methanol (100 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 6.07 (2H, s), 6.51 (2H, brs), 6.54-6.60 (2H, m), 7.08-7.21 (4H, m), 7.40 ( 2H, dd, J = 8.0Hz, 8.0Hz), 7.93 (1H, dd, J = 2.0Hz, 8.0Hz), 8.58 (1H, s).

The starting material 5- (2H-tetrazol-5-yl) -pyridin-2-ylamine was synthesized by the following method.

[Production Example 47-1] 5- (2H-tetrazol-5-yl) -pyridin-2-ylamine

2-Amino-5-cyanopyridine (1.0 g), sodium azide (1.1 g), ammonium chloride (890 mg), and DMF (15 mL) were stirred at 100 ° C. for 2 hours and 15 minutes. The reaction solution was directly purified by silica gel chromatography (ethyl acetate, then ethyl acetate: methanol: concentrated aqueous ammonia = 6: 2: 1) to obtain the title compound (860 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 6.58 (1H, d, J = 8.8 Hz), 6.65 (2H, brs), 7.98 (1 H, dd, J = 2.0 Hz, 8.8 Hz), 8.60 (1H, d, J = 2.0Hz).

Example 48 3- (2- (5-Benzyloxy-thiophen-2-ylmethyl) -2H-tetrazol-5-yl) -pyridin-2-ylamine

(5-Benzyloxy-thiophen-2-yl) -methanol (140 mg) described in Preparation Example 48-1 and 3- (2H-tetrazole- described in Preparation Example 5-1 were prepared in the same manner as in Example 25. The title compound (48 mg) was obtained from 5-yl) -pyridin-2-ylamine (100 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.12 (2H, s), 6.08 (2H, s), 6.32 (1H, d, J = 4.0 Hz), 6.74 (1H, dd, J = 4.8Hz, 8.0Hz), 6.91 (2H, brs), 7.01 (1H, d, J = 4.0Hz), 7.32-7.45 (5H, m), 8.15 (1H, dd, J = 2.0Hz, 4.8Hz), 8.24 (1H, dd, J = 2.0Hz, 8.0Hz).

The starting material (5-benzyloxy-thiophen-2-yl) -methanol was synthesized by the following method.

[Production Example 48-1] (5-Benzyloxy-thiophen-2-yl) -methanol

In the same manner as in Production Example 46-1, the title compound (1.4 g) was obtained from 5-benzyloxy-thiophene-2-carbaldehyde (1.5 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.22 (2H, d, J = 6.0 Hz), 5.10 (2H, s), 5.28 (1H, t, J = 6.0 Hz), 6.19 (1H , d, J = 4.0 Hz), 6.54-6.58 (1H, m), 7.31-7.46 (5H, m).

Example 49 3- (2-Benzyl-2H-tetrazol-5-yl) -pyridin-2-ylamine

In the same manner as in Example 5, from the benzyl bromide (110 mg) and 3- (2H-tetrazol-5-yl) -pyridin-2-ylamine (100 mg) described in Preparation Example 5-1, the title compound (80 mg) Got.
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 6.04 (2H, s), 6.74 (1H, dd, J = 4.8 Hz, 8.0 Hz), 6.91 (2H, brs), 7.36-7.47 (5H , m), 8.15 (1H, dd, J = 2.0Hz, 4.8Hz), 8.24 (1H, dd, J = 2.0Hz, 8.0Hz).

Example 50 3- (2- (4-Ethoxy-benzyl) -2H-tetrazol-5-yl) -pyridin-2-ylamine

In the same manner as in Example 46, the title compound was obtained from 4-ethoxybenzyl alcohol (46 mg) and 3- (2H-tetrazol-5-yl) -pyridin-2-ylamine (150 mg) described in Preparation Example 5-1. (36 mg) was obtained.
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 1.31 (3H, t, J = 7.2 Hz), 4.01 (2H, q, J = 7.2 Hz), 5.93 (2H, s), 6.71-6.76 (1H, m), 6.90 (2H, brs), 6.94 (2H, d, J = 8.0Hz), 7.39 (2H, d, J = 8.0Hz), 8.12−8.16 (1H, m), 8.20−8.25 ( 1H, m).

Example 51 3- (2- (5- (4-Fluoro-phenoxy) -furan-2-ylmethyl) -2H-tetrazol-5-yl) -pyridin-2-ylamine

In the same manner as in Example 46, (5- (4-fluoro-phenoxy) -furan-2-yl) -methanol (120 mg) described in Preparation Example 51-1 and 3- The title compound (18 mg) was obtained from (2H-tetrazol-5-yl) -pyridin-2-ylamine (100 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.75 (1H, d, J = 3.2 Hz), 6.03 (2H, s), 6.72-6.77 (2H, m), 6.90 (2H, brs) , 7.10-7.18 (2H, m), 7.19-7.26 (2H, m), 8.16 (1H, dd, J = 2.0Hz, 4.8Hz), 8.23 (1H, dd, J = 2.0Hz, 8.0Hz).

The starting material (5- (4-fluoro-phenoxy) -furan-2-yl) -methanol was synthesized by the following method.

[Production Example 51-1] (5- (4-fluoro-phenoxy) -furan-2-yl) -methanol

To a solution of p-fluorophenol (3.6 g) in DMSO (50 mL) was added NaH (1.3 g / 60% in oil) at room temperature, and the mixture was stirred at room temperature for 15 minutes. Subsequently, 5-nitro-furan-2-carbaldehyde (5.0 g) was added and stirred at room temperature for 40 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (heptane: ethyl acetate = 2: 1) to give 5- (4-fluoro-phenoxy) -furan-2-carbaldehyde (1.6 g). )
Subsequently, the title compound (860 mg) was obtained from 5- (4-fluoro-phenoxy) -furan-2-carbaldehyde (850 mg) by the same method as in Production Example 46-1.
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.29 (2H, d, J = 6.0 Hz), 5.18 (1H, t, J = 6.0 Hz), 5.67 (1H, d, J = 3.2 Hz) ), 6.28 (1H, d, J = 3.2Hz), 7.10-7.15 (2H, m), 7.20-7.28 (2H, m).

Example 52 3- (2- (3- (5-Methyl-thiophen-2-ylmethyl) -benzyl) -2H-tetrazol-5-yl) -pyridin-2-ylamine

In the same manner as in Example 46, (3- (5-methyl-thiophen-2-ylmethyl) -phenyl) -methanol (40 mg) described in Preparation Example 52-3 and 3- The title compound (16 mg) was obtained from (2H-tetrazol-5-yl) -pyridin-2-ylamine (100 mg) and azodicarboxylic acid dimethyl ester (130 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 2.31 (3H, s), 4.05 (2H, s), 6.00 (2H, s), 6.57-6.59 (1H, m), 6.64 (1H, d, J = 3.2Hz), 6.73 (1H, dd, J = 4.8Hz, 8.0Hz), 6.90 (2H, brs), 7.23-7.30 (3H, m), 7.34 (1H, dd, J = 8.0Hz, 8.0Hz), 8.15 (1H, dd, J = 2.0Hz, 4.8Hz), 8.23 (1H, dd, J = 2.0Hz, 8.0 Hz).

The starting material (3- (5-methyl-thiophen-2-ylmethyl) -phenyl) -methanol was synthesized by the following method.

[Production Example 52-1] (3- [1,3] dioxolan-2-yl-phenyl)-(5-methyl-thiophen-2-yl) -methanol

Magnesium (270 mg) was added to a solution of 2- (3-bromophenyl) -1,3-dioxolane (2.7 g) and 1,2-dibromoethane (150 mg) in THF (20 mL), and the mixture was heated to reflux for 10 minutes. The reaction mixture was cooled to 0 ° C., and a solution of 5-methyl-2-thiophenecarbaldehyde (1.0 g) and THF (5 mL) was added with stirring. The reaction solution was returned to room temperature and stirred for 10 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (1.1 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 2.36 (3H, s), 3.90-3.98 (2H, m), 4.00-4.16 (2H, m), 5.70 (1H, s), 5.85 ( 1H, d, J = 3.6Hz), 6.13 (1H, d, J = 3.6Hz), 6.56-6.59 (1H, m), 6.64 (1H, d, J = 3.6Hz), 7.28-7.41 (3H, m ), 7.47 (1H, s).

[Production Example 52-2] 3- (5-Methyl-thiophen-2-ylmethyl) -benzaldehyde

Trimethylsilyl chloride (2.1 g) was added to a solution of sodium iodide (2.9 g) in acetonitrile (20 mL) with stirring at room temperature. The obtained reaction solution was cooled to −20 ° C., and (3- [1,3] dioxolan-2-yl-phenyl)-(5-methyl-thiophen-2-yl)-described in Production Example 52-1 was used. Methanol (1.1 g) and acetonitrile (5 mL) were added with stirring. The reaction solution was returned to room temperature and stirred for 10 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (360 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 2.36 (3H, s), 4.17 (2H, s), 6.62 (1H, d, J = 3.2 Hz), 6.71 (1H, d, J = 3.2Hz), 7.52-7.62 (2H, m), 7.76-7.80 (2H, m), 9.99 (1H, s).

[Production Example 52-3] (3- (5-methyl-thiophen-2-ylmethyl) -phenyl) -methanol

Sodium borohydride (120 mg) was added to a solution of 3- (5-methyl-thiophen-2-ylmethyl) -benzaldehyde (350 mg) and ethanol (5.0 mL) described in Preparation Example 52-2 at room temperature for 10 minutes. Stir. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (300 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 2.35 (3H, s), 4.03 (2H, s), 4.46 (2H, d, J = 6.0 Hz), 5.15 (1H, t, J = 6.0Hz), 6.58-6.61 (1H, m), 6.65 (1H, d, J = 3.6Hz), 7.09 (1H, d, J = 7.6Hz), 7.14 (1H, d, J = 7.6Hz), 7.19 (1H, s), 7.24 (1H, dd, J = 7.6Hz, 7.6Hz).

Example 53 3- (2- (4- (5-Methyl-furan-2-ylmethyl) -benzyl) -2H-tetrazol-5-yl) -pyridin-2-ylamine

In the same manner as in Example 46, (4- (5-methyl-furan-2-ylmethyl) -phenyl) -methanol (22 mg) described in Preparation Example 53-3 and 3- The title compound (7.0 mg) was obtained from (2H-tetrazol-5-yl) -pyridin-2-ylamine (21 mg) and azodicarboxylic acid dimethyl ester (32 mg / 40% toluene solution).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 2.17 (3H, s), 3.89 (2H, s), 5.92-5.95 (1H, m), 5.95-6. 01 (3H, m), 6.72 ( 1H, dd, J = 4.8Hz, 8.0Hz), 6.89 (2H, brs), 7.25 (2H, d, J = 8.4Hz), 7.37 (2H, d, J = 8.4Hz), 8.14 (1H, dd, J = 2.0Hz, 4.8Hz), 8.23 (1H, dd, J = 2.0Hz, 8.0Hz).

The starting material (4- (5-methyl-furan-2-ylmethyl) -phenyl) -methanol was synthesized by the following method.

[Production Example 53-1] (4-Dimethoxymethyl-phenyl)-(5-methyl-furan-2-yl) -methanol

By the same method as in Production Example 52-1, the title compound (2.7 g) was obtained from 4-bromobenzaldehyde dimethyl acetal (4.0 g) and 5-methylfurfural (1.3 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 2.17 (3H, s), 3.22 (6H, s), 5.34 (1H, s), 5.59 (1H, d, J = 4.8 Hz), 5.88 (1H, d, J = 4.8Hz), 5.94 (2H, s), 7.32 (2H, d, J = 8.0Hz), 7.36 (2H, d, J = 8.0Hz).

[Production Example 53-2] 4- (5-methyl-furan-2-ylmethyl) -benzaldehyde

In the same manner as in Production Example 52-2, the title compound was obtained from (4-dimethoxymethyl-phenyl)-(5-methyl-furan-2-yl) -methanol (1.0 g) described in Production Example 53-1. (20 mg) was obtained.
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 2.19 (3H, s), 4.02 (2H, s), 5.96-5.99 (1H, m), 6.04 (1H, d, J = 0.4 Hz) , 7.44 (2H, d, J = 8.0Hz), 7.86 (2H, dd, J = 1.6Hz, 8.0Hz), 9.97 (1H, s).

[Production Example 53-3] (4- (5-methyl-furan-2-ylmethyl) -phenyl) -methanol

By the same method as in Production Example 52-3, the title compound (22 mg) was obtained from 4- (5-methyl-furan-2-ylmethyl) -benzaldehyde (20 mg) described in Production Example 53-2.
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 2.18 (3H, s), 3.86 (2H, s), 4.45 (2H, d, J = 6.0 Hz), 5.12 (1H, t, J = 6.0Hz), 5.92-5.98 (2H, m), 7.16 (2H, d, J = 8.0Hz), 7.23 (2H, dd, J = 1.2Hz, 8.0Hz).

Example 54 3- (2- (4- (5-Bromo-thiophen-2-ylmethyl) -benzyl) -2H-tetrazol-5-yl) -pyridin-2-ylamine

In the same manner as in Example 46, (4- (5-bromo-thiophen-2-ylmethyl) -phenyl) -methanol (120 mg) described in Preparation Example 54-3, 3- The title compound (28 mg) was obtained from (2H-tetrazol-5-yl) -pyridin-2-ylamine (69 mg) and azodicarboxylic acid dimethyl ester (310 mg / 40% toluene solution).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.11 (2H, s), 5.99 (2H, s), 6.70-6.76 (2H, m), 6.89 (2H, brs), 7.03 (1H, d, J = 3.6Hz), 7.29 (2H, d, J = 8.0Hz), 7.38 (2H, d, J = 8.0Hz), 8.14 (1H, dd, J = 2.0Hz, 4.8Hz), 8.23 (1H , dd, J = 2.0Hz, 8.0Hz).

The starting material (4- (5-bromo-thiophen-2-ylmethyl) -phenyl) methanol was synthesized by the following method.

[Production Example 54-1] (5-Bromo-thiophen-2-yl)-(4-dimethoxymethyl-phenyl) -methanol

In the same manner as in Production Example 52-1, the title compound (3.3 g) was obtained from 4-bromobenzaldehyde dimethyl acetal (5.0 g) and 5-bromo-2-thiophenecarboxaldehyde (2.9 g).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.21 (6H, s), 5.34 (1H, s), 5.87 (1H, d, J = 4.4 Hz), 6.37 (1H, d, J = 4.4Hz), 6.66 (1H, d, J = 4.0Hz), 6.99 (1H, d, J = 4.0Hz), 7.33 (2H, d, J = 8.0Hz), 7.39 (2H, d, J = 8.0Hz) ).

[Production Example 54-2] 4- (5-Bromo-thiophen-2-ylmethyl) -benzaldehyde

In the same manner as in Production Example 52-2, the title compound was obtained from (5-bromo-thiophen-2-yl)-(4-dimethoxymethyl-phenyl) -methanol (3.3 g) described in Production Example 54-1. (1.9 g) was obtained.
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.22 (2H, s), 6.79 (1H, d, J = 3.6 Hz), 7.05 (1H, d, J = 3.6 Hz), 7.47 (2H , d, J = 8.0Hz), 7.85 (2H, d, J = 8.0Hz), 9.96 (1H, s).

[Production Example 54-3] (4- (5-Bromo-thiophen-2-ylmethyl) -phenyl) methanol

The title compound (810 mg) was obtained from 4- (5-bromo-thiophen-2-ylmethyl) -benzaldehyde (1.9 g) described in Preparation Example 54-2 by a method similar to that of Preparation Example 52-3.
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.08 (2H, s), 4.45 (2H, d, J = 5.6 Hz), 5.13 (1H, t, J = 5.6 Hz), 6.74 (1H , d, J = 3.6Hz), 7.03 (1H, d, J = 3.6Hz), 7.20 (2H, d, J = 8.0Hz), 7.25 (2H, d, J = 8.0Hz).

Example 55 3- (2- (1-Benzyl-1H-pyrrol-3-ylmethyl) -2H-tetrazol-5-yl) -pyridin-2-ylamine

(1-Benzyl-1H-pyrrol-3-yl) -methanol (50 mg) described in Preparation Example 55-1 and 3- (2H-tetrazole described in Preparation Example 5-1 were prepared in the same manner as in Example 46. The title compound (5.9 mg) was obtained from -5-yl) -pyridin-2-ylamine (43 mg) and azodicarboxylic acid dimethyl ester (59 mg / 40% toluene solution).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.07 (2H, s), 5.76 (2H, s), 6.12 (1H, dd, J = 2.0 Hz, 2.0 Hz), 6.73 (1H, dd , J = 4.8Hz, 8.0Hz), 6.81 (1H, dd, J = 2.0Hz, 2.0Hz), 6.90 (2H, brs), 7.04 (1H, dd, J = 2.0Hz, 2.0Hz), 7.20 (2H , d, J = 8.0Hz), 7.24-7.60 (1H, m), 7.60-7.78 (2H, m), 8.14 (1H, dd, J = 2.0Hz, 4.8Hz), 8.22 (1H, dd, J = 2.0Hz, 8.0Hz).

The starting material (1-benzyl-1H-pyrrol-3-yl) -methanol was synthesized by the following method.

[Production Example 55-1] (1-benzyl-1H-pyrrol-3-yl) -methanol

By the same method as in Production Example 46-1, the title compound (210 mg) was obtained from 1-benzyl-1H-pyrrole-3-carbaldehyde (260 mg).
¹ H-NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.27 (2H, d, J = 6.0 Hz), 4.54 (1H, t, J = 6.0 Hz), 5.02 (2H, s), 5.96 (1H , dd, J = 2.0Hz, 2.0Hz), 6.69 (1H, dd, J = 2.0Hz, 2.0Hz), 6.73 (1H, dd, J = 2.0Hz, 2.0Hz), 7.19 (2H, d, J = 6.8Hz), 7.23-7.29 (1H, m), 7.30-7.35 (2H, m).

  The compound (I) of the present invention or a salt thereof exhibits excellent GPI anchor protein transport process inhibitory activity, anti-Candida activity, and anti-Aspergillus activity, and is also excellent in terms of physical properties, safety and metabolic stability. It is extremely useful as a prophylactic or therapeutic agent for fungal infections.

[Pharmacological test example]
In order to show the usefulness of the compound (I) of the present invention, the antifungal activity of the compound (I) of the present invention is described as follows. 1. anti-Candida activity and anti-Aspergillus activity; The activity of mice in the Candida systemic infection experimental system was measured.

1. Anti-Candida activity and anti-Aspergillus activity
(1) Preparation of bacterial solution
C. albicans CAF2-1 strain was prepared as a 1.2 × 10 ³ cells / ml bacterial solution obtained by diluting a bacterial solution statically cultured in Sabouraud dextrose liquid medium (SDB) at 30 ° C. for 48 hours with RPMI1640 medium. A. fumigatus Tsukuba strain was prepared by diluting a −80 ° C. cryopreserved strain with RPMI1640 medium to a bacterial solution of 4.5 × 10 ³ cells / ml.

(2). Preparation of drug dilution plate
A specimen diluted solution of 8 specimens / plate (A to H) was prepared using a U-bottom 96 well plate. 10 μl of dimethyl sulfoxide solution was dispensed into the 2nd to 12th rows of each plate. Dissolve the weighed sample in dimethyl sulfoxide to prepare a 2.5 mg / ml solution, add 20 μl of this solution to the first row of the prepared plate, and perform 12-step double dilution on the plate (10 μl solution + dimethyl sulfoxide solution) 10 μl). 1 μl of this sample diluted solution was dispensed into a flat bottom 96 well plate for MIC measurement to prepare a sample diluted plate.

(3). Inoculation and culture of bacterial solution
The bacterial solution prepared in (1) is inoculated into a flat-bottom 96-well plate containing 1 μl / well of the test compound dilution prepared in (2), and aerobically static at 42 ° C for 42-48 hours. Incubated.

(4) .MIC measurement At first glance, the minimum concentration at which bacterial growth was clearly suppressed compared to the control was taken as the minimum inhibitory concentration (MIC).

  1. The anti-Candida activity and the anti-Aspergillus activity were measured for the representative compounds synthesized in the following examples. As a result, as shown in Tables 1 and 2, it was revealed that the compound of the present invention has anti-Candida activity and anti-Aspergillus activity.

2. Experimental system for Candida systemic infection in mice
(1) Preparation of inoculum
The C. albicans E81022 strain was statically cultured on Sabouraud dextrose agar medium (SDA) at 30 ° C. for 48 hours, and the collected cells were suspended in sterile physiological saline. The number of bacteria was counted with a hemocytometer and diluted with sterilized physiological saline to 2 × 10 ⁷ cells / ml was used as an inoculum.

(2). Infection 0.2 ml of the inoculated bacterial solution was inoculated into the tail vein of 4.5-5.5 week old female ICR mice (4 × 10 ⁶ cells / mouse).

(3). Treatment Three times every 4 hours from 0.5 to 1 hour after bacterial inoculation, 0.2 ml of drug solution (dissolved or suspended in sterile physiological saline containing 6.5% dimethylsulfoxide and 3.5% Tween80) Used and administered into the stomach. The drug dose was 2.5 or 10 mg / kg, and the number of animals in one group was 5.

(4). Determination of effect The infection protective effect was determined by observing life and death until 14 days after infection and calculating the average number of days of survival.
As a result, as shown in Table 3, it was clarified that the mice administered with the compound of the present invention survived for a long time as compared with the non-administered group, and the compound of the present invention showed anti-Candida activity even in vivo. It was.

Claims (18)

A compound represented by the following formula (I) or a salt thereof;
In the formula, R ¹ represents a hydrogen atom, a halogen atom, an amino group, a C _1-6 alkyl group, a C _1-6 alkoxy group, or a C _1-6 alkoxy C _1-6 alkyl group;
R ² represents a hydrogen atom or an amino group;
X, Y, Z, and W each independently represent a nitrogen atom, an oxygen atom, a sulfur atom, or —CH—, but at least two of X, Y, and W represent a nitrogen atom. ;
Ring A means a 5 or 6 membered heteroaryl ring or a benzene ring;
Q represents a methylene group, an oxygen atom, —CH ₂ O—, —OCH ₂ —, —NH—, —NHCH ₂ —, or —CH ₂ NH—;
R ³ may have one or two substituents each selected from substituent group α, C _1-6 alkyl group, C _3-8 cycloalkyl group, C _6-10 aryl group, or Means a 5- or 6-membered heteroaryl group.
However, among 5-membered heteroaryl rings containing X, Y, Z, and W, the pyrazole ring is excluded. In addition, the case where R ¹ and R ² are simultaneously hydrogen atoms is excluded.
[Substituent group α]
Halogen atom, C _1-6 alkyl group, C _1-6 alkoxy group, C _3-8 cycloalkyl group, C _2-6 alkenyl group, and C _2-6 alkynyl group Formula (I)
The following formula (II)
The compound or its salt of Claim 1 whose partial structure represented by these is a partial structure chosen from the following group.
Formula (I)
The following formula (II)
The partial structure represented by the formula (V)
The compound or its salt of Claim 1 which is a partial structure represented by these. Formula (I)
The following formula (II)
The partial structure represented by formula (v)
The compound or its salt of Claim 3 which is a partial structure represented by these. Formula (I)
The following formula (II)
The partial structure represented by the following formula (III)
Or a partial structure represented by the following formula (IV)
The compound or its salt of Claim 1 which is a partial structure represented by these. Formula (I)
The following formula (II)
The compound or its salt of Claim 5 whose partial structure represented by these is a partial structure chosen from the following group.
Formula (I)
The following formula (II)
The compound or its salt of Claim 1 whose partial structure represented by these is a partial structure chosen from the following group.
Formula (I)
The following formula (II)
The compound or its salt of Claim 7 whose partial structure represented by these is a partial structure chosen from the following group.
The compound or salt thereof according to any one of claims 1 to 8 R ² is an amino group. The compound or a salt thereof according to claim 9, wherein R ¹ is a hydrogen atom, an amino group, or a C _1-6 alkoxy C _1-6 alkyl group. The compound or a salt thereof according to any one of claims 1 to 8, wherein R ¹ is an amino group and R ² is a hydrogen atom.   The compound or a salt thereof according to any one of claims 1 to 11, wherein the ring A is a pyridine ring, a benzene ring, a furan ring, a thiophene ring, or a pyrrole ring.   The compound or a salt thereof according to claim 12, wherein ring A is a pyridine ring or a benzene ring. Q is an oxygen atom, -CH ₂ O-, or -OCH ₂ - or a salt thereof according to any one of claims 1 to 13.   The pharmaceutical composition containing the compound or its salt of any one of Claims 1 thru | or 14.   A medicament comprising the compound or salt thereof according to any one of claims 1 to 14.   The antifungal agent which uses the compound or its salt of any one of Claims 1 thru | or 14 as an active ingredient.   Use of the compound or a salt thereof according to any one of claims 1 to 14 for the manufacture of an antifungal agent.